Autoimmune
Diseases
sachyhoc.com
Understanding, Management
and Clinical Practice
Syed Khalid Imam
Shamim I. Ahmad
Editors
123
Autoimmune Diseases
Syed Khalid Imam • Shamim I. Ahmad
Editors
Autoimmune Diseases
Understanding, Management
and Clinical Practice
Editors
Syed Khalid Imam
Sultan Bin Abdulaziz Humanitarian City
Riyadh, Kingdom of Saudi Arabia
Shamim I. Ahmad
Nottingham, UK
ISBN 978-3-032-12936-9 ISBN 978-3-032-12937-6 (eBook)
https://doi.org/10.1007/978-3-032-12937-6
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2026
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or
dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the
relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
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editors give a warranty, expressed or implied, with respect to the material contained herein or for any
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This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
If disposing of this product, please recycle the paper.
Editor, SKI wishes to dedicate this book to
the countless individuals around the world
living with autoimmune diseases-silent
warriors who face uncertainty, pain, and
resilience each day. In an era marked by
global health challenges, rising autoimmune
conditions, and the profound impact of
environmental and lifestyle factors on
immune health, this work stands as a tribute
to their strength and to the clinicians,
researchers, and caregivers striving to
unravel the complexities of autoimmunity.
With deepest respect to Dr. Noel Rose, whose
pioneering discoveries laid the scientific
foundation of autoimmunity, and to Sir Frank
Macfarlane Burnet, whose groundbreaking
clonal selection theory shaped our
understanding of immune tolerance and its
failures, may this book contribute to a deeper
understanding and a future of hope, healing,
and precision care for all.
Co-Editor, SIA wishes to dedicate this book
to his late father and mother, Abdul Nasir
and Anjuman Ara, respectively, who played
the important roles to bring the editor to this
stage of academic achievements with their
esteemed love, sound care, and sacrifice.
Dedication also goes to his wife, Riasat Jan,
for her patience, persistence, and
encouragement to produce this book, as well
as to his children, Alisha Ahmad and Arsalan
Ahmad, for providing great pleasure with
their innocent interruptions, leading to the
energy of the editor to be revitalized. Next,
his best wishes go to the people suffering
from autoimmune diseases, for their recovery
from these diseases and avoid all kinds of
ailments resulting by this disease. Finally, his
dedication goes to his loving and caring
Professor Dr. Fumio Hanaoka of Japan, who
is now retired, and Professors Dr. Robert H
Pritchard of Leicester University, England,
and Dr. Abe Eisenstark of University of
Missouri, Columbia, USA, now no more
with us.
Preface
Autoimmune diseases represent a diverse group of complex disorders characterized
by dysregulation of the immune system, in which immune responses are directed
against the body’s own tissues. Affecting millions of individuals worldwide, these
disorders span a wide clinical spectrum, often involving multiple organ systems and
presenting diagnostic and therapeutic challenges across various medical
disciplines.
Over recent decades, significant progress has been made in unraveling the immunopathological mechanisms underlying autoimmunity, alongside the development
of novel immunomodulatory and targeted therapies. Nonetheless, gaps remain in
the early recognition, accurate diagnosis, and long-term management of many autoimmune conditions, particularly in resource-constrained settings or in diseases with
overlapping features.
This book, titled Autoimmune Diseases: Understanding, Management and
Clinical Practice, is designed as a comprehensive and multidisciplinary reference
for clinicians, researchers, and healthcare professionals involved in the care of
patients with autoimmune disorders. It brings together contributions from a wide
range of experts in internal medicine, rheumatology, endocrinology, dermatology,
neurology, immunology, and related fields, reflecting the truly interdisciplinary
nature of autoimmune disease management.
The book is structured to provide both foundational insights and up-to-date clinical guidance. The first chapter focuses on the immunological and molecular basis of
autoimmunity, exploring genetic predisposition, environmental influences, epigenetic mechanisms, and immune tolerance. Subsequent chapters addresses organ-­
specific and systemic autoimmune diseases, integrating current evidence on
epidemiology, diagnostic criteria, clinical presentation, disease progression, and
treatment strategies. Special attention is given to advances in biologic and targeted
therapies, as well as personalized medicine approaches that are reshaping the management landscape.
In addition, the text examines autoimmune disorders in special populations
including pediatric, geriatric, and pregnant patients and considers psychosocial
aspects, quality-of-life impacts, and long-term care challenges. Several chapters are
dedicated to practical issues faced in daily clinical practice, including disease overlap syndromes, atypical presentations, and management of refractory cases. This
book aims to serve a broad audience, including practicing physicians, postgraduate
vii
viii
Preface
and undergraduate medical students, subspecialists, allied healthcare providers, and
professionals in the pharmaceutical and biotechnology sectors involved in autoimmune disease research and drug development.
As editors, we are grateful to the esteemed authors who have contributed their
expertise to this project and to the readers whose engagement continues to advance
the field. We hope this work will serve as both a scholarly reference and a practical
guide, ultimately enhancing patient care and fostering further research into the complex world of autoimmune diseases.
Riyadh, Kingdom of Saudi Arabia
Nottingham, UK Syed Khalid Imam
Shamim I. Ahmad
Acknowledgments
The editor cordially acknowledges the authors of various chapters who contributed
their works, employing their in-depth knowledge, high skills, and professional presentations. Without their input, it would not have been possible to bring out this
valuable book on such highly topical and important subject. We would also like to
acknowledge Melissa Morton, Mahalakshmi Sethish Babu, and the team of Springer
Publication for their input and friendly approach in handling of the work.
ix
Contents
Immunology
and Autoimmunity: Current Concepts and Clinical
Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Naseem Ahmed and Aiyesha Humaira
Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Syed Khalid Imam
Systemic Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Tahira Perveen, Lubna Nazir, and Syeda Rida E Zehra
Spondyloarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Mohamed Bedaiwi
Juvenile Idiopathic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Abhidnya Surve, Avinash Buche, Puja Totala, and Yogita Phadke
Scleroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Muhammad Ishaq Ghauri and Muhammad Shariq Mukarram
Polymyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Rajat Ranka, Venkatesh Srinivasa Pai, and Prasan Kumar Panda
Juvenile Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Mehmet Orhan Erkan, Ozlem Necipoglu Banak, and Seza Ozen
Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Muhammad Ishaq Ghauri and Syeda Urooj Riaz
Sjögren’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Maria Maslinska
Hashimoto’s Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Syed Khalid Imam
Graves’ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
Ali Asghar and Saima Askari
xi
xii
Contents
Type
1 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Syeda Nazish Azim
Addison’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Bhagwan Das, Tehseen Fatima, and Aisha Sheikh
Coeliac Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Syed Tariq Khalil
Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
Faisal Ziauddin
Myasthenia Gravis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
Sara Dehbashi
Anti-NMDAR Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
Nalakath A. Uvais
Autoimmune Hemolytic Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Sukdev Manna and Prasan Kumar Panda
Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Vikram K. Mahajan
Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555
Milaan Shah and Dirk Elston
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
About the Editors
Syed Khalid Imam is a Consultant Internal Medicine
and Endocrinologist, currently serving at Sultan Bin
Abdulaziz Humanitarian City in the Kingdom of Saudi
Arabia. He earned his MBBS degree from Dow Medical
College/University of Karachi, and completed his
Fellowship in Internal Medicine from the College of
Physicians and Surgeons Pakistan (CPSP). He further
pursued a Clinical Fellowship in Diabetes and
Endocrinology at Liaquat National Hospital, Karachi,
and obtained Subspecialty Certification in Diabetes and
Endocrinology from the Royal College of Physicians,
London, UK. Additionally, he was awarded an honorary
Fellowship (FACE) by the American College of
Endocrinology (ACE), USA.
He has held several key academic and administrative
roles, including Head of the Department of Diabetes
and Endocrinology, Program Director of the Internal
Medicine Residency Program, and Chairman of the
Research and Ethics Committee at Liaquat National
Hospital in Karachi. He serves as a supervisor for the
Endocrinology Fellowship at CPSP and is an active
member of the American Association of Clinical
Endocrinologists (AACE). He has also served as the
executive member of Pakistan Endocrine Society (PES),
including a term as General Secretary, and contributed
as an item writer in Endocrinology for the Saudi
Commission for Health Specialties. He has played a
pivotal role in establishing a dedicated Metabolic
Center at his current institution, offering comprehensive, multidisciplinary care for patients with obesity,
diabetes, dyslipidemia, metabolic syndrome, and
genetic conditions. He remains actively involved in
public health initiatives, including community awareness programs.
xiii
xiv
About the Editors
With an academic and research background, he has
authored numerous publications in national and international journals and is a frequent speaker at scientific
conferences. His main areas of clinical and research
interest include obesity, diabetes, and thyroid disorders.
He has edited or co-edited three notable books in these
fields: Obesity: A Practical Guide, Thyroid: Basic
Science and Clinical Practice, and Diabetes: A
Comprehensive Treatise for Patients and Caregivers.
In addition, he contributed three chapters to Diabetes:
An Old Disease, A New Insight (Advances in
Experimental Medicine and Biology). He is currently
part of the research team for the Saudi Genome Research
Project at Sultan Bin Abdulaziz Humanitarian City and
has participated in several national and international
research initiatives. In recognition of his contributions,
he was honored with the “Best Internal Researcher
Award” in 2023 by Sultan Bin Abdulaziz Humanitarian
City Research and Scientific Center.
Shamim I. Ahmad obtained his BSc degree from
TNB College, Bhagalpur, and MSc degree in Botany
from Patna University, India, and his PhD degree in
Molecular Genetics from Leicester University, England.
He joined Nottingham Trent University where after 35
years’ service as Senior Lecturer and another 13 years
as Hourly Paid lecturer he left the university in 2020.
Since 2006, he has been producing books on various
medical subjects. These include Molecular Mechanisms
of Fanconi Anemia; Molecular Mechanisms of
Xeroderma Pigmentosum; Molecular Mechanisms of
Cockayne Syndrome; Molecular Mechanisms of Ataxia
Telangiectasia;
Diseases
of
DNA
Repair;
Neurodegenerative Diseases; Diabetes: An Old Disease
a New Insight; Obesity: A Practical Guide; Thyroid:
Basic Science and Clinical Practice; Ultraviolet Light
in Human Health, Diseases and Environment; Diabetes:
A comprehensive Treatise for Patients and Caregivers;
Reactive Oxygen Species in Biology and Human Health;
Aging: Exploring a Complex Phenomenon; Handbook
of Mitochondrial Dysfunction; and Human Viruses,
Diseases, Treatment and Vaccines, Obesity: Clinical,
Surgical and Practical Guide, Second Edition. Springer
Publication and Taylor and Francis, CRC Press, have
published most books.
About the Editors
xv
His research on different areas of molecular biology/genetics expanded for over 30 years. The key area
of his research was on DNA damage, repair, and mutation, which resulted in discovery of production of various reactive oxygen species (ROS) exposed under near
UV (UVA) light of a number of biological and chemical compounds and their implications on human health
including cancer. Included were 8-methoxypsoralen,
mitomycin C which is used for the treatment of psoriasis, also play roles in Fanconi anemia. Other non-biological and biological compounds were: hydrogen
peroxide, phenyl alanine, tyrosine, tryptophan, histidine and L-mandelate. Other areas of research included
thymineless death in bacteria, which resulted with the
publication of a review in 1998 in the prestigious journal Annual Review of Microbiology. Other research
areas were genetic control of nucleotide catabolism,
development of anti-AIDs drugs, control of microbial
infection of burns, phages of thermophilic bacteria, and
microbial flora of Chernobyl after the incidence at its
nuclear power station. His research collaboration
extended with the University of Osaka, Japan, where he
discovered that a number of biologically produced
enzymes were able to scavenge ROS. In 2020 and
2021, Medical Hypothesis published a paper in which
he proposed a treatment for COVID-19 and another
modified treatment for RNA viruses in his book on
Human Viruses, respectively. Finally, in 2003 he
received a prestigious “Asian Jewel Award” in Britain
for “Excellence in Education.”
Abbreviations
5-ASA
AAV
ACA
ACEi
ACh
AChE
AChR
ACPA
ACR
ACTH
ADA
ADCC
AE
AI
AIDS
AIHA
AIRE
AITD
ALPS
ALT
AMPA
ANA
ANCA
anti-CCP
anti-dsDNA
anti-La
Anti-MDA5
anti-NMDAR
Anti-NXP2
anti-Ro
Anti-SAE
anti-Sm
Anti-TIF1γ
5-Aminosalicylic Acid
ANCA-Associated Vasculitis
Adrenal Cortex Antibodies
Angiotensin-Converting Enzyme Inhibitor
Acetylcholine
Acetylcholinesterase
Acetylcholine Receptor
Anti-Citrullinated Protein Antibody
American College of Rheumatology
Adrenocorticotropic Hormone
American Diabetes Association
Antibody-Dependent Cellular Cytotoxicity
Autoimmune Encephalitis
Artificial Intelligence
Acquired Immunodeficiency Syndrome
Autoimmune Hemolytic Anemia
Autoimmune Regulator
Autoimmune Thyroid Disease
Autoimmune Lymphoproliferative Syndrome
Alanine Aminotransferase
A l p h a - A m i n o - 3 - H y d r o x y - 5 - M e t h y l - 4 -­
Isoxazolepropionic Acid
Antinuclear Antibody
Anti-Neutrophil Cytoplasmic Antibodies
Anti-Cyclic Citrullinated Peptide
Anti-Double-Stranded Deoxyribonucleic Acid
Anti-Sjögren’s-syndrome-related Antigen B
Anti–Melanoma Differentiation-Associated Gene 5
Anti–N-Methyl-D-Aspartate Receptor
Anti–Nuclear Matrix Protein 2
Anti-Sjögren’s-Syndrome-Related Antigen A
Anti–Small Ubiquitin-Like ModifierActivating Enzyme
Anti-Smith Antibody
Anti–Transcriptional Intermediary Factor 1 Gamma
xvii
xviii
anti-U3-RNP
anti–RNA polymerase III
anti–Scl–70
APC
aPL
APS
AS
ASAS
ASCA
ASDAS
ASS
AST
ATD
ATP
axSpA
AZA
B cells
BASDAI
BBB
BCR
BD
BILAG
BMD
BMI
BVAS
C3
C3/C4
C4
CA
CAD
CAM
CAPS
CAR-T
CCP
CD
CENP
CFS
CGM
CHAQ
CHCC
CIITA
CK
CKD
CLEC16A
CLL
Abbreviations
Anti-U3 Ribonucleoprotein Antibody
Anti-RNA Polymerase III Antibody
Anti-Topoisomerase I Antibody
Antigen-Presenting Cell
Antiphospholipid Antibodies
Autoimmune Polyglandular Syndrome
Ankylosing Spondylitis
Assessment of SpondyloArthritis International Society
Anti-Saccharomyces Cerevisiae Antibodies
Ankylosing Spondylitis Disease Activity Score
Antisynthetase Syndrome
Aspartate Aminotransferase
Autoimmune Thyroid Disease
Adenosine Triphosphate
Axial Spondyloarthritis
Azathioprine
B Lymphocytes
Bath Ankylosing Spondylitis Disease Activity Index
Blood Brain Barrier
B Cell Receptor
Behçet’s Disease
British Isles Lupus Assessment Group
Bone Mineral Density
Body Mass Index
Birmingham Vasculitis Activity Score
Complement Component 3
Complement Components 3 and 4
Complement Component 4
Cerebellar Ataxia
Cold Agglutinin Disease
Cancer-Associated Myositis
Cryopyrin-Associated Periodic Syndromes
Chimeric Antigen Receptor T Cell
Cyclic Citrullinated Peptide
Cluster of Differentiation
Centromere Proteins
Chronic Fatigue Syndrome
Continuous Glucose Monitoring
Childhood Health Assessment Questionnaire
Chapel Hill Consensus Conference
Class II Trans-Activator
Creatine Kinase
Chronic Kidney Disease
C-type Lectin Domain Family 16 Member A
Chronic Lymphocytic Leukemia
Abbreviations
xix
CMV
CNS
Coombs test
COX-2
CPK
CR
CR1
CRH
CRMP5
CRP
CS
csDMARDs
Cytomegalovirus
Central Nervous System
Antiglobulin Test
Cyclooxygenase-2
Creatine Phosphokinase
Conventional Radiography
Complement Receptor 1
Corticotropin-Releasing Hormone
Collapsin Response Mediator Protein 5
C-Reactive Protein
Cogan’s Syndrome
Conventional
Synthetic
Disease-Modifying
Antirheumatic Drugs
Computed Tomography
Connective Tissue Disease
Connective Tissue Disease-Overlap Myositis
Cytotoxic T Lymphocyte
Cytotoxic T-Lymphocyte Antigen 4
C-X-C Motif Chemokine Ligand 10
C-X-C Chemokine Receptor 3
Cyclophosphamide
Decay-Accelerating Factor
Damage-Associated Molecular Patterns
Disease Activity Score 28
Direct Antiglobulin Test
Dendritic Cell
Dendritic Cells
Disease Extent Index
Disease Extent Index – Takayasu
Dehydroepiandrosterone
Dehydroepiandrosterone Sulfate
Diabetic Ketoacidosis
Diffuse Large B Cell Lymphoma
Discoid Lupus Erythematosus
Dermatomyositis
Disease-Modifying Anti-Rheumatic Drugs
Deoxyribonucleic Acid
Double-Stranded Deoxyribonucleic Acid
Experimental Autoimmune Myasthenia Gravis
Enteropathy-Associated T Cell Lymphoma
Epstein–Barr Virus
European Crohn’s and Colitis Organization
Electroencephalogram
Eosinophilic Granulomatosis with Polyangiitis
Electronic Health Records
CT
CTD
CTD-OM
CTL
CTLA-4
CXCL10
CXCR3
CYC
DAF
DAMPs
DAS28
DAT
DC
DCs
DEI
DEI.TAK
DHEA
DHEAS
DKA
DLBCL
DLE
DM
DMARDs
DNA
dsDNA
EAMG
EATL
EBV
ECCO
EEG
EGPA
EHR
xx
ELISA
EMA-IgA
EMG
ERA
ERAP1
ESPGHAN
ESR
ESSDAI
ESSPRI
ET-1
EULAR
Fab
Fc
FcγR
FDA
FEA
FFS
FIM
FMT
FNAC
FOXP3
FT3
FT4
GABA
GAD
GAD65
GADA
GBM
GCA
GD
GI
GIT
GM-CSF
GO
GPA
GPI
HAQ
HbA1c
HBV
HCV
HIV
HLA
HLA-B27
HPA axis
Abbreviations
Enzyme-Linked Immunosorbent Assay
Endomysial Antibodies – Immunoglobulin A
Electromyography
Enthesitis-Related Arthritis
Endoplasmic Reticulum Aminopeptidase 1
European Society for Pediatric Gastroenterology,
Hepatology and Nutrition
Erythrocyte Sedimentation Rate
EULAR Sjögren’s Syndrome Disease Activity Index
EULAR Sjögren’s Syndrome Patient Reported Index
Endothelin-1
European League Against Rheumatism
Fragment Antigen-Binding
Fragment Crystallizable
Fc Gamma Receptor
Food and Drug Administration
Finite Element Analysis
Five Factor Score
Functional Index in Myositis
Fecal Microbiota Transplantation
Fine-Needle Aspiration Cytology
Forkhead Box Protein P3
Free Triiodothyronine
Free Thyroxine
Gamma-Aminobutyric Acid
Glutamic Acid Decarboxylase
Glutamic Acid Decarboxylase 65
Glutamic Acid Decarboxylase Antibody
Glomerular Basement Membrane
Giant Cell Arteritis
Graves’ Disease
Gastrointestinal
Gastrointestinal Tract
Granulocyte-Macrophage Colony-Stimulating Factor
Graves’ Orbitopathy
Granulomatosis with Polyangiitis
Glycosylphosphatidylinositol
Health Assessment Questionnaire
Hemoglobin A1c
Hepatitis B Virus
Hepatitis C Virus
Human Immunodeficiency Virus
Human Leukocyte Antigen
Human Leukocyte Antigen B27
Hypothalamic-Pituitary-Adrenal Axis
Abbreviations
HRCT
HSV
HT
HUV
IA-2A
IAA
IBD
IBM
IEC
IEL
IFN
IFN-α
IFN-γ
Ig
IgA
IgAV
IgD
IgE
IgG
IgM
IIM
IL
IL-1
IL-10
IL-17
IL-2
IL-23
IL-4
IL-6
IL23R
ILAR
ILD
IMACS
IMNM
IPAA
IR
ISPAD
ITAS
IV
IVIg
JADAS
JAK
JDM
JIA
xxi
High-Resolution Computed Tomography
Herpes Simplex Virus
Hashimoto Thyroiditis
Hypocomplementemic Urticarial Vasculitis
Insulinoma-Associated-2 Autoantibody
Insulin Autoantibody
Inflammatory Bowel Disease
Inclusion Body Myositis
Intestinal Epithelial Cell
Intraepithelial Lymphocyte
Interferon
Interferon Alpha
Interferon Gamma
Immunoglobulin
Immunoglobulin A
IgA Vasculitis (Henoch-Schönlein)
Immunoglobulin D
Immunoglobulin E
Immunoglobulin G
Immunoglobulin M
Idiopathic Inflammatory Myopathies
Interleukin
Interleukin 1
Interleukin 10
Interleukin-17
Interleukin 2
Interleukin-23
Interleukin 4
Interleukin 6
Interleukin-23 Receptor
International League of Associations for Rheumatology
Interstitial Lung Disease
International Myositis Assessment and Clinical Studies
Immune-Mediated Necrotizing Myopathy
Ileal Pouch-Anal Anastomosis
Insulin Resistance
International Society for Pediatric and Adolescent
Diabetes
Indian Takayasu Arteritis Activity Score
Intravenous
Intravenous Immunoglobulin
Juvenile Arthritis Disease Activity Score
Janus Kinase
Juvenile Dermatomyositis
Juvenile Idiopathic Arthritis
xxii
KD
L-T4
LDH
LFS
LGI1
LN
LPS
M-Health
MAC
MALT
MAS
MBP
MC1R
MG
mGluR5
MHC
miRNA
miRNAs
MMF
MMT
MPA
MPO
MRI
mRNA
MS
MSA
MSGB
MSUS
MTX
MuSK
MXA
MZL
NCGN
NF-κB
NIS
NIV
NK
NK cells
NMDA
NMDAR
NSAIDs
PAH
PAI
PAMPs
Abbreviations
Kawasaki Disease
Levothyroxine
Lactate Dehydrogenase
Lymphocytic Focus Score
Leucine-Rich Glioma Inactivated 1
Lupus Nephritis
Lipopolysaccharide
Mobile Health
Membrane Attack Complex
Mucosa-Associated Lymphoid Tissue
Macrophage Activation Syndrome
Myelin Basic Protein
Melanocortin 1 Receptor
Myasthenia Gravis
Metabotropic Glutamate Receptor 5
Major Histocompatibility Complex
MicroRNA
MicroRNAs
Mycophenolate Mofetil
Manual Muscle Testing
Microscopic Polyangiitis
Myeloperoxidase
Magnetic Resonance Imaging
Messenger Ribonucleic Acid
Multiple Sclerosis
Myositis-Specific Antibodies
Minor Salivary Gland Biopsy
Musculoskeletal Ultrasound
Methotrexate
Muscle-Specific Tyrosine Kinase
Myxovirus Resistance Protein A
Mucosa-Associated Lymphoid Tissue Lymphoma
(Marginal Zone Lymphoma)
Necrotizing Crescentic Glomerulonephritis
Nuclear Factor Kappa B
Sodium-Iodide Symporter
Non-Invasive Ventilation
Natural Killer (Cell)
Natural Killer Cells
N-Methyl-D-Aspartate
N-Methyl-D-Aspartate Receptor
Nonsteroidal Anti-inflammatory Drugs
Pulmonary Arterial Hypertension
Primary Adrenal Insufficiency
Pathogen-Associated Molecular Patterns
Abbreviations
PAN
pANCA
PASI
PBMC
PCH
PD-1
PD-L1
pDC
PET
PFT
PM
PNS
PR3
PRINTO
PRRs
PSC
PTPN22
RA
RAI
RBC
RCD
RF
RNA
RNP
RNS
ROP
ROS
RP-ILD
RTX
SAE1
SAI
SC
SDAI
SGLT2
sJIA
SLE
SLICC
SNP
SNPs
SOV
SpA
SPECT
SRP
SS
xxiii
Polyarteritis Nodosa
Perinuclear Anti-Neutrophil Cytoplasmic Antibodies
Psoriasis Area and Severity Index
Peripheral Blood Mononuclear Cell
Paroxysmal Cold Hemoglobinuria
Programmed Cell Death Protein 1
Programmed Death Ligand 1
Plasmacytoid Dendritic Cells
Positron Emission Tomography
Pulmonary Function Test
Polymyositis
Peripheral Nervous System
Proteinase 3
Pediatric
Rheumatology
International
Trials
Organization
Pattern Recognition Receptors
Primary Sclerosing Cholangitis
Protein Tyrosine Phosphatase Non-Receptor Type 22
Rheumatoid Arthritis
Radioactive Iodine
Red Blood Cell
Refractory Coeliac Disease
Rheumatoid Factor
Ribonucleic Acid
Ribonucleoprotein
Repetitive Nerve Stimulation
Retinopathy of Prematurity
Reactive Oxygen Species
Rapidly Progressive Interstitial Lung Disease
Rituximab
Small Ubiquitin-Like Modifier Activating Enzyme 1
Secondary Adrenal Insufficiency
Subcutaneous
Simplified Disease Activity Index
Sodium-Glucose Co-Transporter-2
Systemic Juvenile Idiopathic Arthritis
Systemic Lupus Erythematosus
Systemic Lupus International Collaborating Clinics
Single Nucleotide Polymorphism
Single Nucleotide Polymorphisms
Single Organ Vasculitis
Spondyloarthritis
Single-Photon Emission Computed Tomography
Signal Recognition Particle
Sjögren’s Syndrome
xxiv
SSA
SSB
SSc
STAT
STIR
T cells
T1DM
T3
T4
TA
TACI
TAI
TAK
TB
TBG
TCR
TGF-β
Th
Th1
Th17
Th2
TIF1γ
TLR
TLRs
TMP-SMX
TNF
TNF-α
TPMT
TPN
TPO
TRAb
TRAPS
Treg
Tregs
TSH
TSI
tTG
TYR
UC
UK
USG
VDI
VGKC
Abbreviations
Sjögren’s Syndrome Antigen A
Sjögren’s Syndrome Antigen B
Systemic Sclerosis
Signal Transducer and Activator of Transcription
Short Tau Inversion Recovery
T Lymphocytes
Type 1 Diabetes Mellitus
Triiodothyronine
Thyroxine
Takayasu Arteritis
Transmembrane Activator and CAML Interactor
Tertiary Adrenal Insufficiency
Takayasu Arteritis
Tuberculosis
Thyroxine-Binding Globulin
T Cell Receptor
Transforming Growth Factor Beta
T Helper
T Helper Cell Type 1
T Helper Cell Type 17
T Helper 2 Cell
Transcriptional Intermediary Factor 1 Gamma
Toll-Like Receptor
Toll-Like Receptors
Trimethoprim-Sulfamethoxazole
Tumor Necrosis Factor
Tumor Necrosis Factor Alpha
Thiopurine Methyltransferase
Total Parenteral Nutrition
Thyroid Peroxidase
TSH Receptor Antibody
TNF Receptor-Associated Periodic Syndrome
Regulatory T Cell
Regulatory T Cells
Thyroid-Stimulating Hormone
Thyroid-Stimulating Immunoglobulin
Tissue Transglutaminase
Tyrosinase
Ulcerative Colitis
United Kingdom
Ultrasonography
Vasculitis Damage Index
Voltage-Gated Potassium Channel
Abbreviations
VVV
WBC
WG
WHO
xxv
Variable Vessel Vasculitis
White Blood Cell
Wegener’s Granulomatosis
World Health Organization
Immunology and Autoimmunity:
Current Concepts and Clinical
Implications
Naseem Ahmed and Aiyesha Humaira
Introduction to Immunology
Immunity refers to the ability to resist diseases, particularly those caused by infectious agents. The immune system encompasses a complex network of cells, tissues,
and molecules that work together to provide this resistance. The collective actions
of these components in response to infectious microorganisms constitute what is
known as the immune response. A primary physiological role of the immune system
is to eliminate infections [1]. This system is generally divided into two principal
components: the innate immune system and the adaptive immune system.
Innate Immune System
The innate immune system serves as the initial defence mechanism against external
pathogens and consists of various physical, chemical, and cellular barriers. These
include the skin, mucous membranes, and specialized immune cells, such as phagocytes and natural killer cells. This type of immunity, often referred to as natural
immunity, exists in healthy individuals and serves to prevent the invasion of
microorganisms.
Adaptive Immune System
The adaptive immune system represents a more specialized and focused response
that requires a certain period for maturation; however, it is significantly more proficient in eradicating particular threats [2].
N. Ahmed (*) · A. Humaira
Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_1
1
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N. Ahmed and A. Humaira
Table 1 Difference between innate and adaptive immune system
Feature
Definition
Innate immune system
First line of defence providing immediate,
non-specific response
Response
speed
Specificity
Rapid (minutes to hours)
Memory
Components
Diversity
Effectiveness
Examples
Non-specific, recognizes common patterns in
pathogens
No memory, same response upon repeated
exposure
Physical barriers (skin, mucous membranes),
phagocytes (macrophages, neutrophils), natural
killer (NK) cells, complement system
Limited diversity, recognizes broad pathogen-­
associated patterns
Effective against a wide range of pathogens but
not always sufficient
Inflammation, fever, phagocytosis
Adaptive immune system
Second line of defence
with a delayed, highly
specific response
Slow (days to weeks)
Highly specific, targets
particular antigens
Has memory, stronger and
faster response upon
re-exposure
B cells, T cells, antibodies
Highly diverse, recognizes
unique antigens
More effective, provides
long-term immunity
Vaccination response,
antibody production
There are two distinct forms of adaptive immunity: humoral immunity and cell-­
mediated immunity. These forms are facilitated by different types of cells and molecules, offering protection against extracellular pathogens and intracellular
pathogens, respectively [1]. The differences between the innate and adaptive
immune systems are listed in Table 1.
Humoral Immunity
It is driven by B cell. The basic B cell response is characterized by the production
of a single class of immunoglobulins, specifically immunoglobulin M (IgM), without the establishment of long-term immunological memory. In contrast, the
advanced B cell response involves a sequential switching of antibody classes,
including IgM, immunoglobulin G (IgG), immunoglobulin A (IgA), and potentially
immunoglobulin E (IgE), while also promoting the generation of long-lived memory plasma cells and enduring memory B cells.
Antibodies play a crucial role in halting microorganisms that come into contact
with mucosal surfaces and circulate in the bloodstream, thereby helping to prevent
infections. However, they are unable to reach microorganisms that reside and multiply within infected cells.
Immunology and Autoimmunity: Current Concepts and Clinical Implications
3
Т-Cell-Mediated Responses
The body’s defence against intracellular microorganisms relies on cell-mediated
immunity, primarily facilitated by T cells. Certain T cells stimulate phagocytes to
eliminate microorganisms that have been engulfed into intracellular vesicles. The
other T cells are responsible for destroying host cells that contain infectious
microbes within their cytoplasm. The inflammatory response mediated by cluster of
differentiation 4 (CD4+ helper T cells) that leads to generation of effector CD4+ T
cells as well as memory CD4+ T cells. Similarly, the cytotoxic response involving
cluster of differentiation 8 (CD8+ cytotoxic T cells) leads to the development of
cytotoxic CD8+ T cells that can induce apoptosis in target cells, along with formation of long-lasting memory CD8+ T cells.
Organs of the Immune System
The immune system comprises a network of organs, cells, and molecules, which
interact in a complex manner to regulate immune functions at two primary levels.
These levels can be categorized as follows:
1. The systemic level, encompassing the bloodstream, thymus, bone marrow, and
spleen, is tasked with defending the body against pathogens that penetrate its
internal environment.
2. The skin and mucosal level, which includes surface and mucosal barriers, tonsils, adenoids, Peyer’s patches, solitary follicles, the appendix, lymph nodes, and
lymphatic vessels, operates when pathogens invade locally or when opportunistic microbes residing within the barriers are reactivated.
The central organs of the immune system are the thymus and bone marrow. All
immune-related cells originate in the bone marrow, where some lymphocytes, specifically B cells, undergo differentiation, while T cells mature in the thymus.
The secondary or peripheral organs of the immune system consist of the
spleen, lymph nodes; various dispersed lymphoid tissues, the appendix, lymphatics, skin, and even the liver. A significant component of these secondary
organs is organized within mucosa-associated lymphoid tissue (MALT), which
serves as a critical site for numerous immune processes associated with both
innate and adaptive immunity, thereby safeguarding the body against a wide
array of pathogens [3].
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N. Ahmed and A. Humaira
Cells of the Immune System
The immune system’s cellular components can be broadly categorized into two primary classes: myeloid and lymphoid cells. Collectively referred to as leukocytes or
white blood cells, these immune cells can be further divided into myeloid and lymphoid subsets. Myeloid cells, which constitute the predominant portion of the innate
immune system, include various types such as macrophages (along with their
monocyte precursors), mast cells, dendritic cells, neutrophils, basophils, and eosinophils. All myeloid cells exhibit some level of phagocytic ability, although basophils demonstrate significantly lower phagocytic activity compared to other myeloid
cell types. These cells are specialized in pathogen detection through pattern recognition receptors (PRRs) located on their membranes or within endosomes, followed
by the engulfment and destruction of infectious agents utilizing a range of destructive enzymes stored in their intracellular granules.
Neutrophils represent the most prevalent type of leukocyte in the bloodstream,
accounting for more than 50% of the total leukocyte population, and are particularly
efficient at phagocytosing and eliminating microbes. However, due to their potential
for tissue damage, neutrophils are restricted from exiting the bloodstream and infiltrating tissues until their necessity is validated by the actions of other innate immune
cells, particularly macrophages and mast cells, as well as soluble PRRs like complement. Macrophages and dendritic cells play crucial roles in the detection of pathogens and the initiation of immune responses, in addition to presenting the antigens
of phagocytosed microbes to lymphoid system cells. Furthermore, activated myeloid
cells are instrumental in amplifying immune responses through the release of various cytokines, chemokines, and other factors that exert significant effects on local
blood vessels [4]. The principal cells of the immune system and their functions are
listed in Table 2.
Table 2 Principal cells of the immune system
Cell type
Lymphocytes
Antigen-presenting cells
Effector cells
Principal functions
B lymphocytes: mediators of humoral immunity
T lymphocytes: mediators of cell-mediated immunity
Dendritic cells: initiation of T cell responses
Macrophages: effector phase of cell-mediated immunity
Elimination of antigens
T lymphocytes: activation of phagocytes, killing infected cells
Macrophages: phagocytosis and killing of microbes
Granulocytes: killing microbes
Immunology and Autoimmunity: Current Concepts and Clinical Implications
5
Role of Chemical Mediators and Antibodies in Immune System
Role of Cytokines
Cytokines are essential in modulating immune responses, inflammation, and haematopoiesis. These signalling molecules are released by various immune cells,
including macrophages, T cells, mast cells, and dendritic cells, and function through
autocrine, paracrine, or endocrine signalling. Cytokines coordinate both innate and
adaptive immune responses, with distinct roles that include:
1. Pro-inflammatory cytokines: Interleukin-1 (IL-1) which is secreted by macrophages and endothelial cells is instrumental in promoting inflammation, inducing fever, and activating T cells. Tumour necrosis factor-alpha (TNF-α) is a key
player in acute inflammation and fever. It facilitates the recruitment of immune
cells to infection sites and initiates apoptosis in infected cells. Interferon-gamma
(IFN-γ) is produced by natural killer (NK) cells and T-helper 1 (Th1) cells, and
activates macrophages, enhancing their capacity to eliminate intracellular pathogens such as Mycobacterium tuberculosis [5].
2. Anti-inflammatory cytokines: Interleukin-10 (IL-10) is secreted by regulatory T
cells (Tregs) and inhibits the production of pro-inflammatory cytokines, thereby
preventing excessive tissue damage. Transforming growth factor-beta (TGF-β) is
a cytokine that suppresses inflammation and fosters tissue repair and immune
tolerance.
3. Cytokines in hematopoiesis: Granulocyte-macrophage colony-stimulating factor
(GM-CSF) stimulates the generation of granulocytes and monocytes within the
bone marrow.
4. Cytokines in adaptive immunity: Interleukin-2 (IL-2) is vital for T cell proliferation and the formation of memory T cells. Interleukin-4 (IL-4) promotes the
differentiation of naïve T cells into T-helper 2 (Th2) cells and boosts IgE production by B cells, which is crucial for combating parasites and mediating allergic
responses.
Classes and Functions of Antibodies
Antibodies are generated by B cells and plasma cells and serve multiple specialized
functions essential for both the innate and adaptive immune responses. Their structure comprises fragment antigen-binding (Fab) site and a fragment crystallizable
(Fc) region that facilitates interactions with various immune system components.
As we know that antibodies play a central role in the humoral arm of the adaptive
immune system, recognizing and neutralizing foreign pathogens. Their structure
and function are tailored to provide specific defence mechanisms against a wide
range of infectious agents. Antibodies are categorized into different classes, each
with distinct roles and distribution in the body. Understanding these classes and
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N. Ahmed and A. Humaira
Table 3 Types of antibodies
Antibody
class
IgG
IgA
IgM
IgE
IgD
Function
Most abundant antibody in circulation; facilitates phagocytosis, complement
activation, and provides long-term immunity after infection or vaccination
Found predominantly in mucosal areas (e.g., respiratory and gastrointestinal
tracts); protects against pathogens at mucosal surfaces
First antibody produced during an initial immune response; highly effective in
complement activation
Binds to allergens and triggers histamine release from mast cells and basophils;
involved in allergic reactions and defence against parasitic worms
Functions primarily as a receptor on naïve B cells, playing a role in initiating B
cell activation
their functions is essential for appreciating the complexity and efficiency of the
immune response and their types and functions are listed in Table 3.
Mechanisms of action of antibodies: Antibodies act through several mechanisms
to protect the body against pathogens. One of the primary mechanisms is neutralization, where antibodies bind to toxins or pathogens, blocking their ability to attach to
and infect host cells. This mechanism is particularly effective against viruses and
bacterial toxins. Another important mechanism is opsonization, in which antibodies
coat the surface of pathogens, enhancing their recognition and uptake by phagocytic
cells such as macrophages and neutrophils. This process promotes phagocytosis and
helps clear pathogens from the body. Additionally, antibodies, especially IgM and
IgG, can initiate the complement activation pathway. This activation triggers a
series of reactions that amplify the immune response, leading to pathogen lysis and
promoting inflammation to further eliminate the invading microorganisms. Together,
these mechanisms work synergistically to provide robust protection against various
pathogens [6].
Role of the Complement System
The complement system consists of a series of proteins that amplify the immune
system’s capacity to eliminate pathogens. Its activation results in inflammation,
opsonization, and the destruction of pathogens. There are three major pathways of
complement activation (Fig. 1).
Classical pathway: Initiated by the formation of antigen-antibody complexes, especially those involving IgM or IgG.
Alternative pathway: Activated directly by the presence of microbial surfaces or
pathogen-associated molecular patterns (PAMPs).
Lectin pathway: Triggered by mannose-binding lectin attaching to carbohydrate
structures on pathogens.
Immunology and Autoimmunity: Current Concepts and Clinical Implications
7
Fig. 1 Complement pathway. https://openstax.org/details/books/anatomy-­and-­physiology-­2e
The complement system plays a crucial role in the immune response through
various mechanisms. One of its key functions is opsonization, where the complement protein C3b binds to microbial surfaces, marking them for phagocytosis by
immune cells. Another important function is inflammation, mediated by complement fragments C3a and C5a, which act as anaphylatoxins. These fragments attract
and activate immune cells such as neutrophils and mast cells, promoting inflammation and enhancing the immune response. Additionally, the complement system
contributes to pathogen lysis through the formation of the terminal complement
complex, known as the membrane attack complex (MAC). The MAC creates pores
in the membranes of target cells, causing osmotic lysis and ultimately leading to cell
death. Together, these functions ensure effective identification, recruitment, and
destruction of pathogens [7].
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Regulation of the complement system: To avoid excessive activation, regulatory
proteins such as decay-accelerating factor (DAF) and complement receptor 1 (CR1)
modulate complement activation on host cells. A deficiency in these regulatory proteins can result in autoimmune disorders or chronic inflammation.
Immune System Function and Regulation
The immune system is an intricate network of cells, tissues, and organs that work
together to protect the body from harmful pathogens while safeguarding against
self-damage. It encompasses both innate and adaptive immune responses, with critical processes such as immune cell development, immune tolerance, and regulation
playing vital roles in maintaining equilibrium and preventing illness.
Immune Cell Development and Differentiation
T cells are generated in the bone marrow and subsequently undergo development
and maturation within the thymus. During this process, positive selection ensures
that T cells can effectively recognize self-MHC molecules, while negative selection
removes those that exhibit excessive binding to self-antigens (Fig. 2). Once matured,
T cells differentiate into various subsets, including helper T cells (CD4+ T cells),
which facilitate the activation of other immune cells, and cytotoxic T cells (CD8+ T
cells), which are responsible for directly eliminating infected or malignant cells.
Additionally, T cells are vital in regulating immune responses, particularly in contexts such as autoimmunity and cancer [8].
B cells are produced and mature in the bone marrow. When they come into contact with particular antigens, they transform into plasma cells that produce antibodies (Fig. 3). These antibodies attach to pathogens, effectively neutralizing them and
signalling for their elimination through mechanisms like opsonization and complement activation. This process plays a vital role in humoral immunity, particularly
against viral and bacterial infections [7]. The activation of B cells is regulated by
cytokines and their interactions with T-helper cells [9].
Macrophages originate from monocytes in the bone marrow and play various
roles in the immune response. Once they migrate into tissues, macrophages engulf
pathogens and release pro-inflammatory cytokines. Additionally, they function as
antigen-presenting cells (APCs) by presenting pathogen fragments to T cells,
thereby enhancing the adaptive immune response [10].
Immunology and Autoimmunity: Current Concepts and Clinical Implications
Fig. 2 Clonal selection and expansion of T lymphocytes
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N. Ahmed and A. Humaira
Fig. 3 Clonal selection of B cells. https://openstax.org/details/books/anatomy-­and-­physiology-­2e
Mechanisms of Immune Response Activation
The immune system is activated when immune cells identify pathogens or injured
tissues. Cells such as dendritic cells and macrophages possess pattern recognition
receptors (PRRs) that can detect pathogen-associated molecular patterns (PAMPs)
and damage-associated molecular patterns (DAMPs), resulting in immune activation. Among these receptors are toll-like receptors (TLRs), which start signalling
pathways that activate innate immune cells and stimulate the release of inflammatory cytokines [8]. The nuclear factor-kappa B (NF-kB) signalling pathway is a key
pathway activated by PRRs and has been thoroughly researched regarding its role in
inflammation and immune responses [11].
After the initiation of the innate immune response, adaptive immune responses
that include T cells and B cells are activated. Dendritic cells play a crucial role as
antigen-presenting cells by delivering antigens to naïve T cells, which promotes
Immunology and Autoimmunity: Current Concepts and Clinical Implications
11
their activation and proliferation. Helper T cells, specifically Th1 and Th2, enhance
the immune response, whereas cytotoxic T cells are responsible for identifying and
eliminating infected cells [8].
Immune Tolerance and Self-Recognition
Immune tolerance is an essential mechanism that safeguards the body by preventing
the immune system from targeting self-antigens, which could result in autoimmune
disorders. Central tolerance is established during the development of T cells in the
thymus and B cells in the bone marrow, where cells that respond to self-antigens are
eliminated. The primary processes involved in central tolerance for T cells include
the elimination of immature T cells and the formation of CD4+ regulatory T cells.
When an incompletely matured lymphocyte encounters a self-antigen, presented as
a peptide associated with a self-major histocompatibility complex (MHC) molecule, it receives signals that initiate apoptosis. Consequently, the self-reactive lymphocyte undergoes cell death prior to achieving functional competence, a
phenomenon known as negative selection. Additionally, peripheral tolerance mechanisms play a vital role in regulating immune responses in peripheral tissues, involving regulatory T cells (Tregs) that inhibit immune activation and help maintain
homeostasis. Peripheral tolerance in T cells is established through various mechanisms. Anergy, which refers to the functional inactivation of T cells, occurs when
antigens are recognized in the absence of co-stimulatory signals. This process
involves a disruption in T cell receptor (TCR) signalling and the activation of inhibitory receptors like cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1(PD-1). Additionally, self-reactive regulatory T cells
play a crucial role in inhibiting potentially harmful T cells. Furthermore, deletion,
or apoptosis, can take place when T cells interact with self-antigens. In B lymphocytes, central tolerance is established when immature cells identify self-antigens
within the bone marrow. This process leads to receptor editing in some cells, while
others undergo apoptosis through negative selection or deletion. Peripheral tolerance is triggered when mature B cells encounter self-antigens independently of T
cell assistance, resulting in either anergy and subsequent cell death or the activation
of inhibitory receptors [7]. The difference between central and peripheral tolerance
is listed in Table 4.
It has indicated that impairments in immune tolerance mechanisms can contribute to the onset of autoimmune diseases, including systemic lupus erythematosus
(SLE) and rheumatoid arthritis. Recent studies have investigated the function of
Tregs in managing autoimmune conditions by suppressing pro-inflammatory T cells
and mitigating tissue damage [12].
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N. Ahmed and A. Humaira
Table 4 Difference between central tolerance and peripheral tolerance
Central tolerance
Thymus (T cells) and bone marrow (B
cells)
Purpose
Elimination of self-reactive
lymphocytes during development
Mechanisms (T Negative selection (apoptosis) and
cells)
formation of CD4+ regulatory T cells
(Tregs)
Mechanisms (B Receptor editing, deletion (apoptosis)
cells)
Signal
Self-antigen recognition presented by
requirement
self-MHC molecules
Outcome of
Potential survival of self-reactive cells
failure
Rarely associated with disease directly
Associated
diseases
Location
Role of Tregs
Formation of Tregs during T cell
development
Peripheral tolerance
Peripheral tissues (outside thymus
and bone marrow)
Regulation of immune responses
after lymphocytes mature
Anergy, suppression by Tregs,
deletion (apoptosis)
Anergy, apoptosis, activation of
inhibitory receptors
Self-antigen recognition in absence
of costimulatory signals
Potential activation of self-reactive
cells causing autoimmunity
Impairment linked to autoimmune
diseases (e.g., SLE, rheumatoid
arthritis)
Suppression of pro-inflammatory T
cells to maintain homeostasis
Immune Checkpoints and Their Role in Maintaining Balance
Immune checkpoints serve as regulatory mechanisms that help maintain immune
balance by curbing excessive immune reactions that could lead to tissue damage.
Prominent immune checkpoints, such as CTLA-4 and PD-1, play a crucial role in
inhibiting T cell activation after the immune response has commenced. If not managed properly, the inhibition of these checkpoints may result in autoimmunity.
Nevertheless, immune checkpoint inhibitors, including anti-CTLA-4 and anti-PD-1
antibodies, have gained significant traction in the field of cancer immunotherapy
[8]. In the context of cancer treatment, these checkpoint inhibitors are designed to
reactivate T cells that have been suppressed by the tumour microenvironment.
However, a blockade of these checkpoints can lead to immune-related adverse
events (AEs), highlighting the importance of maintaining a balanced immune
response [8]. It has been demonstrated that checkpoint blockade has transformed
cancer therapy by enhancing T cell activity against tumour cells [13].
Autoimmunity: An Overview
Autoimmune diseases are defined as immune responses that mistakenly target specific self-antigens, resulting in persistent tissue damage. This misidentification
occurs when the immune system cannot differentiate between the body’s own cells
and foreign invaders, leading to the activation of autoreactive lymphocytes and the
generation of autoantibodies. These autoantibodies, along with autoreactive T cells,
specifically attack self-antigens, resulting in tissue injury. Autoimmune diseases can
Immunology and Autoimmunity: Current Concepts and Clinical Implications
13
be localized, affecting distinct antigens in specific tissues such as the thyroid or
pancreatic β-cells, or they can be systemic, impacting multiple tissues and targeting
a range of autoantigens that are widely expressed throughout the body [14].
Normal immune responses serve as protective mechanisms that detect and eradicate pathogens while ensuring tolerance towards the body’s own cells. This tolerance is upheld through processes like central tolerance, which involves the removal
of self-reactive lymphocytes during their maturation in the thymus and bone marrow, and peripheral tolerance, which manages mature lymphocytes in peripheral
tissues. When these tolerance mechanisms break down, the immune system may
trigger an autoimmune response, thereby differentiating autoimmune diseases from
standard protective immune functions [3].
Breakdown of Immune Tolerance
Immune tolerance is the immune system’s capacity to refrain from attacking the
body’s own cells and tissues. This essential process maintains immune homeostasis
and prevents the onset of autoimmunity. When immune tolerance is disrupted, it can
result in autoimmune diseases, chronic inflammation, and various immune-­mediated
disorders [15].
The breakdown of these mechanisms can occur due to environmental influences,
genetic factors, or infections [16].
Causes of Breakdown in Immune Tolerance
1. Genetic Influences: Genetic mutations affecting immune regulation, such as
those in autoimmune regulator (AIRE), forkhead box protein P3 (FOXP3), and
CTLA-4, can disrupt tolerance mechanisms [17].
Variations in HLA genes can heighten the risk of developing certain autoimmune disorders.
2. Environmental Factors: Pathogens can trigger autoreactive lymphocytes through
molecular mimicry, as seen in streptococcal infections that may lead to
Rheumatic Fever.
Medications and toxins can modify antigen presentation or stimulate immune
responses.
3. Regulatory T cell (Treg) dysfunction: Tregs are essential for preserving immune
tolerance. A reduction in the number or functionality of Tregs can result in
heightened autoimmune activity [18].
4. Inflammation: Chronic inflammation can disturb immune balance and foster
autoimmunity by maintaining antigen presentation and T cell activation [19].
Certain areas of the body are designed to avoid immune responses against pathogens, tumour cells, or incompatible tissue transplants. These regions, referred to as
immune privileged sites, include the eye, testis, brain, ovary, and placenta. The
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N. Ahmed and A. Humaira
immune privilege of the eye is exemplified by the fact that corneal transplants in
humans do not necessitate tissue matching or immunosuppressive treatment. It is
important to note that autoimmunity does not always result in disease. Many individuals have low levels of autoantibodies, and it is common for healthy people to
exhibit significant levels of specific autoantibodies, such as antinuclear antibodies
or rheumatoid factor. Additionally, T cell responses to self-antigens can occur without manifesting any disease symptoms [20].
Pathogenesis of Autoimmune Diseases
Autoimmune diseases encompass a wide range of conditions marked by abnormal
reactivity of B cells and T cells against the body’s own normal components. These
disorders are prevalent across various age groups, with a notable predominance in
women. A key immunological feature of these diseases is the generation of autoantibodies, which serve as important biomarkers for diagnosis, classification, and
monitoring disease activity [21]. The impact of autoimmune diseases is highly variable, affecting different organs and presenting with diverse clinical symptoms.
Some conditions are localized to specific tissues, while others are systemic in
nature. Despite these differences, it is generally accepted that autoimmune diseases
progress through distinct phases, i.e., initiation, propagation, and resolution. Each
of these stages is associated with a breakdown in regulatory mechanisms, with the
resolution phase characterized by a temporary and often incomplete restoration of
the balance between effector and regulatory immune responses [1].
The key contributors to the onset of autoimmunity include the genetic inheritance of susceptibility genes and various environmental factors, including infections. It is believed that these susceptibility genes disrupt the mechanisms of
self-tolerance, allowing self-reactive T and B lymphocytes to persist. Environmental
influences can induce damage to cells and tissues, leading to inflammation and the
activation of these self-reactive lymphocytes. This process ultimately results in the
production of effector T cells and autoantibodies, which play a crucial role in the
development of autoimmune diseases [22].
The core inquiries surrounding autoimmunity focus on the breakdown of self-­
tolerance and the activation of self-reactive lymphocytes. Gaining insights into
these issues is essential for comprehending the causes and development of autoimmune diseases, a significant challenge within the field of immunology.
Molecular Mimicry by Cross-Reactive Microbial Antigens
Autoimmune diseases are categorized into systemic and organ-specific types,
depending on how autoantigens are distributed and recognized by the immune system. Certain infectious agents may have antigens that can mimic self-antigens,
resulting in immune responses that inadvertently attack the body’s own tissues. This
phenomenon is known as molecular mimicry, where the structure of microbial
Immunology and Autoimmunity: Current Concepts and Clinical Implications
15
antigens closely resembles that of self-antigens. A prominent example of this immunological misidentification is rheumatic fever, which can develop after streptococcal infections. In this scenario, antibodies generated against streptococci erroneously
target proteins in the heart, leading to myocarditis due to their accumulation in
cardiac tissue [23]. The idea of molecular mimicry is further supported by evidence
from infections with gram-negative bacteria, such as Klebsiella pneumoniae and
Campylobacter jejuni. These infections stimulate the production of antibodies that
can cross-react with self-antigens, including histocompatibility leukocyte antigen
(HLA)-B27 and gangliosides, which are associated with diseases like ankylosing
spondylitis and Guillain–Barré syndrome, respectively [24].
Molecular mimicry is thought to play a role in various autoimmune disorders,
including type 1 diabetes. Specific peptide fragments derived from Coxsackie virus
and cytomegalovirus have been shown to cross-react with glutamate decarboxylase,
which is a key target for autoreactive T cells in individuals with type 1 diabetes.
Furthermore, peptides from several other viruses, such as cytomegalovirus, measles, and hepatitis C virus, also exhibit cross-reactivity with phosphatase IA-2, an
enzyme produced by pancreatic beta cells, potentially contributing to type 1diabetes
mellitus [25].
Role of Autoreactive T Cell and B Cell
B cells have been primarily recognized for their crucial role in enhancing the
immune response in autoimmune conditions, as they generate plasma cells that produce autoantibodies and facilitate CD4+ T cell responses through antigen presentation. These B cells, which perform these functions, are typically classified as effector
B cells. Recent research has revealed that B cells can also function as negative regulators of the immune response in autoimmunity, with these regulatory characteristics largely linked to the newly identified interleukin 10 (IL-10), regulatory B cell
subset. Emerging therapies are now targeting these B cell populations using drugs
that focus on B cell surface markers (such as CD20 and CD22), activating factors
(like B cell-activating factor of the TNF family (BAFF) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)), or cytokines
(including IL-6, TNFα, and IFNα). A primary strategy for addressing autoimmune
diseases involves the selective elimination of autoreactive effector B cells [26].
In systemic lupus erythematosus (SLE), autoreactive B cells generate anti-­
nuclear antibodies (ANAs) that specifically target components such as DNA, histones, and ribonucleoproteins. The resulting immune complexes can accumulate in
various tissues, including the kidneys, skin, and joints, causing inflammation and
subsequent organ damage. The therapies aimed at depleting B cells, such as rituximab, can alleviate disease severity, underscoring the significant contribution of
autoreactive B cells in the pathogenesis of SLE [27].
T cells have a complex function in autoimmunity. They are essential for maintaining self-tolerance, yet autoreactive T cells contribute significantly to the cellular
and tissue damage associated with autoimmune diseases [28]. Research indicates
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N. Ahmed and A. Humaira
that in both organ-specific and systemic forms of autoimmunity, CD4 T cells are
more closely associated with disease development than CD8 T cells. The cytokine
environment plays a critical role in determining which subsets of T helper cells will
be most prevalent. Initial findings from numerous studies on autoimmune diseases
have highlighted the involvement of autoreactive TH1 cells and the cytokine
IFN-γ [29].
In multiple sclerosis, autoreactive CD4+ T cells, especially Th1 and Th17 subsets, identify myelin basic protein (MBP) along with other myelin-related antigens.
These T cells penetrate the blood-brain barrier, instigating inflammation and causing damage to the myelin sheaths within the central nervous system (CNS), which
results in neurodegeneration and various neurological symptoms. The effectiveness
of T cell-targeted treatments, such as natalizumab (anti-α4 integrin) and fingolimod
(sphingosine-1-phosphate receptor modulator), underscores the involvement of
autoreactive T cells in the pathology of multiple sclerosis (MS) [30].
ole of Cytokine Dysregulation in the Pathogenesis
R
of Autoimmune Diseases
Cytokines are crucial for regulating immune responses, and their improper functioning is associated with the development of numerous autoimmune disorders. A
disruption in the balance between pro-inflammatory and anti-inflammatory cytokines is a significant factor in the initiation and advancement of these diseases.
Elevated levels of pro-inflammatory cytokines, including tumour necrosis factor-­
alpha (TNF-α), interleukin-6 (IL-6), and interleukin-17 (IL-17), are frequently
observed in autoimmune disorders, contributing to tissue damage and sustained
inflammation [31]. In contrast, regulatory cytokines such as interleukin-10 (IL-10)
and transforming growth factor-beta (TGF-β) are vital for preserving immune tolerance. A reduction in these regulatory cytokines can intensify autoimmune reactions [32].
Key Cytokines in Autoimmune Diseases
Tumour Necrosis Factor-alpha (TNF-α)
TNF-α plays a crucial role in the development of rheumatoid arthritis (RA) and the
inflammatory bowel disease (IBD). It facilitates inflammation through the activation of nuclear factor-kappa B (NF-κB) signalling pathways and increases the synthesis of additional pro-inflammatory cytokines [33].
Immunology and Autoimmunity: Current Concepts and Clinical Implications
17
Interleukin-6 (IL-6)
IL-6 is a multifunctional cytokine that plays a significant role in both innate and
adaptive immune responses. Its levels are increased in conditions like systemic
lupus erythematosus (SLE) and rheumatoid arthritis (RA), where it facilitates the
differentiation of B cells and the production of autoantibodies [34].
Interleukin-17 (IL-17)
IL-17 is mainly secreted by T helper 17 (Th17) cells and is essential in the pathogenesis of conditions such as psoriasis and ankylosing spondylitis. This cytokine
promotes the recruitment of neutrophils and intensifies tissue inflammation [35].
I nterleukin-10 (IL-10) and Transforming Growth
Factor-­Beta (TGF-β)
IL-10 and TGF-β play essential roles in immune regulation and the inhibition of
inflammatory responses. A lack of these cytokines has been associated with
increased autoimmune activity, as seen in conditions such as multiple sclerosis
(MS) and type 1 diabetes (T1D) [36].
Inflammatory Pathways and Autoimmune Disease Pathogenesis
Inflammatory pathways are initiated by both innate and adaptive immune responses.
Pattern recognition receptors (PRRs), including toll-like receptors (TLRs), identify
pathogen-associated molecular patterns (PAMPs) and damage-associated molecular
patterns (DAMPs), which activate subsequent signalling cascades. These cascades
lead to the release of pro-inflammatory cytokines, chemokines, and various other
mediators that contribute to the persistence of autoimmune pathology [32].
ey Inflammatory Mediators Pathways
K
in Autoimmune Diseases
Nuclear Factor-Kappa B (NF-κB) Pathway
NF-κB serves as a crucial transcription factor that governs immune and inflammatory responses. In the context of autoimmune disorders like rheumatoid arthritis
(RA) and systemic lupus erythematosus (SLE), the activation of NF-κB results in
the overproduction of tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1),
and interleukin-6 (IL-6), which contributes to persistent inflammation [37].
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N. Ahmed and A. Humaira
J anus Kinase-Signal Transducer and Activator of Transcription
(JAK-STAT) Pathway
The JAK-STAT signalling pathway plays a vital role in immune responses mediated
by cytokines. Abnormal activation of JAK-STAT is associated with diseases such as
psoriasis and multiple sclerosis (MS), where improper signalling results in ongoing
activation of immune cells and excessive cytokine production [38].
Inflammasome Activation
The inflammasome is a complex of multiple proteins that plays a crucial role in the
activation of pro-inflammatory cytokines, including IL-1β and IL-18. Excessive
activation of the inflammasome has been linked to various diseases, such as gout,
type 1 diabetes (T1D), and inflammatory bowel disease (IBD) [1].
Genetic Factors
The inherited risk for most autoimmune diseases is linked to multiple gene loci,
with the major influence stemming from major histocompatibility (MHC) genes.
When one twin develops an autoimmune disease, the likelihood of the other twin
also developing the same condition is higher compared to an unrelated individual
from the general population. Genome-wide association studies have identified several common genetic variations (polymorphisms) that may play a role in various
autoimmune diseases. However, these polymorphisms are often found in healthy
individuals, and their individual impact on the onset of autoimmunity is minimal. In
contrast, some rare variants associated with autoimmunity are mutations that are
virtually absent in healthy populations, and these rare mutations can significantly
influence the development of autoimmune conditions.
Many autoimmune diseases in humans and inbred animals are linked to particular MHC alleles and these are shown in Table 5.
Genetic variations in non-HLA genes have been linked to a range of autoimmune
disorders and may play a role in the breakdown of self-tolerance or the inappropriate activation of lymphocytes. Specifically, polymorphisms in the gene for the tyrosine phosphatase PTPN22 (protein tyrosine phosphatase N22) can result in excessive
activation of both B and T cells, correlating with several autoimmune conditions
such as rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes
Table 5 HLA-associated
diseases
Disease
Ankylosing spondylitis
Rheumatoid arthritis
Type 1 diabetes mellitus
Pemphigus vulgaris
Associated HLA allele(s)
HLA-B27
HLA-DRB1*01, *04, *10
HLA-DRB1*0301, *0401
HLA-DR4 (HLA-DRB1*0402)
Immunology and Autoimmunity: Current Concepts and Clinical Implications
19
mellitus. Additionally, variants of the innate immune cytoplasmic microbial sensor
NOD-2, which lead to diminished resistance to intestinal microbes, have been associated with Crohn’s disease, an inflammatory bowel condition, in certain ethnic
groups [39].
Biomarkers and Clinical Implications
The identification and treatment of autoimmune diseases are significantly dependent on laboratory biomarkers, such as autoantibodies, inflammatory indicators, and
genetic factors. These biomarkers play an important role in diagnosing particular
autoimmune diseases and offer valuable information regarding disease progression
and treatment efficacy. A biomarker is typically defined as a quantifiable characteristic that serves as an indicator of a biological state or condition. Three categories of
medical biomarkers have been proposed: mechanistic markers, clinical disease
markers, and therapeutic markers. An optimal and more precise diagnosis and treatment approach could be achieved by integrating biomarkers from these various categories [40]. Additionally, the emergence of advanced imaging technologies and the
integration of artificial intelligence into diagnostic methods are facilitating the recognition of unique biomarker profiles that enhance the understanding of clinical
conditions. The transition towards a precision medicine-focused strategy is becoming increasingly apparent, as researchers investigate the relationships between
genetic variations (single nucleotide polymorphisms), cytokine profiles, and disease
outcomes to develop more precise diagnostic tools [41].
Autoantibodies: Hallmarks of Autoimmune Diseases
Autoantibodies are a key laboratory characteristic of numerous autoimmune disorders, playing an essential role in both diagnosis and classification of these diseases.
They can act as early markers, often emerging years prior to the onset of clinical
symptoms.
heumatoid Factor (RF) and Anti-Citrullinated Peptide
R
Antibodies (ACPA)
Rheumatoid factor (RF) is an autoantibody that targets the Fc region of IgG. It is
found in about 70% of rheumatoid arthritis (RA) patients but may also be present in
other conditions, including Sjögren’s syndrome and chronic infections. Due to its
relatively low specificity, RF is typically assessed alongside other biomarkers.
Anti-citrullinated peptide antibody (ACPA) has been recognized as a more reliable marker for RA, boasting a specificity of 95% compared to RF. The presence of
ACPA is linked to more severe disease manifestations and an increased risk of joint
erosions [39].
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N. Ahmed and A. Humaira
Antinuclear antibodies (ANA) and disease-specific autoantibodies: Antinuclear
antibodies (ANA) represent a diverse group of autoantibodies that target components within the nucleus and are frequently associated with systemic lupus erythematosus (SLE), scleroderma, and mixed connective tissue disease. A positive ANA
test, particularly at elevated titers, strongly indicates an autoimmune condition but
necessitates further subtyping for confirmation. Anti-neutrophil cytoplasmic antibodies (ANCA) are vital for diagnosing vasculitides, such as granulomatosis with
polyangiitis42. Additionally, anti-double-stranded DNA (anti-dsDNA) and anti-­
Smith (anti-Sm) antibodies are highly specific for SLE, with anti-dsDNA levels
correlating with disease activity and nephritis [42].
Inflammatory markers Autoimmune diseases frequently present with systemic
inflammation, which can be assessed through various laboratory markers. C-reactive
protein (CRP) and erythrocyte sedimentation rate (ESR) are two key indicators.
CRP is an acute-phase protein synthesized by the liver in response to inflammatory
processes. Increased levels of CRP are associated with conditions such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and lupus, with higher concentrations reflecting active disease and systemic inflammation. On the other hand,
ESR evaluates the rate at which red blood cells settle over a specified period.
Although it is a non-specific marker, elevated ESR levels are commonly observed in
conditions like polymyalgia rheumatica, RA, and vasculitis [43].
Cytokines and Other Inflammatory Mediators
Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are found at
increased levels in conditions like rheumatoid arthritis (RA) and psoriatic arthritis,
leading to joint damage and systemic manifestations. Additionally, interleukin-17
(IL-17) is implicated in multiple sclerosis (MS) and ankylosing spondylitis, making
its inhibition a focus for biologic treatment strategies [44].
Genomic biomarkers: The genomic framework of autoimmune disorders includes
DNA variations that play a role in disease vulnerability, advancement, and response
to treatment. Genomic biomarkers consist of single nucleotide polymorphisms
(SNPs), copy number variations (CNVs), and gene expression patterns [45]. Certain
genetic variations are correlated with a heightened risk of particular autoimmune
disorders. For instance, the HLA-DRB1 gene is associated with an increased susceptibility to rheumatoid arthritis, whereas alterations in the CTLA-4 gene have
been connected to type 1 diabetes. Gene expression profiling through methods like
microarrays or RNA sequencing has revealed unique expression patterns linked to
autoimmune disorders. These profiles offer valuable insights into the underlying
mechanisms of diseases, assist in prognosis, and help predict responses to treatment. For instance, variations in the expression of immune-related genes in patients
with systemic lupus erythematosus (SLE) could identify individuals who are at a
higher risk of experiencing severe flare-ups [46].
Immunology and Autoimmunity: Current Concepts and Clinical Implications
21
Conclusion
Autoimmune diseases result from a dysregulated immune system that mistakenly
targets self-antigens, leading to chronic inflammation, tissue destruction, and multi-­
organ involvement. The aetiology of autoimmunity is multifactorial, with a combination of genetic susceptibility, environmental triggers, and immune dysregulation
contributing to disease development. Advances in genomic studies, biomarker identification, and immunomodulatory therapies have enhanced our understanding of
the mechanisms underlying autoimmunity and improved the clinical management
of these diseases.
A key feature of autoimmune diseases is the loss of immune tolerance, which can
be attributed to defective central tolerance (failure to eliminate autoreactive lymphocytes in the thymus and bone marrow) or impaired peripheral tolerance (failure
to suppress immune responses via regulatory T cells, cytokines, and immune checkpoints). Cytokine imbalances, particularly elevated levels of pro-inflammatory
mediators such as TNF-α, IL-6, and IL-17, play a critical role in sustaining inflammation and disease progression.
The development of biologic therapies, such as TNF inhibitors, IL-6 blockers,
and JAK-STAT pathway inhibitors, has transformed autoimmune disease management by offering more precise and effective treatment options. Additionally, immune
checkpoint inhibitors have been successfully employed in treating cancers by boosting immune responses, though their use can sometimes induce autoimmune-like
side effects. B cell-depleting therapies (e.g., rituximab) and T cell-targeting strategies have also demonstrated efficacy in autoimmune diseases such as rheumatoid
arthritis and multiple sclerosis.
Despite these advancements, several challenges remain, including disease heterogeneity, unpredictable treatment responses, and the long-term safety of immunosuppressive therapies. The complexity of autoimmune diseases necessitates a
personalized approach to treatment, leveraging biomarkers, genetic profiling, and
precision immunotherapy to optimize patient outcomes. Future directions in autoimmunity research include stem cell therapy, microbiome modulation, and gene-­
editing technologies such as clustered regularly interspaced short palindromic
repeats (CRISPR), which hold promise for curative interventions.
In conclusion, a deeper understanding of immune system function and regulation
is essential for advancing autoimmune disease research and treatment. By integrating insights from immunology, genetics, and clinical medicine, researchers and clinicians can work towards more effective, individualized, and potentially curative
therapies for patients with autoimmune disorders. Continued innovation in immunotherapy, biomarker discovery, and disease modelling will be crucial in addressing
the complexities of autoimmunity and improving long-term patient care.
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N. Ahmed and A. Humaira
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Rheumatoid Arthritis
Syed Khalid Imam
Introduction
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized
by persistent synovial inflammation, progressive joint damage, and variable extra-­
articular manifestations. Globally, RA affects approximately 0.5–1% of the adult
population, with a female predominance and peak onset between 40 and 60 years of
age [1, 2]. The disease imposes significant morbidity, disability, and healthcare burden if not diagnosed and treated early.
The pathogenesis of RA involves a complex interplay of genetic predisposition,
environmental exposures, and immune dysregulation. Genetic associations, particularly involving the shared epitope of the HLA-DRB1 gene, confer increased susceptibility and severity [3]. Environmental factors such as smoking, periodontal
infections, and altered microbiota are implicated in triggering the autoimmune cascade in genetically predisposed individuals [4]. Central to RA pathogenesis is synovial inflammation driven by activated T cells, B cells, macrophages, and
fibroblast-like synoviocytes, producing pro-inflammatory cytokines including
tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 (IL-1),
resulting in pannus formation and joint destruction [5].
Clinically, RA presents with symmetrical polyarthritis involving small joints,
prolonged morning stiffness, and progressive joint deformities if untreated [6].
Extra-articular manifestations such as rheumatoid nodules, interstitial lung disease,
vasculitis, and cardiovascular complications contribute to systemic disease burden
and increased mortality [7]. Diagnosis is based on a combination of clinical features, serological markers—rheumatoid factor (RF) and anti-cyclic citrullinated
peptide (anti-CCP) antibodies—and imaging techniques like ultrasound and MRI
that detect early synovitis and erosions [8]. Early diagnosis and prompt initiation of
S. K. Imam (*)
Sultan Bin Abdulaziz Humanitarian City, Riyadh, Kingdom of Saudi Arabia
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_2
25
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S. K. Imam
treatment are critical to prevent irreversible joint damage. Methotrexate remains the
anchor drug among conventional synthetic disease-modifying antirheumatic drugs
(csDMARDs). Biologic DMARDs targeting TNF-α, IL-6 receptors, and B cells,
along with Janus kinase (JAK) inhibitors, have revolutionized the management of
RA, offering targeted control of inflammation and structural damage [9]. Current
management emphasizes a treat-to-target approach, aiming for remission or low
disease activity through regular monitoring and timely therapy adjustment [10].
This chapter provides an overview of the current understanding of RA, covering
epidemiology, pathogenesis, clinical manifestations, diagnostic approach, therapeutic strategies, and future directions for improving patient outcomes. Juvenile idiopathic arthritis (JIA), sometimes referred to as juvenile rheumatoid arthritis (JRA), is
the most common form of childhood arthritis and will be covered separately in
Chapter “Juvenile Idiopathic Arthritis”.
Epidemiology
Rheumatoid arthritis (RA) demonstrates significant geographic and demographic
variability in its prevalence. Higher rates are reported in Western and Northern
Europe, North America, and regions with populations of European descent, such
as Australia, whereas lower prevalence is observed in Central and South America,
and even lower rates are reported in East Asia and Africa [1]. The estimated annual
incidence of RA in the United States and other Western nations of Northern
Europe is approximately 40 cases per 100,000 individuals [11]. Epidemiological
data consistently indicate that RA is more prevalent among women, with a lifetime risk of 3.6% compared to 1.7% in men [12]. The risk of developing RA also
increases with advancing age, with the highest incidence noted between 65 and
80 years [13].
Socioeconomic and environmental factors further influence RA distribution. The
period prevalence of RA is higher in urban populations (0.69%) than in rural areas
(0.54%) [14]. Similarly, high-income countries report a higher period prevalence
(0.49%) compared to low-income countries (0.35%) [5]. Overall, RA prevalence
remains higher in North America and Europe, while lower rates are consistently
observed in Asia and South America (Table 1).
Table 1 Pooled prevalence
of RA [14]
Country
South America
Asia
Africa
Europe
North America
Global
Prevalence
0.3%
0.3%
0.52%
0.54%
0.70%
0.46%
Rheumatoid Arthritis
27
Pathogenesis and Risk Factors
The understanding of rheumatoid arthritis (RA) pathogenesis has progressed from
early infectious and environmental theories to its current recognition as a multifactorial autoimmune disease [6]. First described as distinct in the nineteenth century
by Sir Alfred Baring Garrod, RA was initially linked to infections due to its systemic inflammation. The mid-twentieth century discovery of rheumatoid factor
(RF) established its autoimmune basis, further clarified by identifying T cell activation and key cytokines like TNF-α and IL-1, leading to targeted therapies. In the
twenty-first century, the discovery of anti-citrullinated protein antibodies (ACPAs)
and citrullination highlighted RA’s autoimmune mechanisms [5].
Despite being one of the most common forms of inflammatory arthritis and
extensively studied as a model of autoimmunity, the exact etiology of rheumatoid
arthritis (RA) remains unclear. Both genetic predisposition and environmental factors such as smoking or infection contribute to its development and progression.
The established pathogenesis involves autoantibody production, immune cell activation, inflammatory pathway signaling, and synovial proliferation. However, these
insights have yet to translate into curative treatments, highlighting gaps in fully
understanding the disease process.
1. Environmental Factors
Cigarette smoking is recognized as the strongest environmental risk factor for
rheumatoid arthritis (RA), particularly in individuals positive for anti-­citrullinated
protein antibodies (anti-CCP), where it interacts with the shared epitope (SE) to
significantly increase RA risk [15]. Other environmental exposures linked to
seropositive RA include silica, asbestos, textile dust, and Porphyromonas gingivalis infection [16]. These findings suggest that exposure to external antigens at
sites distant from the joints such as the lungs, oropharynx, and gastrointestinal
tract may initiate autoimmune responses that subsequently target the joints. In
rheumatoid arthritis (RA), the gut microbiome undergoes dysbiosis, with
reduced microbial diversity compared to healthy individuals. Certain bacterial
genera, including Actinobacteria, Collinsella, Eggerthella, and Faecalibacterium,
are found in increased abundance. Notably, Collinsella has been linked to altered
gut mucosal permeability and greater disease severity in RA patients [17].
Dietary risk factors for RA include red meat intake, Vitamin D deficiency, excessive coffee consumption, and high salt intake.
2. Hormonal Factors
Sex hormones are believed to influence the development of RA, as suggested by
the higher prevalence of the disease in females, its improvement during pregnancy, its flare-up in the early postpartum period, and the lower incidence
observed in women using oral contraceptives. Additionally, elevated prolactin
levels (hyperprolactinemia) may contribute as a potential risk factor for RA [18].
3. Epigenetic Factors
Epigenetics refers to heritable changes in gene expression that occur without
modifications to the underlying DNA sequence, involving mechanisms such as
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S. K. Imam
DNA methylation, histone modifications, and regulation by non-coding RNAs.
In rheumatoid arthritis, fibroblast-like synoviocytes (RA-FLS) exhibit overexpression of the tyrosine phosphatase SHP-2, encoded by the protein tyrosine
phosphatase, non-receptor type 11 (PTPN11) gene, compared to synoviocytes
from osteoarthritis (OA) patients, contributing to the aggressive and invasive
behavior characteristic of RA-FLS [19].
4. Genetic Factors
Rheumatoid arthritis (RA) has a significant genetic component, with heritability
estimated between 40% and 65% for seropositive RA and around 20% for seronegative RA. The genetic contribution is especially notable in ACPA-­positive
patients, where heritability estimates range from 53% to 68% [20]. The strongest
genetic association is with HLA-DRB1 alleles located within the MHC region,
accounting for approximately 20% of RA’s genetic risk [21]. A large twin study
from the UK reported an overall concordance rate of 15% in monozygotic twins
compared to 5% in dizygotic twins, highlighting the genetic influence [22].
Beyond the MHC region, multiple genes such as PTPN22 and PADI4 also contribute to RA susceptibility [23, 24]. Genome-wide association studies (GWAS)
have identified over 100 loci associated with RA risk, although most show only
modest individual effects [25]. Table 2 below highlights some important genes
associated with rheumatoid arthritis.
5. Role of T and B Lymphocytes
In rheumatoid arthritis, B and T lymphocytes infiltrate the synovium either diffusely or as organized aggregates, sometimes forming ectopic germinal centers
with the help of follicular dendritic cells, contributing to loss of self-­tolerance
and disease progression. T cells, predominantly CD4+ over CD8+, are the main
lymphocytes present in affected joints. Local cytokines drive T cell differentiation toward pro-inflammatory Th1 and Th17 cells, with reduced Treg development [26]. B cells play multiple roles, including cytokine production, ectopic
germinal center formation, antigen presentation, T cell activation, and differentiation into antibody-producing cells [27]. B cells and plasma cells generate
rheumatoid factor (RF) and anti-modified protein antibodies (AMPAs), such as
ACPAs, anti-carbamylated, and anti-acetylated protein antibodies.
6. Role of Proinflammatory Cytokines
In rheumatoid arthritis, most proinflammatory cytokines originate from macrophages and fibroblast-like synoviocytes (FLS), including TNF-α, IL-1, and IL-6.
TNF-α amplifies inflammation by activating the NF-κB pathway, increasing
TNFR II expression, and promoting RANKL secretion from FLS to drive osteoclast formation [28]. IL-1, mainly produced by macrophages, triggers strong
inflammatory responses, promotes FLS proliferation, and induces production of
IL-6, IL-8, GM-CSF, collagenase, prostaglandins, and adhesion molecules.
Elevated IL-6 in RA synovial fluid further sustains inflammation via the JAK1/
STAT3 signaling pathway in FLS [29].
7. Role of Autoantibodies
Autoantibodies, particularly anti-citrullinated protein antibodies (ACPAs), can
be detected years before the clinical onset of rheumatoid arthritis (RA) and are
Rheumatoid Arthritis
29
Table 2 Important genes associated with RA [20–22]
Name of the
gene
HLA-DRB1
Function
Antigen presentation
PADI4
Converts arginine to citrulline
PTPN22
CTLA4
A negative regulator of T cell receptor signaling
Transmits an inhibitory signal to T cells
IL2RA
T cell activation (and also other lymphoid cells)
STAT4
Signal transduction of INF-gamma and IL-12 stimulation
TRAF1
CCR6
Mediates the signal transduction from various receptors of
TNF
B cell maturation
IRF5
Involves in type 1 interferon signal transduction
IL6R
Abnormal responses to IL-6 and downstream signals
TNFAIP3
Abnormal responses to TNF and downstream signals
FOXP3
Abnormality in the differentiation of Tregs
AIRE
Abnormality in the expression of autoantigens
CD40
Abnormal responses to TNF and downstream signals
CCL21
Abnormality in homing of lymphocytes to secondary
lymphoid organs
Ancestry
European or
Asian
European or
Asian
European
European or
Asian
European or
Asian
European or
Asian
European or
Asian
European or
Asian
European or
Asian
European or
Asian
European or
Asian
European or
Asian
European or
Asian
European or
Asian
European or
Asian
Abbreviations: HLA-DRBI human leukocyte antigen-DRB1; PADI4 peptidyl arginine deiminase 4;
PTPN22 protein tyrosine phosphatase non-receptor type 22; CTL4 cytotoxic T-lymphocyte associated protein 4; IL2RA interleukin 2 receptor subunit alpha; STAT4 signal transducer and activator
of transcription 4; TRAF1 TNF receptor associated factor 1; CCR6 C-C motif chemokine receptor
6; IRF5 interferon regulatory factor 5; IL6R interleukin 6 receptor; TNFAIP3 TNF alpha induced
protein 3; FOXP3 forkhead box P3; AIRE autoimmune regulator; CCL21 C-C motif chemokine
ligand 21
widely used in diagnosis. The enzyme peptidyl arginine deiminase (PADI) drives
citrullination, a post-translational modification converting arginine residues to
citrulline leading to loss of immune tolerance in RA patients [30]. Citrullinated
proteins bind more strongly to HLA-DR molecules and are more immunogenic
than native proteins [31]. Neutrophil extracellular traps (NETs) are a key source
of these citrullinated proteins, with higher levels found in the blood and synovial
fluid of RA patients. ACPAs not only serve as specific biomarkers but also contribute to joint inflammation, bone erosion, and increased cardiovascular risk.
Other relevant autoantibodies include rheumatoid factor (RF), anti-carbamoyl
peptide antibodies, and autoantibodies targeting cartilage-specific proteins (e.g.,
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S. K. Imam
type II collagen, gp39) and extracellular antigens such as glucose-6-phosphate
isomerase and heterogeneous nuclear ribonucleoprotein-­A2, all linked to RA
development and progression [32].
8. Pathogenic Mechanism in Rheumatoid Arthritis
The pathogenic mechanism of rheumatoid arthritis (RA) involves a complex
interplay of genetic, environmental, and immunologic factors leading to chronic
synovial inflammation and joint destruction (Fig. 1). The hallmark of RA is
severe sustained synovitis with marked expansion of synovial lining and sublining layers. There exist two types of synoviocytes in the synovium, namely
macrophage-­like synoviocytes and FLS. In genetically susceptible individuals
especially those carrying HLA-DRB1 alleles, environmental triggers such as
cigarette smoke, silica, and Porphyromonas gingivalis promote loss of immune
tolerance, often through post-translational modifications like citrullination
driven by peptidyl arginine deiminase (PADI). This process generates citrullinated proteins, which bind to HLA-DR molecules with high affinity and trigger
the production of anti-citrullinated protein antibodies (ACPAs), detectable years
before clinical onset.
Immune dysregulation is central to RA pathogenesis. Neutrophil extracellular traps (NETs) serve as a source of citrullinated antigens, further fueling the
autoimmune response. T cells, predominantly CD4+, infiltrate the synovium
Fig. 1 Pathogenesis of rheumatoid arthritis and interplay among genetic, epigenetic, and environment factors
Rheumatoid Arthritis
31
and differentiate preferentially into pro-inflammatory Th1 and Th17 subsets due
to local cytokine signaling, while regulatory T cell (Treg) function is suppressed. B cells contribute by producing RF and anti-modified protein antibodies (AMPAs), including ACPAs, and participate in antigen presentation, cytokine
secretion, and formation of ectopic germinal centers. Macrophages and fibroblast-like synoviocytes (FLS) produce key proinflammatory cytokines—TNF-α,
IL-1, and IL-6—which drive synovial inflammation. TNF-α activates NF-κB
signaling, promotes TNFR II expression, and induces RANKL production by
FLS, contributing to osteoclastogenesis and bone erosion. IL-1 enhances FLS
proliferation and induces additional inflammatory mediators, while IL-6 perpetuates inflammation via the JAK/STAT3 pathway in FLS. Collectively, these
mechanisms lead to synovial hyperplasia, cartilage destruction, and bone erosion characteristic of RA.
Clinical Presentation of Rheumatoid Arthritis (RA)
The clinical onset of rheumatoid arthritis (RA) is typically preceded by a pre-­
rheumatoid arthritis (pre-RA) stage. The progression from pre-RA to established
RA is generally divided into the following phases [33]:
Phase I: Interaction of genetic predisposition with environmental risk factors.
Phase II: Development of RA-related autoantibodies, such as rheumatoid factor
(RF) and anti-cyclic citrullinated peptide (anti-CCP).
Phase III: Appearance of joint symptoms like arthralgia or stiffness, without clinical
signs of arthritis.
Phase IV: Onset of arthritis in one or two joints, referred to as early undifferentiated
arthritis; if the joint inflammation is intermittent, it is known as palindromic
rheumatism.
Phase V: Established RA.
It is important to note that not every individual follows this full sequence.
Ongoing research focuses on identifying those at risk of progression and exploring
strategies to delay or prevent the development of RA.
Articular Manifestations
RA typically presents insidiously over weeks to months, with joint pain and swelling being the most common symptoms. Initial involvement usually affects the
small joints of the hands and feet, progressing later to larger joints. Morning stiffness is a hallmark feature [34]. In some cases, patients exhibit an episodic pattern
of joint symptoms, known as palindromic rheumatism. Not all such patients progress to RA, and many respond well to hydroxychloroquine, suggesting that palindromic rheumatism may represent a distinct RA phenotype [35]. RA predominantly
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involves small peripheral joints, particularly in the hands. Axial joint involvement
is limited to the cervical spine, as it contains synovial joints; the lumbar spine is
typically spared. While polyarticular involvement is common, some patients may
present with monoarticular or extra-articular manifestations, such as lung involvement (Fig. 2).
Without using disease-modifying antirheumatic drugs (DMARDs), RA progresses to joint destruction, deformity, disability, and increased mortality. Table 3
provides the clinical stages of rheumatoid arthritis.
Physical Signs [4]
•
•
•
•
•
Tender joints, with or without swelling
Synovial thickening with a characteristic boggy feel
Joint warmth and erythema are usually absent
Wrist involvement may cause carpal tunnel syndrome
Reduced grip strength in cases with multiple joint involvement
Signs of Advanced Disease
• Ulnar deviation: fingers bend towards the pinky ulnar side of the hand
• Metacarpophalangeal joint subluxation
• Swan neck deformity: middle joint of a finger (proximal interphalangeal or PIP
joint) is hyperextended, while the fingertip joint (distal interphalangeal or DIP
joint) is bent or flexed.
• Boutonniere deformity: middle joint of a finger or toe bends down (flexed) while
the end joint bends back (hyperextended)
• Bowstring sign: presence of prominent and tight tendons on the dorsum side of
the hand.
• Limited range of motion in shoulders, elbows, and knees
• Hallux valgus deformity (bunion): big toe deviating towards the second toe,
often accompanied by a bony prominence at the base of the big toe joint
Fig. 2 Clinical manifestations of rheumatoid arthritis
Rheumatoid Arthritis
33
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S. K. Imam
Table 3 Stages of rheumatoid arthritis (RA) as defined by ACR [9]
Stage
Stage I (early
RA)
Description
Characterized by mild symptoms such as joint pain, swelling, and stiffness
Inflammation is present in the synovium
No destructive changes on X-rays (possible osteoporosis), synovial
membrane inflammation begins, joint stiffness, especially in the morning
Stage II
Joint pain and stiffness become more pronounced
(moderate RA) Limited range of motion in affected joints
Limited joint mobility. No joint deformity. Adjacent muscle atrophy
X-rays show evidence of osteoporosis. Possible slight cartilage destruction
Stage III (severe Severe pain, swelling, and stiffness in the joints
RA)
Significant decrease in range of motion and joint instability
Joint deformity without fibrous or bony ankylosis
Extensive muscle atrophy
Subcutaneous nodules may appear
X-rays show osteoporosis and cartilage and bone destruction
Stage IV
Inflammation may subside, but joint damage is severe and irreversible
(end-stage RA)
Fibrous or bony ankylosis. Severe joint deformity
Functional loss and disability
X-rays show severe bone and cartilage destruction
Extra-Articular Manifestations of Rheumatoid Arthritis
Extra-articular manifestations of rheumatoid arthritis affect various organs beyond
the joints and contribute significantly to the overall disease burden. These systemic
features can involve the skin, lungs, eyes, and other tissues, often indicating more
severe or advanced disease. Here is a brief overview of the extra-articular manifestations of rheumatoid arthritis.
Constitutional Symptoms
•
•
•
•
•
Low grade fever
Fatigue
Malaise
Loss of appetite
Weight loss
Patients with rheumatoid arthritis (RA) often struggle with performing activities
of daily living (ADLs), including dressing, standing, walking, maintaining personal
hygiene, and using their hands. Additionally, depression is a common feature of
RA, especially among those with long-standing active disease and significant physical disability.
Rheumatoid Arthritis
35
Rheumatoid Nodules (RNs) [36]
• Most common extra-articular manifestation.
• Typically occur over pressure points such as the olecranon, joints of the hands
and feet, patella, and Achilles tendons. When multiple, this phenomenon can be
related to methotrexate therapy and is called accelerated rheumatoid nodulosis.
Interstitial Lung Disease (ILD) [37]
• Affects 5–16% of RA patients
• Associated with RA-specific autoantibodies (RF, ACPA) and increased mortality
• In some cases, ILD may precede joint symptoms, with patients showing positive
RF and ACPA
RA-associated ILD is linked to [38]:
• Anti-citrullinated protein antibodies (ACPA)
• Anti-carbamylated protein antibodies (anti-CarP)
• Anti-malondialdehyde-acetaldehyde antibodies (anti-MAA)
Ophthalmologic Manifestations [39]
• Secondary Sjögren syndrome, presenting as dry eyes and dry mouth
• Episcleritis and scleritis, though now rare due to modern RA therapies
• Felty syndrome characterized by:
Long-standing seropositive RA (RF and ANA positive)
Leukopenia
Splenomegaly
Felty syndrome is rare but associated with:
Chronic non-healing ulcers
Increased risk of bacterial infections
Rheumatoid Vasculitis [40]
•
•
•
•
Rare but can be a presenting feature of RA
Involves medium and small-sized vessels
Lesions may present as palpable purpura, skin ulcers, or digital infarcts
Clinical signs may include:
Mononeuritis multiplex
Asymmetric polyneuropathy
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S. K. Imam
Pyoderma gangrenosum is a painful, rapidly progressing ulcers and it can be
associated with RA. It is a neutrophilic dermatosis, not a vasculitis and may be
misdiagnosed as vasculitis in RA patients due to overlapping features.
Vascular and Metabolic Features
Coronary artery disease (CAD) is strongly linked to rheumatoid arthritis (RA), with
RA recognized as an independent risk factor for its development. The progression
of CAD tends to be accelerated in RA patients, largely due to chronic inflammation-­
driven atherosclerosis, which is a leading cause of morbidity and mortality in this
population, contributing to both coronary and peripheral vascular disease [41].
Asymptomatic pericardial effusions are frequently observed in RA, while symptomatic pericarditis and constrictive pericarditis are relatively rare. RA also increases
the risk of venous thromboembolic disease [42].
Additionally, insulin resistance and diabetes mellitus are commonly associated
with RA, likely as a result of chronic systemic inflammation.
Rheumatoid Arthritis and Lymphoma Risk
RA patients have an elevated risk of lymphoma, particularly non-Hodgkin lymphoma, with diffuse large B cell lymphoma being the most prevalent subtype. This
increased risk is more pronounced in individuals with persistently active disease
[43]. Notably, the use of biologic DMARDs has not been shown to further elevate
lymphoma risk [44].
Investigations
1. Complete blood count (CBC)
It typically shows anemia of chronic disease. Neutropenia may be observed in
cases of Felty syndrome. The presence of hypochromic anemia may indicate
blood loss, often due to NSAID-induced gastrointestinal bleeding. Anemia can
also result from the use of disease-modifying antirheumatic drugs (DMARDs).
Thrombocytosis is commonly seen and often correlates with active disease.
2. Acute phase reactants
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are
typically elevated in patients with active disease. These markers should be measured, as they help assess and monitor disease activity in individuals with RA.
3. Rheumatoid factor (RF)
Rheumatoid factor (RF) is detected in 80–90% of patients with rheumatoid
arthritis, showing a sensitivity of 69% and a specificity of 85%. However, its
Rheumatoid Arthritis
37
presence is not specific to RA, as RF can also be found in other connective tissue
diseases, including systemic lupus erythematosus, Sjogren’s syndrome, scleroderma, and granulomatosis with polyangiitis, as well as in 1–5% of healthy individuals. Notably, the presence of RF is associated with an increased risk of
radiographic bone erosions, regardless of disease activity [45].
4. Antinuclear antibody (ANA)
ANA assays are positive in approximately 40% of patients with RA. However,
test results for antibodies to most nuclear antigen subsets are negative.
5. Anti-cyclic citrullinated peptide (anti-CCP) antibody
Anti-citrullinated protein antibody (ACPA) assays are commonly used in the
diagnosis of RA, with antibodies detected in 70–80% of cases. These tests have
a sensitivity of 67% and a high specificity of 95% [46]. The simultaneous presence of both anti-CCP antibodies and RF is highly specific for RA. Similar to
RF, the presence of anti-CCP antibodies is associated with a poorer prognosis.
Patients who test positive for RF, ACPA, or both are classified as having seropositive RA. Approximately 10% of patients are considered seronegative, lacking both RF and ACPA.
6. Synovial fluid examination
Synovial fluid analysis typically shows a leukocyte count ranging from 1500 to
25,000 cells/mm3, predominantly consisting of polymorphonuclear cells. Counts
exceeding 25,000 cells/mm3 are uncommon and usually indicate very active disease, but such findings should prompt evaluation to exclude infection.
Additionally, synovial fluid in RA often demonstrates reduced C3 and C4 complement levels, even when serum complement levels are normal or elevated [47].
7. Plain radiographs
They demonstrate periarticular osteopenia, joint space narrowing, and bony erosions. While cartilage and bone erosions are considered characteristic of RA,
they are not entirely specific to the disease. Nonetheless, these radiographic features are indicative of advanced-stage RA [48].
8. Magnetic resonance imaging (MRI)
MRI is valuable in detecting early rheumatoid arthritis, before bone erosions
become visible on standard radiographs. Bone marrow edema appears as a
reduced signal on T1-weighted images and on gadolinium-enhanced scans. MRI
can also identify synovial thickening, which has been linked to the future development of bony erosions [49]. However, the exact role of MRI in routine clinical
practice and its inclusion in RA diagnostic criteria are yet to be clearly defined.
Table 4 below provides a summary of the findings from investigations in rheumatoid arthritis.
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S. K. Imam
Table 4 Investigations and findings in rheumatoid arthritis
Investigations
Complete blood count (CBC)
Acute phase reactants
Rheumatoid factor (RF)
Antinuclear antibody (ANA)
Anti-cyclic citrullinated peptide
(anti-CCP) antibody
Synovial fluid examination
Findings
Anemia of chronic disease
Thrombocytosis
Neutropenia
Hypochromic anemia
Elevated ESR and CRP levels
Present in 80–90% of RA patients
Positive in ~40% of RA patients; specific nuclear antigen
antibodies usually negative
Present in 70–80% of RA cases
Leukocyte count 1500–25,000/mm3, predominantly
polymorphonuclear cells
Low C3 and C4 complement levels
Plain radiographs
Periarticular osteopenia
Joint space narrowing
Bony erosions
Magnetic resonance imaging (MRI) Detects early disease before radiographic erosions
Bone marrow edema
Synovial thickening
Diagnostic Criteria of Rheumatoid Arthritis
No single test result is definitive for diagnosing rheumatoid arthritis (RA). Instead,
diagnosis relies on a combination of clinical evaluation, laboratory findings, and
imaging studies. The American College of Rheumatology (ACR) and the European
League Against Rheumatism (EULAR)—now known as the European Alliance of
Associations for Rheumatology—have established formal diagnostic criteria. With
the development of serologic markers, the diagnostic approach has been updated.
The 2010 ACR/EULAR classification criteria assess RA based on four key domains:
joint involvement, serologic markers, acute phase reactants, and symptom duration.
010 ACR/EULAR Diagnostic Criteria for Rheumatoid Arthritis
2
(RA) [8]
1. Joint involvement
• Two to ten large joints (shoulders, elbows, hips, knees, ankles): one point
• One to three small joints (MCPs, PIPs, 2nd–5th MTPs, thumb IP joints,
wrists): two points
• Four to ten small joints: three points
• More than ten joints (including at least one small joint): five points
Rheumatoid Arthritis
39
2. Serology
• Low-positive rheumatoid factor (RF) or anti-citrullinated protein antibody
(ACPA): two points
• High-positive RF or ACPA: three points
3. Acute phase reactants
• Elevated ESR or CRP: one point
4. Duration of symptoms
• Symptoms lasting ≥6 weeks: one point
A total score greater than or equal to 6 classifies the patient as having RA.
Clinical Assessment Tools for Disease Activity
Various clinical assessment tools have been developed to help clinicians evaluate
disease activity in patients with rheumatoid arthritis (RA), with several options
available for this purpose. Among them, the Disease Activity Score 28 (DAS28),
Clinical Disease Activity Index (CDAI), and Routine Assessment of Patient Index
Data 3 (RAPID3) are considered simple and practical for use in routine clinical
practice, and online calculators are available to measure disease activity.
Disease Activity Score 28 (DAS28) [50]
DAS28 is a widely accepted tool for assessing RA disease activity. It evaluates 28
joints for tenderness and swelling, incorporates the patient’s global health assessment, and uses either erythrocyte sedimentation rate (ESR) or C-reactive protein
(CRP) as an inflammatory marker. Scores greater than 5.1 typically indicate high
disease activity, while scores below 3.2 suggest low disease activity or remission.
Clinical Disease Activity Index (CDAI) [51]
The CDAI measures RA disease activity without requiring laboratory data. It combines the tender and swollen joint counts (28-joint assessment) with both patient
and physician global assessments (0–10 visual analog scale). The total score categorizes disease activity as remission (≤2.8), low (2.9–10), moderate (10.1–22), or
high (>22).
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S. K. Imam
Routine Assessment of Patient Index Data 3 (RAPID3) [52]
RAPID3 is a patient-reported outcome measure that evaluates physical function,
pain, and overall health assessment, without relying on joint counts or lab tests.
Total scores range from 0 to 30, with higher scores reflecting more severe disease
activity.
Treatment of Rheumatoid Arthritis
Optimal management of rheumatoid arthritis (RA) relies on a comprehensive, multidisciplinary approach that combines both pharmacologic and nonpharmacologic
interventions. Nonpharmacologic strategies such as physical therapy, structured
exercise programs, dietary modifications, stress management techniques, massage
therapy, psychological counseling, and, when necessary, surgical intervention play
a supportive yet vital role in overall care. Engaging patients and their families in the
planning and execution of the treatment plan not only fosters better understanding
of therapeutic goals but also enhances motivation, adherence, and overall treatment
outcomes.
The primary goal of management in rheumatoid arthritis (RA) is early diagnosis
and prompt initiation of therapy to prevent irreversible joint damage, achieve sustained clinical remission, and improve quality of life by minimizing symptoms and
signs of inflammation [53]. A treat-to-target approach is recommended for RA, with
the target being low disease activity or remission, as determined by validated instruments for measuring disease activity [54]. For patients with moderate to severe
disease activity, regular assessment of disease activity is recommended monthly. In
contrast, for those in remission or with low disease activity, monitoring should
occur every 3–6 months.
Pharmacological Intervention
Pharmacologic treatment options for rheumatoid arthritis include multiple drug
classes such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids,
and both nonbiologic and biologic disease-modifying antirheumatic drugs
(DMARDs). Initiating DMARD therapy early in the disease course is now considered the standard of care, as it more effectively slows disease progression and offers
a greater chance of achieving remission compared to delayed treatment [6].
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs work by inhibiting the cyclooxygenase (COX) enzyme, which reduces
prostaglandin production, thereby alleviating pain and inflammation. Although they
do not alter the underlying disease process, NSAIDs are widely used to manage
Rheumatoid Arthritis
41
symptoms of joint inflammation and pain in rheumatoid arthritis. Commonly prescribed NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac. Side-effect profiles vary among individual agents. Notably, NSAIDs carry a
class-wide Black Box warning regarding cardiovascular risk, though the degree of
cardiovascular impact differs across specific drugs. Additional risks include gastrointestinal, renal, and hematologic toxicity [55].
Traditional NSAIDs are nonselective COX inhibitors, targeting both COX-1 and
COX-2 enzymes. In contrast, selective COX-2 inhibitors, such as celecoxib, primarily inhibit COX-2, offering similar anti-inflammatory effects with a lower risk of
gastrointestinal complications. However, adverse effects like fluid retention, elevated blood pressure, and abnormal liver enzymes can occur with both nonselective
and selective NSAIDs. The choice of NSAID should be individualized based on the
patient’s comorbid conditions and clinician experience with specific agents.
Analgesics
Acetaminophen, tramadol, codeine, opiates, and various other analgesic medications can also be used to reduce pain. These agents do not affect swelling or joint
destruction.
Corticosteroids
Corticosteroids are powerful anti-inflammatory agents frequently used in rheumatoid arthritis (RA) patients as a bridging therapy until disease-modifying antirheumatic drugs (DMARDs) become effective. Their use is recommended in specific
situations. In newly diagnosed patients with highly active RA, corticosteroids can
help control inflammation while DMARD treatment is initiated [6 Smolen]. Shortterm corticosteroid courses are helpful in managing mild RA flares, while intraarticular corticosteroid injections are suitable for isolated joint flares, and some
studies suggest that early corticosteroid use may improve outcomes and slow radiographic disease progression [56], although other research has not demonstrated significant long-term benefits from bridging therapy [57]. Approximately 50% of RA
patients require ongoing low-dose corticosteroids (prednisone 2.5–7.5 mg daily) to
maintain disease control. However, prolonged corticosteroid use carries risks,
including weight gain, osteoporosis and related fracture, and increased susceptibility to infections.
DMARDs Therapy in Rheumatoid Arthritis
Initiating DMARD therapy early in the course of rheumatoid arthritis ideally within
the first few months of symptom onset not only slows disease progression more
effectively than delayed treatment but also increases the likelihood of achieving
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S. K. Imam
Table 5 Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis
Biological DMARDs
1. Tumor necrosis factor (TNF) inhibitors
Etanercept
Infliximab
Adalimumab
Golimumab
Certolizumab pegol
2. Interleukin-6 (IL-6) receptor inhibitors
Tocilizumab
Sarilumab
3. B cell depletion therapy
Rituximab
4. T-cell co-stimulation blockers
Abatacept
5. Interleukin-1 (IL-1) receptor antagonist
Anakinra
6. Janus kinases (JAKs) inhibitors
Tofacitinib
Baricitinib
Upadacitinib
Non-biological DMARDs
Methotrexate (MTX)
Sulfasalazine (SSZ)
Hydroxychloroquine (HCQ)
Azathioprine (AZA)
Leflunomide
Cyclosporine
Gold salts
D-penicillamine
Minocycline
remission [58]. As a result, starting DMARDs within 6 months of symptom onset is
now considered the standard of care [9]. DMARDs can be classified into biological
and non-biological agents (Table 5).
Non-Biological DMARDs
Regarding remission rates and time to therapeutic effect, methotrexate (MTX) and
sulfasalazine (SSZ) are among the most effective options, offering the most favorable risk-benefit profiles. MTX, whether used as monotherapy or combined with
other medications, is now considered the first-line treatment for patients with moderate to severe rheumatoid arthritis (RA) [6]. If patients show inadequate response
or intolerance to oral methotrexate, switching to subcutaneous administration can
be beneficial [59]. For patients receiving methotrexate at doses of 15 mg/week or
higher who continue to exhibit disease activity, splitting the dose (e.g., 10 mg in the
morning and 10 mg in the evening on the same day each week) has been shown to
improve methotrexate bioavailability. Triple therapy combining methotrexate,
hydroxychloroquine, and sulfasalazine has proven effective for RA management.
However, its tolerability is limited, leading to discontinuation in a significant number of patients.
Methotrexate dosage: oral (initial): 7.5 mg as a single weekly dose, or 2.5 mg
every 12 hours for three doses per week.
Dose adjustment: gradually increase based on clinical response; maximum single oral dose should not exceed 20 mg per week due to the risk of bone marrow
Rheumatoid Arthritis
43
suppression. Taper to the lowest effective dose once disease control is achieved.
Supplementation with folic acid or folinic acid is recommended to minimize
methotrexate-­related side effects.
Subcutaneous (SC) injection (initial): 7.5 mg once weekly as a single SC dose.
Adjust the autoinjector dose in 2.5 mg increments as clinically indicated.
Sulfasalazine is a conventional synthetic disease-modifying antirheumatic drug
(csDMARD) commonly used in the management of rheumatoid arthritis (RA) [60].
It acts primarily through anti-inflammatory and immunomodulatory mechanisms,
although its exact mode of action remains incompletely understood. Sulfasalazine is
often utilized as part of combination therapy, especially in patients with early or
moderately active RA, and has demonstrated efficacy in reducing joint pain, swelling, and slowing disease progression. Gastrointestinal upset and rash are its common adverse effects, but it generally has a favorable safety profile when monitored
appropriately.
Delayed-release sulfasalazine dosage: initial dose: 0.5–1 g per day orally, divided
into two doses. Titration: increase gradually each week to a maintenance dose of 2 g
per day, divided into two doses. If response inadequate: after 12 weeks of treatment,
the dose may be increased to a maximum of 3 g per day.
Hydroxychloroquine (HCQ), an antimalarial agent, is commonly used as a
disease-­modifying antirheumatic drug (DMARD) in rheumatoid arthritis (RA), particularly in mild to moderate disease or as part of combination therapy. Evidence
shows that HCQ can improve joint symptoms and reduce disease activity, though it
is generally less potent than methotrexate or sulfasalazine when used as monotherapy [9]. Its favorable safety profile, especially regarding hepatic and hematologic
toxicity, makes it suitable for long-term use. Regular ophthalmologic monitoring is
recommended due to the risk of retinopathy, particularly with prolonged use or
doses exceeding 5 mg/kg/day.
Hydroxychloroquine dosage: 400–600 mg/day (310–465 mg base/day) per oral
once daily or in two divided doses. When a good response is obtained, reduce dosage by 50% and continue maintenance dose of 200–400 mg/day.
Leflunomide is the member of the nonbiologic DMARDs, demonstrating efficacy comparable to sulfasalazine (SSZ) and methotrexate (MTX). It can be considered for patients who cannot tolerate or have contraindications to MTX [6].
Minocycline may exert disease-modifying effects through its inhibition of matrix
metalloproteinases (MMPs). Injectable gold salts and penicillamine are now rarely
used, as they seldom produce sustained remission and have been largely replaced by
more effective therapies.
Biological DMARDs
DMARDs represent the key measure in the successful treatment of RA. These
agents can retard or prevent disease progression and, thus, joint destruction and
subsequent loss of function. Successful DMARD therapy may eliminate the need
for other anti-inflammatory or analgesic medications; however, until the full action
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S. K. Imam
of DMARDs takes effect, anti-inflammatory or analgesic medications may be used
as bridging therapy to reduce pain and swelling.
1. Tumor necrosis factor–α (TNF-α) inhibitor
The recognition of tumor necrosis factor–α (TNF-α) and interleukin (IL)-1 as
central proinflammatory cytokines has led to the development of biologic agents
that block these cytokines or their effects. In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions. The TNF inhibitors include etanercept, infliximab,
adalimumab, certolizumab, and golimumab. Biologic agents are expensive and consensus statements do not recommend their use until at least one nonbiologic
DMARD, usually MTX, has been administered without sufficient success. In clinical trials, as many as 70% of patients achieve significant responses, but remissions
are not usually observed. However, studies have shown that adding TNF inhibitors
in patients who have failed methotrexate therapy is better than adding another nonbiologic DMARD [61]. The most concerning adverse effect of these agents is
opportunistic infections and reactivation of latent tuberculosis. Reactivation of hepatitis B virus (HBV) can occur during anti–TNF-α therapy in both HBsAg-positive
individuals and those who are HBsAg-negative but anti-HBc–positive, indicating
occult HBV infection. Prophylactic antiviral treatment has been shown to significantly lower the risk of HBV reactivation in these patients [62]. Acute infection,
advanced heart failure, demyelinating disease, and recent malignancies are contraindications for using these agents [9].
Dosages of Tumor necrosis factor–α (TNF-α) inhibitor
Etanercept injection 50 mg subcutaneously once weekly
Infliximab injection 3 mg/kg IV at 0, 2, and 6 weeks, then every 8 weeks thereafter.
If incomplete response is noted, dose may be increased to 10 mg/kg or increasing
the dosing frequency to every 4 weeks.
Adalimumab injection 40 mg subcutaneously every 2 weeks
Golimumab injection 50 mg subcutaneously every month
Certolizumab pegol injection: initial: 400 mg subcutaneously (2 injections of
200 mg), repeat at 2 and 4 weeks. Maintenance: 200 mg every 2 weeks or 400 mg
every 4 weeks.
2. Interleukin-6 (IL-6) receptor inhibitors
Tocilizumab, an interleukin-6 (IL-6) receptor antagonist, is approved for the
treatment of moderate to severe active rheumatoid arthritis (RA) in adults who have
shown inadequate response to TNF inhibitors. Clinical improvements have been
observed in such patients receiving tocilizumab therapy [6]. Sarilumab, another
Rheumatoid Arthritis
45
IL-6 receptor blocker, has also demonstrated effectiveness in improving clinical
outcomes in patients with RA not controlled by TNF inhibitor treatment [63].
Dosage: tocilizumab: intravenous (IV) infusion: start with 4 mg/kg every
4 weeks; may increase to 8 mg/kg every 4 weeks based on clinical response (maximum dose: 800 mg per infusion).
Subcutaneous (SC) injection:
• Weight < 100 kg: 162 mg every other week; increase to weekly if needed based
on response. Weight ≥ 100 kg: 162 mg weekly.
Sarilumab: 200 mg subcutaneous injection every 2 weeks.
3. B cell depletion therapy
Rituximab is commonly used in combination with methotrexate (MTX) and is
effective in reducing disease activity in adults with moderate to severe rheumatoid
arthritis (RA) who have not responded adequately to one or more TNF inhibitors
[64]. Its therapeutic action involves depletion of CD20+ B cells. According to
Bingham et al., administering polysaccharide and primary vaccines prior to rituximab infusion may help optimize vaccine responses [65]. Treatment outcomes tend
to be more favorable in seropositive patients and when rituximab is combined with
methotrexate. It is also considered a preferred option in patients with coexisting
lymphoproliferative disorders.
Dosage: rituximab 1000 mg IV infusion, followed by a second 1000 mg infusion
2 weeks later (this two-dose regimen constitutes one treatment course). Repeat
courses may be given every 24 weeks or based on clinical assessment, but not earlier
than 16 weeks after the previous course.
4. T-Cell Co-stimulation blockers
Abatacept works by inhibiting T-cell activation through binding to CD80 and
CD86. It is effective in patients with active rheumatoid arthritis who have not
responded adequately to methotrexate and TNF inhibitors, with evidence supporting its sustained efficacy from 6 months up to 5 years of treatment [66].
Dosage:
Intravenous (IV) infusion:
• <60 kg: 500 mg
• 60–100 kg: 750 mg
• 100 kg: 1000 mg
Maintenance: repeat the same dose at 2 weeks and 4 weeks after the initial infusion, then every 4 weeks thereafter.
46
S. K. Imam
Subcutaneous (SC) injection: 125 mg SC once weekly.
Can be started with or without an initial IV loading dose.
If an IV loading dose is used, the first SC injection should be given within 1 day
after the infusion.
When switching from IV to SC, administer the first SC dose at the time of the
next scheduled IV dose.
5. Interleukin-1 (IL-1) receptor antagonist
Anakinra occupies the IL-1 receptor without triggering it and prevents receptor
binding of IL-1. In clinical trials, patients treated with anakinra were significantly
more likely to demonstrate an American College of Rheumatology 20% improvement response (ACR20), compared with those receiving placebo [67].
Dosage: 100 mg subcutaneously once daily.
6. Janus kinases (JAKs) inhibitors
Janus kinases (JAKs) are a family of cytoplasmic non-receptor tyrosine kinases
consisting of four members: JAK1, JAK2, JAK3, and TYK2. They mediate cytokine
signaling through the JAK-STAT pathway, which controls the transcription of genes
involved in inflammatory, immune, and cancer-related processes. JAK inhibitors,
such as tofacitinib, baricitinib, and upadacitinib, are FDA-approved for second-line
treatment of rheumatoid arthritis (RA), particularly in patients who have an inadequate response to methotrexate or other disease-modifying antirheumatic drugs
(DMARDs) [68].
These agents are associated with side effects, including an increased risk of
infections, herpes zoster, and venous thromboembolism. Certain JAK inhibitors,
like tofacitinib, have also been linked to a higher risk of lung cancer and lymphoma, especially in older adults and individuals with a history of smoking.
Although some studies suggest a reduced risk of breast cancer in women using
JAK inhibitors, concerns regarding overall cancer risk persist, particularly in
high-risk groups.
Dosages:
•
•
•
•
Tofacitinib 5 mg per oral twice daily
Tofacitinib XR: 11 mg per oral once daily
Baricitinib 2 mg per oral once daily
Upadacitinib 15 mg per oral once daily
Table 6 provides the summary of safety consideration with Biological DMARDs
Rheumatoid Arthritis
47
Table 6 Safety consideration associated with DMARDs treatment
Safety concern
1. Serious infections
2. Opportunistic
infections (TB,
fungal)
3. Thrombosis
4. Cardiovascular
events
5. Congestive heart
failure (CHF)
6. Herpes zoster
7. Demyelinating
diseases
8. Neutropenia
9. Elevated LFTs and
cholesterol
Associated agents
All biologic and
targeted synthetic
DMARDs
All biologic and
targeted synthetic
DMARDs
JAK inhibitors
JAK inhibitors
TNF inhibitors
JAK inhibitors
TNF inhibitors
IL-6 inhibitors, JAK
inhibitors, rituximab
IL-6 inhibitors, JAK
inhibitors
Important notes
Two to three times higher risk; hold during
active infection/surgery; avoid live vaccines;
screen for latent TB
Screen all patients for latent TB before
starting therapy
Increased risk of thromboembolic events
Includes risk of major adverse cardiovascular
events (MACE)
Use cautiously in patients with heart failure
Higher incidence; consider vaccination prior
to treatment
Avoid in patients with a history of
demyelinating disorders
Monitor complete blood counts regularly
Monitor liver enzymes and lipid profile
periodically
Surgical Procedures
Surgical management of rheumatoid arthritis (RA) is considered when medical
therapy fails to control symptoms or prevent joint damage. Common procedures
include synovectomy, joint debridement, tendon repair, and joint replacement
(arthroplasty), especially in advanced cases with severe joint destruction. Surgery
aims to relieve pain, improve joint function, and enhance quality of life. However,
it does not treat the underlying disease process.
anagement of Rheumatoid Arthritis (RA)
M
in Pregnancy [69–71]
Pregnancy presents unique challenges in women with rheumatoid arthritis (RA),
requiring careful management to balance maternal disease control with fetal safety.
RA often improves during pregnancy but may flare postpartum. Preconception
counseling, medication adjustment, and close monitoring are essential for optimizing outcomes. The key aspects are outlined below.
48
S. K. Imam
1. Preconception counseling
• Disease remission or low disease activity is recommended before conception.
• Adjust medications to pregnancy-safe options several months before trying to
conceive.
2. Medication management
Safe medications during pregnancy
• Hydroxychloroquine (HCQ)
• Sulfasalazine (with folic acid supplementation)
• Low-dose prednisone (≤10 mg/day)
• Certolizumab pegol (TNF inhibitor with minimal placental transfer)
Medications to avoid
• Methotrexate (MTX): teratogenic, stop at least 3 months before conception
• Leflunomide: teratogenic; use cholestyramine washout before conception
• Tofacitinib and other JAK inhibitors: insufficient safety data; avoid during
pregnancy
3. Disease monitoring
• Monitor disease activity clinically; laboratory markers like ESR/CRP may be
unreliable due to physiological pregnancy changes
• Adjust therapy to balance maternal disease control and fetal safety
4. Management during flares
• Use short-term corticosteroids for flares
• NSAIDs can be used cautiously during the first and second trimesters, but
should be avoided in the third trimester due to the risk of premature closure
of the ductus arteriosus
5. Delivery and postpartum
• Plan delivery based on obstetric indications; RA itself is not an indication for
cesarean delivery
• Postpartum flares are common: closely monitor and adjust therapy
• Consider breastfeeding safety when selecting postpartum medications
Figure 3 outlines the stepwise approach and treatment algorithm in patients with
rheumatoid arthritis.
Fig. 3 Stepwise approach and treatment algorithm in patients with rheumatoid arthritis [6]
Rheumatoid Arthritis
49
50
S. K. Imam
Prognosis
The prognosis of rheumatoid arthritis (RA) has improved significantly over recent
decades, largely due to earlier diagnosis and the use of aggressive, evidence-based
treatment strategies. Evidence indicates that early initiation of disease-modifying
antirheumatic drugs (DMARDs), particularly methotrexate and biologic agents, can
slow or halt disease progression and reduce joint damage. Prognostic factors associated with more severe disease include high levels of rheumatoid factor (RF) and
anti-cyclic citrullinated peptide (anti-CCP) antibodies, elevated inflammatory markers (ESR, CRP), early joint erosions, and extra-articular manifestations. Poor functional outcomes are more likely in patients with delayed treatment initiation and
persistent high disease activity. The use of treat-to-target strategies, aiming for clinical remission or low disease activity, is supported by strong clinical evidence and is
associated with better long-term functional outcomes and quality of life. Despite
therapeutic advances, some patients continue to experience progressive disability,
highlighting the need for individualized and timely management.
uture Developments in Rheumatoid Arthritis (RA) Treatment
F
[6, 72, 73]
Despite significant advancements in RA treatment, no existing regimen offers a
definitive cure, and most patients require lifelong management. As a result, numerous emerging therapies are currently being investigated in both preclinical and clinical studies.
1. Personalized and precision medicine
Advances in genetic profiling, biomarkers, and machine learning are paving the
way for individualized treatment strategies, targeting therapies based on patientspecific disease pathways.
2. Novel biologic and small molecule agents
• Development of next-generation JAK inhibitors with improved safety profiles
• Exploration of Bruton’s tyrosine kinase (BTK) inhibitors, currently in clinical
trials, showing promise in modulating B cell and macrophage signaling
3. Targeting fibroblast-like synoviocytes (FLS)
Therapies aiming to inhibit aggressive synoviocytes, potentially slowing or halting joint damage more effectively than current treatments.
4. Microbiome-based therapies
Gut microbiome modulation through probiotics, prebiotics, or fecal microbiota
transplantation is being explored as a novel adjunct in RA management.
5. Cell-based therapies
Research into mesenchymal stem cell therapies for their immunomodulatory and
tissue-repair properties is ongoing, though still largely experimental.
Rheumatoid Arthritis
51
Conclusion
Rheumatoid arthritis (RA) is a progressive, immune-mediated disease that not only
affects the joints but also presents with systemic manifestations, contributing to
significant morbidity and impaired quality of life. Early recognition and diagnosis
are essential, as joint damage begins early in the disease process and is often irreversible. The 2010 ACR/EULAR classification criteria, along with serological
markers such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-­
CCP) antibodies, have improved diagnostic accuracy, particularly in early
RA. Management strategies have evolved significantly over the past two decades.
The current cornerstone of RA treatment is the treat-to-target approach, aiming for
clinical remission or low disease activity. Conventional synthetic DMARDs, primarily methotrexate, remain first-line agents; however, biologic DMARDs targeting TNF-α, IL-6, CD20, and T-cell co-stimulation pathways, as well as targeted
synthetic DMARDs such as Janus kinase (JAK) inhibitors, have expanded therapeutic options for patients with inadequate response to conventional agents. Regular
monitoring using validated tools like DAS28, patient education, and shared
decision-­making are crucial components of optimal care.
Management of extra-articular manifestations and comorbidities is essential for
holistic patient care. Multidisciplinary management, patient education, and attention to mental health and quality of life are integral to successful RA outcomes.
Future directions include the development of precision medicine strategies, reliable
biomarkers for disease prediction and monitoring, and approaches to achieve sustained drug-free remission. RA is no longer considered an inevitably disabling disease, but a condition that, when managed appropriately, can allow most patients to
lead active, productive lives.
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Systemic Lupus Erythematosus
Tahira Perveen, Lubna Nazir, and Syeda Rida E Zehra
Introduction
Systemic lupus erythematosus is a chronic autoimmune disease where the body’s
immune system turns against itself, and instead of protecting the body’s organs, it
starts damaging healthy tissues. As a result, inflammation leads to problems across
various organs. This complex condition can affect the skin, joints, kidneys, heart,
and nervous system. Symptoms vary widely from fatigue and joint pain to more
serious complications, making lupus a challenging condition to diagnose and
manage [1].
While anyone can develop lupus, it is far more common in women, particularly
during child bearing age. Researchers believe that its onset is contributed to by a
combination of genetics, hormonal, and environmental triggers (like sunlight or
infections) [2]. The diagnosis and management of SLE require a personalized and
holistic approach, as the disease varies widely between individuals. There is no cure
yet, but proper treatment, including medications and lifestyle adjustments, can
enable many people with lupus to lead active and fulfilling lives [3]. To keep symptoms under control and prevent long-term damage, early diagnosis and tailored care
are prioritized [4]. The ongoing research continues to explore better therapies and a
deeper understanding of this enigmatic disease [5].
This chapter provides a comprehensive overview of systemic lupus erythematosus (SLE) and aims to outline the current understanding of its pathogenesis, highlight diagnostic challenges, and review recent advancements in classification criteria
and biomarkers. Additionally, it will discuss the spectrum of clinical features, disease monitoring tools, and evidence-based management strategies to guide clinicians in delivering optimal care to patients with SLE.
T. Perveen (*) · L. Nazir · S. R. E. Zehra
Liaquat National Hospital, Karachi, Pakistan
e-mail: tahira.perveen@lnh.edu.pk; lubna.nazir@lnh.edu.pk; rida.zehra@lnh.edu.pk
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_3
57
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Pathogenesis
Systemic lupus erythematosus (SLE) is orchestrated through a complex interplay
between genetic predispositions and environmental factors, which activates the
innate immune system, impaires tolerance mechanisms, and dysregulates adaptive
immune responses.
Genetics
Systemic lupus erythematosus (SLE) shows significant familial clustering, with
monozygotic twins showing greater concordance than dizygotic twins, and a similar
risk for first-degree relatives as seen in dizygotic twins [6]. More than 91 genetic
loci are associated with the onset of SLE, with the HLA region emerging as the most
prominent common risk factor, particularly HLA-DR alleles. Several genes involved
in lymphocyte signaling, including those encoding adaptor proteins, kinases, transcription factors, and cytokines, are studied in the pathogenesis of SLE. Variants in
genes such as PTPN22 (protein tyrosine phosphatase nonreceptor type 22), CSK
(C-terminal Src kinase), and BANK1 (B cell scaffold protein with ankyrin repeats
1) further enhance B and T lymphocytes signaling.
he Intersection of Innate and Adaptive Immunity,
T
and the Role of IFN Signature
The initiation of lupus pathogenesis often stems from aberrant activation of the
innate immune system, which senses self-derived cellular and nuclear debris. These
debris elements, potentially released during apoptosis or via neutrophil extracellular
traps (NETs), expose intracellular autoantigens to the immune system. NETosis is a
unique process of neutrophil death characterized by the release of chromatin and
antimicrobial proteins, which are highly capable of triggering immune responses [7].
Impaired Clearance Mechanism
Inefficient removal of apoptotic debris and immune complexes is a core pathogenic
defect in SLE. Under normal conditions, macrophages clear cellular debris efficiently and without triggering inflammation, a process mediated by TAM (Tyro-3,
Axl, and Mer) family receptors. When these receptors malfunction, immune
responses can remain chronically active [8]. Similarly, DNASE1L3 (deoxyribonuclease 1-like 3) loss-of-function variants compromise chromatin breakdown,
increasing the likelihood of immune recognition [9]. The complement cascade also
plays a central role in debris clearance; C1q deficiency disrupts the removal of
Systemic Lupus Erythematosus
59
apoptotic cells and is strongly associated with early-onset lupus [10]. Genetic alterations in C4A, C4B, and the C1Q subunits (C1QA, C1QB, C1QC) further contribute to impaired clearance of immune complexes and heightened disease
susceptibility [11].
The Cellular Interaction
Toll-Like-Receptors (TLRS), T Cells, and IFN
The autoantigens—particularly chromatin—act as danger-associated molecular
patterns (DAMPs) and are picked up by antigen-presenting cells such as dendritic
cells (DCs) via Toll-like receptors (TLRs) particularly TLR7 and TLR9 which are
overexpressed in lupus [12]. Upon TLR engagement, these DCs internalize the
chromatin and present antigen-derived peptide on major histocompatibility complex (MHC) molecules to circulating helper T cells via T cell receptors (TCRs).
Stimulation of Toll-like receptors (TLRs) activates transcription factors such as
IRF3 and NF-κB, promoting the synthesis of type I interferons (IFN-I) [12].
Majority of the patients with lupus have a characteristic IFN signature—marked
by elevated IFN-I levels in the blood and amplified expression of interferon-­
responsive genes based on the gene expression profiles [13, 14]. A murine study
demonstrated that type I interferon receptor scarcity confers protection against the
onset of lupus-like condition in mice, highlighting the pivotal role of type I interferon signaling in lupus pathogenesis [15]. Type I interferons not only modulate
adaptive immunity but also impact early B cell maturation by increasing the threshold for activation for B cell receptor (BCR) signaling, thereby permitting the survival of autoreactive B cell clones that would normally be eliminated [16]. The
majority of type I interferon is primarily generated by plasmacytoid dendritic cells
upon activation through Toll-like receptors, although other immune cells also contribute to its production, notably monocytes/macrophages, follicular dendritic cells,
and keratinocytes [17]. In addition to type I interferons, individuals with lupus
exhibit elevated levels of pro-inflammatory and B cell–supporting cytokines such as
IL-1, IL-6, IL-12, TNF, and BAFF (B-cell activating factor) promoting B cell survival. IL-33 in NET-rich environments, neutrophil defensins, and DNA damage
response genes like ATR further link innate signals to lupus flares and organ damage
[18]. Markers such as activated leukocyte cell adhesion molecule and IL-16 in urine
correlate with active nephritis and represent potential biomarkers for renal disease
[19, 20].
The dendritic cells also migrate to the lymph nodes via lymphatic vessels, where
they interact with mature CD4+ T cells in the interfollicular T cell zones. This
encounter triggers CD4+ T cell activation and differentiation into various T helper
(Th) cell subsets some of which exit into circulation and propagate systemic
inflammation.
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T- and B-Cell Interaction
In SLE, T cells become hyperactive, producing inflammatory cytokines and driving
B cells to generate autoantibodies [21]. An imbalance among T cell subsets is pivotal in lupus pathogenesis: T follicular helper (Tfh) cells augment B cell maturation
and somatic hypermutation through the secretion of IL-21, while T regulatory
(Treg) cells, reliant on IL-2 for their function, are diminished or dysfunctional due
to reduced IL-2 levels [22]. T peripheral helper (Tph) cells and memory T cells
derive the persistence of chronic inflammation [19]. Furthermore, CD8+ T cells,
once considered peripheral, are now recognized for their involvement in lupus
nephritis and their role in mediating cytotoxic damage [19].
B cells are central players, functioning both as producers of antibodies and as
antigen-presenting cells. Some helper T cells within the lymph nodes migrate
toward B cell zones within the lymph nodes, where they encounter B cells. T cell–B
cell interaction results in CD40L expression on T cells, which binds to CD40 on B
cells, initiating B cell proliferation and differentiation into plasma cells—potent
producers of autoantibodies. Dysregulated B cell receptor (BCR) signaling, augmented BAFF (B cell activating factor or B lymphocyte stimulator BlyS—a cytokine that supports survival and proliferation of B cells) signaling, and defective
negative selection contribute to loss of tolerance [12]. Genetic variants in CSK
enhance BCR-mediated activation, while increased BAFF levels are associated with
the production of anti-dsDNA and other autoantibodies [23]. A recently identified
subset, age-associated B cells (ABCs), expand as a result of TLR7 (Toll-like receptor 7) activation and contribute to autoantibody production [24]. Plasmablasts,
which are elevated during active disease, serve as a significant source of anti-dsDNA
antibodies [25]. In addition, type I transitional B cells, which are rich in autoreactive
properties and display altered CD19/CD21 expression, show impaired responses to
TLR9 activation, linking innate and adaptive defects in B cell function [17].
Gender Bias and Environmental Influences in SLE Pathogenesis
The female-to-male ratio in SLE is about 9:1—indicating a strong female predominance. This is attributed to X chromosome genetics and hormonal factors [26]. Men
with Klinefelter syndrome (47,XXY) exhibit an increased risk of developing systemic lupus erythematosus (SLE), supporting the involvement of X chromosome-­
linked genes in SLE pathogenesis [27, 28]. Regarding hormones; estrogen
contributes to disease flare-ups, as seen during pregnancy or with estrogen therapy,
by promoting B cell survival, upregulating anti-apoptotic proteins like Bcl-2 and
increasing BAFF expression which supports autoreactive B cells persistence and
enhancing type I interferon responses [6, 28, 29].
Environmental factors, such as UVB radiation, cigarette smoke, and silica, exacerbate SLE by hindering the clearance of apoptotic cells, promoting inflammatory
cytokines and DNA hypomethylation in T cells [12].
Systemic Lupus Erythematosus
61
Certain viruses have been associated with pathogenesis of SLE like CMV and
parvovirus B19 of particular note is the Epstein–Barr virus (EBV) infection which
is strongly linked to SLE owing to molecular mimicry [30–32].
Drugs such as hydralazine and procainamide are known to induce drug-induced
lupus, particularly in individuals with slower acetylation rates. This occurs due to
the formation of reactive metabolites and epigenetic alterations, including T cell
DNA hypomethylation and the generation of NETs [33, 34].
Collectively, these hormonal and environmental factors interact with genetic and
immune abnormalities to initiate and accelerate the autoimmune cascade characteristic of SLE.
Clinical Features
SLE has complex and multifactorial nature that demands a detailed history, thorough physical examination, and pertinent investigations. The most common clinical
features of SLE are constitutional symptoms like fever, malaise, fatigue, and weight
loss. As these symptoms are nonspecific, it may delay in appropriate diagnosis and
also mandates to recognize other etiologies such as fibromyalgia, depression, infection, malignancy, endocrinopathy, or other connective tissue diseases which may
mimic or coexist with lupus [35].
Other frequent manifestations include musculoskeletal and mucocutaneous
involvement, renal, neurological, and gut involvement.
Joint Involvement Joint involvement is one of the most frequent clinical features
of systemic lupus erythematosus (SLE), occurring in nearly 90% of patients. For
many, joint symptoms are the first sign of the disease, appearing in 60–80% of initial cases, and they are also common during disease flares, affecting up to 60% of
patients. While SLE can impact any joint, the small joints of the hands and wrists
are most commonly affected. The presentation can sometimes resemble rheumatoid
arthritis (RA). SLE-related joint disease can manifest in several ways:
Arthralgia (Joint Pain) Without Visible Inflammation
Nondeforming, nonerosive (NDNE) arthritis or mild polyarthritis that does not
cause permanent joint damage
Jaccoud’s arthropathy (JA), a rare (3–13% of cases) deforming but nonerosive
joint condition
Rhupus, a rare overlap syndrome (3–5% of patients) where SLE coexists with
RA-like erosive arthritis. These patients may test positive for rheumatoid factor
(RF) or anticyclic citrullinated peptide (anti-CCP) antibodies [36].
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Dermatological Involvement Cutaneous manifestations represent a well-­
documented clinical feature of systemic lupus erythematosus (SLE). These dermatologic presentations are systematically classified into three distinct categories
according to their clinical evolution and temporal characteristics: acute, subacute,
and chronic lesions (Table 1) [35].
Nonspecific Cutaneous Involvement Nonspecific lesions are skin manifestations
not included in the diagnostic criteria of SLE; however, they pose important clinical
element of disease activity and may significantly affect the quality of life (Table 2).
Serositis The spectrum of serosal disease observed in SLE includes pleuritis, pericarditis and peritonitis [35].
Pleurisy presents as chest pain, dyspnea, tachycardia, and fever with pleural effusion seen in up to 60% of lupus patients. Pleural effusions are mostly mild to moderate and bilateral; however, unilateral and large effusions have also been reported.
Biochemical analysis reveal pleural fluid to be exudative by light’s criteria with a
total protein of >3.5 gm/dl, glucose levels of around 60 mg/dl, and low LDH levels.
Pleural fluid ANA titers are also >1:160 homogenous pattern [26]. Pericarditis is
seen in up to 25% of SLE patients during their disease course with tamponade seen
in a few patients. Clinical presentation and ECG findings are same as seen with any
other cause of acute pericarditis. Imaging studies help confirm the diagnosis.
Pericardiocentesis is rarely indicated to rule out other etiologies [40]. Peritonitis is
a rare entity and presents with abdominal pain and discomfort and rarely as massive
ascites which need to be thoroughly investigated for alternative causes [41].
Mucosal Involvement Oral involvement is common in SLE, presenting with
ulcers, keratotic plaques, erythema, purpura, petechiae, and cheilitis. Painful oral
ulcers are the most frequent manifestation, appearing as shallow pale-yellow or
grayish-white lesions on the buccal mucosa, tongue, or palate. Palatal ulcers, when
present, are the most specific for SLE. Nasal and genital ulcers are also reported [42].
Appendageal Manifestations SLE may also affect epidermal appendages, notably presenting as diffuse alopecia or periungual telangiectasia. See Table 2. Hair
loss affects over 50% of SLE patients during their disease course. The most common presentation is nonscarring alopecia, characterized by diffuse hair thinning and
fragility, occurring in 40–70% of cases. This must be differentiated from other
causes of nonscarring alopecia. A distinctive feature is “lupus hair”—frontal scalp
hair breakage often associated with disease flares, potentially representing telogen
effluvium [38].
Cardiovascular System Majority of patients with SLE will have cardiac involvement at any time during their disease course and is one of the leading causes of
morbidity and mortality as it may often go unrecognized [43]. It may manifest itself
by involving any part of the heart such as pericardium, myocardium, endocardium,
Subacute
CLE
(SCLE)
category
Acute
cutaneous
lupus
Maculopapular rash
(UV-exposed)
Tense blisters
Widespread macules, papules,
and erythematous lesions with
blistering
Photosensitive
eruption
Bullous SLE
TEN-like SLE
Annular-polycyclic Erythematous rings (trunk/arms)
resemble psoriasis or eczema
SCLE
Papulosquamous
SCLE
Clinical presentation
Erythema over cheeks + nose,
nasolabial folds are spared
Lesion
Malar (butterfly)
rash
Table 1 Cutaneous lesions in SLE [37–39]
Anti-Ro/SSA (70%);
photosensitive
Severity does not correlate to
the duration of sun exposure
and can occur days or weeks
after sun exposure
Bullae on sun-exposed skin
Resolve without scarring
No drug trigger
Active SLE serology
Mucosal involvement
Diagnostic clues
Photosensitivity; flares with
disease activity
Subepidermal blister
Neutrophilic infiltrate
Interface dermatitis
Keratinocytic cell death
Interstitial mucin
deposition
Interface vacuolar changes
with cytoid bodies
Atrophy of the epithelium
Biopsy findings
Vacuolar interface
dermatitis
Perivascular lymphocytic
infiltrate
Data not available
(continued)
Dust-like epidermal
IgG
Positive lupus band test
in 65–80% cases
Linear IgG at dermo
epidermal junction
Data not available
Data not available
Direct IF patterns
Granular IgM/IgG at
dermoepidermal
junction
Systemic Lupus Erythematosus
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Nasal/oral ulcers
(seen in 40% SLE)
Chilblain lupus
LEP or lupus
profundus
Lesion
Discoid lupus
(DLE)
TEN toxic epidermal necrolysis
Mucosal
SLE
category
Chronic
CLE
Table 1 (continued)
Clinical presentation
Coin-shaped plaques with
scaling + scarring (can be
localized or disseminated)
Mucosal DLE: Erosions or
macules with radiating striae
(lips, palate, gingiva, or other
mucosal surfaces)
Indurated subcutaneous nodules
or plaques that tend to occur in
the face, scalp, upper torso,
buttocks, and proximal
extremities
Tender red-purple papules/
nodules (fingers/toes/ears/ nose /
heels)
Painful or painless ulcers (hard
palate, buccal mucosa, nasal
septum)
Cold exacerbation
Often with DLE or SCLE
Normal cryoglobulin levels
Active SLE marker
Palatal ulcers are the most
specific for SLE,
Reticular dermal
lymphohistiocytic
infiltrate. Papillary edema
Data not available
Dermoepidermal
junction deposition of
IgM, IgA and C3
Data not available
Lobular panniculitis, need Ig and C3 at
dermoepidermal
to rule out panniculitis-­
junction
like T cell lymphoma
Lesions can resolution of
lesions leaves lipoatrophic
areas
Direct IF patterns
Granular IgG/IgM/C3
at dermoepidermal
junction
Biopsy findings
Follicular plugging
hyperkeratosis
Basal layer vacuolization
Dermal mucin
Interface dermatitis with
adnexal involvement
Diagnostic clues
Follicular plugging
“Carpet tack” sign
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Systemic Lupus Erythematosus
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Table 2 Nonspecific manifestations of lupus [37, 38]
Category Manifestation
Vascular Livedo reticularis
Description
Net-like purple pattern (vasospasm/occlusion) strongly
associated with APS
Raynaud’s phenomenon Mostly seen in overlap with scleroderma or APS
Atrophie blanche
Vasculopathy
Thrombophlebitis
Tender, cord-like veins
Erythromelalgia
Burning pain + redness in extremities
Leukocytoclastic
Manifests as palpable purpura or urticarial vasculitis
vasculitis
Polyarteritis nodosa-like Deeper dermis and subcutaneous tissues can be involved,
presentation
resulting in nodules or ulceration
Nailfold changes
Periungual telangiectasia, splinter hemorrhages
Hairs
Alopecia (nonscarring) Diffuse hair thinning or “lupus hair” (broken frontal hairs)
during active SLE
Nodules Rheumatoid nodules
Firm subcutaneous nodules (elbows/hands). Seen in
5–10% SLE
Bullous Bullous SLE
The inflammation in bullous LE is neutrophilic, the blister
is subepidermal. Skin biopsy shows linear IgG at the
dermal–epidermal junction
Papulonodular
Waxy papules/plaques (dermal mucin deposition) mostly
mucinosis
seen on upper trunk, arms, and face
Psoriasiform lesions
Scaly plaques resembling psoriasis
Cutaneous calcinosis
Firm, white/yellow subcutaneous deposits sometimes with
white-yellow discharge
Photosensitivity
Skin rash in sun-exposed areas after exposure to UV light
valves, conduction system, and coronary arteries. Pericardial involvement is the
most common manifestation in SLE; some of the features like valvular abnormalities and possibly coronary artery disease have been linked to antiphospholipid antibodies as well [44]. Lupus myocarditis though uncommon constitutes a serious
cardiac implication due to its effects on the function of the heart and cardiac conducting system [32]. First described in 1924, Libman–Sacks endocarditis (LSE) is
a classical valvular involvement which is a noninfectious verrucous lesion that
occurs in SLE and antiphospholipid syndrome targeting heart valves, especially the
mitral valve, causing valve stenosis, or regurgitation. However, any valve may be
affected, and multivalvular involvement has been reported [44, 45]. Cardiovascular-­
related mortality in SLE is bimodal, early deaths are connected to disease activity,
and late peak is a consequence of atherosclerosis [45].
Neonatal Lupus and Congenital Heart Block Neonatal lupus is a congenital disorder in which the cardiac conduction system is affected by passively transferred
autoimmunity from mother to child. Anti-SSA antibodies are implicated as the
cause as they cross the placenta and are directed against the child’s conduction system tissue resulting in structural damage or maldevelopment of the cardiac conduction system sometimes leading to complete heart block [44].
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Lung Parenchymal Involvement Up to 90% of SLE patients will experience
some form of lung problems during their course of disease [45]. In addition to pleurisy (which is the most common manifestation of lung involvement), other pulmonary involvements include lupus pneumonitis, interstitial lung disease, pulmonary
embolism, pulmonary hemorrhage, pulmonary vasculitis, pulmonary arterial hypertension [35], and shrinking lung syndrome [46]. Acute lupus pneumonitis is a rare
manifestation of systemic lupus erythematosus and carries poor prognosis. It clinically and pathologically manifests itself similar to pneumonia and it is a diagnosis
of exclusion so infections, pulmonary embolism, hemorrhage, drug toxicity, cardiac
failure, and malignancy should be excluded [47]. Interstitial lung disease (ILD) is
also uncommon in SLE and mostly seen in elderly, long standing disease or in overlap with scleroderma. Clinical features are similar to ILD due to any other cause
which includes dry cough and dyspnea; some may be asymptomatic. Diagnostic
testing requires high-resolution CT scanning which may show nonspecific interstitial pneumonia (NSIP), organizing pneumonia and usual interstitial pneumonia.
Pulmonary function testing will show restrictive pattern and reduced DLCO (diffusing capacity for carbon monoxide). Diffuse alveolar hemorrhage or pulmonary vasculitis is a rare condition with a mortality of up to 90%. It may be the first presentation
of lupus in up to 20% of patients. Its clinical features mimic pneumonia, thus making it a diagnostic challenge. Shrinking lung syndrome (SLS) is another rare clinical
manifestation with unknown etiology and no specific diagnostic testing [47].
Neuropsychiatric Lupus (NPSLE) SLE can affect both the central and peripheral
nervous system. Clinical manifestation of NPSLE involves both localized or diffuse
systemic, psychiatric, central, or peripheral nervous system and can range from
mild disease to severe organ-threatening condition. Up to 50% of patients suffer
from NPSLE and mostly occur in early stages of disease. Headache and mood disturbance are the most common symptoms; however, expression of disease may
range from subtle cognitive dysfunction to acute confusional states, psychosis, and
seizures [48]. The American College of Rheumatology (ACR) published a consensus statement that defined 19 NP syndromes. These NP syndromes can be divided
into 12 CNS and 7 PNS syndromes (Table 3) [48–57]. There are no specific criteria
to diagnose NPSLE and are based on the diagnosis of exclusion and expert opinion.
Renal Involvement In SLE, renal impairment results due to glomerular, tubule-­
interstitial, and vascular lesions. It can be seen in up to 70% of SLE patients mostly
seen in first 5 year of diagnosis [35, 58]. Lupus nephritis is one of the most common
and highly morbid organ-threatening conditions (up to 30% developing end-stage
renal disease ESRD) and one of the most common causes of mortality in SLE [59].
Renal involvement demonstrates significant clinical variability, with manifestations
spanning from silent urinary abnormalities to highly symptomatic nephrotic or
nephritic syndrome or rapidly progressive renal failure reflecting its diverse phenotypic expression [45]. Renal biopsy continues to serve as a cornerstone diagnostic
Systemic Lupus Erythematosus
67
Table 3 Neuropsychiatric syndromes of SLE
Clinical features
Syndrome
Central nervous system (CNS)
Aseptic meningitis
Headache, fever,
meningismus
Cerebrovascular disease
Demyelinating syndrome
Headache (including tension
headache and migraine)
Movement disorders
Myelopathy
Seizure disorders
Acute confusional state
Anxiety disorder
Cognitive dysfunction
Mood disorder
Psychosis
Lab and neuroimaging
Antiribosomal P, CSF:
Lymphocytic pleocytosis, ↑
protein, normal glucose
MRI: Leptomeningeal
enhancement
aPL antibodies, lupus
Stroke (focal deficits),
anticoagulant
transient ischemic attack
MRI/CT: Acute infarcts,
(TIA)
microbleeds, vasculitic changes
Anti-TPI, anti-aquaporin-4
Multiple sclerosis-like
(NMOSD overlap)
symptoms (optic neuritis,
MRI: White matter lesions
ataxia)
(periventricular, spinal), optic
nerve enhancement
Chronic headache, migraine Nonspecific (may correlate with
with aura
disease activity), aPL antibodies,
MRI: Often normal, nonspecific
WM changes
Chorea, ataxia,
aPL antibodies, anti-MAP-2 Ab
parkinsonism
in chorea MRI: Nonspecific.
Functional imaging shows
hyperreactivity in basal ganglia
aPL antibodies, antiribosomal P,
Weakness, sensory loss,
anti-AQP4/anti-NMO (if
bladder dysfunction
NMOSD overlap), CSF
(overlap with Devic’s
oligoclonal bands
syndrome)
MRI: Longitudinally extensive
myelitis (T2 hyperintensity)
Focal/generalized seizures, aPL antibodies, anti-MAP-2 Ab,
status epilepticus
anti-TPI, anti-ribosomal P
Delirium, agitation, altered ↑ CSF cytokines (IL-6),
consciousness
antiribosomal P MRI: Diffuse
cortical/T2 hyperintensities
Panic attacks, generalized
Nonspecific
anxiety
Memory loss, executive
aPL antibodies, anti-NMDAR,
dysfunction
antiribosomal P
MRI: Cortical atrophy, WM
lesions
Depression, mania, bipolar Antiribosomal P, anti-NMDAR,
features
anti-TPI
MRI: Nonspecific changes
Hallucinations, delusions,
Antiribosomal P, aPL antibodies,
disorganized speech
anti-MAP 2, anti-TPI,
anti-NMDAR
MRI: Normal or nonspecific
WM lesions
(continued)
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Table 3 (continued)
Clinical features
Syndrome
Peripheral nervous system (PNS)
Ascending paralysis,
Acute inflammatory
areflexia
demyelinating
polyradiculoneuropathy
(Guillain-Barré)
Autonomic neuropathy
Orthostatic hypotension, GI
dysmotility
Mononeuropathy (single or
Focal motor/sensory deficits
multiplex)
(e.g., carpal tunnel, wrist
drop, foot drop)
Myasthenia gravis
Fatigable weakness, ptosis,
diplopia
Cranial neuropathy
Plexopathy
Polyneuropathy
Bell’s palsy, optic neuritis,
diplopia (common CN
involved are eighth, third,
fourth, sixth, fifth, and
seventh nerves)
Brachial/lumbosacral pain,
weakness
Distal sensory/motor
deficits, paresthesias
Lab and neuroimaging
CSF: ↑ protein
(albuminocytologic dissociation)
Nerve conduction abnormalities
Autonomic testing abnormalities
aPL antibodies
NCS: Focal or multifocal pattern
of involvement
Anti-acetylcholinesterase
receptor (anti-AChR) antibody,
anti-muscle-specific kinase
(anti-MuSK) antibody
aPL antibodies
MRI: Nerve enhancement (e.g.,
optic nerve)
Rare presentation of lupus
Anti-TPI, anti-MAP-2 Ab
(sensory neuropathy)
NCS: Axonal/demyelinating
pattern
CSF cerebrospinal fluid, MRI magnetic resonance imaging, CT computerized tomography, aPL
antiphospholipid, NMOSD neuromyelitis optica spectrum disorder, Anti-TPI triose phosphate
isomerase, MAP-2 microtubule-associated protein 2, WM white matter, AQP4 aquaporin-4,
NMDAR N-methyl-D-aspartate receptor
modality, enabling histopathological classification of renal lesions and delineating
the degree of disease activity versus chronicity. See Table 4 for indications of renal
biopsy. These critical insights directly inform therapeutic decision-making and
prognostic stratification; another reason to do biopsy is frequent discrepancies
between clinical presentation and histology [59]. Besides the histological patterns
mentioned in classification, other findings not included are glomerular crescents,
lupus podocytopathy, tubulointerstitial lesions, and thrombotic microangiopathy
(TMA) [46]. To ensure diagnostic accuracy, a sufficient renal tissue specimen must
contain no fewer than ten glomeruli. Evaluation should incorporate light microscopy (LM) and immunofluorescence (IF), with electron microscopy (EM) included
when available. A repeat biopsy is indicated under certain specific conditions.
According to International Society of Nephrology/Renal Pathology Society
(ISN/RPS) 2003 Classification of Lupus Nephritis and 2018 Revision, there are six
histologically distinct classes of lupus nephritis, defined by specific microscopic
lesions and distribution of immune complexes (Table 5). Besides these classes,
some patients may exhibit mixed form like III + IV or IV + V [58].
Systemic Lupus Erythematosus
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Table 4 Indications for renal biopsy in lupus nephritis (LN) [58]
Lab parameter
Proteinuria
Threshold for consideration
>500 mg/24 h or spot urine
protein to creatinine ratio
(UPCR) >500 mg/g
Persistent hematuria/
pyuria
Unexplained renal
insufficiency
After exclusion of infection,
stones, or other causes
Elevated creatinine/reduced GFR
Even with normal urinalysis
Additional considerations
Especially if accompanied by:
Impaired renal function (↑ Cr, ↓
GFR)
Active urinary sediment
(hematuria, cellular casts)
Requires further evaluation if
unexplained
Rule out other causes before
biopsy
Table 5 ISN/RPS 2003 classification of lupus nephritis and 2018 revision [58]
Class
Class I
Class II
Class III
Class IV
Class V
Class VI
Nomenclature
Minimal mesangial LN
Mesangial proliferative LN
Focal LN [<50% of the glomeruli involved]
A: Active lesions
A/C: Active and chronic lesions
C: Chronic lesions
Diffuse LN [50% of the glomeruli involved]
A: Active lesions
A/C: Active and chronic lesions
C: Chronic lesions
Membranous
Advanced sclerosing LN [90% glomeruli involved]
Diagnosis of Systemic Lupus Erythematosus (SLE)
The diagnosis and monitoring of systemic lupus erythematosus (SLE) necessitates a
multifaceted approach, leveraging an extensive panel of diagnostic investigations in
conjunction with established clinical criteria, notably “The revised Systemic Lupus
International Collaborating Clinics (SLICC)” classification criteria, which synthesize clinical manifestations with immunological parameters to enhance diagnostic
precision [60]. This section outlines the investigations crucial for the diagnosis and
management of SLE, highlighting their clinical utility and inherent limitations.
Diagnostic Criteria
Historical Perspective and Criteria Development
The diagnostic framework for systemic lupus erythematosus (SLE) has undergone
substantial evolution since the inaugural classification criteria by the American
Rheumatism Association (now the American College of Rheumatology, ACR) in
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T. Perveen et al.
1971. Subsequent significant revisions in 1982 and 1997 incrementally improved
diagnostic specificity without compromising sensitivity. The introduction of the
2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria marked
a pivotal advancement, as they incorporated noncriteria manifestations and additional immunological markers, thereby broadening the diagnostic scope and improving clinical utility [61].
The 2019 EULAR/ACR Classification Criteria (2023 Updates)
The current standardized classification for systemic lupus erythematosus (SLE) represents a substantial advancement from prior frameworks by:
1. Mandating ANA positivity (≥1:80 by HEp-2 IFA) as an absolute entry criterion
2. Implementing a weighted scoring system (≥10 points required for
classification)
3. Incorporating histopathological findings (e.g., lupus nephritis biopsy results)
4. Adding new immunologic markers (e.g., anti-β2GP1 antibodies)
The 2023 Revisions Have Further Refined These Criteria By
• Adjusting point values for certain clinical manifestations
• Clarifying definitions for neuropsychiatric SLE
• Incorporating emerging biomarkers in research settings
Clinical Domains (Maximum 7 Points)
• Constitutional (2 points)
• Hematologic (3 points)
• Neuropsychiatric (5 points)
• Mucocutaneous (5 points)
• Serosal (5 points)
• Musculoskeletal (6 points)
• Renal (10 points)
Immunologic Domains (Maximum 12 Points):
• Anti-dsDNA (6 points)
• Anti-Smith (6 points)
• Antiphospholipid antibodies (4 points)
• Low complement (4 points)
• Direct Coombs test (4 points)
Special Considerations in Application
Several important aspects must be considered when applying these criteria:
Systemic Lupus Erythematosus
71
• ANA-negative SLE: While rare (<2% of cases), these patients typically have
anti-Ro/SSA antibodies detectable only by ELISA
• Pediatric SLE: Often presents with more severe renal and hematologic
involvement
• Late-onset SLE: More frequently manifests with serositis and pulmonary
involvement rather than classic rash or nephritis
Clinical Laboratory Investigations
1. Hematological Tests
• Complete Blood Count (CBC)
Anemia in SLE is frequently normocytic, normochromic, and has multiple
causes, resulting from chronic inflammation, renal insufficiency, or autoimmune hemolysis. Reticulocyte count and Coombs test are performed if hemolysis is suspected [62].
• Leukopenia, especially lymphopenia (<1500/mm3), is a common finding and
correlates with disease activity [62].
• Thrombocytopenia may reflect immune-mediated platelet destruction or be a
marker of secondary antiphospholipid syndrome (APS) [63]. Serial monitoring is recommended, as cytopenia can fluctuate with disease course or medication side effects.
• Coagulation Profile
Prolonged activated partial thromboplastin time (aPTT) is suggestive but not
diagnostic of lupus anticoagulant presence. Confirmatory tests (e.g., dilute
Russell viper venom test) are essential due to false positives from anticoagulants or sample handling errors [63].
• ESR: It is typically elevated in active SLE, but may remain high in remission
(poor
specificity),
as
it
is
influenced
by
anemia
and
hyper-gammaglobulinemia.
• CRP: It is often normal or mildly elevated in SLE flares, but marked elevation
would suggest infection, serositis, synovitis, or concurrent inflammatory
condition
2. Biochemical Tests
• Renal Function and Urinalysis
Early detection of lupus nephritis requires routine monitoring of serum creatinine, estimated glomerular filtration rate (eGFR), and urinalysis for proteinuria, hematuria, or cellular casts. Spot urine protein-to-creatinine ratio is a
practical surrogate for 24-h proteinuria [64].
• Liver Enzymes
Elevated transaminases require differentiation between drug toxicity, viral
hepatitis, and autoimmune overlap syndromes such as autoimmune hepatitis [65].
72
T. Perveen et al.
3. Immunological Tests
The SLICC criteria emphasize immunologic abnormalities alongside clinical
features for SLE diagnosis [62].
• Antinuclear Antibodies (ANA)
The ANA test is usually the first-line investigation for SLE. A positive ANA
is required for SLE classification per SLICC criteria but is not sufficient alone
due to its low specificity [62].
ANA testing by indirect immunofluorescence (IIF) on HEp-2 cells remains
the gold standard, offering both high sensitivity (>95%) and valuable pattern
recognition (homogenous, speckled, nucleolar, centromere), which helps narrow differential diagnoses [66]. ELISA tests are increasingly used for screening but may have variable sensitivity and lack detailed pattern information
[62]. ANA results may be false positive in infections, malignancy, and the
elderly, as well as transient positivity during viral illnesses.
Pattern Interpretation:
1.
Homogenous (diffuse): Associated with anti-dsDNA and antihistone
antibodies
2. Speckled: Suggests anti-ENA antibodies (Sm, RNP, SSA, SSB)
3. Nucleolar: More common in systemic sclerosis
4. Centromere: Typical of limited scleroderma
5. Cytoplasmic: May indicate antimitochondrial or antiribosomal P antibodies
• Anti-dsDNA Antibodies
Anti-double-stranded DNA antibodies are highly specific for SLE, especially
associated with lupus nephritis and disease flares. Quantitative assays
(ELISA) and qualitative assays (Crithidia luciliae immunofluorescence) are
complementary, and serial measurements help in predicting renal relapse
[64–68].
• Anti-Smith (Sm) Antibodies
Although less sensitive (present in ~30% of patients), these antibodies are
highly specific for SLE and do not usually fluctuate with disease activity
[62, 69].
• Anti-ENA Antibodies
SSA Ro52, SSB, centromere B (CENPB), Jo1, PmScl, PCNA and native
purified antigens SSA Ro60, Scl70, SmRNP, Sm, U1RNP, ribosomal P, and
histone [70, 71].
Clinically, it has been suggested that anti-Ro60 (Ro60 Ab) or anti-Ro52
antibodies (Ro52 Ab) in patients may associate with different phenotypes
such as systemic lupus, neonatal lupus, and fetal atrioventricular blockade,
primary Sjögren’s syndrome, or inflammatory myositis
• Complement Levels (C3, C4)
Decreased complement levels reflect active immune complex formation and
disease activity and can serve as an important tool for monitoring treatment
response or disease relapse. [72]
Systemic Lupus Erythematosus
73
• Antiphospholipid Antibodies (aPL)
Detection of lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I
antibodies is essential for identifying APS, which may coexist with SLE and
influence management due to thrombosis risk [63].
Table 6 provides a summary of laboratory workup and its clinical significance.
4. Imaging Studies
• Chest X-Ray (CXR)
Useful for detecting pleural effusions and lung disease. However, interstitial
lung disease can be missed on plain X-rays so high-resolution CT (HRCT) is
preferred [73].
• Magnetic Resonance Imaging (MRI)
It is helpful for evaluating neuropsychiatric manifestations such as ischemia,
vasculitis, or white matter changes in neuropsychiatric SLE (Table 3) [74].
• Renal Ultrasound
Ultrasound can exclude other causes of hematuria or identify chronic damage, but biopsy is needed for histological classification and prognostication in
lupus nephritis [63].
5. Renal Biopsy
A kidney biopsy is essential in the diagnosis and management of lupus nephritis
(LN). It remains the gold standard for classifying lupus nephritis per ISN/RPS
criteria [63], guiding immunosuppressive therapy (Tables 4 and 5). It provides
critical insights into the type and extent of kidney involvement, informing treatment strategies and monitoring therapeutic response. By offering detailed
Table 6 Summary of investigations
Test
Category
Hematological Complete blood
count
Coagulation
profile
Biochemical
Renal function
tests
Liver enzymes
Immunological ANA
Anti-dsDNA
Anti-Sm
antibodies
Complement
levels
Antiphospholipid
Abs
Significance
Limitations
Identifies anemia, leukopenia,
May overlap with
and thrombocytopenia
other conditions
Detects lupus anticoagulant and APTT may not always
assesses thrombosis risk
correlate with APS
Requires follow-up
Indicates nephritis through
imaging or biopsy
elevated creatinine and
proteinuria
Screens for overlap syndromes
Nonspecific findings
(e.g., autoimmune hepatitis)
High sensitivity; screens for
Low specificity for
autoimmune involvement
SLE alone
Specific for SLE, correlates with False positives in
disease activity
certain infections
Highly specific but less sensitive; Low prevalence in
diagnostic for SLE
SLE patients
Tracks disease activity and
May be normal in
response to treatment
early or treated disease
Assesses APS risk; guides
Requires confirmatory
thrombosis management
tests
74
T. Perveen et al.
pathological information that cannot be obtained through clinical evaluation
alone, the biopsy enables a more individualized and effective approach to
patient care.
A multidisciplinary approach is essential in managing SLE due to the complexity
of the disease. This approach not only addresses the varied medical issues but also
stresses the importance of equipping the patient to cope with the condition. With the
world advancing, the treatment of SLE has also evolved over time. Initially, the
focus was on survival, but over time it has shifted toward preventing organ damage
and improving the patient’s quality of life.
Treatment
General Measures
1. UV protection and vitamin D deficiency
UV radiation induces reactive oxygen species and increased DNA damage, leading to antigen accumulation and subsequent inflammatory response, including the
production of type I interferons [75]. Broad-spectrum sunscreens with SPF 30 or
higher is recommended along with other photoprotective measures like use of protective clothing.
One downside of photoprotection is the potential for vitamin D deficiency in
patients with SLE which can contribute to fatigue. We encourage intermittent testing when feasible and supplementation, as a 2013 study by Michelle et al. showed
significant improvements in disease activity scores and proteinuria with vitamin D
supplementation. A target blood level of 40 ng/mL should be aimed for, as higher
levels did not show additional therapeutic benefit [76].
2. Diet and Lifestyle
There is increasing interest in the role of gut microbiota dysbiosis in the development of SLE. However, there is currently no specific diet recommendation for lupus
patients or the general population to prevent lupus. A Mediterranean diet is generally recommended to help minimize cardiovascular risk factors. Additionally, smoking avoidance and regular exercise are important lifestyle factors for overall health
and reducing disease risk.
3. Vaccination
Vaccinations should adhere to EULAR guidelines [77]. Influenza and pneumococcal vaccines are strongly recommended during periods of stable disease. HPV
vaccination should be considered, while hepatitis A, B, and zoster vaccines are recommended for at-risk populations.
Systemic Lupus Erythematosus
75
Pharmacologic Therapy
Pharmacologic management of systemic lupus erythematosus (SLE) is guided by
disease severity, organ involvement, and individual patient factors. The cornerstone
of treatment typically includes antimalarials such as hydroxychloroquine, corticosteroids, and various immunosuppressive or immunomodulatory agents. Therapeutic
options range from symptomatic management to targeted immunotherapy, aiming
to control disease activity while minimizing treatment-related toxicity. Treatment
plans are individualized, balancing efficacy and safety to reduce flares and prevent
long-term organ damage.
The following section outlines the pharmacological agents used in the management of SLE, with a summary of drug treatments provided in Table 7.
1. Corticosteroids
Corticosteroids remain a fundamental part of SLE treatment, providing rapid and
effective immunosuppression. They are often used as bridging therapy to control
inflammation. The dosing regimen varies based on disease phenotype, with lower
doses for cutaneous and articular manifestations, and higher IV pulse doses ranging from 125 mg to 1 g per day for 3–5 days for more severe disease manifestations, followed by scheduled tapering. The acceptable daily prednisone dose for
maintenance treatment is 5 mg/day, compared to the previous 7.5 mg/day.
Short- and long-term side effects of corticosteroid should be taken into
account as a significant proportion of damage in SLE patients can be attributed
to the use of corticosteroid as demonstrated in a 15 years’ prospective Canadian
cohort [78].
2. Antimalarial Agents
Antimalarial drugs have been in use since the nineteenth century, with hydroxychloroquine (HCQ) being the first-line treatment and cornerstone of therapy for
most SLE patients. In addition to its anti-inflammatory properties, HCQ has
been found to improve survival in SLE patients through its positive effects on
endothelial function, reducing cardiovascular and thrombotic risks, preventing
neoplasia, and lowering infection rates [79]. Chloroquine may also be an alternative, however, more toxic.
Irreversible retinal toxicity is a devastating complication of CQ and
HCQ. American Association of Ophthalmology [80] therefore recommends
baseline retinal exam followed by annually after 5 years of drug use.
3. Glucocorticoid Sparing Agents
Conventional Therapies
Immunosuppressives are utilized when hydroxychloroquine (HCQ) alone is
insufficient to control systemic lupus erythematosus (SLE). Several conventional therapies have been in use for decades, with selection guided by disease
phenotype. Methotrexate is favored for musculoskeletal and cutaneous manifestations, while azathioprine is commonly used for cutaneous disease and lupus
nephritis (LN) maintenance. Mycophenolate mofetil and cyclophosphamide are
preferred for moderate to severe disease, particularly in organ-threatening cases.
Antimalarial that modulates
immune response by
inhibiting antigen
presentation, cytokine
production, and T cell
activation.
Purine analog that inhibits
DNA synthesis and T cell
proliferation.
Hydroxychloroquin
(HCQ)
Azathioprine (AZA)
Mechanism of action
Suppresses inflammation and
modulates immune response
by inhibiting phospholipase
A2
Drug
Corticosteroid
Table 7 Drugs used in the treatment of SLE
Compatible
Compatible
Compatible
Compatible
Compatible
Retinopathy (long-term
use), gastrointestinal
disturbances, skin
pigmentation, myopathy,
cardiomyopathy
1–2 mg/kg/day (oral) Bone marrow
suppression,
hepatotoxicity, GI
disturbances, infections,
increased risk of
malignancy
Compatible
Paternity
Compatible
Adverse events
Weight gain,
hypertension,
hyperglycemia,
osteoporosis, mood
changes, GI irritation,
risk of infections,
cataracts, acne
Perinatal exposure
Pregnancy
Lactation
Compatible
Compatible
Dose [61]
Mild to moderate
disease: ≤20 mg/day
Severe or organ-­
threatening disease:
IV MP
125–1000 mg/day
followed by
0.3–0.5 mg/kg/d
tapering to ≤5 mg/
day
5 mg/kg/day
Up to 400 mg/day
(oral)
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T. Perveen et al.
Inhibits inosine
monophosphate
dehydrogenase, reducing
purine synthesis and T/B cell
proliferation.
Remission induction
in LN:
MMF 2–3 g/day in 2
doses—MPA:
1.44–2.16 gr/day in
2 doses
Maintenance
therapy:
1–2 g/day in 2
doses
MPA 720–1440 mg/
day in 2 doses
10–25 mg weekly
(oral or
subcutaneous)
Methotrexate (MTX)
Inhibits dihydrofolate
reductase, blocking DNA
synthesis, and suppressing T
cell activation and cytokine
production.
Compatible
Evidence
lacking
(VOC)
Compatible
(TAC, Cic)
Not
compatible
Not
recommended
(VOC)
Compatible
(TAC, Cic)
Not compatible
VOC not
recommended
TAC and CsA:
Compatible
(continued)
Compatible
Not
compatible
Not compatible
Compatible
Not
compatible
Not compatible
Diarrhea, nausea,
vomiting,
myelosuppression,
infections, teratogenicity,
risk of malignancy
Hepatotoxicity, bone
marrow suppression,
mucositis,
gastrointestinal issues,
lung toxicity,
teratogenicity
Leflunomide (LFN)
Inhibits dihydroorotate
10–20 mg/day
Hepatotoxicity, diarrhea,
dehydrogenase (DHODH).
nausea, leukopenia,
hypertension, rash, hair
loss, infections,
peripheral neuropathy,
teratogenicity
Calcineurin inhibitors Bind to immunophilins in the VOC: 23.7 mg/day
Nephrotoxicity,
(CNIs):
TAC: 2–4 mg/day in hypertension,
cytoplasm and inhibits
hyperkalemia,
2 doses
calcineurin blocking
Voclosporin VOC
Tacrolimus (TAC) calcium-dependent pathways CsA: 1–3 mg/kg/day hyperglycemia, tremors,
for signal transduction thereby or up to 400 mg/day infection susceptibility,
Ciclosporin A
hepatotoxicity
in 2 doses
interfering with T cell
(CsA)
activation
Mycophenolate
mofetil (MMF)/
mycophenolic acid
(MPAA)
Systemic Lupus Erythematosus
77
Rituximab (RTX)
Anifrolumab (ANIF)
Belimumab (BEL)
Drug
Cyclophosphamide
(CYC)
Table 7 (continued)
Monoclonal antibody
targeting CD20 on B cells,
depleting B cells, and
reducing autoantibody
production.
Compatible
Insufficient
evidence
Compatible
Consider stopping Compatible
at conception
Severe disease if
no alternatives
Insufficient
evidence
Insufficient
evidence
Consider stopping Compatible
at conception
Severe disease if
no alternatives
Infusion reactions,
infections, headache,
gastrointestinal issues,
fatigue, depression,
hypersensitivity reactions
Paternity
Not
compatible
Perinatal exposure
Pregnancy
Lactation
Considered in
Not
cases of severe
compatible
organ/life-­
threatening
maternal disease if
no alternative
Adverse events
Myelosuppression,
hemorrhagic cystitis,
infertility, bladder cancer,
infections, nausea,
vomiting, alopecia,
fatigue
Infusion reactions, upper
respiratory tract
infections, headache,
diarrhea, hypersensitivity,
cytopenias
Infusion reactions,
1000 mg 2 doses
infections (e.g., PML,
2 weeks apart
Repeat 6 monthly or hepatitis B reactivation),
cytopenias, fever, fatigue,
when needed
rash
Dose [61]
Euro-lupus regime:
500 mg IV 2 weekly
for 12 weeks
NIH regime:
0.75–1 g/m2 BSA/
month IV for
6 months
10 mg/kg IV every
Inhibits B cell activating
2 weeks for the first
factor (BAFF), reducing
B-cell survival and activation. 3 doses, then every
4 weeks
Or
200 mg SC weekly
300 mg IV every
Monoclonal antibody
4 weeks
targeting type I interferon
receptor, blocking interferon
signaling.
Mechanism of action
Alkylates DNA, causing
cross-linking and DNA
damage, leading to cell death
and immunosuppression.
78
T. Perveen et al.
Systemic Lupus Erythematosus
79
Calcineurin inhibitors have been described for joint and skin involvement and
are now included in recent recommendations for lupus nephritis treatment.
Biologic Immunosuppressives
1. Anifrolumab
Anifrolumab is the most recent biologic to be FDA-approved for SLE, based
on the phase III RCT TULIP-2 results, which demonstrated efficacy across
multiple organ systems through reduced disease activity and reduced steroid
dose [81]. A long-term extension study reinforced its efficacy and highlighted
a positive benefit–risk profile [82].
2. Belimumab
Belimumab was the first biologic to be FDA-approved for SLE gaining evidence from four large phase III RCTs including four with IV belimumab
(BLISS-52 [83], BLISS-76 [84], BLISS NEA [85], and EMBRACE [86],
and one with subcutaneous belimumab (BLISS SC [87]). These studies demonstrated its effectiveness in patients with serologically active disease significant reductions in disease activity and enabling a decrease in steroid use. A
long-term extension data [88] over 11 year shows sustained efficacy and stable safety profile. Recently, FDA extended approval for its use in lupus
nephritis also.
3. Rituximab
Although rituximab (RTX) is not FDA-approved for the treatment of SLE
due to the absence of robust trial evidence, its efficacy has been demonstrated
in numerous observational studies [61, 89]. The European League Against
Rheumatism (EULAR) recommends considering rituximab therapy for the
treatment of severe refractory lupus [90].
Nonrenal Lupus Management
Nonrenal lupus management involves individualized treatment strategies based on
the severity and type of organ involvement. Therapeutic approaches typically
include the use of antimalarials, corticosteroids, and immunosuppressive agents,
with a focus on controlling inflammation, reducing disease activity, and minimizing
long-term organ damage while balancing treatment-related risks. Table 8 summarizes Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and pharmacological intervention in nonrenal lupus erythematosus.
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T. Perveen et al.
Table 8 SLEDAI and pharmacological intervention in nonrenal lupus erythematosus
Mild disease
SLEDAI ≤6
BILAG score showing
only:
All BILAG C
≤BILAG B
manifestation
Skin rash (≤9%
BSA)
Mild arthritis
Platelet count
50–100,000
Constitutional
symptoms
Moderate disease
SLEDAI 7–12
≥2 BILAG B
manifestation
Skin rash (9–18%
BSA)
Moderate to severe
arthritis
Platelet count
20–50,000
Serositis
Severe disease
SLEDAI ≥12
≥ 1 BILAG A manifestation
Skin rash ≥18% BSA
Platelet count <20,000
Major organ threatening
disease or TTP or MAS
HCQ
Recommended for all patients unless contraindicated.
Glucocorticoids (oral or IV)
Maybe used to control active disease; tapered to <5 mg/d as quickly as possible and
discontinued when feasible.
MMF
1st line
HCQ
MTX
BEL
AZA
ANI
MMF
CYC
BEL
RTX
ANI
CNI
CYC
MMF
2nd line
MTX
RTX
BEL
AZA
ANI
MMF
CNI
BEL
ANI
CNI
MTX methotrexate, AZA azathioprine, MMF mycophenolate mofetil, BEL belimumab, ANI anifrolumab, CNI calcineurin inhibitor, CYC cyclophosphamide, RTX rituximab
Organ-Specific Management
1. Cutaneous LE
(a) Mild CLE
Mild malar rashes and other photosensitive skin conditions typically improve
with photoprotection and preventive measures. Topical agents like corticosteroids (GCs) and calcineurin inhibitors are used, with the latter being preferred for the face due to lesser potential for atrophy. Systemic HCQ can
also be used.
(b) Refractory CLE
Methotrexate (MTX) is found to be effective in refractory subacute cutaneous lupus erythematosus (SCLE) and discoid lupus erythematosus (DLE)
[91]. A small retrospective study [62, 92] found similar response rates
Systemic Lupus Erythematosus
81
between methotrexate and mycophenolate mofetil. EULAR 2023 outlines
second- or third-line options for treatment, including CNIs, azathioprine,
retinoids, dapsone, to be used in consultation with dermatologists [61].
Thalidomide is utilized for severe refractory cases. A recent small case
series [93] described lenalidomide as an alternate option with lower neuropathic side effects. Anifrolumab and belimumab have also demonstrated
efficacy in recalcitrant cutaneous LE [94, 95].
2. Arthritis
For mild arthritis, antimalarials are typically used. In cases of persistent or
aggressive arthritis, treatment options include methotrexate, leflunomide, or
rituximab—especially for overlap with rheumatoid arthritis (RA). Recently,
phase I/II trials of sirolimus have proven efficacy in treating arthritis and tendinitis [96]. Additionally, an anti-BDCA2 antibody, litifilimab, has demonstrated significant effectiveness in reducing swollen and tender joints in phase
2 LILAC trial [97].
3. Hematological
Common and significant hematological manifestations that often require treatment include immune thrombocytopenia (ITP) and hemolytic anemia. In cases
of thrombocytopenia, a peripheral smear is essential to exclude conditions such
as microangiopathic hemolytic anemia (MAHA) and thrombotic microangiopathy (TMA).
(a) Mild Cytopenias
Hydroxychloroquine (HCQ) and regular monitoring are usually sufficient
for management, with short courses of low-dose steroids occasionally
needed if the condition worsens or symptoms require additional control.
(b) Moderate Cytopenias
Steroid-sparing agents, such as azathioprine, mycophenolate, and ciclosporin, are often needed to reduce steroid dependence. Early initiation of immunosuppressive therapy has been demonstrated to decrease relapse rates in
SLE patients with immune cytopenias [98].
(c) Severe Cytopenias
High-dose glucocorticoid are the first-line treatment for cytopenias. If the
cytopenias are resistant to steroids, additional treatment options include
intravenous immunoglobulin (IVIG), cyclophosphamide (CYC), rituximab
(RTX). Evidence suggests superior efficacy of CYC for managing severe
SLE cytopenias [99].
(d) Refractory Cases
Observational data suggests thrombopoietin (TPO) agonists and splenectomy for refractory cases. However, the former should be avoided in patients
with antiphospholipid antibodies due to risk of thromboembolism [61].
4. Neuropsychiatric Lupus
Neuropsychiatric (NP) events in systemic lupus erythematosus (SLE) vary from
mild cognitive dysfunctions to major manifestation including seizures, cerebrovascular accidents, and myelitis. Each should be treated individually, with symptom-specific management tailored to the patient’s needs.
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T. Perveen et al.
Inflammatory Origin NPSLE
Aggressive immunosuppression with agents like cyclophosphamide and
rituximab are preferred for severe inflammatory origin NPSLE, with plasmapheresis and IVIG utilized in life-threatening and refractory conditions [100].
Thrombotic/Embolic NPSLE
In case of ischemic strokes secondary to antiphospholipid antibodies thrombosis, use of long-term anticoagulation and antiplatelet therapy along with statin
therapy is the usual practice. In a large autopsy study of NPSLE patients, 70%
had cerebrovascular accidents, typically related to widespread lupus activity.
The study found that microthrombi, present only in NPSLE, were associated
with deposits of C4d and C5b-9, suggesting that complement activation is pivotal in the interplay between autoantibodies and thromboischemic damage in
SLE [74]. These findings support the EULAR recommendation to adopt a low
threshold for immunosuppressive treatment in stroke, particularly when generalized lupus activity is evident and aPL antibodies or significant atherosclerotic
risk factors are not present [61].
5. Lupus Nephritis
Lupus nephritis (LN) is a serious and potentially organ-threatening manifestation of SLE which contributes to long-term morbidity. Prompt identification is
essential to prevent irreversible loss of function of the kidney.
(a) Class I/II
Class I and II lupus nephritis represent the milder forms of kidney involvement in patients with systemic lupus erythematosus (SLE) , based on the
ISN/RPS classification. Patients are generally asymptomatic, but may present with mild hematuria or proteinuria, though nephrotic-range proteinuria
is rare, and kidney function is generally preserved. Treatment is guided by
extra-renal manifestation of SLE, along with supportive measures such as
ACE inhibitors or ARBs if proteinuria is present. The EULAR/ERA-­EDTA
guidelines [61] suggest initiating immunosuppressive therapy when proteinuria surpasses 1 g per day, especially in the presence of active urinary sediment or declining kidney function.
When nephrotic-range proteinuria is present, lupus podocytopathy should
be suspected. Diagnosis is supported by findings of diffuse podocyte effacement on electron microscopy [101]. Affected patients typically show a good
response to corticosteroid treatment. For people with previous relapses,
immunosuppressives like mycophenolic acid analogs (MPAA), azathioprine, or a CNI are considered.
(b) Class III/IV With or Without Class V
Treatment of proliferative glomerulonephritis (Class III/IV with or without
V) is outlined in Table 9.
Class III or IV LN represents the more aggressive and proliferative forms
of kidney involvement in systemic lupus erythematosus (SLE). Prompt and
effective medical intervention is required to preserve long-term renal function by arresting ongoing inflammation and preventing further nephron damage.
Systemic Lupus Erythematosus
83
For decades, the standard-of-care therapy for active proliferative LN
consisted of glucocorticoids and high-dose cyclophosphamide (CYC).
However, the significant adverse effects of high glucocorticoid doses and
cyclophosphamide toxicity led to the search for better alternatives. The
breakthrough came with the pioneering Euro-Lupus Trial by Houssiau
et al., which demonstrated that low-dose cyclophosphamide (6 doses of
500 mg IV 2 weekly) was just as effective for LN induction as high-dose
cyclophosphamide [102]. As a result, low-dose CYC became the preferred
treatment for Caucasian patients with Class III and IV LN. While the initial trials mainly involved European (largely Caucasian) participants, subsequent studies revealed that the same dosing regimen yielded similar
response rates in patients of different racial backgrounds [103].
Mycophenolate mofetil also became a standard option after it was shown
to have comparable efficacy to cyclophosphamide for induction of remission in proliferative lupus nephritis [104].
With the recent FDA approval of belimumab in 2020 and voclosporin in
2021 for the treatment of lupus nephritis, EULAR 2023 [61], ACR 2024
[105], KDIGO 2024 [101] all recommend consideration for combination
therapy for induction of proliferative LN as described in Table 9.
Evidence for voclosporin stemmed from a pivotal phase III RCT
AURORA-1 [106] which demonstrated improved renal outcomes including
reduced proteinuria with the addition of voclosporin to MMF as a part of
induction therapy for class III and IV LN. A long-term extension study
AURORA-2 [107] proved efficacy and safety of voclosporin for an additional 2 years following the AURORA-1 RCT, showing no decline in renal
functions.
The efficacy of belimumab is supported by the landmark BLISS-LN
study, which showed that adding belimumab to standard therapy (MMF or
Table 9 Treatment of proliferative glomerulonephritis (Class III/IV with or without V)
Induction
Maintenance
IV MP pulse (500–2500 over 1 to 3 days followed by 0.3–0.5 mg/kg/d tapering to <5 mg/d in
6 months
+
HCQ all patients unless contraindicated
Dual therapy (SoC): Steroid plus one of:
MMF or AZA +/− BEL
MMF or
Euro-lupus103 CYC or
High dose CYC
Triple therapy: Steroid plus one of:
Euro-lupus CYC/MMF + BEL or
MMF + CNI (VOC or TAC)
RTX for refractory / relapse disease
MMF mycophenolate mofetil, CYC cyclophosphamide, BEL belimumab, CNI calcineurin inhibitor, TAC tacrolimus, AZA azathioprine, RTX rituximab
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Table 10 Treatment of class V lupus nephritis
Proteinuria <1 G/day
Proteinuria >1G/day
BP control, renin–angiotensin system (RAS) blockade, prevent or treat complications like
thrombosis, edema, dyslipidemia
+
HCQ
Dual therapy
Triple therapy comprising calcineurin
inhibitor
CYC) significantly improved renal outcomes in class III/IV lupus nephritis,
with greater complete renal response and proteinuria reduction compared to
placebo.
The ideal duration for maintenance therapy is not yet established; it is,
however, recommended to be continued for at least 4 years.
For refractory lupus nephritis, data from some observational studies suggest considering rituximab. Additionally, if triple combination therapy was
not previously chosen, the addition of belimumab or voclosporin may be
an option.
(c) Class V: Treatment of class V lupus nephritis is outlined as below in Table 10.
(d) Thrombotic microangiopathy (TMA)
SLE patients with positive antiphospholipid antibodies may have evidence
of thrombotic microangiopathy on renal biopsies. Such patients should be
anticoagulated. There is growing evidence supporting the use of C5 monoclonal antibody—eculizumab in patients with complement mediated TMA.
(e) Adjunctive measures
Hypertension in lupus nephritis should primarily be managed with renin–
angiotensin blockade in patients without contraindications. The target blood
pressure (BP) for these patients is 130/80 mmHg [108] to help protect renal
function and reduce cardiovascular risk.
Owing to the presence of SGLT-2 receptors on kidney biopsies in patients with
SLE as demonstrated by Hakroush et al. [109], addition of SGLT-2 inhibitors in
these patients may seem like a reasonable option.
Monitoring Disease Activity
Validated Scores to Measure Disease Activity
1. SLE Disease Activity Index (SLEDAI-2 K, SELENA-SLEDAI)
2. British Isles Lupus Assessment Group (BILAG)
3. Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)
Systemic Lupus Erythematosus
85
Targets
• Remission (DORIS): Clinical SLEDAI = 0, HCQ, GC ≤5 mg/day. Physician
Global Assesment <0.5
• Lupus low disease activity state (LLDAS): SLEDAI ≤4, HCQ, GC ≤5 mg/day.
Physician Global Assessment <1.0. Immunosuppressive drugs including biologics at stable dose.
• Lupus nephritis therapeutic goals:
– At 3 months: ≥25% reduction in proteinuria with stable glomerular filtration
rate (GFR; ±10% of baseline value)
– At 6 months: ≥50% reduction in proteinuria with stable proteinuria
– At 12–24 months: proteinuria <0.5–0.7 g/24 h with stable GFR at
12–24 months
For Cumulative SLE Damage Assessment
BILD (Brief Index of Lupus Damage)
Ongoing Clinical Trials in SLE
1. Obinutuzumab: A next-generation anti-CD20 monoclonal antibody designed
for enhanced B cell depletion. The phase III REGENCY trial [110] found that
in patients with active lupus nephritis, obinutuzumab combined with standard
therapy led to a statistically significant and clinically meaningful improvement
in the primary endpoint of complete renal response (CRR), compared to standard therapy alone.
2. Lanalumab (VAY736): A dual-acting anti-BAFF/anti-CD40 monoclonal antibody that depletes B cells and modulates immune activity. Two phase III trials
SIRUS-SLE1 (NCT05639114) and SIRUS-SLE2 (NCT05624749) are currently underway to establish its efficacy in patients with SLE.
3. Dapirolizumab pegol: A pegylated anti-CD40L monoclonal antibody fragment
that blocks the interaction between CD40 and CD40L thereby suppressing
autoreactive B cell activation and also T cell-driven inflammation. Currently,
phase III trials results are awaited.
4. Litifilimab (BIIB059): A monoclonal antibody targeting BDCA2, a receptor on
plasmacytoid dendritic cells, reducing type I interferon production. Promising
phase II LILAC trial [111] results in cutaneous and arthritis manifestation of
SLE. Currently in phase III trial.
5. Anifrolumab: Fully humanized monoclonal antibody that targets type I interferon receptor subunit 1 (IFNAR) FDA-approved for moderate-to-severe SLE
showed promising results for lupus nephritis in phase II trial TULIP-LN [112].
6. Atacicept: Reduces B cell activation and survival by inhibiting BAFF/
APRIL. Phase II trial ADDRESS demonstrated significant improvement in disease activity.
7. Telitacicept: A recombinant fusion protein targeting BAFF and
APRIL. Currently in phase III trials.
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T. Perveen et al.
8. Deucravacitinib: A selective TYK2 inhibitor currently in phase III trials
[POETYK SLE-1 (NCT05617677), POETYK SLE2 (NCT05620407)] for
active SLE.
9. Avacopan: A C5a receptor antagonist, approved for ANCA vasculitis. Currently
under investigation for lupus.
10. CAR-T cell therapy: A case series published in 2024 showed efficacy of CAR-T
cells infusion in attaining remission in severe SLE patients. Clinical trials are
underway to establish its efficacy and safety.
11. Daratumumab: A CD38-targeting monoclonal antibody, being explored for
SLE due to its effects on long-lived plasma cells. Phase II [113] trial significantly reduced pathogenic anti-dsDNA antibodies in moderate-to-severe SLE
with a favorable safety profile.
Comorbidity
1. Cardiovascular:
SLE is an independent risk factor [114] for cardiovascular disease (CVD) due to
both traditional and disease-related factors, such as ongoing disease activity,
lupus nephritis, antiphospholipid antibodies, and the use of immunosuppressive
drugs. Risk stratification is crucial as CVD has recently emerged as a leading
cause of mortality [115] in patients with SLE. The 10-year CVD risk assessment
using SCORE [116] is advised to guide treatment of dyslipidemia and hypertension, aiming to reduce vascular events. A general target of <140/90 mmHg for
blood pressure has been recommended for patients with SLE [117]. However, a
lower target of <130/80 mmHg is aimed for individuals with clinical cardiovascular disease (CVD) or an estimated CVD risk greater than 10% [118].
2. Malignancy:
Malignancy patterns in SLE differ from the general population, with increased
risks for hematological cancers; particularly lymphoma. Increased incidence is
also observed in vulvovaginal, cervical, thyroid, and lung cancers with breast
and prostate cancers appearing less common [119].
3. Infections:
There is an increased risk of infections in SLE due to disease-related immune
dysregulation and immunosuppressive therapies. Prompt recognition of infection is crucial in SLE, as clinical features often mimic as disease flare, yet the
treatment strategy differs and early intervention can save lives. C-reactive protein (CRP) can serve as a useful marker, with significantly elevated levels more
indicative of infection than flare [117]. The quick Sepsis-related Organ Failure
Assessment (qSOFA) score [120]—which assesses altered mental status, respiratory rate ≥22/min, and systolic blood pressure ≤100 mmHg—can be utilized
to identify patients at increased risk of poor outcomes.
Systemic Lupus Erythematosus
87
4. Osteoporosis:
Treatment of SLE may require the use of corticosteroids, which are associated
with an increased risk of osteoporosis; therefore, patients should receive concomitant calcium and vitamin D supplementation and also undergo periodic
fracture risk assessment during long-term therapy.
Pregnancy and SLE
In women with systemic lupus erythematosus (SLE) planning pregnancy, preconception counseling and disease optimization are essential. Ideally, conception
should occur when the disease is in remission or at a low level of activity for at least
6 months, as active disease at conception increases the risk of flares and adverse
pregnancy outcomes. Medication review is crucial, with teratogenic drugs like
cyclophosphamide, mycophenolate mofetil discontinued and replaced with
pregnancy-­safe alternatives such as hydroxychloroquine (HCQ) and azathioprine.
Cyclophosphamide, particularly, is known to reduce fertility, and longstanding
active SLE may also impair reproductive potential. Antiphospholipid antibodies
(aPL) are associated with recurrent miscarriages and adverse obstetric outcomes;
thus, screening is recommended. The PROMISSE study [120] identified risk factors
for poor prognosis in pregnant women with SLE, including active disease, presence
of lupus anticoagulant, low complement levels, and renal involvement. SLE can
flare during pregnancy, often in the same organ system that was active in 6 months
prior to conception [121]. However, distinguishing a flare from other pregnancy
complications such as pre-eclampsia can be challenging, as complement levels are
not always reliable markers during pregnancy. Increased Bb and sC5b-9 levels early
in pregnancy are strong predictors of adverse pregnancy outcomes, underscoring
the role of alternative complement pathway activation [122].
All pregnant women with SLE should remain on HCQ throughout pregnancy,
which helps reduce flare risk and may decrease the likelihood of neonatal lupus and
congenital heart block. For patients with obstetric antiphospholipid syndrome, prophylactic anticoagulation with enoxaparin 40 mg subcutaneously once daily is recommended (till 6 weeks postpartum), and for those with a history of thrombosis, a
therapeutic dose (e.g., twice daily) is advised. Aspirin is recommended to prevent
pre-eclampsia. In mothers positive for anti-Ro and/or anti-La antibodies, there is a
risk of congenital heart block, particularly between 16 and 24 weeks of gestation.
The risk of heart block is about 1% in the first affected pregnancy but rises to as high
as 17% in subsequent pregnancies [122]. HCQ has a protective effect and reduces
this risk. In cases of developing heart block, fluorinated corticosteroids such as
dexamethasone are used to treat incomplete heart block; however, once congenital
complete heart block occurs, it is typically irreversible and requires permanent
pacemaker placement [123]. Neonatal lupus can also present with a transient facial
rash, which usually fades within 6 months.
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Conclusion
Systemic lupus erythematosus is a complex autoimmune disorder shaped by an
interplay of genetic predisposition, hormonal influences, and environmental triggers, resulting in widespread immune dysregulation. Clinical manifestations can
vary greatly, ranging from mild skin and joint involvement to life-threatening
renal, neurologic, or hematologic disease, demanding vigilant assessment and
individualized care. While clinical features often raise suspicion, comprehensive
immune workup refines diagnosis, assesses the risk of major organ involvement,
and helps guide prognosis. Hydroxychloroquine remains foundational for nearly
all patients unless contraindicated, given its proven disease-modifying and protective benefits. Corticosteroids are adjusted according to disease severity, with
the goal of tapering to the lowest effective dose, ideally under 5 mg/day, to minimize long-term damage. Immunosuppressives and DMARDs are used strategically to limit steroid burden and sustain remission. Special attention must be given
to comorbidities such as infections, cardiovascular risk, and osteoporosis, which
can complicate disease and therapy. Pregnancy in SLE requires meticulous planning and coordination between rheumatologists and obstetricians to optimize
maternal health and fetal outcomes. Ongoing research into safer targeted therapies and personalized treatment approaches continues to improve prognosis and
quality of life, underscoring the importance of a multidisciplinary, patient-centered approach to this complex disease.
Acknowledgments Authors gratefully acknowledge Mr. Mustafa Hussain and Miss. Wajeha
Umer for their valuable support in the preparation of this chapter.
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Spondyloarthritis
Mohamed Bedaiwi
Introduction
Spondyloarthritis (SpA) refers to a group of interrelated chronic inflammatory disorders that primarily affect the axial skeleton, peripheral joints, and entheses—the
regions where ligaments and tendons attach to bone [1]. The umbrella term encompasses several clinical entities, including ankylosing spondylitis (AS), psoriatic
arthritis, reactive arthritis, enteropathic arthritis (associated with inflammatory
bowel disease), and undifferentiated spondyloarthritis [2]. These conditions share
common features such as inflammatory back pain, HLA-B27 genetic association,
asymmetric arthritis, and the potential for extra-articular involvement.
Historically, AS was among the earliest described forms, with recognition dating
back to the sixteenth century. Pioneering observations by Bekhterev, Strümpell, and
Marie in the nineteenth century established AS as a distinct clinical entity [3]. The
modern classification of SpA as a spectrum of diseases was refined by the Assessment
of Spondyloarthritis international Society (ASAS) to include both axial and peripheral forms [4].
Typically presenting in early adulthood, SpA has a chronic and progressive
course. Delayed diagnosis may result in significant disability and reduced quality of
life. Modern imaging techniques, notably MRI, have improved early detection of
inflammation before irreversible damage occurs [5]. The emergence of targeted biologics has revolutionized treatment, leading to substantial improvements in disease
control and functional outcomes [6, 7]. Furthermore, SpA serves as a model for
studying the interaction between mucosal immunity, microbiota, and systemic
inflammation [8].
M. Bedaiwi (*)
Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University,
Riyadh, Saudi Arabia
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_4
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M. Bedaiwi
This chapter provides an overview of autoimmune spondyloarthritis, highlighting its pathophysiology, clinical features, diagnostic criteria, and current treatment
options. It emphasizes the genetic and immunological underpinnings particularly
the roles of HLA-B27 and cytokine imbalance and examines both axial and peripheral disease forms to support evidence-based clinical management.
Epidemiology
Spondyloarthritis affects 0.5–1.5% of the global population, with AS being more
prevalent in populations where HLA-B27 is common, particularly among northern
Europeans (up to 1–2%) [9, 10]. Prevalence is markedly lower in African and Asian
populations due to genetic variability in HLA-B27 distribution [11]. The disease
often starts before the age of 40 and demonstrates a clear male predominance (male-­
to-­female ratio 2:1 to 3:1), although peripheral forms have a more balanced sex
distribution [12].
The incidence ranges from 0.5 to 14 cases per 100,000 person-years, depending
on diagnostic criteria and population studied [13]. Diagnosis is frequently delayed
due to insidious onset and nonspecific symptoms [14]. However, MRI advancements have increased recognition of early and nonradiographic axial SpA [5].
Extra-articular manifestations like uveitis, psoriasis, and IBD significantly
impact disease burden and vary with ethnicity and geography [15, 16]. Environmental
and mechanical triggers such as infections and joint stressors also modulate disease
onset and course, particularly in genetically predisposed individuals [17].
Risk Factors
The etiology of SpA involves complex interactions among genetic, environmental,
and hormonal factors. HLA-B27 remains the most significant genetic marker, present in over 90% of patients with AS, though its frequency varies by ethnicity [18,
19]. HLA-B27 alone is insufficient for disease development, highlighting the role of
additional genetic contributors such as Endoplasmic Reticulum Aminopeptidase 1
(ERAP1), IL23R, and other genes in the IL-23/IL-17 pathway [20–22].
A positive family history further increases risk, with first-degree relatives showing elevated prevalence [23]. Environmentally, gut dysbiosis, microbial infections,
and altered intestinal permeability are key factors, supporting the gut–joint axis
theory in SpA [24–26]. Repeated mechanical stress at entheses may also serve as a
trigger in susceptible individuals [27]. Hormonal influences remain under investigation. Evidence suggests androgens may modulate immune responses, potentially
explaining the male predominance in AS [28].
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Pathophysiology
Spondyloarthritis (SpA) pathophysiology involves a complex interaction between
genetic predisposition, immune system dysregulation, and environmental triggers,
leading to chronic inflammation primarily targeting the entheses and axial skeleton.
The hallmark genetic factor is the human leukocyte antigen B27 (HLA-B27), which
is present in a majority of patients with ankylosing spondylitis (AS) and other SpA
subtypes. HLA-B27 is thought to contribute to disease pathogenesis through several
mechanisms, including aberrant antigen presentation, misfolding and endoplasmic
reticulum stress, and formation of homodimers that activate innate immune
responses [29, 30].
The IL-23/IL-17 axis plays a pivotal role in the inflammatory cascade of
SpA. IL-23 promotes the expansion and survival of Th17 cells, which secrete pro-­
inflammatory cytokines such as IL-17A, IL-17F, and TNF-α, driving inflammation
and new bone formation at entheseal sites [20, 31]. This pathway links innate and
adaptive immunity and is a key therapeutic target in SpA management.
Enthesitis, inflammation at tendon and ligament insertion sites, is a primary
lesion in SpA and is characterized by infiltration of innate immune cells including
macrophages, neutrophils, and innate lymphoid cells. Mechanical stress and microdamage at entheses may trigger local immune activation in genetically susceptible
individuals [27, 32].
Furthermore, emerging evidence supports a role for the gut–joint axis, whereby
intestinal dysbiosis and increased gut permeability contribute to systemic immune
activation and SpA pathogenesis. Altered gut microbiota composition and subclinical gut inflammation are common in SpA patients and may serve as a reservoir of
immune stimuli [24, 26].
Osteoproliferation and pathological new bone formation, such as syndesmophytes and ankylosis, result from aberrant repair mechanisms influenced by inflammatory cytokines and Wnt signaling pathways, contributing to structural damage and
functional impairment [33].
Laboratory Findings
Although not entirely specific to spondyloarthritis (SpA), testing for human leukocyte antigen (HLA)-B27 is a pivotal component in the evaluation of suspected
SpA cases. Acute phase reactants such as erythrocyte sedimentation rate (ESR)
and chain reactive protein (CRP) can provide additional but less specific diagnostic clues.
HLA-B27: The majority of patients with axial SpA—ranging from 85% to 95%
depending on ethnicity—and approximately 75–85% of those with other SpA subtypes carry the HLA-B27 allele. Consequently, HLA-B27 testing is frequently performed in patients with suspected SpA. However, it is important to note that
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M. Bedaiwi
HLA-B27 positivity alone does not confirm the diagnosis, since a significant portion of healthy individuals also carry this allele. Conversely, absence of HLA-B27
does not exclude SpA. Axial SpA is less likely if both HLA-B27 and imaging
(including MRI) fail to demonstrate sacroiliitis, although diagnosis should consider
the entire clinical context [34, 35].
Acute phase response: ESR and CRP are elevated in approximately 35–50% of
patients with axial SpA. Raised CRP levels are prognostically significant, as they
correlate with radiographic progression and may indicate a reduced likelihood of
response to tumor necrosis factor (TNF) inhibitor therapy [36].
Imaging
Imaging modalities play a central role in diagnosing axial SpA. Sacroiliitis, best
visualized on plain radiographs, is considered a relatively specific finding.
Syndesmophytes and other spinal changes further support the diagnosis but typically appear later in the disease course. Enthesitis and erosive joint disease may also
be observed but lack specificity. Some patients with peripheral SpA may have sacroiliac joint involvement even without back pain [37].
Plain radiographs: Early disease may show normal radiographs, but definitive
sacroiliitis strongly supports axial SpA diagnosis. Radiographic evaluation of the
spine, peripheral joints, and entheses reveals abnormalities primarily in longstanding disease [38].
Radiographic grading of sacroiliitis: Sacroiliac joint changes are graded from
0 (normal) to 4 (total ankylosis). Grade 2 bilaterally or grade 3 unilaterally typically indicates definite sacroiliitis. Nonradiographic axial SpA patients generally
lack these radiographic changes. However, radiographic findings can be absent
early and may never develop in some patients. Interobserver variability among
clinicians interpreting radiographs is a known issue, particularly with mild
changes [39, 40].
Radiographs of peripheral joints: Severe peripheral joint involvement in axial
SpA is most evident in the hips, whereas knees and shoulders often display minor
changes. Enthesitis-related radiographic features such as fluffy erosions can
occasionally be detected at tendon insertions but are not specific. Psoriatic arthritis frequently exhibits distinctive radiographic patterns including joint destruction, new bone formation, and characteristic features like the “pencil-in-cup”
deformity. In inflammatory bowel disease-associated arthritis, peripheral joint
radiographs may show soft-tissue swelling and mild periostitis without significant erosions.
Magnetic resonance imaging (MRI): MRI is crucial for early detection of
sacroiliitis and spinal inflammation, revealing bone marrow edema and other
inflammatory changes before radiographic abnormalities appear. Typical sacroiliac MRI findings include subchondral bone marrow edema on STIR or fatsuppressed T2 sequences. Active sacroiliitis may be accompanied by structural
lesions such as fat metaplasia, erosions, and ankylosis. However, bone marrow
Spondyloarthritis
101
edema can also occur in healthy individuals and various conditions; therefore,
MRI findings must be interpreted alongside clinical features [35, 37]. Spinal
MRI shows triangular-shaped lesions at vertebral corners consistent with spondylitis but lacks specificity [15].
Other imaging modalities: Ultrasonography identifies enthesitis through changes
in tendon thickness, Doppler activity, and structural alterations but is mainly a
research tool rather than routine diagnostic practice [41]. Computed tomography
(CT) detects bony erosions and sclerosis more sensitively than plain radiographs but
exposes patients to radiation and is less informative about soft tissue inflammation
[42, 43]. Bone scintigraphy shows increased uptake in inflamed areas but lacks
specificity and is rarely used for SpA diagnosis [44].
Management of Axial Spondyloarthritis
Goals and General Principles
The primary objective in managing axial spondyloarthritis (axSpA) is to enhance
long-term quality of life by controlling symptoms, maintaining functional capacity, preventing structural damage, minimizing extra-articular manifestations, and
supporting mental and social health. Management should be coordinated by a
rheumatologist and often involves collaboration with dermatologists, gastroenterologists, and ophthalmologists, especially when managing psoriasis, IBD, or
uveitis [45–47]. Disease activity must be regularly assessed to guide personalized therapeutic strategies. Nonpharmacologic interventions, including education, exercise, smoking cessation, and peer support, form the cornerstone of
treatment. Pharmacologic therapies—NSAIDs, conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs), and biologics—are added based
on disease activity and treatment response [34, 35]. Oral corticosteroids have
limited utility, but local injections can be helpful in selected patients. Shared
decision-making is essential to align the management plan with patient goals and
disease trajectory [45].
onpharmacologic and Initial Pharmacologic Strategies
N
Newly diagnosed patients benefit from education on disease mechanisms, long-­
term care requirements, and the importance of physical activity. Smoking cessation
is emphasized due to its detrimental effects on disease progression and cardiovascular health [39, 45]. Depression screening and psychosocial support are critical for
mental well-being. Exercise, including postural training and stretching, improves
quality of life, reduces disease activity, and enhances cardiovascular health [48].
Both home-based and supervised exercise programs are effective, though structured
programs may provide greater benefit. NSAIDs are typically the first pharmacologic step, relieving symptoms in most patients. There is no clear evidence of superiority among NSAIDs, and both nonselective and COX-2 selective agents are
acceptable. NSAID use should be reassessed after 2–4 weeks, with switching to an
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alternative agent if no improvement is observed. Continuous NSAID use in asymptomatic patients is not recommended due to unclear benefits regarding radiographic
progression [46].
Advanced Pharmacologic Therapies
Failure to respond to two NSAIDs necessitates escalation to biologic or targeted
synthetic DMARDs. In patients with active peripheral arthritis, csDMARDs such as
sulfasalazine may be used. TNF inhibitors—including etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol—are highly effective and preferred in
patients with concurrent IBD or uveitis [45, 49, 50]. IL-17 inhibitors (secukinumab,
ixekizumab, bimekizumab) are especially useful in patients with coexistent psoriasis, though they may exacerbate IBD and are less effective in treating uveitis [49,
51]. Prior to initiating these agents, fibromyalgia and other mimickers must be
excluded. Janus kinase (JAK)inhibitors, including upadacitinib and tofacitinib,
offer an oral alternative in patients who fail biologics. However, due to associated
risks—such as thrombosis, infections, and malignancy—these agents require careful selection and monitoring [50, 51].
Managing Treatment Failure
Treatment failure is classified as primary (no response after 12 weeks) or secondary
(initial benefit followed by loss of efficacy). Reevaluation of the diagnosis, especially to exclude fibromyalgia or psoriatic arthritis, is crucial. In cases of failure,
switching within or across biologic classes or to JAK inhibitors is recommended
[45, 52]. Though response rates decrease with each subsequent switch, many
patients still derive benefit. For psoriatic SpA, anti-IL-23 agents may be used,
though their role in axial disease is limited. Evidence beyond multiple biologic
failures remains sparse, and clinical decisions must be individualized [52].
Refractory Disease and Additional Options
Systemic corticosteroids have limited efficacy in axial disease and are generally
avoided. However, image-guided injections for isolated sacroiliitis may provide
relief [35]. Non-NSAID analgesics can be used for additional symptom control,
while opioids should be reserved for short-term, select situations. Biologic agents
not targeting TNF or IL-17, such as abatacept or rituximab, have not demonstrated
benefit in axSpA [46].
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103
Tapering, Monitoring, and Duration of Therapy
Biologic therapies are typically continued indefinitely. Tapering may be attempted
after at least 6 months of sustained remission. Dose reduction has been successful
with TNF inhibitors and ixekizumab, though full withdrawal often results in relapse
[53]. Disease activity should be monitored using validated tools like Bath Ankylosing
Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease
Activity Score (ASDAS). Monitoring intervals depend on disease control: every
2–4 weeks initially, then less frequently once stable. Imaging should be reserved for
cases where findings would influence treatment decisions [45].
Peripheral Arthritis, Surgery, and Special Populations
Peripheral arthritis in axSpA may respond to csDMARDs or biologics. In severe
cases, surgical interventions such as hip arthroplasty or spinal corrective surgery
may be necessary. Hip replacement offers significant symptomatic relief, although
it carries risks like heterotopic ossification [47]. Multidisciplinary care is important
in managing extra-articular features. Uveitis, psoriasis, and IBD influence treatment
selection—IL-17 inhibitors should be avoided in IBD due to potential exacerbation
[34]. Though fertility is typically unaffected, IL-17 and JAK inhibitors are avoided
in pregnancy. Early onset of osteopenia necessitates bone density monitoring and
management [47].
Recent Advances
A post hoc analysis of a clinical trial showed that ixekizumab significantly
improved structural outcomes in the sacroiliac joints. Patients on biweekly dosing
had superior results compared to monthly dosing. Those transitioning from adalimumab to ixekizumab also experienced continued benefit. These findings support
IL-17 inhibitors’ potential to reduce structural progression, warranting further
investigation [49].
Conclusion
Axial spondyloarthritis (axSpA) is a chronic inflammatory disorder with considerable impact on patients’ quality of life. Advances in understanding its pathophysiology have led to improved diagnostic criteria and the development of targeted
therapies. Biologic treatments, particularly tumor necrosis factor (TNF) inhibitors
and interleukin-17 (IL-17) inhibitors, have demonstrated significant efficacy in
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M. Bedaiwi
reducing symptoms and improving functional outcomes in patients with
axSpA. Recent evidence also highlights the potential of IL-17 inhibitors, such as
ixekizumab, not only to alleviate clinical symptoms but also to reduce structural
joint damage, especially in the sacroiliac joints, which may alter disease progression. However, long-term studies are required to confirm the sustained structural
benefits of these agents and to explore if other IL-17 inhibitors offer similar advantages. Management strategies emphasize a multidisciplinary approach combining
pharmacologic and nonpharmacologic interventions, including patient education,
physical therapy, and lifestyle modifications such as smoking cessation, to optimize
outcomes. Regular monitoring of disease activity and adjustment of therapy are
essential to achieving remission or low disease activity states, improving overall
prognosis.
Despite the progress, challenges remain in treatment-resistant cases and special
populations. Ongoing research into new therapeutic targets and personalized medicine approaches holds promise for these patients.
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Juvenile Idiopathic Arthritis
Abhidnya Surve, Avinash Buche, Puja Totala,
and Yogita Phadke
Introduction
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in
children, characterized by persistent arthritis lasting more than 6 weeks in individuals under 16 years of age, with no identifiable cause. It is a heterogeneous group of
disorders with varied clinical manifestations and immunopathogenic mechanisms.
It is a multifactorial disease with a complex interplay of genetic predisposition,
immune dysregulation, and environmental triggers. Previously known as chronic
arthritis in children, the American College of Rheumatology (ACR) labeled it as
JRA (juvenile rheumatoid arthritis), whereas the European League Against
Rheumatism (EULAR) termed them as JCA (juvenile chronic arthritis). This created confusion in the medical community and at the end of the twentieth century;
the International League of Associations for Rheumatology (ILAR) gave certain
criteria for diagnosis of arthritis in pediatric population and the term JIA [1].
Diagnostic Criteria for JIA
Following all three criteria to be met for diagnosis of JIA:
1. Arthritis beginning before the age of 16
2. Arthritis persisting for longer than 6 weeks
3. Exclusion of other conditions associated with or mimicking arthritis
A. Surve (*) · A. Buche · P. Totala · Y. Phadke
R.K. Damani Medical College, ShriRamchandra Institute of Medical Sciences
and Dr. Hedgewar Hospital, Chhatrapati Sambhajinagar, Maharashtra, India
e-mail: abhidnyasurve@gmail.com; avinash-buche@hedgewar.org
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_5
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A. Surve et al.
Classification of JIA
The subtypes of JIA are differentiated on the basis of the number of joints, severity
of the disease, and extra-articular organ involvement. There are three classification
systems available to differentiate subtypes of JIA—ACR, EULAR, ILAR
(Table 1) [2].
The ACR criteria system recognizes three subtypes depending on number of
joints involved and systemic involvement as polyarticular, pauciarticular, and systemic. The EULAR criteria for JIA are based on characteristics present at the
onset: pauciarticular (1–4 joints), polyarticular (≥5 joints), presence of RF (two
positive tests at least 3 months apart), systemic onset with characteristic features,
juvenile ankylosing spondylitis, and juvenile psoriatic arthritis. The ILAR classification system is the most widely used system and has classified JIA into seven
major subtypes [3]. Each of them has distinct phenotypes, genetic predisposition,
pathophysiology, laboratory findings, disease course, and prognosis. The subtypes include systemic JIA (sJIA), oligoarticular JIA, RF-positive polyarticular
JIA, RF-negative polyarticular JIA, psoriatic JIA, enthesitis-related JIA (ERA),
and undifferentiated JIA.
The classification systems have some limitations with further lack of definitive
diagnostic tests for JIA. Hence the diagnosis of JIA largely depends on excluding
other potential causes. In 2019, the Pediatric Rheumatology International Trials
Organization (PRINTO) Consensus revised the ILAR classification criteria better
identifying the underlying immunological and clinical heterogeneity of JIA [4].
They proposed a new category termed early-onset ANA-positive JIA independent of
involvement of joint or skin. This category included disease seen only in children
while the other is those with adult counterparts including systemic arthritis,
RF-positive arthritis, and enthesitis-related arthritis. Rest were categorized as “other
JIA disorders.”
Table 1 Classification of juvenile idiopathic arthritis—ACR, EULAR, ILAR, PRINTO
EULAR
ACR
Polyarticular
Systemic
Pauciarticular Juvenile rheumatoid arthritis
Polyarticular (RF positive)
Juvenile ankylosing
spondylitis
Juvenile psoriatic arthritis
ILAR
Systemic
Oligoarticular
RF-negative
Polyarticular
RF-positive
Polyarticular
Enthesitis related
arthritis
Psoriatic arthritis
Undifferentiated
arthritis
PRINTO
Juvenile counterparts of
adult diseases
Systemic JIA
RF positive JIA
Enthesitis-related
arthritis
Only seen in children
Early-onset, ANA-­
positive JIA
Other JIA disorders
JIA juvenile idiopathic arthritis; ACR American College of Rheumatology; EULAR European
League Against Rheumatism; ILAR International League of Associations for Rheumatology;
PRINTO Pediatric Rheumatology International Trials Organization; RF rheumatoid factor
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Juvenile Idiopathic Arthritis
Table 2 Frequency and age of onset in various JIA subtypes
Type
Systemic onset
Oligoarthritis
RF positive polyarthritis
RF negative polyarthritis
Frequency (%)
5–15
30–60
3–7
10–25
Enthesitis related arthritis
Psoriatic arthritis
5–10
3–10
Undifferentiated arthritis
10–20
Age of onset
Any age
Early childhood
Late childhood or adolescence
Biphasic: early <6 years, late
>6 years
Late childhood or adolescence
Biphasic: early <6 years, late
>6 years
Epidemiology
JIA affects approximately 1 in 1000 children worldwide, with variations in prevalence based on geographic and ethnic factors and is the most common rheumatic
disease in children (Table 2). The incidence is estimated at 1–22 per 100,000 children per year and prevalence of 3.8–400 per 100,000 worldwide [1]. JIA is of global
health concern as it is estimated to impact about 3 million children and young adults
worldwide. It can occur at any age but commonly shows two peaks, one at 1–3 years
and the other at 8–12 years [2] (Table 2). Female predisposition is seen in most
subtypes except ERA which mainly affects males and systemic JIA which affect
both males and females equally [5]. Relative risk of JIA in a sibling varies from 15
to 30 [6]. Among the subtypes, oligoarticular is the most common seen accounting
for 50–60%, 11–28% for RF-negative polyarthritis, 10–20% for systemic arthritis,
2–15% for psoriatic arthritis, 2–7% for RF positive polyarthritis, and 1–7% for
enthesitis-related arthritis [7].
Pathogenesis
JIA is an autoimmune disorder with genetic, environmental, and immune-mediated
factors contributing to its pathogenesis. The dysregulated immune response leading
to synovial inflammation and joint destruction in JIA. Though the exact etiology
and pathogenesis is still not completely understood, the key aspects include the
following:
Genetic predisposition:
HLA associations, particularly HLA-DR and HLA-B27, vary by subtype, e.g.,
HLA-DR4 in RF-positive polyarthritis, HLA-B27 in ERA [6, 8]. JIA is a genetically complex disorder in which multiple genes are important for disease onset and
manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility
locus. Associations have been found between specific HLA alleles and clinical subtypes of JIA. There is association with HLA class II molecules (A2, DRB1, DPB1)
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A. Surve et al.
mostly for nonsystemic subtypes while for sJIA there is lack of association with
HLA genes. Oligoarticular JIA is associated with A2, DRB1*11, DRB1*08,
DPB1*02, DRB1*13, DRB1*15*01, and DRB1*01, while for RF- polyarticular the
most commonly associated genes are DPB1:03 and DRB1:08, and for RF+ JIA,
DRB1*04 and DRB1*01. The main gene associated with ERA is HLA-B27, with
other genes predisposing the development of ERA being DRB1*01, DQA1*01, and
DQB1*05. HLA-B27 is also found in late-onset psoriatic JIA. Polymorphism in
genes encoding endoplasmic reticulum resident aminopeptidases (ERAP1 and
ERAP2) predisposes to ERA, while genes encoding IL1, IL6, IL10, and MIF
increase the risk of sJIA.
• Environmental triggers: Certain environmental exposures including infectious
agents, vaccinations, antibiotics, smoking, vitamin D deficiency, stress, and
trauma are likely to induce epigenetic changes, modulate the immune system, or
alter the microbiome. Infectious viruses (Epstein–Barr virus, parvovirus B,
Rubivirus, hepatitis B virus) and bacteria (Salmonella spp., Shigella spp.,
Campylobacter spp., Streptococcus pyogenes, Bartonella henselae, Mycoplasma
pneumoniae, Chlamydophila pneumonia) have been reported as causal factors
provoking JIA . Gastrointestinal infection leading to loss of gut microbiome
diversity and disrupted tryptophan metabolism increases the risk of ERA.
• Immune dysregulation: Imbalance between regulatory T cells, Th1 (interferon
gamma secreting T cells), and Th17 (IL 17 secreting T cell) and pro-­inflammatory
(TNF-α, IL-1, IL-6) cytokines is seen in JIA.
– Cytokine dysregulation: Elevated IL-1, IL-6, and TNF-α drive systemic and
synovial inflammation, particularly in sJIA.
– T cell and B cell dysfunction: Th17 cells and regulatory T cells (Tregs) play
crucial roles in disease modulation, while autoantibody production (RF, anti-­
CCP) contributes to polyarticular forms.
– Macrophage activation: MAS, a life-threatening complication of sJIA, is
driven by hyperinflammatory macrophage and T cell activation, with high
ferritin and soluble IL-2 receptor levels.
Oligoarticular and pJIA is characterized by autoreactive antigen-specific T cells
and high titers of autoantibodies and typically show strong associations with
MHC class II alleles and thus a pivotal role for CD4+ T helper (Th) cells.
Inflammation is considered to be a consequence of disrupted balance between
pro-inflammatory Th1/Th17 and anti-inflammatory regulatory T cells (Treg) and
results in the production of pro-inflammatory cytokine IL17, which may induce
production of IL6, MMP1 and 3, IL8 (a chemoattractant for neutrophils) by
synoviocytes, resulting in subsequent joint destruction.
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111
Clinical course
Disease course in JIA is highly unpredictable ranging from self-limiting disease to
unremitting disease-causing significant disability.
Joint involvement Synovitis and joint effusion presents as pain, swelling, and stiffness of joints. With disease progression, osteopenia and bone erosion can cause
permanent deformities while epiphyseal growth disturbance and premature physeal
fusion can cause limb length inequalities. The number of joints involved varies with
the subtype and severity of disease (Fig. 2a).
Clinical presentation The presentation varies according to disease subtypes as
follows:
• Systemic JIA (sJIA):
Characterized by fever of at least 2-week duration preceding arthritis and accompanied with at least one of the following—evanescent (non-fixed) erythematous
rash, generalized lymphadenopathy, hepatosplenomegaly, or serositis (pericarditis, pleuritis, peritonitis). The fever is usually high grade with two peaks in a day
which rapidly return to the baseline with intense myalgia or abdominal pain. The
child may be normal during the afebrile phase. The rash is evanescent, nonfixed
and erythematous accompanied by onset of fever and is sometimes associated
with itching. It can be induced by rubbing or scratching the skin.
Hepatosplenomegaly is often present along with generalized lymphadenopathy.
Symmetric arthritis is seen but may be absent at the onset and develop later in the
course of disease. Symptomatic serositis is rare and often revealed by imaging.
It is associated with macrophage activation syndrome (MAS). Laboratory tests
include leukocytosis, elevated ESR and CRP, anemia, hyperferritinemia, and
thrombocytosis. No gender prediction and may present at any age. Uveitis is seen
only in 1% cases with systemic arthritis [10]. This subtype of JIA has the highest
rate of morbidity and mortality.
• Oligoarticular JIA:
The most common subtype, affecting fewer than five joints in the first 6 months
of onset of disease. It is further categorized as persistent (four or less joints) or
extended (more than four joints) depending on joint involvement after 6 months.
Peak age of onset is 2–4 years with female predominance. Large joints, predominantly lower limb, are commonly involved in asymmetric manner. In 30–50%
cases the presentation may be monoarticular. The onset is insidious though, as
compared to acute onset in cases of patients with septic arthritis. Usually there
are no associated systemic symptoms. Inflammatory markers are not raised generally. Oligoarticular JIA has high titer of ANA (70–80% cases) and indicates a
risk of chronic iridocyclitis [11]. Uveitis seen is asymptomatic, painless, chronic,
anterior, nongranulomatous, and bilateral in two-third cases.
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A. Surve et al.
• RF-positive polyarticular JIA:
Affects five or more joints during the first 6 months of disease with positive RF
on two tests 3 months apart. It is characterized by female predominance and
presents in late childhood or adolescent females. Clinically, it is an aggressive
disease like adult rheumatoid arthritis usually with symmetrical arthritis affecting wrist and small joints of hands and feet. It is the only JIA category with anti-­
CCP antibodies positive and hence included in diagnostic criteria [4].
Inflammatory markers are raised, and low-grade fever, lymphadenopathy, rheumatoid nodules, aortic valve insufficiency, and lymphocytic interstitial pneumonitis are the extra-articular features present in few patients. It is a progressive
disease with poor prognosis and high risk of joint damage.
• RF-negative polyarticular JIA:
A heterogeneous group affecting five or more joints within the first 6 months of
disease onset with negative RF. This type accounts for 15–20% of JIA cases and
is a heterogeneous category. Two distinct phenotypes are observed.
1. Overt symmetric onset arthritis of large and small joints, onset in school age,
elevated ESR, and negative ANA
2. Asymmetric onset arthritis with ANA positivity. This subtype resembles oligoarthritis type and has high risk of chronic iridocyclitis. This type sometimes presents with arthritis in less than five joints. Prognosis is worse than
oligoarticular arthritis.
3. A very rare form is also reported known as “dry synovitis.” This arthritis has
very minimal synovial thickening. ESR is raised, and this form progresses to
destructive arthritis rapidly. This form is usually refractory to therapy.
• Psoriatic JIA:
Psoriatic arthritis is seen in around 10% of JIA patients. Characterized by arthritis with psoriasis or arthritis with at least two of the following—dactylitis, nail
pitting/onycholysis, or family history of psoriasis (first-degree relative). Small
joints are more commonly involved, and 10–20% cases with psoriatic arthritis
does develop uveitis. Unlike adult psoriatic arthritis, psoriatic arthritis in children present typically in two forms: symmetric polyarthritis and asymmetric oligoarthritis. ANA positivity is seen in oligoarthritis group which has risk of
asymptomatic iridocyclitis and hence needs periodic eye examination every
3 months.
• Enthesitis-related JIA (ERA):
ERA is considered as adult counterpart of ankylosing spondylitis and seen in
5–10% of all JIA patients. Arthritis with enthesitis or at least two of the following is required for diagnosis—SI joint tenderness, inflammatory lumbosacral
pain, positive HLA-­B27, male with onset at age more than 6 years, acute anterior
uveitis, ankylosing spondylitis history, ERA, sacroiliitis with inflammatory
bowel disease, reactive arthritis, acute anterior uveitis in first-degree relative.
Arthritis can be oligo- or polyarticular commonly affecting hip and joints of
lower extremities. ERA most commonly involves calcaneal insertion of Achilles
tendon, plantar fascia, tarsal area, and knees. Enthesitis is also seen at greater
Juvenile Idiopathic Arthritis
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trochanter of femur, iliac crest, pubic symphysis, ischial tuberosity, and costochondral junction. Symptoms of sacroiliitis develop later and are seldom present
at the onset. Acute recurrent anterior uveitis with relatively good prognosis is
seen in 7–15% cases [10, 12]. The uveitis is unilateral usually and recurrent but
does not result in long-term damage. Aortic insufficiency is rare extra-articular
manifestation. The inflammatory markers are generally elevated, and HLA B27
is positive in 90% of patients. A family history of similarly affected relative is
available generally.
• Undifferentiated JIA:
Does not meet the criteria for other subtypes or has overlapping features. This
group accounts for 11–21% of all JIA patients [13].
• Early-onset ANA-positive JIA—Proposed by PRINTO, this condition specific
to pediatric cases includes up to 50% of all JIA cases. This classification is an
addition to the previous ILAR classification, which grouped up all ANApositive cases irrespective of joint or skin involvement. Cases prominently
from oligoarthritis, RF-negative polyarthritis, and psoriatic arthritis are
included in this group.
Extra-articular involvement includes skin and eye involvement. Growth disturbances and systemic inflammation may also be seen.
Extra-Articular Involvement
Eye Involvement
JIA is the most common systemic association of uveitis in children [11]. Uveitis is
rare in systemic onset JIA and juvenile-onset rheumatoid arthritis. Cases with early-­
onset ANA-positive oligoarticular JIA have the highest risk of developing chronic
iridocyclitis. Recurrent acute symptomatic iridocyclitis is seen in enthesitis-related
arthritis. JIA-associated uveitis especially oligoarticular arthritis presents as bilateral insidious-onset chronic nongranulomatous anterior uveitis (Fig. 1a, b). Because
of insidious onset and chronic disease, complications like band-shaped keratopathy,
posterior synechiae, cataract, glaucoma, hypotony, and macular edema occur
(Fig. 1c, d).
To avoid poor visual prognosis, screening programs are developed based on
relative risk of uveitis in different subtypes, ANA positivity, age of onset of
arthritis, and duration of arthritis. Early detection and regular 3 monthly slit lamp
screening of JIA oligoarthritis patients is recommended to prevent complications. In most cases, arthritis precedes uveitis while only 3–7% cases presented
with uveitis first [12]. In general, uveitis is idiopathic in more than 50% cases,
and hence a thorough physical examination by a pediatrician or pediatric rheumatologist and appropriate systemic investigations is important before labeling
as idiopathic. Most of these cases are females with ANA positivity and may
never even develop arthritis [11].
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b
c
Fig. 1 Clinical image (a) of 14-year-old male with enthesitis-related arthritis showing swelling of
left wrist (white arrow). Radiographical imaging (b) of left wrist showing decreased intercarpal
joint space with soft tissue swelling (white arrow) as compared to normal intercarpal space of right
hand suggestive of acute synovitis of left wrist. Radiographical imaging of pelvis (c) showing
irregular and decreased space at sacroiliac joint suggestive of chronic arthritis (black arrow)
Diagnosis
Diagnosis is mainly clinical based on history and physical examination, supported
by laboratory tests and radiological imaging with exclusion of other causes of
arthritis in children as it is a diagnosis of exclusion.
History taking includes age of onset, joints involved, duration of arthritis, associated symptoms. Diagnosis of JIA is considered in children less than 16 years of age
with arthritis for more than 6 weeks and exclusion of other causes of chronic
arthritis.
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Laboratory findings The laboratory tests in JIA are not specific and their presence
or absence does not definitively indicate presence of JIA.
• Elevated inflammatory markers—erythrocyte sedimentation rate (ESR) and
C-reactive protein (CRP) levels. ESR and CRP are raised usually in systemic
onset and polyarticular disease. They are generally not elevated in oligoarticular JIA.
• Complete blood count to look for anemia.
• ANA positivity (especially in oligoarticular JIA). Presence of ANA is not specific for JIA and is seen in multiple disorders but has predictive significance
especially with regard to risk of chronic iridocyclitis [14]. ANA can be detected
by immunofluorescence and ELISA method. IF method is gold standard.
• Rheumatoid factor (RF) antibody in polyarticular JIA—little value for diagnosis
but does indicate poorer disease course and prognosis.
• Anticyclic citrullinated peptide (anti-CCP) antibody—it is positive in small percentage of JIA patient who are RF positive also. Anti CCP positivity may suggest
severe deforming arthritis.
• Human leukocyte antigen (HLA) B27—seen in ERA.
• Lipid profile: Patients with JIA are at increased risk of atherosclerosis and cardiovascular disease. Hence, lipid profile may be deranged in these cases [15].
• Ferritin, fibrinogen, AST, triglyceride, and solubleIL-2 receptor levels—elevated
in macrophage activation syndrome. Cytopenia is also seen in MAS.
• S100 proteins (S100A8/A9, S100A12): These myeloid-related proteins are useful in predicting disease flares and macrophage activation syndrome (MAS).
I maging
Radiological imaging allows for examination of joint structure for bone integrity,
damage, fluid accumulation, and inflammatory changes. Though used in symptomatic joint involvement, early stage of JIA may not show any changes. Conventional
radiography (CR), musculoskeletal ultrasound (MSUS), and magnetic resonance
imaging (MRI) are used for diagnosis, assessing disease and predicting outcomes of
JIA patients. MSUS and MRI are more sensitive than CR in diagnosis and assessing damage.
1. Conventional radiography (CR): CR is the first imaging modality used in a child
with joint pain and swelling. It excludes other causes like trauma, osteochondroses, bone tumors, skeletal dysplasia, etc. CR is also useful to demonstrate structural damage in established JIA cases. Typical findings seen on CR include joint
space narrowing, bone erosions, growth abnormalities, and soft tissue swelling
(Fig. 2b, c). However, it is difficult to assess cartilage loss in children due to various factors in a growing child.
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a
b
c
d
Fig. 2 Case of acute nongranulomatous uveitis (a) anterior segment imaging (ASI) showing small
fine keratic precipitates (white arrow) on endothelium. Healed uveitis (b) ASI showing clear cornea with few pigments on lens. Complication of uveitis—ASI showing band-shaped keratopathy
(c), posterior synechiae (d), and cataract (c, d)
2. Musculoskeletal ultrasound (MSUS): MSUS is useful in assessing synovitis and
joint effusion. It is also helpful in detecting tenosynovitis in complex joints like
ankle and wrists. MSUS is also helpful in detecting extent of cartilage loss.
MSUS is useful in guiding joint injections in patients with synovitis. Diagnosis
of enthesitis is possible with MSUS but requires experience. This modality is
relatively inexpensive and noninvasive and nonionizing so patient cooperation is
good. Further, ultrasound in addition to detecting synovitis can be used as a
guide for effusion tap or intra-articular corticosteroids injections.
3. Magnetic resonance imaging (MRI): MRI with contrast is the most sensitive
method for detection of synovitis and differentiates between active inflammatory
pannus and inactive fibrotic pannus. It can also be used to assess treatment
response. Early detection of erosions in large joints is possible with MRI as
compared to MSUS and CR. Detection of small joint erosions is not accurate
sometimes in growing children and needs further studies. MRI is the most sensitive imaging technique and is considered gold standard modality for JIA [9].
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Differential Diagnosis
Arthritis or arthritis-like symptoms may be present in many conditions in pediatric
age group with JIA being diagnosis of exclusion. Thus, to make a clinical diagnosis
of JIA, the first step is to exclude arthritis with known etiologies. Key differentials
include (Table 3):
1. Infectious arthritis
• Septic arthritis: Acute-onset monoarthritis with fever, elevated WBC, and
positive synovial fluid culture (common pathogens: Staphylococcus aureus,
Streptococcus spp.).
• Viral arthritis: Transient arthritis following viral infections (e.g., parvovirus
B19, Epstein–Barr virus, hepatitis B/C). The fever associated is not intermittent, and the rash pattern varies according to the type of virus.
• Tuberculous arthritis: Chronic monoarthritis, often affecting weight-bearing
joints, associated with positive tuberculin skin test and synovial biopsy
findings.
• Other infections like malaria and typhoid may also mimic sJIA and is usually
associated with fever, chills, or diarrhea.
Table 3 Differential diagnosis depending on the number of joint involvement
Monoarthritis
Septic
arthritis
Reactive
arthritis
Hemarthrosis
Malignancy
Trauma
Solid tumor
Oligoarthritis
Reactive arthritis–—
poststreptococcal
reactive arthritis,
Lyme arthritis
Acute rheumatic
fever
Toxic synovitis
Septic arthritis
Osteomyelitis
Pyomyositis
Steroid-induced
osteonecrosis
Sickle cell disease
Hemophilia
Scurvy
Trauma
Pigmented
villonodular
synovitis
Malignancy
Systemic
Polyarthritis
arthritis
Infection
Reactive arthritis–
Acute
poststreptococcal
rheumatic
reactive arthritis,
fever
Lyme arthritis
Syndrome of
Acute rheumatic
periodic fever
fever
Aphthous
Scurvy
stomatitis
Osteomyelitis
Pharyngitis
Trauma
and cervical
Other connective
tissue diseases (SLE, adenitis
Sjogren,
Auto-­
scleroderma)
inflammatory
Sarcoidosis
syndromes
Blau syndrome
Systemic
Arthritis associated vasculitis
with inflammatory
Inflammatory
bowel disease
bowel disease
Farber disease
Malignancy
Benign
Castleman
hypermobility joint disease
syndrome
Amplified
musculoskeletal pain
syndrome
Enthesitis-related
arthritis
Apophysitis
Inflammatory
bowel disease
Chronic recurrent
multifocal
osteomyelitis
Amplified
musculoskeletal
pain syndrome
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2. Reactive arthritis
• Poststreptococcal reactive arthritis: Arthritis following Group A streptococcal infection, differentiated from acute rheumatic fever by the absence of
carditis.
• Enteric reactive arthritis: Occurs after gastrointestinal infections (Salmonella,
Shigella, Yersinia, Campylobacter).
• Lyme arthritis: Late-stage Borrelia burgdorferi infection causing intermittent
monoarthritis, diagnosed by ELISA and Western blot.
3. Autoimmune and rheumatic diseases
• Systemic lupus erythematosus (SLE): Arthritis with systemic features (malar
rash, nephritis, cytopenias, positive ANA, and dsDNA antibodies).
• Juvenile dermatomyositis: Proximal muscle weakness, heliotrope rash,
Gottron’s papules, elevated muscle enzymes.
• Sarcoidosis: Granulomatous inflammation presenting with arthritis, uveitis,
and lung involvement.
• Vasculitides (Kawasaki disease, polyarteritis nodosa): Arthritis with fever,
rash, and systemic vasculitis features.
4. Other inflammatory and genetic disorders
• Autoinflammatory syndromes (periodic fever syndromes): Familial
Mediterranean fever, TRAPS, and CAPS present with recurrent fever, rash,
and arthritis.
• Malignancies (leukemia, lymphoma, neuroblastoma): Bone pain, cytopenias,
hepatosplenomegaly, and abnormal bone marrow findings.
• Metabolic and genetic conditions: Mucopolysaccharidoses, Farber disease,
and Stickler syndrome may present with joint stiffness and dysmorphic
features.
• Pigmented villonodular synovitis: Episodic swelling of a single large joint
due to inflammation and overgrowth of the synovium; synovial fluid is often
bloody and can be distinguished with magnetic resonance imaging (MRI).
Management
Management of JIA requires pharmacotherapy and physiotherapy with nutritional and psychosocial support. The aim is to promote remission through timely,
individualized, well-coordinated interdisciplinary care to preserve functional
status of patient. Thus, it is a team effort involving rheumatologist, pediatrician,
physiotherapist, occupational therapist, psychologist, and others. The treatment
strategies for JIA primarily depend on the disease activity, level of damage, and
the JIA type [2, 13].
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Assessment of Disease Activity
• Juvenile Arthritis Disease Activity Score (JADAS) is a clinically relevant tool to
assess the disease activity [16]. There are various forms of JADAS validated, but
commonly used is 28-joint JADAS. It includes physician global assessment, parent global assessment, ESR, and number of joints with active disease.
• ACR Pediatric is a composite score developed to assess the treatment response.
It is mainly used in clinical trials due to its complicated calculations [17].
The 6 JIA core set variables in ACR Pediatric are:
1. Number of joints with active arthritis
2. Number of joints with limited range of motion
3. Physician global assessment
4. Parents global assessment of child’s well-being
5. Validated measure of functional ability like CHAQ (Childhood Health assessment Questionnaire)
6. Inflammatory markers (ESR, CRP)
7. For patients with systemic onset JIA, additional feature of absence of fever
is added
Based on the above parameters, ACR Pediatric 30, 50, 70, 90, 100 are described
for response to therapy when at least 30%, 50%,70%, 90%, and 100% change in
3 out of 6 domains described above respectively.
Treatment
There are two approaches for the treatment of JIA patients, step-up approach and
aggressive treatment approach. Step-up approach was used traditionally, but there is
no consensus on use of any particular recommendation.
Pharmacologic Therapy
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): First-line drugs for symptom
relief for all subtypes (Table 4). They are mainly used for control of joint pain
and fever. A trial of 2–3 months of NSAIDs is generally indicated before starting
of DMARDs in step-up approach. With the DMARDs and biologics, the use of
NSAIDS has decreased over time. NSAIDs inhibit cyclooxygenase, an enzyme
involved in prostaglandin synthesis. Potential gastrointestinal toxicities and
nephrotoxicity are seen and hence need to be informed to family.
• Disease-Modifying Antirheumatic Drugs (DMARDs)—Table 5
– Methotrexate (first-line drug for polyarthritis)—Methotrexate is the conventional drug of choice when NSAIDs fail. It is inhibitor of tetrahydrofolate
dehydrogenase inhibitor which inhibits DNA synthesis. It is used in all types
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Table 4 Commonly used NSAIDs and doses in JIA
Drug
Naproxen
Age
All
Ibuprofen
6 months to
12 years
Indomethacin 2–14 years
Meloxicam
>2 years
Celecoxib
>2 years
Weight
Not
specified
Not
specified
Not
specified
Not
specified
10–25 kg
>25 kg
Dose
10–20 mg/kg in two
divided doses
30–40 mg/kg/day in two
to four divided doses
2–3 mg/kg/day in two to
four divided doses
0.125 mg/kg once a day
Remarks
Max dose 200 mg/day
Max 200 mg/day.
Administer with food
Max dose 7.5 mg/day
50 mg twice a day
100 mg twice a day
Table 5 DMARDs used in JIA treatment
Drug
Methotrexate
Leflunomide
Sulfasalazine
Dose
10–15 mg/m2/
week
Max 20 mg/
week
<40 kg–10 mg
once a day
>40 kg–20 mg/
day
50 mg/kg/day
Max dose
2 g/day
Hydroxychloroquine Up to 5 mg/kg/
day
–
–
–
•
Indication
All JIA categories
Common adverse effects
Cytopenia, liver toxicity, nausea,
vomiting
Off label
Cytopenia, liver toxicity, nausea,
vomiting, teratogenic potential
Polyarticular JIA
and enthesitis-­
related arthritis
Not recommended
in systemic onset
JIA
No clear indication,
usually add-on
therapy
Rashes, gastrointestinal
intolerance, liver toxicity,
leukopenia, decrease in serum
immunoglobulin concentration
Dyspepsia, retinal toxicity with
long-term use (usually dose
>5 mg/kg)
of JIAs as second-line drug of choice. The max efficacy is seen in children
with polyarthritis and extended oligoarthritis as compared to systemic
JIA [18].
Leflunomide (alternative to methotrexate)
Sulfasalazine
Hydroxychloroquine
Biologic agents: Biologics have revolutionized the treatment paradigm but
they are not used as commonly as in adults mainly due to lack of trials in
pediatric population [19, 20] (Table 6).
– TNF inhibitors (etanercept, adalimumab) for refractory cases
– IL-6 inhibitors (tocilizumab) for systemic disease
– IL-1 inhibitors (anakinra, canakinumab) for refractory systemic JIA cases
– JAK inhibitors (tofacitinib) for polyarticular JIA
– T cell inhibitor (abatacept) for refractory polyarticular JIA
– Anti-CD20 (rituximab)
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Table 6 Biologic DMARDs used in JIA
Medication
Etanercept
Mechanism of
action
TNF inhibitor
Adalimumab
TNF inhibitor
Abatacept
Tocilizumab
Anakinra
Dose
0.8 mg/kg max
50 mg/week SC
> 2 years
<30 kg—20 mg
every 15 days
>30 kg—40 mg
every 15 days
Subcutaneously
Binds to CD80/86 6 mg/kg IV
and inhibits T cell infusion every
month
costimulatory
molecule
IL-6 inhibitor
<30 kg—12 mg/kg
IV
>30 kg—8 mg/kg
IL-1 inhibitor
Canakinumab IL-1 inhibitor
Indication
Polyarticular JIA
not responding to
Methotrexate
Adverse reactions
Injection site
reaction,
infections, TB
reactivation
Polyarticular JIA, Injection site
uveitis
reaction,
infections, TB
reactivation
Polyarticular JIA
not responding to
Mtx and TNF
inhibitors
Systemic
JIA—every
15 days
>2 years
Polyarticular
JIA—every
month
1–2 mg/kg/day SC Steroid-­
(max up to 100 mg dependent
/day)
systemic JIA
4 mg/kg every
month SC
Steroid-­
dependent
systemic JIA
aged >2 years
Allergic reactions,
hepatitis,
macrophage
activation
syndrome,
cytopenia
Allergic reaction,
infections,
macrophage
activation
syndrome
Local reactions,
infections
• Corticosteroids: Intraarticular corticosteroids are indicated in oligoarticular JIA
as a first-line agent and in other types to prevent deformities secondary to contracture and leg length discrepancy, resolve Baker’s cyst, and improve tenosynovitis [21]. They are also indicated in polyarticular JIA before the systemic therapy
effect is seen. Triamcinolone hexacetonide in dose 0.25–1 mg/kg in large joints
and methylprednisolone acetate in dose 5–40 mg in smaller joints. The side
effects include local atrophy of skin, depigmentation, and calcinosis. The incidence of infection is low in experienced hands (1 in 10,000 injections). Systemic
corticosteroids are rarely indicated in JIA except systemic onset JIA. They are
used in dose up to 2 mg/kg (max 60 mg/day). The usual adverse drug reaction
includes weight gain, moon face, acne, and growth suppression. Long-term steroids are to be avoided and may lead to osteoporosis, glaucoma, hypertension,
diabetes, sleeping problems, and mood changes. Children on long-term steroids
are also prone for infections including viral infections like chicken pox.
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• Novel biologic and targeted therapies
– IL-18 inhibitors and IL-17 inhibitors are under investigation for refractory
systemic and polyarticular JIA.
– Janus kinase (JAK) inhibitors like baricitinib and upadacitinib offer targeted
small-molecule options for severe disease.
– Nanomedicine approaches using nanoparticle drug delivery systems improve
bioavailability and reduce systemic side effects.
Nonpharmacologic Therapy
• Physical therapy: Maintains joint function and prevents contractures. Emphasis
on improving the range of motion with minimal stress on joints. Swimming is
often a good option.
• Occupational therapy: Enhances daily activities and quality of life.
• Psychosocial support: Addresses emotional and developmental challenges.
• Ophthalmologic screening: Routine uveitis monitoring in ANA-positive JIA.
Eye Management in Juvenile Idiopathic Arthritis
Ocular involvement, particularly uveitis, is a significant complication of JIA, especially in oligoarticular and ANA-positive cases. Management strategies include:
1. Screening and monitoring
• Regular ophthalmologic examinations are crucial, with slit-lamp evaluations
every 3–12 months depending on risk factors.
• High-risk patients (ANA-positive, young age at onset) require more frequent
screening.
2. Pharmacological treatment
• Topical corticosteroids: First-line drugs for anterior uveitis; frequent monitoring required to prevent glaucoma and cataracts.
• Systemic corticosteroids: Used in severe or refractory cases.
• Immunosuppressive therapy: Methotrexate is the first-line DMARD for
steroid-­sparing effects.
• Biologic agents: TNF inhibitors (adalimumab, infliximab) are effective in
refractory uveitis.
3. Surgical interventions
• Cataract surgery for steroid-induced cataracts.
• Glaucoma management may require surgical intervention.
• Vitrectomy for severe complications like retinal detachment.
4. Patient education and lifestyle modifications
• Emphasizing adherence to ophthalmologic follow-ups.
• Sun protection and proper eye hygiene to reduce complications.
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Guidelines in Juvenile Idiopathic Arthritis
1. American College of Rheumatology (ACR) Guidelines
• Emphasize early diagnosis and aggressive treatment to prevent long-term
joint damage.
• Recommend NSAIDs and intra-articular corticosteroids as first-line therapy
for mild disease.
• Methotrexate is the preferred DMARD for moderate to severe disease, with
early escalation to biologics if needed.
• Biologic agents such as TNF inhibitors, IL-6 inhibitors, and JAK inhibitors
are recommended for refractory cases.
• Regular ophthalmologic screening is advised for early detection of uveitis.
2. European League Against Rheumatism (EULAR) Guidelines
• Stress a treat-to-target approach with frequent monitoring and therapy
adjustments.
• Recommend nonpharmacologic interventions such as physical therapy and
psychosocial support.
• Highlight the importance of shared decision-making between clinicians,
patients, and caregivers.
• Encourage research into personalized treatment strategies based on
biomarkers.
3. International League of Associations for Rheumatology (ILAR) Recommendations
• Advocate for global collaboration in JIA research and treatment
standardization.
• Promote early screening for systemic complications like macrophage activation syndrome.
• Support the development of new therapeutic agents targeting specific immune
pathways.
Criteria for defining clinical inactive disease in oligoarticular, polyarticular,
and systemic onset JIA [22]:
1. No joints with active disease
2. No fever, rash, serositis, organomegaly, lymphadenopathy attributed to JIA
3. No active uveitis as defined by the SUN working group
4. ESR, CRP within normal range and if elevated not attributable to active disease
5. Physician’s global assessment of disease activity score of best possible on the
scale used
6. Duration of morning stiffness of 15 minutes
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A. Surve et al.
Advances in Juvenile Idiopathic Arthritis
• Digital health technology: E-Health and M-Health in juvenile idiopathic arthritis
Use of digital health technology like E-Health and mobile health (M-Health) is
helpful in supplementing JIA management. E-Health is described by WHO
while M-Health is a subbranch of E-Health that uses wireless technology.
E-Health platforms provide telemedicine consultations, electronic health
records (EHRs), and remote disease monitoring. M-Health applications assist in
tracking disease activity, medication adherence, and symptom monitoring.
Wearable devices measure physical activity levels, joint function, and patientreported outcomes in real-time. Benefits include improved accessibility to specialist care especially in remote areas, patient involvement by self-monitoring,
early disease detection and flare prediction, and remote monitoring of treatment
response. This decreases the patients visits, detects disease early, and improves
treatment adherence [23–25].
• AI in juvenile idiopathic arthritis
Artificial intelligence can help to improve early detection of JIA and guide the
management approach with the help of large dataset. AI-driven predictive models identify high risk patients for severe disease progression based on biomarkers
and genetic profiles. Automated image analysis of MRI and ultrasound can help
in detecting early joint damage and inflammatory patterns. Apart from diagnostic
help, AI can be used to tailor biologic therapy and analyze treatment response
data. Further, AI can help in remote patient assessment, monitoring, and disease
management [26, 27].
• Personalized and precision medicine
Advances in genomic and biomarker research have enabled precision medicine
approaches, tailoring treatments based on cytokine profiles and genetic susceptibility markers. Biomarkers like S100 proteins, CXCL9, and IL-18 help in predicting disease course and therapy response [28, 29].
• Gene therapy and regenerative medicine
Gene therapy is emerging as a promising approach for the treatment of JIA,
focusing on modifying immune responses at a genetic level to provide long-­
lasting therapeutic effects. It aims to downregulate the inflammatory cytokines
and promote regulatory T cell function. Stem cell therapy is being explored for
refractory cases, with mesenchymal stem cells showing immunomodulatory
potential. Gene-editing techniques like CRISPR hold promise for modifying
autoimmune pathways in JIA potentially correcting the dysregulated immune
pathways in JIA.
• Biomechanics in juvenile idiopathic arthritis
– Gait and postural analysis: Patients with JIA often experience altered gait
mechanics due to joint pain and stiffness. Advanced motion capture systems
and force plate analysis help assess biomechanical abnormalities.
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125
– Joint load and stress analysis: Computational modeling and finite element
analysis (FEA) are used to evaluate the stress distribution on affected joints,
aiding in personalized treatment planning.
– Orthotic and assistive device development: Biomechanical insights guide the
creation of custom orthoses and supportive devices to reduce joint stress and
improve mobility.
• 3D printing in juvenile idiopathic arthritis
– Custom orthotic devices: 3D printing enables the production of patient-­
specific orthoses that improve joint alignment and reduce pain.
– Prosthetics and assistive aids: Lightweight, custom-designed prosthetic
joints and assistive devices enhance functionality and comfort for children
with severe joint deformities.
– Surgical planning models: 3D-printed anatomical models provide surgeons
with precise preoperative planning tools, improving surgical outcomes in
severe JIA cases requiring joint reconstruction.
– Drug delivery innovations: Bioprinting techniques are being explored to
develop targeted drug delivery systems that release medications directly into
affected joints, minimizing systemic side effects.
Prognosis and Long-Term Outcomes
The prognosis varies by subtype, timing of diagnosis, onset of treatment, and presence of extra-articular features. The best outcome is of oligoarticular JIA while
systemic or polyarticular JIA is more disabling [30, 31].
• Disease remission: Nowadays with prompt and accurate diagnosis and early biologic therapy, long-term joint preservation and functional status have been
improved. Some studies support the possibility of the existence of a “window of
opportunity” in early disease, during which prompt treatment includes higher
rates of remission and improves long-term outcomes [32].
• Long-term morbidity: If not treated, uncontrolled inflammation increases the risk
of growth retardation, osteoporosis, and cardiovascular complications. It may
also lead to residual problems, including musculoskeletal problems, early need
for joint replacement therapy, and severe disability in adulthood. Thus, regular
monitoring for complications like uveitis and growth impairment is crucial.
• Mortality: The overall mortality rate is low in children with JIA, although higher
rates are seen in children with more severe disease and in adults with a history
of sJIA.
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Complications of Juvenile Idiopathic Arthritis
JIA can lead to several systemic and musculoskeletal complications, including:
1. Musculoskeletal complications
• Joint damage and deformities: Chronic inflammation can cause joint erosions, contractures, and functional disability.
• Growth abnormalities: Chronic inflammation and corticosteroid use can lead
to growth retardation, limb length discrepancies, and osteoporosis.
• Osteoporosis: Long-term corticosteroid use increases the risk of fractures and
reduced bone mineral density.
2. Ocular complications
• Uveitis: Chronic anterior uveitis, particularly in ANA-positive oligoarticular
JIA, can lead to vision loss if untreated.
• Cataracts and glaucoma: Inflammation itself and long-term corticosteroid
therapy increase the risk of these complications.
3. Systemic complications
• Macrophage activation syndrome (MAS): MAS is a rare complication associated with autoimmune disease especially systemic JIA and characterized by
severe, life-threatening hyperinflammatory state with features of cytokine
storm and hemophagocytosis [33–35]. The mortality rate is up to 20% in
these patients, and remaining significant number of patients have long-term
morbidity. Early detection and initiation of immunosuppression is important.
• Amyloidosis: Chronic inflammation can lead to secondary amyloidosis, causing kidney, heart, gastrointestinal, and other organ dysfunctions. It is a complication of poorly treated disease and mainly seen in patients with systemic
JIA. This complication is becoming rare with the availability of effective
treatment strategies.
• Cardiopulmonary involvement: Pericarditis, myocarditis, and pulmonary
hypertension can occur in severe cases.
4. Psychological and social impact
• Chronic pain and fatigue: Persistent inflammation and treatment side effects
contribute to fatigue and pain syndromes.
• Depression and anxiety: Reduced quality of life due to functional limitations
and chronic disease burden.
• School and social limitations: Frequent hospital visits and disability impact
academic and social development.
5. Impact of DMARDs
Patients with sJIA who were diagnosed and managed prior to the availability of
DMARDs often have substantial disease- and treatment-related morbidity. With
more common and earlier usage of DMARDs such as IL-1 and IL-6 inhibitors,
complications like growth retardation and osteoporosis are less likely to occur,
but long-term outcomes in the era of DMARD treatment still need to be studied.
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Future Directions
Advancements in biologic therapies and personalized medicine hold promise for
improved outcomes. Research continues to explore novel biomarkers, genetic predisposition, and early intervention strategies.
Conclusion
Juvenile idiopathic arthritis (JIA) represents a complex and heterogeneous group of
autoimmune disorders with varied clinical phenotypes, immunopathogenesis, and
long-term implications. Despite its diagnostic challenges due to overlapping presentations and absence of definitive tests, timely recognition using established classification systems—particularly the evolving ILAR and PRINTO criteria—remains
critical. Advances in immunogenetics, biologic therapies, digital health technologies, and personalized medicine have significantly transformed the diagnostic and
therapeutic landscape of JIA. These innovations, alongside a multidisciplinary
treatment approach, have improved patient outcomes, reduced disability, and
enhanced quality of life.
However, the burden of systemic complications, particularly ocular involvement,
growth disturbances, and psychosocial impact, underlines the need for vigilant
monitoring and patient-centered care. Early diagnosis, aggressive yet tailored treatment strategies, adherence to standardized guidelines, and long-term follow-up are
essential in minimizing disease progression and ensuring optimal outcomes. Future
directions involving AI integration, precision medicine, and novel therapeutics continue to offer hope in redefining the management and prognosis of JIA.
References
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Scleroderma
Muhammad Ishaq Ghauri
and Muhammad Shariq Mukarram
Introduction
Scleroderma is a rare, chronic autoimmune connective tissue disease with an enigmatic or complex pathogenesis [1]. The basic defect has been identified as endothelial dysfunction, accompanied by progressive fibrosis of the skin and internal
organs [2].
Scleroderma encompasses various phenotypes with high patient-to-patient variability, depending on clinical characteristics, autoantibodies, and prognosis. The
disease can be divided into two primary forms: localized scleroderma and systemic
sclerosis [1, 2]. Localized scleroderma includes morphea and linear scleroderma,
while systemic sclerosis (SSc) can further be classified as limited systemic sclerosis/scleroderma (previously known as CREST syndrome) or diffuse systemic sclerosis/scleroderma [3]. This classification is based on clinical and serological criteria.
Systemic sclerosis, as its name suggests, is characterized by systemic manifestations and multi-organ involvement, with a high mortality rate. In contrast, localized
scleroderma primarily affects the skin and subcutaneous tissue [4]. Limited cutaneous systemic sclerosis, once known as CREST syndrome (calcinosis, Raynaud’s
phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), is characterized by thickening of the skin distal to the elbows and knees with or without
involving the face. It does not involve the trunk, however. Antinuclear antibodies
(ANAs) are present in more than 90% of the cases, and up to 70% of the patients test
positive for at least one of the more specific autoantibodies (anticentromere, anti-­
SCl 70, and anti-RNA polymerase III). The multiple organs commonly involved in
scleroderma are the skin, gastrointestinal tract, lungs, kidneys, skeletal muscles, and
pericardium. Localized scleroderma, nevertheless, is not associated with Raynaud’s
phenomenon, distal ischemia, or internal organs. ANA may be present in up to 50%
of cases. However, specific autoantibodies are absent here [5, 6].
M. I. Ghauri (*) · M. S. Mukarram
Department of Medicine, Jinnah Medical College Hospital, Karachi, Pakistan
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_6
131
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M. I. Ghauri and M. S. Mukarram
Epidemiology
The epidemiological data on scleroderma is limited due to the rarity of the disease.
The prevalence and incidence are highly influenced by the geographical location
[1]. An estimated incidence of 19.3 new cases per million adults annually was
reported in a study conducted in the United States, with a prevalence of 242 cases
per million adults in Detroit from the year 1989 to 1991 [7]. Another study from
Quebec in 2003 reported a prevalence of 443 cases per million adults [8].
The prevalence rates are significantly higher in the United States and Australia
compared to Europe and Asia (Specifically Japan and Taiwan) [9, 10].
The disease has a female predominance, with a female–male ratio of almost 5.1.
The peak age of onset is between 45 and 54 in African American women and
between 55 and 64 in European American females. Systemic sclerosis (SSc) is a
rarity among children and teenagers [11].
Etiology
The exact etiology of scleroderma is still not completely understood; it is believed
that genetic factors (predominantly) and environmental factors contribute to its
development.
Genetic Factors
Scleroderma and systemic sclerosis are clustered with multiple other autoimmune
diseases. The association of specific human leukocyte antigens (HLAs), particularly
HLA-DRB1*1104, DQA1*0501, and DQB1*0301, with scleroderma, has been
known for a long time [12].
Environmental Factors
Several environmental triggers have been identified with the development of
scleroderma.
Among the infections are cytomegalovirus (CMV), Ebstein–Bar virus (EBV),
and parvovirus B19 [13]. Among the potential environmental risk factors, occupational exposures have received some attention. Exposure to silica dust is long associated with the development of SSc. [1]. A meta-analysis that included 16 studies
concluded that silica exposure might be a significant risk factor for developing SSc,
specifically in males [14].
Scleroderma
133
Risk Factors
Despite the genetic predisposition and the environmental factors mentioned earlier,
some groups have a higher risk of developing the disease. The following factors
may affect the risk.
Sex: Scleroderma is more common in women.
Age: The disease usually occurs between 30 and 50 years of age.
Race: It can affect people of all races and ethnic groups, but the disease is more
common and severe in African Americans.
Pathophysiology
The pathophysiology of the disease is complex. It is characterized by three main
features: autoimmunity, vascular insult, and tissue fibrosis. Variations in the contribution of these factors in each patient are attributed to the different clinical phenotype of the disease [1].
Inflammation and immune dysregulation play a pivotal role in the pathogenesis
of scleroderma. There is a dysfunction of both innate and humoral immune systems.
The presence of activated T cells is predominant in the tissue and peripheral blood
in patients with scleroderma. There is an imbalance between type 1 and 2 helper T
cell cytokines. This contributes to enhanced fibrosis through increased collagen
synthesis and myofibroblast transdifferentiation, which is driven by various profibrotic cytokines, including transforming growth factor-beta (TGF-β) and interleukins 4, 5, and 13 [1].
The damaged and activated endothelial cells release ET-1, which is a potent
vasoconstrictor, and it promotes leukocyte adhesion, proliferation of vascular
smooth muscle, and activation of fibroblast [15]. These activated endothelial cells
differentiate into mesenchymal cells, which exhibit poor responsiveness to vasodilators. In addition, activated platelets release thromboxane A2, platelet-derived
growth factor, and transforming growth factor B. It also activates thrombin and, as
a result, causes coagulation, thrombosis, vasoconstriction, and fibroblast activation.
This ultimately results in tissue hypoxia [1].
The pro-inflammatory cytokine interleukin 6 is more abundant during the early
stage of the disease and is linked to the severity [16]. Immune response and vascular
damage are closely linked and may even be interdependent.
Neutrophils produce cytokines like TGFB and IL-6 and release reactive oxygen
species that result in the activation of the fibroblasts by the release of TEFB from its
extracellular matrix-bound state [17–19].
Dendritic cells contribute to the pathophysiology of the disease by activating
naive T cells to present antigens, which influence the immune response [20]. There
is increasing evidence that TGFB is the major profibrotic cytokine in the fibrotic
process of the disease. Transforming growth factor-β was identified as a biomarker
in SSc skin and lung fibrosis [21, 22]. Almost all patients with scleroderma manifest
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M. I. Ghauri and M. S. Mukarram
humoral autoimmunity and the presence of autoantibodies produced by the activated B cells [23].
Histopathology
Vascular fibrosis is the predominant feature in scleroderma, affecting different
organs beyond the skin. Fibrosis can occur in organs such as the gastrointestinal
tract, thyroid, and salivary glands. Perivascular inflammatory infiltrates of CD4+ T
lymphocytes may be observed in the initial stages of the disease but are absent in
chronic cases. The vasculopathy is characterized by intimal proliferation, thickening of basement membrane, capillary rarefaction, platelet aggregation, and microthrombi formation [1].
Types of Scleroderma (Fig. 1)
Fig. 1 Types of
scleroderma
Scleroderma
Localized
Scleroderma
Systemic Sclerosis
Morphea
Limited
Cutaneous
Scleroderma
Linear
Scleroderma
Diffuse Cutaneous
Scleroderma
Scleroderma
135
Clinical Manifestations
Scleroderma is a complex, multisystem disease, and its clinical manifestations differ according to the patient.
Limited cutaneous scleroderma typically involves skin thickening limited to the
face, fingers, and distal extremities. Other clinical characteristics may include telangiectasia (dilated blood vessels) and internal organ involvement, such as the heart,
lungs, and esophagus [24].
Diffuse cutaneous scleroderma is characterized by generalized skin involvement,
including the distal extremities as well as the trunk. It is rapidly progressive and is
associated with a higher risk of internal organ damage, including the lungs, heart,
kidneys, and gastrointestinal tract [25].
Raynaud’s phenomenon is a common condition observed in more than 95% of
patients. This condition is characterized by pain in response to cold and stress, secondary to vasospasms, along with triphasic color changes. There is initial pallor
with a clearly defined white demarcation followed by a dusky blue appearance due
to ischemia. In the third stage, there is red discoloration because of hyperemia.
Raynaud’s phenomenon is common in both forms of the disease [24, 26, 27].
Telangiectasias are often observed on the face, hands, and rarely on the trunk.
These blanch upon pressure. Their presence is associated with the development of
PAH. Subcutaneous calcinosis occurs due to localized deposits of calcium hydroxyapatite and typically manifests over areas prone to trauma, commonly on the extensor surface of the elbows. This predisposes the skin to infection and ulceration [28].
Arthralgia and myalgia are commonly reported symptoms by patients who have
scleroderma. Inflammatory arthritis that phenotypically resembles rheumatoid
arthritis is also seen. Interestingly, there is also evidence of SSc overlapping with
rheumatoid arthritis [29, 30].
Esophageal dysmotility due to fibrosis affects the distal two-thirds and results in
dysphagia and heartburn. The lower esophageal sphincter loses its tone, aggravating
acid reflux. Barret’s esophagus is a common complication [31, 32].
Hypothyroidism occurs in up to 15% of the patients, usually those with limited
form. The primary pathology is thought to be thyroid gland fibrosis.
Criteria
ACR published the updated classification criteria. A score of 9 or higher (counting
only higher score) indicates systemic sclerosis (Table 1).
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M. I. Ghauri and M. S. Mukarram
Table 1 2013 ACR classification criteria for systemic sclerosis [1]
Characteristics
Bilateral skin thickening proximal to metacarpophalangeal joints
Skin thickening of fingers between distal and proximal interphalangeal joints
Skin thickening of fingers or puffy fingers
Fingertip pitting scars only
Digital ulceration
Telangiectasia
Abnormal nailfold capillaries
Raynaud’s phenomenon
Lung disease, ILD
Lung disease, PAH
Positive systemic sclerosis-specific antibodies (anticentromere, anti-Scl-70, and
anti-RNA polymerase III)
Points
9
4
2
3
2
2
2
3
2
2
3
Investigations
Autoantibodies are an essential diagnostic tool in scleroderma, offering a prediction
toward the disease phenotype and prognosis [1].
(i) Antinuclear antibodies (ANAs):
ANA is detected in more than 90% of the cases through direct immunofluorescence [33].
(ii) Anticentromere antibody:
These antibodies target four centromere antigens (CENP, -B, -A, -C, -D).
These are predominantly present in limited cutaneous systemic sclerosis. They
can also be positive in other autoimmune diseases like Sjogren syndrome and
systemic lupus erythematous. The presence of these antibodies is associated
with a higher risk of pulmonary artery hypertension (PAH) [34].
(iii) Antitopoisomerase I/Scl 70 antibody:
These antibodies target the catalytic region of DNA helicase topoisomerase
I. These are predominantly observed in the diffuse cutaneous form of SSc. The
presence of these antibodies is linked to a higher risk of interstitial lung disease
(ILD) and cardiac involvement [34].
(iv) Anti-RNA polymerase III antibody:
These antibodies target the eukaryotic RNA polymerase III. These are specifically linked to the diffuse cutaneous form and associated with poor prognosis
along with renal crisis. Diseases with these antibodies have a lower risk of
PAH and ILD [35].
(v) Anti-U3-RNP antibody
These antibodies are prevalent in African Americans and are associated with an
overall poor prognosis. Their presence corresponds with increased internal
organ involvement, a diffuse cutaneous form of the disease, ILD, PAH, renal
crisis, myositis/myopathy, and cardiac complications [35].
Scleroderma
137
Other Investigations
A renal function test and a 24-h urinary protein test should be done due to the risk
of renal impairment. A complete blood count may reveal anemia that can be multifactorial [36]. Muscle enzymes may be elevated in the presence of myositis. A muscle biopsy may be warranted. X-rays of extremities can reveal calcinosis and loss of
distal phalanges. Musculoskeletal ultrasound can be done to reveal tenosynovitis.
High-resolution CT scan is the investigation of choice for ILD. Pulmonary function
tests, such as spirometry, lung volumes, and diffusion capacity, can detect a restrictive pattern of lung disease. When PAH is suspected, transthoracic echocardiography is usually performed. This may also detect any pericardial effusion if present.
In cases with esophageal and upper gastrointestinal involvement, upper gastrointestinal endoscopy, esophageal manometry, and barium swallow studies may be helpful. A characteristic finding of esophageal dysmotility is a dilated esophagus and
excessive air on a CT scan [1, 31, 37].
Complications
Gastric telangiectasias lead to gastric antral vascular ectasia, also known as watermelon stomach. This results in occult and massive gastrointestinal bleeding. Rectal
prolapse can occur due to a reduction in tone of the anal sphincter.
Pulmonary complication is a major cause of death in patients with scleroderma.
ILD and PAH are the most common pulmonary complications. ILD is more prevalent in African Americans, males, and patients with positive antitopoisomerase I
antibodies with the diffuse form of the disease. PAH can be asymptomatic or may
even lead to right heart failure. It usually occurs late in the disease, often 10 years
after the diagnosis. Its incidence is higher in cases of limited systemic sclerosis.
Patients with multiple telangiectasias and the presence of anti-U3-RNP antibodies
are at a higher risk of developing PAH. Other rare pulmonary complications may
include pulmonary hemorrhage, pleuritis, and cryptogenic organizing pneumonia
[38, 39].
Patchy myocardial fibrosis may give rise to dilated cardiomyopathy. Arrhythmias
have also been reported secondary to fibrosis within the conduction pathways [1].
Before the introduction of angiotensin-converting enzyme inhibitors (ACEi),
scleroderma renal crisis was the primary cause of death in these patients. This complication is found in approximately 10% of patients with scleroderma, mainly those
with diffuse cutaneous scleroderma. Use of high-dose or chronic low-dose corticosteroids and the presence of anti-RNA polymerase III antibodies are known risk
factors for scleroderma renal crisis. Advanced age and a serum creatinine level
greater than 3 mg/dL are indicators of poor outcomes. Clinically, this condition
manifests with new-onset hypertension or malignant hypertension along with renal
insufficiency. Hemolytic anemia and thrombocytopenia may occur due to microangiopathy [40, 41].
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M. I. Ghauri and M. S. Mukarram
Differential Diagnosis
The most common differential diagnosis of scleroderma is eosinophilic fasciitis, a
condition characterized by eosinophilic inflammation of the deep fascia, resulting in
a thick and woody induration of the lower extremities. It is differentiated from
scleroderma by the absence of Raynaud’s phenomenon and the absence of autoantibodies [42].
The other common differential diagnosis for scleroderma is scleromyxedema,
which is usually found in patients with monoclonal gammopathy or multiple
myeloma. It is characterized by papular waxy lesions on the face, neck, fingers, and
extremities, unlike scleroderma. Raynaud’s phenomenon and autoantibodies are
absent in this condition. Patients may exhibit signs of central nervous system such
as seizures and dementia. The histological findings of scleromyxedema are different
from those of scleroderma and include dermal fibrosis without perivascular inflammation [43].
A rare acquired condition that resembles scleroderma is nephrogenic systemic
fibrosis, observed in patients with end-stage renal disease who have been exposed to
gadolinium contrast. Cobblestone-like nodular plaques on extremities, trunk, hands,
and feet characterize it. The face is, however, spared. Raynaud’s phenomenon and
autoantibodies are also absent in this condition. A skin biopsy reveals dermal and
epidermal fibrosis without perivascular inflammation [1].
Treatment
Unfortunately, there is no definitive treatment for scleroderma that can alter the
course of the disease. The best strategy remains to manage the systems affected.
Patient counseling education regarding the disease and its outcomes plays an important role.
Corticosteroids are usually avoided due to the risk of precipitating renal crisis.
Out of the immunosuppressants, cyclophosphamide, mycophenolate mofetil, methotrexate, azathioprine, and hydroxychloroquine are frequently used for skin and
lung disease along with inflammatory arthritis, if present. Among the biological
agents, the use of rituximab and infliximab has limited data [1].
Patients with Raynaud’s phenomenon are advised to keep their extremities and
body warm and avoid smoking. Calcium channel blockers, such as nifedipine
(30–120 mg/day) or amlodipine (5–20 mg/day), are the first-line drugs. The aim is
to prevent digital ischemia and ulcers. Prostacyclin analogs (iloprost) and endothelin receptor antagonists (bosentan) can be used in refractory cases with digital
ulcers [44].
For pulmonary involvement in scleroderma, the only Food and Drug
Administration-approved drug is nintedanib, a tyrosine kinase inhibitor, approved
in 2019 for managing interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). Although cyclophosphamide has shown promising results, its efficacy
Scleroderma
139
diminishes by 24 months. Supplemental oxygen, diuretics, and anticoagulation are
also recommended [1].
In patients with PAH, vasodilator therapy is recommended that may include
phosphodiesterase 5 inhibitor (tadalafil 40 mg/day, sildenafil 20 mg thrice a day),
endothelin receptor antagonist (bosentan 62.5–125 mg twice daily), prostacyclin
analogs (beraprost and iloprost) [1].
Patients experiencing heartburn and acid reflux can significantly improve their
condition through lifestyle modifications. It is important to educate them about
dietary adjustments, elevating the head end of the bed, avoiding late-night large
meals, and opting for small, frequent meals. Proton pump inhibitors are the mainstay of the treatment for this issue [32]. Patients with gastroparesis may benefit from
motility agents like metoclopramide. Laser coagulation is a viable option for managing bleeding secondary to antral vascular ectasia [1].
Angiotensin-converting enzyme inhibitors are the sole effective treatment for
scleroderma renal crisis. Captopril, with its dosing flexibility, stands out as the preferred choice, offering patients a more adaptable treatment option [45].
Conclusion
Scleroderma is an autoimmune, multisystem complexed connective tissue disease
associated with significant morbidity and mortality. Pulmonary complications
(PAH/ILD), cardiac involvement, and scleroderma renal crisis are manifestations
leading to worsening of quality of life. Digital ulceration, depression, and arthritis
are frequently reported complaints by patients with scleroderma. Unfortunately,
there is no definitive treatment for this illness. However, an early diagnosis is crucial
for achieving improved outcomes.
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Polymyositis
Rajat Ranka, Venkatesh Srinivasa Pai,
and Prasan Kumar Panda
Introduction
Idiopathic inflammatory myopathies (IIMs) comprise a group of autoimmune diseases characterized by shared features of muscle weakness, typically proximal,
and muscle inflammation. The five main subtypes of IIM include dermatomyositis
(DM), polymyositis (PM), antisynthetase syndrome (ASS), immune-mediated
necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Additionally,
connective tissue disease-overlap myositis (CTD-OM) and cancer-associated
myositis (CAM) are recognized subtypes of inflammatory myositis, though they
are not considered idiopathic. These subtypes are distinguished by the presence or
absence of cutaneous manifestations, characteristic serology, and histopathological findings [1].
This chapter provides a structured overview of PM, covering its epidemiology,
risk factors, pathophysiology, clinical manifestations, diagnostic approach, therapeutic strategies, and prognosis. A synthesis of current guidelines, emerging
research, and clinical insights will be presented to support evidence-based decision-­
making in patient management.
R. Ranka · V. S. Pai
Division of Clinical Immunology and Rheumatology, Department of General Medicine, All
India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
P. K. Panda (*)
Department of General Medicine, All India Institute of Medical Sciences,
Rishikesh, Uttarakhand, India
e-mail: prasan.med@aiimsrishikesh.edu.in
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_7
143
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Epidemiology
IIM is a relatively uncommon disorder, with a reported incidence of 11 per million
person-years and a prevalence of 14 per 100,000 population in a Swedish study
[2]. As with all autoimmune diseases, there are significant regional and ethnic
variations. The incidence of PM has been reported to range between 4.1 and 7.5
cases per million per year, which is lower than that of DM [3, 4]. Over the past
few decades, our understanding of PM has evolved considerably. However, accurately determining its incidence remains challenging due to the limitations of
diagnostic criteria used in epidemiological studies. PM exhibits a slight female
predominance and is more common in individuals of African descent compared to
those of European ancestry [5]. It is primarily a disease of adulthood and is rarely
seen in children [6].
Risk Factors
The risk factors for IIM can be broadly classified as genetic and environmental
(Table 1). The role of genetic predisposition is suggested by occasional familial
clustering of cases and epidemiological associations with specific immune response
genes. Among these, the human leukocyte antigen (HLA) genes play a crucial role
in shaping T cell development, tolerance, and immune responses. In individuals of
European descent, the HLA-DRB1*0301 and HLA-DQA1*0501 alleles are the
strongest known genetic risk factors for all forms of myositis [7]. In contrast, among
individuals of African descent, HLA-DRB1*08 is the most significant risk allele,
whereas HLA-DRB1*14 appears to be protective [8]. Interestingly, no strong HLA
associations have been identified in certain populations, such as Koreans and
Mesoamericans. In PM, specific associations have been found between HLA-­
DRB1*0301, HLA-DQA1*0501, and HLA-DQB1*0201 alleles and the presence of
Table 1 Etiology of myositis
1. Genetic factors
HLA DRB1*0301
HLA-DQA1*0501
HLA-DRB1*08
2. Environmental factors
A. Infections
Viruses—influenza, SARS-Cov2, coxsackie, echoviruses, human T cell lymphotropic virus 1
Certain bacteria (Staphylococcus, Mycobacteria, Clostridia) and parasites (Toxoplasma,
Trypanosoma, Borrelia)
B. Noninfectious agents
Drugs—statins, fibrates, immune checkpoint inhibitors, TNF inhibitors
Silica exposure
Malignancy
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myositis-specific antibodies [9]. As with other complex multigenic disorders, non-­
HLA immune response genes—such as cytokine receptors, immunoglobulin (Ig)
heavy-chain allotypes, complement components (e.g., C4, C2), and T-cell receptors—also contribute to disease susceptibility [10]. However, the precise mechanisms through which these genetic factors influence disease pathogenesis remain
unclear.
Despite these genetic associations, many affected individuals lack known genetic
risk factors, and conversely, many individuals carrying predisposing genetic variants never develop myositis. This underscores the role of environmental triggers in
disease onset. Environmental factors can be further categorized into infectious and
noninfectious agents. Among infectious agents, respiratory and gastrointestinal
viruses are major contributors, as they can induce a persistent state of immune activation and chronic inflammation [11, 12]. Recently, reports linking PM to COVID-19
infection and vaccination have renewed interest in the role of viral triggers in disease pathogenesis [13].
Noninfectious environmental factors have also been implicated in PM, including
exposure to certain drugs (e.g., statins, fibrates, immune checkpoint inhibitors, and
TNF inhibitors), malignancies, dust, and smoke. However, these associations are
generally weaker compared to the well-established links between malignancy and
ultraviolet exposure with DM, smoking with anti-Jo-1-positive ASS, and statin use
with IMNM.
Pathophysiology
Myofiber damage in PM occurs through both immune-mediated (cellular and
humoral) and nonimmune mechanisms. Following skeletal muscle injury, damage-­
associated molecular patterns (DAMPs) are released, triggering the activation of
antigen-presenting cells (APCs) via Toll-like receptor (TLR) signaling in genetically susceptible individuals. These APCs, in turn, activate CD4+ T cells through
major histocompatibility complex class II (MHC-II) molecules, leading to a cascade of cellular and humoral autoimmune responses. A hallmark of PM is the overexpression of MHC class I on muscle fibers, which results in CD8+ T cell-mediated
cytotoxicity. This immune response is accompanied by the release of multiple pro-­
inflammatory cytokines, including interleukin-21 (IL-21), tumor necrosis factor
(TNF), and interferon-gamma (IFN-γ) [14].
Beyond their direct cytotoxic effects, certain cytokines such as interleukin-1
(IL-1) and interleukin-17 (IL-17) further amplify muscle damage by upregulating
nuclear factor kappa B (NF-κB), which impairs myofibril differentiation and
increases MHC class I expression [15]. Additionally, these inflammatory mediators
contribute to vascular injury, thereby exposing myofibers to further humoral immune
attacks.
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Clinical Features
Although muscle weakness and fatigue are the predominant presenting features in
most patients with IIM, it is important to recognize that these are systemic diseases
(connective tissue diseases, CTDs) with frequent multi-organ involvement. As our
understanding of IIM has evolved, the classification of myositis subtypes has
expanded, leading to a more restricted scope for PM, which is now largely considered a diagnosis of exclusion. A recent study analyzing data from 255 IIM patients,
including 37 initially classified as PM, found that only 9 (3.5%) retained their diagnosis of PM, while the remainder were reclassified into other subtypes [16]. In this
study, PM was diagnosed in cases presenting with symmetrical muscle weakness
without skin involvement, a favorable response to immunosuppressants, and an
absence of fulfilment of diagnostic criteria for other IIM subtypes.
PM typically manifests as bilaterally symmetric, progressive weakness of the
proximal girdle muscles and neck flexors, sometimes accompanied by pain. Early
involvement of hip extensors often leads to difficulty in climbing stairs or rising
from a sitting or squatting position [17]. Patients may also report difficulty with
overhead abduction and early muscle fatigability with repetitive tasks. As the disease progresses to distal muscles, fine motor activities, such as writing or playing
musical instruments, may become impaired. Systemic symptoms can include mild
fever, loss of appetite, joint pain, and weight loss. In rare cases, PM may lead to
cardiomyopathy due to myocarditis or bulbar muscle involvement, resulting in nasal
regurgitation and aspiration.
Traditionally, PM has also been associated with interstitial lung disease (ILD),
Raynaud’s phenomenon, and arthritis, particularly in individuals with anti-tRNA
aminoacyl synthetase antibodies. However, such cases are now classified under ASS
rather than PM.
A thorough physical examination should assess both motor and sensory functions. Sensory function typically remains intact, while motor assessment often
reveals reduced muscle strength. Tendon reflexes are usually preserved, except in
cases of severe muscle atrophy, which helps differentiate PM from neuropathic
weakness. Muscle strength can be systematically evaluated using scoring systems
such as Manual Muscle Testing-8 [18]. Involvement of nasopharyngeal muscles
may lead to nasal speech, while lung crackles may be heard in patients with ILD or
aspiration. If PM is associated with malignancy, cancer-specific signs—such as
lymphadenopathy in non-Hodgkin’s lymphoma—may be present. Additionally,
skin rashes, sclerodactyly, and mechanic’s hands should be carefully examined, as
they may provide the only clinical distinction between PM and other IIM subtypes.
In cases diagnosed using the ACR/EULAR classification criteria, PM is primarily a clinical diagnosis, with muscle biopsy and antibody testing serving as useful
adjuncts to differentiate it from other IIM subtypes [19]. Historically, PM and DM
were diagnosed based on the Peter and Bohan criteria (1975), with the presence or
absence of cutaneous findings being the key distinguishing factor [20].
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Complications
The inflammatory process in PM may extend to the cardiac muscles, leading to
myocarditis, which can result in dilated cardiomyopathy, heart failure, or sudden
cardiac death due to arrhythmias. Prevalence estimates vary widely, with an autopsy
study of 20 PM patients revealing histological evidence of myocarditis in 6 (30%)
cases, of whom 4 (20%) had prior symptoms of heart failure [21].
Severe PM can also cause bulbar muscle weakness, characterized by nasal regurgitation, nasal intonation, dysphagia, and aspiration. Respiratory muscle involvement may lead to respiratory failure and death. High-risk patients should undergo
regular monitoring of respiratory function, including single-breath count and
breath-holding time. Furthermore, the treatment of PM itself carries significant
risks, including infections, osteoporotic fractures, and avascular necrosis of bone.
Diagnostic Evaluation
In any suspected case of PM, a multimodal diagnostic approach—including serological tests, biochemical markers, imaging, histopathology, and electromyography—is essential. These investigations not only help differentiate PM from clinical
mimics of IIM but also aid in prognostication, treatment selection, and follow-up.
Serum Markers of Muscle Breakdown
The initial step in evaluating suspected myositis involves measuring serum markers
of muscle breakdown. Creatine kinase (CK) is the most widely used muscle enzyme
due to its superior sensitivity and specificity compared to aldolase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase
(LDH). The elevation of these enzymes also helps distinguish myositis from steroid
myopathy and neuropathic weakness [22].
At initial evaluation, CK levels are elevated in 80–90% of PM patients; however,
levels may be near normal in advanced disease due to muscle mass loss or the presence of CK inhibitors [23, 24]. While CK levels correlate with overall disease activity, they do not reliably predict an individual’s muscle strength or functional status.
They are useful for monitoring treatment response or disease flares, but fluctuations
in CK levels may occur without corresponding changes in muscle power. Therefore,
CK results should always be interpreted in the appropriate clinical context.
Importantly, CK elevation is not specific to PM and can occur in conditions such as
muscular dystrophy, hypothyroidism, and rhabdomyolysis.
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Autoantibody Testing
Multiple autoantibodies, including antinuclear antibody (ANA), myositis-specific
autoantibodies (MSA), and myositis-associated autoantibodies, may be elevated in
PM, though none are exclusive to the condition. ANA is positive in approximately
30–40% of PM patients and should be followed by testing for extractable nuclear
antigen antibodies [16, 25]. Due to variations in PM definitions across studies, the
exact prevalence of individual autoantibodies is difficult to determine.
Certain autoantibodies are specific to other IIM subtypes, such as:
• Dermatomyositis (DM): Anti-Mi2, anti-MDA5, anti-TIF1γ, anti-NXP2,
anti-SAE1
• Immune-mediated necrotizing myopathy (IMNM): Anti-HMGCR, anti-SRP
• Antisynthetase syndrome (ASS): Anti-aminoacyl t-RNA synthetase (e.g.,
anti-Jo-1)
The presence of these autoantibodies should prompt evaluation for features of
the associated IIM subtype [26].
Electromyography (EMG)
EMG is a highly sensitive but nonspecific test in PM, with nearly all patients showing myopathic abnormalities. Key abnormalities are summarized in Table 2, among
which spontaneous electrical activity correlates best with disease activity. Since PM
can have a patchy distribution, EMG also serves as a valuable guide for selecting the
biopsy site. Typically, EMG is performed on one limb, while muscle biopsy is
obtained from the contralateral limb to avoid artifact-related histopathological
changes [27].
Imaging Studies
Magnetic resonance imaging (MRI) has emerged as a crucial diagnostic tool for
myositis, with greater accuracy than computed tomography (CT) and ultrasonography. MRI is useful for distinguishing active inflammation from atrophy, guiding
Table 2 EMG findings of myositis
1. Abnormal electrical irritability
- Increased insertional activity
- Trains of positive sharp waves
- Fibrillation potentials
2. Short duration and low amplitude of motor unit potentials
3. Increased percentage of polyphasic motor unit potentials (increased polyphasia)
4. Rapid firing of the motor unit potentials in relation to the level of activity (increased
recruitment)
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biopsy sampling, and identifying features suggestive of specific IIM subtypes, such
as DM, IBM, and IMNM [28]. Additionally, MRI is expected to serve as an outcome measure in future IIM trials.
Muscle Biopsy
Although not mandatory for diagnosis, muscle biopsy is more frequently performed
in PM than in other IIM subtypes due to the absence of characteristic skin findings
or specific autoantibody associations. Histopathological findings in PM include
myofiber necrosis, regeneration, degeneration, variation in fiber diameter, and infiltration by CD4+ and CD8+ T cells, along with macrophages. A key feature is the
upregulation of MHC class I molecules on myofibers.
Endomysial mononuclear cell invasion of non-necrotic muscle fibers is characteristic of both PM and IBM, but the presence of red-rimmed vacuoles, inclusions,
and amyloid deposits distinguishes IBM from PM [29].
Additional Investigations
Additional tests should be performed based on individual patient presentations,
including:
• Pulmonary function tests and high-resolution CT (HRCT) for suspected interstitial lung disease.
• Thyroid function tests to rule out hypothyroid myopathy.
• Nailfold capillaroscopy for associated connective tissue disease features.
• Comprehensive malignancy screening, given the established association between
PM and certain cancers. Clinicians should refer to the recent guidelines from the
International Myositis Assessment and Clinical Studies (IMACS) group for the
same [30].
Management
Specific Treatment
The management of PM and other types of IIM is multidisciplinary and guided by
disease severity. As with many rare diseases, high-quality randomized controlled
trial data are lacking, and most recommendations are based on case series and expert
consensus. Treatment primarily involves pharmacotherapy (Fig. 1) and physical
therapy, which together form the foundation of disease management.
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Assess for disease severity (based on
strength, functional limitation,
dysphagia, single breath count) and
presence of ILD
Mild-moderate myositis
±
Mild-moderate ILD
Severe myositis
OR
Severe/ RP-ILD
Oral Prednisolone 0.75-1 mg/kg/day for 4-8
weeks
Give MPS pulse if severe ILD or life-threatening respiratory/
bulbar muscle involvement present; Oral Prednisolone 0.751 mg/kg/day for 4-8 weeks.
Taper prednisone with a goal of 5 mg or less
by 12 months
Slowly taper glucocorticoids to 5-10 mg/ day as per clinical
response
Add Steroid sparing agent upfront as follows
Myositis without ILD
-
Methotrexate
Azathioprine
Mycophenolate
Not Improving
Add Steroid sparing agent upfront as follows
Myositis without ILD
Myositis with ILD
-
Azathioprine
Mycophenolate
Tacrolimus
Not Improving
Switch to next level: Tacrolimus, Mycophenolate,
Rituximab, IVIg, or combinations
If progressive lung fibrosis
add anti-fibrotic
-
Mycophenolate
Tacrolimus
IVIg (as a rescue therapy)
Myositis with ILD
Induction with Rituximab
AND/OR Cyclophosphamide;
Maintenance with
Mycophenolate, Tacrolimus
or Rituximab
Not Improving
Not improving
Switch treatment to different drug or add drug for
combination or add JAK inhibitor or abatacept
If progressive lung fibrosis
add anti-fibrotic
Once patient is improving, gradually taper off steroids; taper
non-steroidal immunosuppression to lowest possible dose
Fig. 1 Pharmacotherapy algorithm of polymyositis. Abbreviations: RP rapidly progressive, ILD
interstitial lung disease, MPS methylprednisolone sodium succinate
1. Pharmacological Therapy
Glucocorticoids remain the mainstay of treatment, with initial oral prednisolone
dosed at 0.75–1 mg/kg/day for 4–8 weeks, followed by gradual tapering to <10 mg/
day at 6 months and <5 mg/day by 12 months. Every effort should be made to discontinue glucocorticoids beyond 1 year of use to minimize adverse effects.
Early initiation of steroid-sparing agents is strongly recommended [31–33]:
• Mild to moderate disease: Methotrexate, azathioprine, or mycophenolate
mofetil (MMF)
• Severe disease: MMF or tacrolimus
• Severe cases requiring induction therapy: Methylprednisolone pulse therapy
Polymyositis
151
For patients with inadequate response to first-line treatment, second-line agents
include Janus Kinase (JAK) inhibitors and abatacept [34, 35]. Rituximab is another
option, particularly in patients with anti-Jo-1, anti-Mi2 antibodies, or ILD [36, 37].
Intravenous immunoglobulin (IVIg) is an effective option for refractory or severe
disease, though its benefits are often transient, necessitating monthly infusions for
sustained efficacy [38]. Cyclophosphamide induction is now reserved for severe or
rapidly progressive ILD due to its associated toxicity.
Treatment Monitoring and Response Assessment
The steroid tapering schedule and treatment efficacy should be guided by standardized clinical outcome measures. Commonly used tools include:
• Clinical assessments: Manual Muscle Test (MMT8), Functional Index in
Myositis (FIM-3 versions), and timed functional tests (e.g., 6-min walk distance,
30-s chair stand test, Timed Up-and-Go test) [18, 39]
• Laboratory markers of disease activity: CK, LDH, AST, ALT, aldolase, and MRI
findings
Experts recommend using a combination of clinical and laboratory tools for disease monitoring. However, no head-to-head comparisons of these clinical tools
exist, so physicians may choose a system based on availability and convenience.
Managing Adverse Effects of Immunosuppression
Side effects of immunosuppression are common and should be systematically monitored at each patient visit.
• Osteoporosis prevention: PM patients face a high risk of osteoporosis due to
glucocorticoid use and reduced mobility. Routine prophylaxis with calcium
(1200 mg/day), vitamin D (800–1000 IU/day), and bisphosphonates is recommended [40].
• Steroid myopathy vs. inflammatory myositis: Chronic steroid use may lead to
steroid myopathy, which can be difficult to differentiate from persistent myositis.
Key differentiating features include:
– Normal CK levels.
– Isolated worsening of muscle strength in an otherwise quiescent disease state.
– In such cases, slow tapering of steroids with careful monitoring is advised.
• Infection prevention: Patients on long-term immunosuppression should receive
pneumocystis prophylaxis as well as age- and risk-appropriate vaccinations per
regional and international guidelines as elaborated below [41].
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2. Physical Therapy
Historically, PM/IIM patients were discouraged from exercising due to concerns
about exacerbating muscle inflammation. However, recent evidence supports personalized submaximal exercise regimens, which have been shown to [42]:
• Increase muscle fiber regeneration (type I, slow-twitch)
• Reduce muscle inflammation and fibrosis
Exercise regimens should include both aerobic and strength training components
and must be supervised by a physiotherapist to prevent muscle overuse. Specialists
would tailor exercise regimens based on disease severity and progression.
While immunosuppression and physical therapy in combination are both safe
and effective, therapy should be initiated as early as the disease condition permits.
Notably, the benefits of physiotherapy are short-term, necessitating long-term
adherence for sustained functional improvements [43].
Supportive Management
Supportive therapy plays a crucial role in PM and other IIMs to enhance treatment
outcomes, improve quality of life, and prevent complications.
1. Respiratory Support
• Patients with ILD or respiratory muscle involvement may require pulmonary
rehabilitation.
• Noninvasive ventilation (NIV) may be needed in severe cases with respiratory muscle weakness.
• Regular pulmonary function tests (PFTs) help assess lung involvement and
guide therapy.
2. Cardiovascular (CV) and Metabolic Health
• Regular cardiovascular risk assessment should be done since chronic inflammation increases CV risk (2.37 times of the general population) [44].
• Statins can be used cautiously, while closely monitoring for any worsening of
myopathy [45].
• Weight management and lifestyle modifications are essential to prevent metabolic syndrome.
3. Swallowing and Nutrition Support
• Oropharyngeal muscle weakness in PM may lead to dysphagia.
• Swallowing evaluation (by speech therapists) and modified diets can prevent
aspiration.
• Nasogastric or percutaneous endoscopic gastrostomy feeding may be required
in severe cases.
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4. Infection Prevention and Vaccination
• Immunosuppressive therapy increases infection risk; thus, appropriate vaccination is recommended [41]:
– Annual influenza vaccine
– Pneumococcal vaccines (PCV13, PPSV23)
– Varicella zoster vaccine
– Hepatitis B vaccine if at risk
– COVID-19 vaccination and boosters as per guidelines
• Prophylaxis against Pneumocystis jirovecii pneumonia with trimethoprim-­
sulfamethoxazole (TMP-SMX) should be initiated in patients on prolonged
immunosuppression (>20 mg/day prednisolone equivalent for more than a
month and any additional potent immunosuppressant) [46].
5. Mental Health and Psychosocial Support
• Chronic disease and disability increase the risk of anxiety and depression.
• Counselling and support groups can improve coping strategies.
• Cognitive therapy is recommended for patients with fatigue-related cognitive
dysfunction.
6. Cancer Screening
• PM has a higher malignancy risk, requiring age-appropriate cancer screening
(as per IMACS guidelines). Risk factors include male sex, age at onset
>40 years, moderate to severe dysphagia, and immunosuppression-resistant
disease [30].
• CT scans, tumor markers, and endoscopic evaluations may be considered
based on risk factors.
Compared to other IIMs, certain therapeutic considerations are particularly relevant to the PM subtype. PM frequently requires early and aggressive use of steroid-­
sparing agents such as methotrexate, azathioprine, or MMF to achieve disease
control. Tacrolimus has shown particular efficacy in PM patients with refractory
muscle involvement or ILD. In cases resistant to conventional treatment, rituximab
is often effective, especially in seropositive patients. PM may respond well to
aggressive immunosuppression, but it often requires prolonged therapy to maintain
remission.
Prognosis
PM is a chronic condition with a substantial long-term impact, carrying an estimated 10% mortality rate, primarily due to malignancy and pulmonary complications. While the majority of patients respond to glucocorticoids, only 20%
achieve sustained, medication-free remission. Poor prognostic factors include
refractory disease, age >50 years, female sex, Black ethnicity, and systemic
involvement [47].
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Recent Advances
CD19-targeting CAR-T cell therapy has recently emerged as a breakthrough in the
treatment of refractory systemic autoimmune diseases. This approach involves the
use of genetically modified T cells to eliminate autoreactive B cells by targeting the
CD19 molecule on B cell lineage cells. Emerging reports have documented successful use of CAR-T cell therapy in treatment-resistant IIM, and a Phase II clinical trial
is currently underway [48]. JAK inhibitors, including tofacitinib and baricitinib,
have shown promise in case reports and small studies for refractory PM by modulating the JAK-STAT pathway, which plays a central role in myositis-­related inflammation. Some patients have achieved steroid-free remission with JAK inhibitors,
positioning them as a potential second-line therapy [34].
Artificial intelligence (AI)-driven MRI analysis is enhancing the differentiation
of PM from other IIM subtypes and helping distinguish active inflammation from
chronic muscle damage [49]. Therapeutic plasma exchange (TPE) has been explored
in cases of refractory PM, particularly in patients with rapidly progressive interstitial lung disease (RP-ILD) or severe dysphagia [50]. Additionally, altered gut
microbiota composition has been linked to IIM pathogenesis, suggesting a role in
immune dysregulation [51]. Future research is likely to explore microbiome-­
targeted therapies, including probiotics and fecal microbiota transplantation (FMT),
as potential adjunct treatments for immune modulation.
Conclusions
Polymyositis (PM) is a chronic, systemic autoimmune disease associated with significant morbidity. Once considered a prominent subtype of idiopathic inflammatory myopathies (IIM) alongside dermatomyositis (DM), its classification has
become increasingly restricted with the identification of myositis-specific autoantibodies and related subtypes such as immune-mediated necrotizing myopathy
(IMNM) and antisynthetase syndrome (ASS). As a result, PM is now regarded as a
diagnosis of exclusion. Despite its evolving classification, PM remains a clinically
significant entity that imposes a substantial burden on patients, necessitating a multidisciplinary approach to evaluation and management. Long-term immunosuppressive therapy is often required, warranting careful monitoring for drug-related
complications. Therefore, comprehensive patient counseling is essential following
diagnosis to ensure adherence to treatment including physical therapy and mitigate
potential adverse effects.
Polymyositis
155
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Juvenile Dermatomyositis
Mehmet Orhan Erkan , Ozlem Necipoglu Banak ,
and Seza Ozen
Introduction
Idiopathic inflammatory myopathies (IIMs), collectively known as myositis, encompass a diverse spectrum of muscle diseases characterized by chronic inflammation
and progressive muscle weakness. While dermatomyositis (DM), polymyositis
(PM), and inclusion body myositis (IBM) are the predominant subtypes observed in
adults, JDM represents the most common form encountered in pediatric patients.
Epidemiology
JDM is a rare autoimmune disease in childhood, with an incidence of approximately
1.9–4.1 cases per 1,000,000 children per year. The frequency of the disease may
vary across geographical regions and ethnic groups [1–3]. From a gender perspective, JDM is slightly more common in girls than boys, with an overall female-to-­
male ratio of approximately 2.3:1 [3, 4]. Although the mean age at onset is
approximately 7 years, large cohort studies report that a significant proportion present before the age of 4. A recent study of 286 patients found that 25% exhibited
symptoms before age 4. Early-onset JDM is suggested to be associated with more
severe clinical features and poorer prognosis [5].
M. O. Erkan · O. N. Banak · S. Ozen (*)
Division of Pediatric Rheumatology, Department of Pediatrics, Faculty of Medicine,
Hacettepe University, Ankara, Turkey
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_8
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M. O. Erkan et al.
Etiology and Pathogenesis
While the precise triggers of disease in JIIM are still not fully understood, recent
studies have suggested the involvement of novel or interrelated mechanisms affecting the skin, vasculature, and muscle. These potential pathways are explored in
more detail in this section (Figs. 1, 2, 3, and 4).
Genetic Background
JDM develops through the interaction of complex genetic and environmental factors. Although familial transmission is rare, certain genetic variants linked to autoimmune diseases contribute to its pathogenesis. The human leukocyte antigen
(HLA) system, essential for immune regulation, is a major determinant of genetic
susceptibility. Specific HLA class I and II alleles, particularly HLA-DRB103, HLA-­
DQA105, HLA-DQB102, and the ancestral haplotype HLA-B08–DRB103:01–
DQA105:01–DPB1*01:01, have been strongly associated with increased risk [6–8].
A 2022 international genetic study on JDM using dense exome single nucleotide
polymorphism (SNP) genotyping identified a strong association between the HLA-­
DRB1*03:01 allele and the 37th amino acid position of HLA-DRB1 [9].
Additionally, the HLA-DRB1*03-DQA1*05-DQB1*02 haplotype has been
associated with more severe clinical manifestations and heightened autoimmune
activity in affected patients [10]. HLA variants may trigger exaggerated immune
responses to environmental factors such as viral infections or UV radiation, promoting T cell-mediated autoantigen attacks and chronic inflammation. Additional
genetic polymorphisms regulating autoimmunity have also been identified in
JDM. The tumor necrosis factor alpha (TNF-α) gene, a key mediator of inflammation, has polymorphisms like TNF-α G308A and TNF-α-238GG, which are
Fig. 1 Both MHC and
non-­MHC genetic loci
have been associated with
increased susceptibility
and pathogenesis of the
disease
Juvenile Dermatomyositis
161
Fig. 2 Environmental
factors potentially
contributing to the onset of
juvenile idiopathic
inflammatory myopathies
include ultraviolet
radiation, hormones,
climate changes,
environmental pollutants,
and microbial infections
associated with increased autoimmune risk and muscle damage in JDM patients
[11, 12]. IFN-related gene expression profiles indicate markedly elevated type I IFN
responses in JDM, highlighting the role of immune dysregulation. The STAT4 gene,
critical for immune regulation, is associated with enhanced inflammation in
JDM. Similarly, the PTPN22 C1858T polymorphism is a major genetic risk factor
for autoimmune diseases, including JDM. Associations with genes such as TYK2,
UBE2L3, and BLK have also been identified in JDM [13, 14].
Environmental Factors
Environmental factors can lead to excessive activation of the immune system and
trigger autoimmune processes. Viral infections, ultraviolet (UV) radiation exposure,
climate changes, hormones, and environmental toxins are the primary external factors influencing the development and severity of JDM [15].
Infections play a significant role in the pathogenesis of many autoimmune diseases. In JDM, viral or bacterial exposures prior to disease onset or flare-ups are
commonly reported. Viruses such as Epstein-Barr virus (EBV), parvovirus B19,
coxsackievirus, influenza virus, and adenoviruses can trigger excessive immune
responses, initiating autoimmunity [5, 16–18]. Viruses may contribute to JDM
pathogenesis through molecular mimicry or by stimulating immune cells to overproduce cytokines such as IFN, TNF-α, and interleukin (IL)-6, leading to chronic
inflammation. Infections with Group A Streptococcus, Borrelia burgdorferi, and
Toxoplasma have also been linked to JDM [17, 19]. Some patients have presented
with myositis following SARS-CoV-2 infection or vaccination against SARS-­
CoV-­2, but causality awaits confirmation by larger epidemiological studies [20, 21].
Exposure to UV radiation has been implicated in the onset and exacerbation of
JDM. Epidemiological studies have demonstrated that diagnoses of JDM are more
frequent during the spring and summer months [22]. Gottron’s papules, heliotrope
rash, and V-shaped chest rash typically appear on sun-exposed areas [23–25]. UV
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Fig. 3 Depicts the immunopathogenesis of juvenile dermatomyositis, highlighting complement
activation, endothelial damage, and immune cell infiltration. Immune complexes and cytokines
induce adhesion molecule expression (VCAM-1, ICAM-1, E-selectin), promoting recruitment of
CD4+ T cells and pDCs. The lower panel shows perivascular inflammation in muscle tissue,
reflecting the vasculopathic nature of JDM
radiation contributes to DNA damage in skin cells and increased autoimmune activation, which can exacerbate JDM [26].
Studies reported that JDM is more frequently observed in children living in
colder climates. Vitamin D deficiency can impair immune system regulation,
increasing susceptibility to autoimmune diseases. Some studies suggested that JDM
incidence is higher in regions with lower vitamin D levels [25, 27].
Environmental toxins, including pesticides, heavy metals, and organic solvents,
may contribute to immune overactivation and JDM development. Secondhand
smoke exposure enhances pro-inflammatory responses, increasing JDM risk.
Pesticide exposure, particularly in children from agricultural regions, has been associated with a higher incidence of autoimmune diseases [28].
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Fig. 4 Types of interferon (IFN) signaling Type 1 IFN signaling is considered a key contributor to
the pathological alterations observed across multiple tissue types
Since JDM is more commonly observed in girls, female sex hormones have been
suggested to contribute to an increased risk of autoimmune diseases [29, 30]. The
pubertal period can lead to a more aggressive disease course in JDM patients, suggesting that hormonal changes influence immune system activity and the progression of JDM [31].
Immunological Mechanisms
The core immunopathological features of JDM involve dysregulation of innate and
adaptive immunity, cytokine disturbances, production of disease-specific autoantibodies, and prominent vascular inflammation. The innate immune system plays a
central role, with a marked increase in type I IFN (IFN-α and IFN-β) responses [19].
Viral infections, such as EBV, parvovirus B19, and coxsackievirus, can excessively
activate this IFN pathway [32]. In JDM, activated macrophages accumulate in muscle and vascular endothelium, intensifying inflammation [33]. Elevated proinflammatory cytokines, including TNF-α, IL-1, and IL-6, contribute to muscle fiber
damage, necrosis, and vasculitis [11].
In JDM, plasmacytoid dendritic cells (pDCs) are increased in muscle and skin
lesions, presenting autoantigens to activate T cells and recognizing viruses via TLR-9
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to initiate immune responses [34–36]. pDCs, the primary producers of type I IFNs,
promote dendritic cell maturation and T cell activation. Aberrant adaptive immune
activation leads to autoantibody production and T cell–mediated inflammation [37,
38]. CXCR5+ TFH cells in JDM preferentially differentiate into TH2 and TH17 lineages, promoting B cell activation and pro-inflammatory responses, with TH17 polarization noted across DM subtypes. Inflamed muscle tissue shows infiltration by
inflammatory T cells, activated B cells, and macrophages, with CD4+ T cells secreting
cytokines like TNF-α and IFN-γ to amplify inflammation [39, 40]. Type I IFNs further
enhance B cell proliferation and autoantibody generation [41–43].
A distinct type I IFN gene expression signature has been identified in the muscle
tissue and peripheral blood of JDM patients. Elevated serum IFN-α activity, particularly in newly diagnosed, treatment-naïve cases, underscores its role in early pathogenesis [41–44]. Muscle biopsy analyses also show increased IFN-γ expression and
upregulation of IFN-γ–responsive genes in JDM compared to muscular dystrophy
and healthy controls, suggesting its role in maintaining muscle inflammation [45].
JDM is characterized as an autoimmune vasculopathy affecting both muscles
and blood vessels. Autoimmune targeting of endothelial cells increases vascular
permeability, resulting in edema and muscle ischemia. Nailfold capillary abnormalities, including capillary loss and dilation, serve as early markers of vascular
inflammation [44]. Microvascular inflammation restricts oxygen supply to muscle
tissues, resulting in necrosis of muscle fibers.
Chimerism
Chimerism refers to the coexistence of genetically distinct cell populations within
an organism. Maternal chimerism, the persistence of maternal cells in offspring, has
been implicated in JDM pathogenesis [46].
Maternal cells may be recognized as foreign, triggering T cell activation and
abnormal immune responses. Elevated maternal DNA levels have been detected in
the muscle and PBMCs of JDM patients compared to controls. Maternal cells may
promote autoimmunity by enhancing type I and II IFN responses, stimulating autoantibody production, and targeting endothelial cells, thereby exacerbating muscle
ischemia and vascular inflammation [46, 47].
Clinical Manifestations
JDM is characterized by proximal muscle weakness and distinctive cutaneous manifestations, including heliotrope rash, Gottron’s papules, photosensitivity, and periungual
capillary abnormalities. Some patients develop vasculopathic ulcers and soft tissue calcifications. Beyond skin and muscle, JDM may involve multiple organ systems, leading
to arthritis, dysphagia, ILD, and cardiac complications. Disease onset can be acute, subacute, or insidious, with considerable variability in severity and course among individuals (Fig. 5). The frequency of clinical symptoms is summarized in Table 1.
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165
Constitutional Symptoms and Signs
Constitutional symptoms, common in early JDM, include fatigue, subfebrile fever,
and weight loss. Fatigue often precedes muscle weakness, impairing daily activities
and academic performance. Fever, linked to muscle inflammation and vasculitis,
may mimic viral infections and delay diagnosis. Chronic inflammation, malabsorption, and increased metabolic demands contribute to weight loss, with long-term
disease potentially leading to growth retardation and developmental delays [48].
Fatigue and the chronic nature of JDM can cause irritability, depression, and difficulty concentrating in affected children. Mood changes related to corticosteroid
therapy are also common. Sleep disturbances and anxiety may develop over the
long-term course of the disease [49, 50].
Musculoskeletal Disease
Proximal muscle weakness and myositis are hallmark musculoskeletal features of
JDM. Myositis leads to muscle fiber degeneration, predominantly affecting the hips,
shoulders, and neck, and causing difficulty with walking, climbing stairs, and lifting
arms. Early weakness is typically symmetrical and progressive, with Gowers’ sign
often present. Without timely treatment, persistent inflammation may cause fibrosis,
contractures, and irreversible functional deficits [51, 52].
Fig. 5 Symptoms of juvenile dermatomyositis
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M. O. Erkan et al.
Table 1 Frequencies of clinical features of pediatric patients with juvenile dermatomyositis [3,
63, 65, 80–84]
Clinical feature
Constitutional symptoms and signs Fatigue
Fever
Weight loss
Lymphadenopathy
Musculoskeletal disease
Muscle weakness
Muscle pain or tenderness
Arthritis
Contractures
Mucocutaneous disease
Heliotrope rash
Gottron papules
Photosensitive rash
Malar rash or facial erythema
Periungual nailfold capillary changes
V sign or shawl sign
Raynaud phenomenon
Cutaneous ulceration
Calcinosis
Lipodystrophy
Mechanic hands
Cardiopulmonary involvement
Cardiac involvement
Lung involvement
Gastrointestinal disease
Dysphagia or dysphonia
Gastrointestinal symptoms
At presentation (%)
82–100%
9.5–36%
9.5–61%
23–25%
81.4–95%
48–90%
16–49%
59.9–73%
63–90.4%
29%
55–79%
35–68%
2.6–31%
1.7–28%
4.3–23%
1.9–25%
1.7–4%
11%
1.7–25%
0.9–36.7%
10.3–45%
13–25%
Approximately 50–75% of JDM patients experience joint involvement (arthralgia and arthritis). Joint involvement is typically symmetrical and affects large joints
(knees, elbows, shoulders, and wrists). Inflammatory joint involvement is usually
temporary and does not cause permanent damage, but in chronic cases, joint deformities may develop [53]. Tenosynovitis may also be observed in JDM patients.
JDM can negatively impact skeletal development, particularly in patients with
long-term disease progression and those receiving corticosteroid treatment. Chronic
inflammation negatively affects muscle and bone development, leading to skeletal
deformities such as scoliosis [54, 55].
Mucocutaneous Disease
Mucocutaneous involvement is a key clinical feature of JDM, critical for assessing
disease severity and prognosis [37, 56]. Cutaneous manifestations including heliotrope rash, Gottron papules, V-sign, shawl sign, ulcerations, nailfold capillary
changes, and calcinosis (Figs. 6, 7, 8, 9, and 10) result from vascular inflammation
and autoimmunity. The heliotrope rash appears as violaceous eyelid discoloration
with periorbital edema, while Gottron papules present as erythematous to
Juvenile Dermatomyositis
167
Fig. 6 V-sign
Fig. 7 Calcinosis and skin
ulceration
violaceous lesions over metacarpophlangeal (MCP) and proximal interphalangeal
(PIP) joints, often extending to extensor surfaces [37, 57, 58]. Nailfold capillary
abnormalities, such as dilated capillaries, dropout, and hemorrhages, reflect smallvessel vasculopathy [59, 60]. Calcinosis is characterized by the dystrophic deposition of calcium hydroxyapatite in the skin, soft tissues, or muscles. It is more
commonly found at pressure points such as the elbows, knees, and buttocks,
although it can occur anywhere on the body. Calcinosis, involving dystrophic calcium deposition in skin and soft tissues, usually develops later in the disease course.
It can present in different forms, including:
• Superficial plaques or nodules (“calcinosis superficialis”).
• Deep and localized calcifications (“calcinosis circumscripta”).
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M. O. Erkan et al.
Fig. 8 Loss of capillary
density accompanied by
dilated and abnormally
tortuous capillaries
Fig. 9 Gottron’s papule
• Diffuse deposits along tendons or muscles (“calcinosis universalis”).
• Extensive exoskeleton-like calcium deposits.
Calcinosis can lead to functional limitations due to associated pain, skin ulcers, and
joint contractures [61, 62]. Lipodystrophy is observed in approximately 3–10% of
patients with JDM and involves a gradual loss of subcutaneous fat, which may be
either localized or widespread. This condition is linked to several metabolic disturbances, including insulin resistance, hyperlipidemia, acanthosis nigricans,
Juvenile Dermatomyositis
169
Fig. 10 Mechanic hand
hirsutism, abnormal fat distribution, polycystic ovary syndrome, and nonalcoholic
steatohepatitis. Inflammation and injury of muscle tissue may result in the loss of
insulin receptors, contributing to the onset of lipodystrophy [63–67].
Cardiopulmonary Involvement
In JDM, cardiac involvement may affect the myocardium, pericardium, and coronary vessels. The Single Hub and Access point for Paediatric Rheumatology in
Europe (SHARE) initiative recommends echocardiography (ECHO) and electrocardiogram (ECG) at diagnosis [68, 69]. Chronic inflammation can cause myocarditis,
pericarditis, and conduction abnormalities, detectable via troponin, BNP, and imaging [70, 71].
Although ILD is rare, it is a severe complication, particularly associated with
anti-MDA5 antibodies, and carries high mortality in East Asian populations [70,
71]. High resolution computed tomography (HRCT) and pulmonary function tests
are advised for early diagnosis [69].
Diaphragmatic weakness, aspiration pneumonia, and alveolar hypoventilation
can further compromise respiratory function. Given these risks, a multidisciplinary
approach is essential for management.
Other Manifestations
Gastrointestinal (GI) involvement in JDM, though rare, may present as abdominal
pain, ulceration, or bleeding, with severe vasculopathy leading to mortality in some
cases [72, 73]. Early symptoms require close monitoring. Neurological complications, including seizures, neuropathy, depression, and rare brainstem infarctions,
have been reported [74, 75]. Renal involvement is uncommon but may manifest as
glomerulonephritis, nephrotic syndrome, or IgA nephropathy; most cases respond
to standard JDM therapy [76–78]. Ocular involvement affects about half of patients,
typically presenting as heliotrope rash, blepharitis, or corticosteroid-induced cataracts, warranting regular ophthalmologic evaluations [79].
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Classification and Diagnostic Criteria
The criteria defined by Bohan and Peter in 1975 are considered a classical approach
in the diagnosis of JDM and other inflammatory myopathies [85]. The Bohan and
Peter criteria, developed to differentiate DM from other myopathies in both adults
and children, remain widely used. Diagnosis certainty is based on the combination
of clinical signs and symptoms. Five main criteria are evaluated: a definitive diagnosis requires characteristic skin manifestations (heliotrope rash, Gottron’s papules) plus at least three of the following: proximal muscle weakness, elevated serum
muscle enzymes, electromyographic (EMG) evidence of chronic inflammatory
myositis, and muscle biopsy consistent with inflammatory myopathy. A “probable”
JDM diagnosis is made if typical skin rash and two criteria are present. MRI, commonly used in pediatric assessments, is not included in the Bohan and Peter criteria.
In 2017, the European League Against Rheumatism (EULAR) and the American
College of Rheumatology (ACR) introduced new criteria for a more objective diagnosis and classification. The 2017 EULAR/ACR system uses a scoring algorithm
based on clinical and laboratory findings, allowing standardized JDM diagnosis
with or without muscle biopsy, with each parameter assigned a score to determine
the likelihood of JDM or another IIM subtype. The total score correlates with the
probability of an IIM diagnosis as follows:
<5.3: suggests a non-myositis diagnosis
5.3–5.5: 50–55% probability of IIM (possible IIM)
5.5–7.5: 55–90% probability of IIM (probable IIM)
≥7.5: 90% or greater probability of IIM (definite IIM)
For patients evaluated without a muscle biopsy, a minimum score of 5.5 suggests
inflammatory myopathy, while a score of ≥7.5 confirms a definite diagnosis. In
patients with a muscle biopsy, a score of ≥7.5 confirms a definite myositis diagnosis. This scoring system is highly effective in defining inflammatory myopathies
such as DM and PM in both adult and pediatric patients. These criteria were tested
in 976 patients with IIM and 624 patients without myositis. The study results demonstrated that the EULAR/ACR criteria have high sensitivity and specificity:
Without muscle biopsy: sensitivity: 87%, specificity: 82%.
With muscle biopsy: sensitivity: 93%, specificity: 88%.
These findings suggest that the EULAR/ACR criteria provide a more precise and
reliable classification method than the Bohan and Peter criteria. Additionally, incorporating myositis-specific autoantibodies (MSA) into the diagnostic process further
enhances the accuracy of these criteria. While a muscle biopsy is not required for a
definite diagnosis, biopsy results improve diagnostic accuracy [69].
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Laboratory Examination/Investigations
Muscle Enzymes
Laboratory evaluation in JDM typically shows elevated serum muscle enzymes,
including creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and aldolase, which indicate
muscle damage and inflammation. Aldolase may be more sensitive than CK in some
cases. About 90% of JDM patients have elevated muscle enzyme levels, which are
used to monitor disease activity. However, some patients with active disease may
present with normal enzyme levels, and normal values do not exclude active inflammation. Moreover, initial enzyme elevations do not necessarily predict disease progression or prognosis.
Other Biomarkers
JDM patients can be monitored using various biomarkers assessing diagnosis,
inflammation, vascular damage, immune response, fibrosis, and muscle degradation. Complete blood count may reveal leukocytosis, lymphopenia, anemia due to
chronic inflammation, and thrombocytosis from vascular inflammation and endothelial activation. Erythrocyte sedimentation rate (ESR) and C-reactive protein
(CRP) reflect inflammation but may remain normal in JDM patients. Soluble thrombomodulin (sTM) and CD163, if available, can indicate endothelial damage and
vascular inflammation in JDM [86, 87]. JDM is characterized by excessive activation of IFN pathways. The IFN signature has been observed in most JDM patients
and serves as an indicator of disease severity and autoimmune activity.
Autoantibodies
JDM is an autoimmune inflammatory myositis associated with various autoantibodies that help define disease subtypes, associations with other connective tissue diseases, prognosis, and related complications. These autoantibodies are classified into
two main groups: MSA and myositis-associated autoantibodies (MAA). Below, all
autoantibodies associated with JDM, along with their mechanisms of action, targets, and clinical correlations, are detailed (Table 2).
Myositis-Specific Autoantibodies
Anti-Mi-2
Mi-2 protein is a nuclear helicase involved in DNA transcription regulation, chromatin remodeling, and gene expression control. It also influences immune regulation and cell growth. Through transcriptional regulation, Mi-2 ensures normal gene
function [88, 89].
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Table 2 Main clinical associations of myositis-specific and myositis-associated autoantibodies in
children
Autoantibody Target antigen
Myositis-specific autoantibodies
Anti-Mi-2
NuRD (nucleosome
remodeling and
deacetylase) complex
Anti-NXP-2 Nuclear matrix protein 2
(NXP-2)
Anti-TIF-1γ Transcriptional-­
intermediary factor 1
gamma (TIF-1γ)
Prevalence
(%)
Clinical manifestations
15–20%
15–25%
17–35%
Anti-MDA5
6–38%
Melanoma-­
differentiation-­
associated protein 5
(MDA5)
0.3–9.1%
Anti-SAE
Small ubiquitin-like
modifier activating
enzyme (SAE)
Immune-mediated necrotizing myopathy
Anti-SRP
Signal recognition
1.6–4%
peptide (SRP)
Anti-­
HMGCR
3-hydroxy-3-­
methylglutarylcoenzyme A reductase
(HMGCR)
1.1%
Prominent skin findings (heliotrope
rash, Gottron’s papules), moderate
muscle involvement, good prognosis
Severe muscle weakness, widespread
calcinosis, aggressive disease course
Unlike adult-onset IIM, malignancy is
not associated with childhood cases.
Anti-TIF1 antibodies are more prevalent
in children, who also show V-sign less
frequently than adults
Severe interstitial lung disease, skin
ulcers, mild muscle involvement,
aggressive course
Anti-SAE antibodies are rarely found in
JIIM, making the clinical features and
treatment response poorly characterized
Although anti-SRP antibody-positive
IIM is less common in children than
adults, the clinical phenotype is largely
similar. Compared to adult-onset cases,
children exhibit lower rates of
palpitations and mortality, but may
present with greater distal weakness,
muscle atrophy, and frequent falls.
While younger patients might
experience a more severe disease
course, overall mortality remains lower
in childhood-onset disease
This subtype is uncommon in JIIM but
exhibits a phenotype similar to
adult-onset IIM. Children, typically
statin-naïve, may have a worse
prognosis, with cutaneous involvement
more frequently observed
(continued)
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Table 2 (continued)
Autoantibody Target antigen
Anti-synthetase autoantibodies
Anti-Jo-1
Histidyl-tRNA
synthetase
Anti-PL-7
Threonyl-tRNA
synthetase
Anti-PL-12
Alanyl-tRNA synthetase
Anti-EJ
Glycyl-tRNA synthetase
Anti-OJ
Isoleucyl-tRNA
synthetase
Anti-KS
Asparaginyl-tRNA
synthetase
Anti-Zo
Phenylalanyl-tRNA
synthetase
Myositis-associated autoantibodies
Anti-PM/Scl PM/Scl complex protein
Prevalence
(%)
Clinical manifestations
1–5%
<1%
<1%
<1%
<1%
<1%
Although this subtype presents with a
similar clinical phenotype in both
juvenile and adult-onset forms, it is
significantly less common in children.
Core clinical features such as Raynaud’s
phenomenon, mechanic’s hands, and
ILD are observed less frequently in
juvenile-onset cases compared to those
with adult-onset disease
<1%
3–5%
Anti-Ku
Ku DNA-binding protein 5–10%
Anti-Ro52
Ro52 protein
6–14%
Anti-U1-­
RNP
U1-ribonucleoprotein
4–5.6%
Polymyositis-scleroderma overlap
syndrome, muscle and skin involvement
Associated with mixed connective tissue
disease, mild muscle involvement
Frequently observed in myositis
patients, these findings are often
associated with other myositis-specific
autoantibodies (particularly anti-Jo-1
and anti-MDA5) and are commonly
linked to overlap syndromes
Mixed connective tissue disease,
vascular complications
Anti-Mi-2 autoantibodies disrupt gene expression in muscle cells, impairing
protein synthesis and cellular function, and promote inflammation through macrophage and T cell-mediated muscle damage [90]. They are commonly associated
with classic JDM phenotype, characterized by cutaneous manifestations such as
heliotrope rash, Gottron’s papules, and nailfold capillary abnormalities [91, 92].
Although patients may experience moderate, progressive proximal muscle weakness and risks like dysphagia or edema, the disease generally responds well to
treatment and severe complications are rare. Unlike other autoantibodies, antiMi-2 is not strongly linked to ILD, and its presence is associated with a more
favorable prognosis [19].
Anti-NXP-2
NXP-2 (nuclear matrix protein 2) regulates gene expression, chromatin dynamics,
and nuclear organization, and it is essential for muscle development, regeneration,
and calcium metabolism. Anti-NXP-2 autoantibodies disrupt gene expression and
calcium distribution in muscle cells, leading to abnormal calcium deposition and the
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formation of calcinosis plaques in skin and muscle tissues. Anti-NXP-2 autoantibodies impair muscle regeneration, exacerbate inflammation, and promote chronic
weakness and atrophy. While not strongly associated with ILD, this autoantibody is
linked to severe JDM, characterized by early-onset, widespread muscle weakness,
and significant physical disability [93, 94].
Anti-TIF-1 γ
TIF-1γ (transcription intermediary factor 1 gamma), a member of the TRIM protein
family, regulates DNA transcription, cellular differentiation, immune responses,
and it is involved in tumor suppression and oncogenesis. It functions in muscle,
skin, and connective tissue by controlling cell growth, differentiation, and DNA
repair, and also modulates immune system activity [95–97]. The development of
anti-TIF-1γ autoantibodies activates intracellular stress pathways, triggering inflammation and apoptosis in muscle tissue, leading to damage. Muscle and skin manifestations are often severe, with frequent findings including Gottron’s papules,
heliotrope rash, and red plaques. There is a high risk of skin necrosis and ulceration,
requiring aggressive treatment [52, 91, 92, 98, 99].
Anti-MDA5
Melanoma differentiation-associated protein 5 (MDA5) is a cytoplasmic RNA helicase crucial for innate immune responses. As part of the RIG-I-like receptor (RLR)
family, it detects cytoplasmic double-stranded RNA (dsRNA), initiating antiviral
signaling and promoting IFN-α and IFN-β production. MDA5 serves as an essential
immune regulator against viral infections under normal conditions [100–103]. In
JDM, excessive production of anti-MDA5 autoantibodies leads to uncontrolled
immune activation. MDA5 protein promotes the production of type I IFNs (IFN-α,
IFN-β) and type III IFNs (IFN-λ) [104]. JDM patients with anti-MDA5 autoantibodies exhibit heightened IFN responses, leading to excessive inflammation and
immune overactivation. These autoantibodies target small vessels, causing vasculitis, tissue necrosis, and skin ulcers. They also promote severe lung inflammation,
contributing to ILD, which may progress to fibrosis and respiratory failure if not
promptly diagnosed. Notably, muscle involvement is generally milder compared to
classic JDM [92, 105, 106].
Anti-SAE
SAE1 and SAE2 (small ubiquitin-like modifier activating enzyme) are enzyme
complexes involved in intracellular protein regulation via the ubiquitin-proteasome
system (UPS). The ubiquitin system is essential for maintaining protein homeostasis and controlling cellular stress responses [107–109]. Anti-SAE autoantibodies
bind to the SAE1/SAE2 complex, disrupting protein homeostasis and triggering
autoimmune processes in muscle cells, leading to cellular stress, inflammation, and
apoptosis. Muscle involvement is typically mild and progresses slowly. Skin
involvement is more significant. There is no strong association with ILD, and severe
pulmonary complications are rare. Anti-SAE positive patients generally respond
well to immunosuppressive therapy, with a favorable long-term prognosis [19,
92, 110].
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Anti-Synthetase Autoantibodies
Anti-synthetase autoantibodies target tRNA synthetase enzymes, impairing protein
synthesis and inducing muscle cell dysfunction, inflammation, and fibrosis [111,
112]. These autoantibodies define anti-synthetase syndrome (ASS), characterized
by myositis, ILD, arthritis, Raynaud’s phenomenon, and mechanic’s hands, reflecting a multisystemic presentation [92, 113]. Though rare in JDM, ASS cases may
exhibit severe myositis and ILD, with lung involvement assessed via HRCT, PFTs,
and diffusion capacity testing (DLCO) [114–117]. Proximal muscle weakness,
inflammatory arthritis, and cutaneous features like photosensitive rashes and
mechanic’s hands are common, and ILD can progress to respiratory failure [52, 118].
I mmune-Mediated Necrotizing Myopathy (Anti-SRP
and Anti-HMGCR)
Anti-SRP and Anti-HMGCR autoantibodies, part of the MSA group, are associated
with immune-mediated necrotizing myopathy (IMNM). Although rare in JDM, they
are linked to severe, rapidly progressive, and treatment-resistant muscle weakness.
Unlike classic JDM, significant skin involvement is uncommon, and widespread
muscle necrosis is prominent [119, 120].
Anti-SRP autoantibodies target the signal recognition peptide (SRP), which
plays a crucial role in protein synthesis and transport within muscle cells [121].
These autoantibodies are associated with severe, rapidly progressive necrotizing
myopathy and often show resistance to corticosteroid and immunosuppressive therapy [122]. These patients have the highest CK levels among myositis subtypes, typically ranging between 5000 and 15,000 U/L. Corticosteroids alone are often
insufficient, necessitating the use of potent immunosuppressive agents such as
MTX, azathioprine (AZA), mycophenolate mofetil (MMF), or rituximab [123].
Anti-HMGCR autoantibodies, associated with IMNM, target HMGCR, a key
enzyme in cholesterol biosynthesis. While statin use can trigger this autoimmune
response, anti-HMGCR myositis can also occur in statin-naïve individuals. These
autoantibodies disrupt lipid metabolism, impair energy production, and cause metabolic stress, leading to muscle necrosis. Statin therapy should be discontinued if
present. Aggressive treatment and long-term rehabilitation are often necessary to
preserve muscle function [123–125].
Myositis-Associated Autoantibodies
JDM is a chronic autoimmune disease marked by muscle inflammation and vasculopathy. Some patients also exhibit MAA alongside MSA, influencing disease progression, organ involvement, and prognosis, particularly regarding vascular
complications, ILD, and skin involvement. Anti-PM/Scl autoantibody is associated
with polymyositis-scleroderma overlap in JDM, leading to scleroderma-like skin
thickening, vasculopathy, lipoatrophy, and calcinosis, and may increase ILD risk
with a slowly progressive course. Anti-Ku, primarily linked to mixed connective
tissue disease (MCTD), can also appear in JDM, often associated with mild muscle
involvement but a higher risk of arthritis, Raynaud’s phenomenon, and ILD [92].
Anti-Ro52 can enhance inflammatory processes in JDM and trigger vascular
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inflammation. Skin involvement may be pronounced, and pulmonary hypertension
should be carefully evaluated. The presence of this autoantibody may increase the
risk of ILD and be associated with a more treatment-resistant form of JDM [91,
126]. Anti-­U1-­RNP may increase the risk of vascular inflammation and Raynaud’s
phenomenon in JDM. It is found in JDM-MCTD overlap cases and may be associated with ILD [127].
Electromyography
EMG is used to assess muscle involvement and myopathy in JDM by measuring
muscle electrical activity. It helps detect myositis, fiber inflammation, and functional abnormalities. In JDM, EMG typically reveals findings consistent with
inflammatory myopathy, such as increased spontaneous activity (fibrillation potentials, sharp waves), indicating muscle fiber excitability due to inflammation and
damage. EMG alone is insufficient for diagnosis and should be interpreted alongside muscle biopsy, MRI, and laboratory tests. In cases of mild inflammation, EMG
findings may be normal. Performing EMG in pediatric patients can be challenging
due to procedural anxiety [37, 128].
Muscle Biopsy
Muscle biopsy is a critical diagnostic tool in JDM, aiding in disease identification,
activity assessment, and differentiation from other muscle disorders. It reliably
demonstrates muscle fiber inflammation, vascular changes, and autoimmune-­
mediated tissue damage, ensuring accurate diagnosis.
Key histopathological findings in JDM biopsy include muscle fiber degeneration
and regeneration, necrosis, perivascular inflammation, capillary loss, and endothelial proliferation. Characteristic features are perifascicular atrophy, muscle fiber size
heterogeneity, and prominent perivascular inflammation [129]. In JDM, CD4+ T
cells, macrophages, and pDCs accumulate perivascularly, while B cell infiltration is
minimal. Vasculopathy is a hallmark feature, characterized by capillary loss, endothelial proliferation, and vascular wall thickening. Markers such as von Willebrand
factor (vWF), CD31/CD34, and C5b-9 complement staining are used to evaluate
vascular inflammation and endothelial injury [130, 131].
A hallmark of JDM is upregulated major histocompatibility complex (MHC)
Class I expression in muscle cells, reflecting their recognition as autoimmune
targets. Increased expression of IFN-α/β-inducible myxovirus resistance A
(MxA) protein is also notable, with MxA staining correlating with disease activity [43, 132]. Biochemical and immunohistochemical analyses, such as CD4/
CD8 T cell staining, CD68 macrophage markers, and mitochondrial function
staining (SDH, COX), enable detailed assessment of muscle inflammation and
alterations in energy metabolism [133, 134].
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Muscle biopsy aids in distinguishing JDM from PM, metabolic myopathies, and
neurogenic disorders. Nonetheless, biopsy is essential for early diagnosis and disease monitoring in JDM, and its diagnostic accuracy improves when combined with
MRI and EMG [37, 135].
Radiological Examination
Radiological imaging is essential for diagnosing JDM, assessing disease activity,
and monitoring treatment response. MRI is the most sensitive modality for detecting muscle inflammation, while USG offers a fast, non-invasive alternative. CT and
X-rays are used to evaluate lung involvement and soft tissue calcinosis.
Plain radiographs effectively detect and assess calcinosis and can screen for pulmonary abnormalities; if ILD is suspected, HRCT provides more detailed evaluation. Muscle USG, a non-invasive and cost-effective tool, detects muscle
inflammation, edema, atrophy, and fatty infiltration. Active inflammation appears as
increased echogenicity and reduced muscle volume, while chronic phases show
atrophy and fibrosis. Calcinosis is seen as hyperechoic foci with posterior acoustic
shadowing. USG findings correlate with disease activity and reflect both acute and
chronic muscle changes [136, 137].
MRI has become a key tool for diagnosing JDM and assessing myositis activity,
offering the advantage of avoiding ionizing radiation in pediatric patients and evaluating muscle inflammation without intravenous contrast. T2-weighted and fat-­
suppressed sequences, especially STIR (short tau inversion recovery), are highly
sensitive for detecting soft tissue edema and inflammatory changes. Elevated signal
intensity on STIR images indicates inflammation and edema, while T1-weighted
sequences are used in chronic stages to detect muscle atrophy and fatty infiltration
(Figs. 11 and 12) [138]. As proximal muscles are predominantly affected in JDM,
MRI commonly targets the pelvis and thighs to detect active disease and guide
biopsy, reducing false negatives [138, 139].
Fig. 11 The radiograph of an 8-year-old boy with juvenile dermatomyositis shows calcium
deposits in both cheeks, the submental area, the supraclavicular region, and the thigh
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b
c
Fig. 12 Coronal STIR (a), T1W (b), and axial T2 weighted fat-saturated (c) images show generalized myofascial edema of whole pelvic and thigh muscles consisted with myositis and fasciitis.
Extensive subcutaneous soft tissue edema is seen as reticular intensitites. There is no muscle atrophy
The juvenile dermatomyositis MRI score (JIS) is a novel MRI-based scoring
system specifically developed for JDM to objectively assess muscle inflammation
activity in pediatric patients [135]. This system quantifies disease extent and severity by evaluating the degree of inflammation, the volume of affected muscle, and the
presence of intramuscular and perifascicular edema, generating a score ranging
from 0 (normal) to 100 (severe disease).
Differential Diagnosis
JDM diagnosis is straightforward in patients with proximal muscle weakness and
characteristic skin rash. However, in the absence of typical skin findings, differential diagnosis becomes challenging. Muscle weakness must be distinguished from
other IIMs, infectious myopathies, muscular dystrophies, metabolic and endocrine
myopathies, drug-induced myopathies, and malignancies (Table 3).
Amyopathic DM shares characteristic skin findings such as Gottron’s papules
and heliotrope rash but lacks significant muscle involvement. Juvenile PM presents
with progressive muscle weakness but lacks the distinctive skin lesions of JDM [127].
JDM may present with clinical features overlapping those of other autoimmune
diseases, complicating diagnosis. Differentiation from overlap myositis associated
with JSLE, juvenile systemic sclerosis, or MCTD is particularly challenging due to
shared features such as muscle weakness and skin involvement. JSLE typically
involves renal pathology and arthritis, while MCTD is marked by Raynaud’s phenomenon and anti-U1-RNP positivity. Autoantibody profiling supports diagnosis:
anti-Mi-2, anti-NXP-2, and anti-TIF-1γ are associated with JDM; ANA and anti-­
dsDNA with SLE; and anti-U1-RNP with MCTD [127].
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Table 3 Differential diagnosis of juvenile dermatomyositis
Amyopathic
dermatomyositis
Juvenile polymyositis
Myositis with other
connective tissue
diseases (overlap
myositis)
Duchenne muscular
dystrophy
Becker muscular
dystrophy
Congenital myopathies
Viral myositis
Bacterial myositis
Fungal myositis
Parasitic myositis
Metabolic myopathies
Endocrinological
disorders
Mitochondrial
myopathies
Toxins
Drug-induced
myopathies
Malignancy-associated
dermatomyositis
Juvenile systemic lupus erythematosus, juvenile systemic sclerosis,
mixed connective tissue disease
Nemaline myopathy, central core disease, congenital fiber-type
disproportion
Influenza virus, enterovirus, EBV, coxsackievirus, human
immunodeficiency virus, adenovirus, parvovirus B19, dengue virus
Staphylococcus aureus, Streptococcus pyogenes
Candida species, Aspergillus species, Cryptococcosis, histoplasmosis
Trichinella spiralis (trichinosis), Toxoplasma gondii, Cysticercosis
Glycogen storage diseases (Pompe disease, McArdle disease, Cori
disease), lipid storage disorders (carnitine palmitoyltransferase II
deficiency, primary carnitine deficiency, multiple Acyl-CoA
dehydrogenase deficiency, myoadenylate deaminase deficiency,
phosphofructokinase deficiency, acid maltase deficiency, lactate
dehydrogenase deficiency
Hypothyroidism, hyperthyroidism, Cushing syndrome,
hyperparathyroidism, hypoparathyroidism, diabetes
Kearns-Sayre syndrome, MELAS syndrome (mitochondrial
encephalopathy, lactic acidosis, stroke-like episodes), MERRF
syndrome (myoclonic epilepsy with ragged red fibers)
Organophosphates, heavy metals (lead, mercury), alcohol
Corticosteroids, statins, hydroxychloroquine
Acute lymphoblastic leukemia, neuroblastoma, rhabdomyosarcoma-­
associated myositis
JDM can also be confused with genetic muscle disorders such as Duchenne and
Becker muscular dystrophies (DMD and BMD), which are characterized by progressive proximal muscle weakness and may mimic JDM [139]. DMD and BMD
are genetic dystrophinopathies lacking inflammatory features. Diagnosis is supported by family history and male predominance. DMD presents at 2–3 years with
muscle weakness and calf pseudohypertrophy; BMD has later onset. CK levels in
DMD are markedly elevated (>10,000 U/L), while JDM shows moderate, variable
elevations due to inflammation. Unlike JDM, DMD, and BMD lack skin involvement, and biopsy reveals degeneration, regeneration, and dystrophin deficiency
without inflammation.
Congenital myopathies present at birth with marked hypotonia and lack inflammatory features. Conditions such as nemaline myopathy, central core disease, and
congenital fiber-type disproportion are characterized by structural abnormalities on
muscle biopsy and are non-autoimmune in nature [140, 141].
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The differential diagnosis of JDM should consider infectious myositis, common
in children and caused by viral, bacterial, fungal, or parasitic agents. Viral myositis—often from influenza, enteroviruses, EBV, coxsackievirus, or parvovirus B19—
may mimic JDM with muscle pain and elevated CK, but is usually self-limiting. In
contrast, JDM is a chronic inflammatory disease with persistent systemic features
[142–145]. Bacterial myositis, commonly caused by Staphylococcus aureus or
Streptococcus pyogenes, typically presents with fever, severe muscle pain, and possible abscess formation. Muscle biopsy shows neutrophilic infiltration, in contrast
to the lymphocytic infiltration seen in JDM [37, 146]. Parasitic myositis should be
suspected in individuals with a history of consuming contaminated food, eosinophilia, or recent travel to endemic areas [142].
JDM may resemble metabolic and endocrine myopathies, complicating early
diagnosis. Differential diagnoses include glycogen storage diseases (e.g., Pompe,
McArdle, Cori), lipid metabolism disorders (e.g., CPT II deficiency, primary carnitine deficiency, MADD), and mitochondrial myopathies (e.g., MELAS, Kearns-­
Sayre, MERRF), which present with muscle dysfunction and distinct metabolic
abnormalities on biopsy [37, 147].
Endocrine disorders such as hypothyroid myopathy, hyperthyroidism, Cushing’s
syndrome, hyperparathyroidism, and diabetes can cause muscle weakness. However,
unlike JDM, these conditions do not involve muscle inflammation, and diagnostic
evaluation should include thyroid function tests, serum electrolytes, fasting glucose,
or hormone levels [145].
Toxin and drug-induced myopathies should be considered in JDM differential
diagnosis. Agents like organophosphates, heavy metals, alcohol, corticosteroids,
statins, and hydroxychloroquine (HCQ) can cause muscle damage without
inflammation; biopsy typically shows myofibril loss and mitochondrial changes.
Malignancy-associated DM, though rare in children, may mimic JDM and is
linked to malignancies such as ALL, lymphoma, neuroblastoma, and rhabdomyosarcoma. Muscle involvement is often paraneoplastic, with atypical rashes,
lymphadenopathy, or splenomegaly; malignancy should be suspected in atypical
presentations [145].
Treatment
JDM treatment is complex and varies by clinician, institution, and country, reflecting the disease’s rarity, heterogeneous clinical presentation, and the absence of
standardized management protocols [68]. In recent years, various efforts have
been made to develop evidence-based guidelines aimed at standardizing the clinical management and treatment strategies for these patients [148]. The importance
of multidisciplinary, personalized approaches in managing pediatric JDM is
increasingly recognized. This model integrates individualized pharmacological
therapy, pain management, early intensive physiotherapy, psychological support,
patient adherence, functional preservation or restoration alongside remission, and
improved participation in education, career, and daily activities [68, 149]. Early
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intervention and timely treatment initiation are essential to prevent irreversible
soft tissue and organ damage and to improve quality of life. Initial treatment decisions are guided by clinical presentation, including severe organ involvement,
ulcerative skin lesions, extensive calcinosis, pulmonary involvement, and marked
muscle weakness [149].
Clinical guidelines support healthcare providers in managing and monitoring JDM. In 2010 and 2012, the Childhood Arthritis and Rheumatology
Research Alliance (CARRA), a North American pediatric rheumatology consortium, developed treatment plans stratified by disease severity [150, 151]. In
2016 and 2017, these treatment plans were expanded to include the management of skin involvement as well [152, 153]. The SHARE published its evidence-based and consensus-driven recommendations in 2017 after conducting
a systematic literature review [154]. Since 2012, these recommendations have
been shaped through expert consensus among pediatric rheumatologists. In
parallel, Paediatric Rheumatology International Trials Organisation (PRINTO)
has emphasized treatment response evaluation, developing guidelines to assess
therapeutic efficacy and disseminate updated data on disease management
advancements [155, 156].
Pharmacological treatments include glucocorticoids, disease-modifying anti-­
rheumatic drugs (DMARDs), and biological agents. Alternative treatment options
for severe disease course and complications of JDM patients are summarized in
Fig. 13. Supportive treatments involve sun protection, physical therapy, and psychological support.
Fig. 13 Alternative treatment options for severe disease course and complications of JDM
patients. JDM juvenile dermatomyositis, JAK Janus kinase, IVIG intravenous immunoglobulin,
MMF mycofenolate mofetil, TNF tumor necrosis factor. (Adopted from Refs. [68, 154, 160,
262–264])
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Pharmacological Treatments
Corticosteroids
High-dose glucocorticoids are the mainstay of both induction and maintenance
therapy in JDM, though optimal dosing and duration remain undefined. Treatment
strategies vary across guidelines. SHARE and PRINTO recommend initiating therapy in newly diagnosed patients with intravenous methylprednisolone (IV MP)
(15–30 mg/kg/day, up to 1 g/day) for 3 days, followed by oral prednisone at 1–2 mg/
kg/day (maximum 60 mg/day), tailored to clinical status [154, 157]. In a treatment
study conducted by CARRA, for patients with moderate disease, prednisone is initiated at 2 mg/kg/day (maximum 60 mg/day), while in severe cases, IV MP is preferred [151]. Despite this, a separate study found no superiority of IV MP over oral
prednisone therapy [158].
Another topic that arises regarding intravenous therapy is the clinician’s concern
about GI absorption of oral corticosteroids [154]. In JDM patients with severe GI
involvement—particularly GI vasculopathy with thrombus formation and vascular
occlusion—oral prednisolone absorption may be impaired. Consequently, intravenous methylprednisolone is often preferred in such cases [159].
The optimal tapering strategy for glucocorticoid therapy. Clinical improvement
remains the primary determinant guiding dose reduction [149, 154, 157]. According
to the 2019 PRINTO study, following initial pulse therapy, prednisolone is initiated
at 2 mg/kg/day. If clinical assessment tools (DAS, CMAS, MMT) show ≥50%
improvement within 2 months, tapering to 1 mg/kg/day is recommended. At months
2 and 4, a ≥ 20% improvement allows reduction to 0.5 mg/kg/day. After maintaining this dose for at least 2 months, tapering to 0.2 mg/kg/day—safer for growth—is
advised between months 6 and 12. Further tapering to 0.1 mg/kg/day may occur
after month 6, aiming for complete discontinuation by 18–24 months [157].
According to CARRA recommendations, with adequate clinical control, tapering to
0.2 mg/kg/day of prednisone may be achieved within 9 months. High-dose prednisone is maintained during the first month post-diagnosis, followed by biweekly dose
reductions until 0.5 mg/kg/day is reached, then tapered further based on monthly
clinical evaluations [150].
Combination therapy with MTX or cyclosporine A is more effective for disease
control than the use of glucocorticoids alone. Due to the side effects and safety
profile of cyclosporine A, the combination of (MTX) and prednisone is generally
favored in treatment [160]. Combining glucocorticoids with a DMARD reduces
dependency on steroids and results in fewer side effects [149]. Achieving remission
without steroids is only possible with the addition of a DMARD or other immunosuppressive agents to the treatment regimen.
Methotrexate
MTX is a commonly used corticosteroid-sparing DMARD in DM. It is initiated at
diagnosis, administered orally or preferably subcutaneously at 15–20 mg/m2/week
(maximum 40 mg/week). Approximately 70% of patients respond favorably; treatment intensity should be reassessed based on response within the first 12 weeks
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[154, 161]. The combination of MTX and prednisone is more commonly preferred
over cyclosporine A–prednisone due to the need for careful monitoring of side
effects and drug levels [161]. MTX typically shows its therapeutic effect within the
first 3 months of initiation and is evaluated for treatment continuity in the first year
following steroid tapering [154, 160]. In one study, 13% of patients required a
change in therapy due to MTX-related side effects [162]. MTX toxicity generally
presents as cytopenia or elevated liver enzymes (more than twice the normal
level) [163].
MTX may cause side effects such as immunosuppression, hepatotoxicity, and GI
symptoms including nausea and vomiting. Folic acid supplementation (1 mg/day or
≥ 5 mg/week) is routinely used to mitigate folate-related adverse effects, such as
anemia and mucosal ulcers [164, 165]. In patients who develop intolerance to MTX
therapy, treatment is switched to other DMARDs such as cyclosporine A, MMF, or
AZA [166]. MTX therapy may not produce an adequate response in all patients. In
cases of severe disease, the addition of intravenous immunoglobulin (IVIG) should
be considered, and in patients with predominant skin findings, HCQ may also play
a role in disease management [153, 162, 166]. Other options include cyclophosphamide (CYC), tacrolimus, HCQ, and biological agents [167].
Cyclosporine A
The efficacy of dual therapy with cyclosporine A and corticosteroids is higher than
corticosteroids alone [154]. However, side effects such as hypertension, hirsutism,
hypertrichosis, and abdominal pain limit its use. In a study by Ruperto et al., adverse
events involving the skin, subcutaneous tissue, and GI system were more frequent
in patients receiving prednisone plus cyclosporine compared to those on prednisone
alone or with MTX. Infection rates were also higher with combination therapy than
with prednisone monotherapy [160]. According to PRINTO recommendations, the
primary indication for cyclosporine use is intolerance to MTX therapy [157, 168].
The standard dosage is 3–5 mg/kg/day, with serum level monitoring required. The
optimal serum level is 90–150 ng/mL [152].
Mycophenolate Mofetil
MMF is generally used as a second-line treatment in JDM, particularly when MTX
causes side effects or intolerance [166]. It is recommended for both muscle and skin
involvement, including calcinosis [154]. Its growing use in ILD management is
promising [169]. MMF is favored in non-severe lung involvement due to its effect
on improving FVC and stabilizing DLCO. In patients receiving MMF, steroid
dependency is resolved more quickly [170].
Azathioprine
Although AZA is not frequently used in children, it is preferred in cases of MTX
intolerance and treatment resistance [37, 154, 167]. The dosage is 1–3 mg/kg/day
[149]. Based on early side effects and response, dose escalation is considered, with
optimal improvement after 6–8 weeks. Side effects include hepatotoxicity, nausea,
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vomiting, bone marrow suppression, and increased infection risk [171]. AZA is
preferred in pregnant patients or those planning pregnancy due to its safety profile
[172]. It is used as a corticosteroid-sparing agent and improves FVC and DLCO. In
major organ involvement like pulmonary disease, MMF is favored over AZA due to
fewer adverse effects [170].
Intravenous Immunoglobulin
IVIG is a secondary treatment in JDM, used in steroid and MTX-resistant patients
or those with severe skin involvement [154, 173]. Its minimal improvement rate is
higher than placebo, with effects seen around day 35, including improved muscle
strength, skin resolution, and reduced disease activity [174]. IVIG acts by inhibiting
membrane attack complex formation, inactivating C3, modulating cytokines and
chemokines, reducing endogenous immunoglobulin, and lowering autoantibody
levels [173, 175]. Side effects are most common in the first 3 days and include headache, flu-like symptoms, fever, nausea-vomiting, and rarely aseptic meningitis
[176–178]. Both JDM and IVIG pose a thromboembolic risk, therefore close monitoring is needed [174, 179, 180].
Patients with severe skin involvement and anti-TIF1-γ antibodies respond better,
while those with lung involvement show lower response. However, after skin
improvement, response differences by antibody status diminish [181]. IVIG is beneficial in moderate-to-severe disease with muscle involvement and dysphagia [37,
161]. CARRA recommends 2 g/kg (max 70 g), three doses every 2 weeks, then
monthly [152]. In a trial by Aggarwal et al., 2 g/kg was given every 4 weeks for
16 weeks [176].
Cyclophosphamide
CYC is an immunosuppressive agent used in many autoimmune diseases [177].
Because of its toxicity, it is rarely used in JDM. It is effective for rapidly progressive, treatment-resistant, and life-threatening cases. EULAR recommends
500–750 mg/m2 doses biweekly or monthly [182].
In ILD patients with anti-MDA5, combination therapy with tacrolimus, CYC,
and corticosteroids showed improvement at 6 and 12 months [183]. A review highlighted the efficacy of combining CYC with calcineurin inhibitors in DM-ILD with
this autoantibody [184]. Before treatment, CBC, renal function, and vaccine status
(especially hepatitis B) should be assessed. Opportunistic infections (e.g., CMV)
may trigger ILD flares, so prophylaxis and monitoring are essential [183]. Common
side effects include cytopenia, nausea, hepatotoxicity, hair loss, hemorrhagic cystitis, allergic reactions, dyspnea, and infertility (2%). Some clinicians advocate for
gonadal protective measures [185]. In addition, pregnancy screening is necessary
before starting treatment [186].
Hydroxychloroquine
HCQ may be used as secondary treatment in DM with mild-to-moderate skin and
mild muscle involvement. It can be given as monotherapy, combined with MTX, or
as triple therapy with MTX and corticosteroids [152]. Compared to MTX, it has
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more frequent cutaneous side effects, requiring monitoring when used alone. Side
effect frequency decreases with age but increases with prolonged use and overdose
[187, 188]. Some reports note skin worsening during treatment [189]. Some autoantibodies may raise the risk of HCQ-related skin flares—anti–SAE-1/2 increases
risk, while anti-MDA5 is linked to lower risk [190].
Although HCQ’s exact mechanism in DM is unclear, it likely reduces B cell
activation, antibody production, proinflammatory cytokines, classical complement
activity, and neutrophil extracellular traps [191–193]. The therapeutic dose is
3–5 mg/kg/day, up to 400 mg/day [149, 153]. Major long-term risks are ocular and
cardiac toxicity [188]. Eye accumulation increases with high doses and long-term
use, especially above 5 mg/kg/day, and may cause severe vision loss or blindness.
Retinopathy can progress up to 6 months after discontinuation [194]. Use beyond
5 years and over 5 mg/kg/day are key risk factors. Annual ophthalmologic screening
is recommended [195].
acrolimus and Calcineurin Inhibitors
T
Calcineurin inhibitors are among the topical treatment options; however, these therapies are often insufficient for pruritus, and systemic treatment is usually required
[196]. Systemically, they act as glucocorticoid-sparing agents. In treatment-­resistant
DM, especially with ILD, they significantly reduce CK levels and improve FVC,
relieving muscle and lung symptoms. Renal function and blood pressure should be
monitored during treatment [197]. Other side effects include tremor, gynecomastia,
infection risk, and hypomagnesemia [198]. The starting dose is 0.075 mg/kg/day or
1–3.5 mg/day, titrated to maintain a serum level of 5–20 ng/mL [197].
nti-Tumor Necrosis Factor Agents
A
According to CARRA recommendations, anti-TNF alpha therapies like adalimumab and infliximab are options for recurrent mild-to-moderate disease [152].
SHARE recommends etanercept less frequently [154], though a 2024 review of 495
patients showed its high use in resistant and recurrent JDM. Infliximab has been
effective for calcinosis, while adalimumab improves skin lesions [199]. Larger studies are needed to assess treatment response. Rituximab, abatacept, and tocilizumab
are also alternative biologics for refractory cases [200].
Abatacept
Abatacept, a recombinant CTLA4 fusion protein that inhibits T-cell activation, is
increasingly used in DM patients as a glucocorticoid-tapering agent [199]. Case
series report reduced muscle edema and improved disease activity scores [201]. It
may also help treat refractory calcinosis [202]. It is administered at a dose of 10 mg/
kg: the first three doses are given every 2 weeks, followed by maintenance doses
every 4 weeks [203].
Rituximab
Rituximab is used in refractory and advanced-stage disease, with responses typically seen within 6 months [154, 167]. It is the most commonly used biologic,
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mainly for severe skin and muscle involvement, as well as complications like recurrent disease, GI, and pulmonary involvement. Response rates exceed 60% [199].
Among biologics, rituximab has the highest rate of adverse effects [199, 204].
Common side effects and adverse events include widespread skin rash, hypotension, anaphylactic reactions, urinary tract infections, cellulitis, herpes infections,
and pneumonia [205–207]. Infusion-related events are the most frequent and concerning [208–210]. In a randomized controlled trial including 152 adult polymyosi
tis/dermatomyositis (PM/DM) patients and 48 JDM patients, over 80% showed
improvement [211]. Better responses are seen with anti-Mi-2 positivity and high
type I IFN expression [212, 213]. Rituximab is usually given at 375–500 mg/m2 per
dose, weekly or biweekly. Adults may tolerate up to 750 mg/m2. Some studies used
500 mg weekly or 1000 mg biweekly [214]. Low-dose regimens (e.g., 100 mg/
week) have been suggested, especially for anti-MDA5–positive patients, to slow
disease progression [215].
Janus Kinase İnhibitors
In JDM, a heightened type I IFN response leads to endothelial damage, prompting
interest in Janus Kinase (JAK) inhibitors for advanced disease [216]. Tofacitinib,
ruxolitinib, and baricitinib have been used for multi-organ involvement. Commonly
preferred for skin disease, JAK inhibitors also improve muscle activity scores.
Though not first-line, they are options for complications like severe skin ulcers,
calcinosis, ILD, arthralgia, and GI involvement [217, 218]. Their use is recommended in combination therapy rather than as monotherapy. They are recommended
as part of combination therapy. Notably, in adults, CDASI scores improve; in JDM,
MMT-8 scores show significant gains [217].
Tofacitinib has been shown to downregulate genes involved in viral infection
pathways. It carries an increased risk of herpes zoster infection [219, 220]. Therefore,
symptoms should be closely monitored and antiviral precautions considered [221].
Although most patients receive concurrent immunosuppression, an open-label study
showed JAK inhibitor monotherapy can be effective [159]. Many patients were able
to reduce or stop corticosteroids, supporting the role of JAK inhibitors in DM. While
no JAK inhibitor is specifically approved for DM or JDM, their clinical use has
increased. Available options include baricitinib (a JAK1/2 inhibitor), upadacitinib (a
JAK1 inhibitor), and tofacitinib (a JAK1/2/3 inhibitor) [74]. In a 2024 clinician-­
based evaluation, baricitinib was suggested to be potentially more effective than
MTX in the treatment of JDM; however, considerable uncertainty regarding its use
was noted [222].
Non-pharmacological Treatments
un and UV Protection
S
UV radiation is known to influence the development and clinical features of DM
[15, 223]. In JDM, sunscreen use (SPF ≥30), sun avoidance, and protective clothing
are recommended [154, 166]. Sunscreens help reduce both skin and muscle
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involvement [161]. In a 2020 study by Parks et al., examining the relationship
between UV exposure and DM, it was found that this association was more significant in women, with sunburns being a more frequent contributing factor; whereas in
men, occupational UV exposure showed a stronger correlation. Individuals with
lower sun sensitivity and a tanning tendency had higher DM risk, associated with
inadequate sun protection [224]. UV exposure has also been associated with antiTIF-1γ, anti-­NXP-­2, and anti-Mi-2 autoantibodies [26, 225, 226].
Vitamin D
Serum 25-hydroxyvitamin D deficiency is implicated in the pathogenesis of DM, as
in other autoimmune diseases such as Sjögren’s syndrome, SLE, and Graves’ disease [223]. One study identified IL-37 as a potent inducer of active vitamin D, with
elevated IL-37 levels in vitamin D deficiency and in the muscle tissue of PM and
DM patients. Both IL-37 and vitamin D play roles in the type I IFN pathway [227].
Vitamin D supplementation is widely recommended, and higher serum levels are
considered potentially protective in DM [166, 228].
Physical Therapy and Exercise
Physical therapy and aerobic exercise improve aerobic capacity and muscle strength,
reduce expression of inflammation-related genes, and increase expression of genes
linked to capillary growth, mitochondrial biogenesis, and muscle hypertrophy
[229]. A meta-analysis identified benefits after a minimum 12-week aerobic program, including improved lung capacity, muscle strength, quality of life, and
reduced disease activity. Exercise is recommended even during active disease
[229–231]. Physical therapy helps prevent complications of a sedentary lifestyle,
such as obesity, cardiovascular disease, and hyperlipidemia [149]. Exercise is also
emphasized as important in managing lipodystrophy, which is one of the complications resulting from long-term steroid use in patients with JDM [68].
Psychological Support
The burden of disease can be exhausting for both the patient and their caregivers.
Inability to carry out daily activities independently, school absenteeism, challenges
in peer relationships, frequent hospital visits, and anxiety related to the illness are
among the main factors contributing to this demanding process [68]. Anxiety and
depression are common, yet access to psychological support is often limited by time
and location [232, 233]. Additionally, the transition from pediatric to adult services
in childhood-onset disease supports a patient-centered treatment approach, with
trust transferred from pediatric to adult providers, facilitating continued follow-up
and treatment. The trust established with the pediatrician is transferred to the adult
physician during this transition, making it easier to continue and complete the
patient’s follow-up and treatment [234].
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Complications and Management
Calcinosis and Management
Patients with DM should be specifically evaluated for calcinosis during physical
examination. Plain radiographs that allow screening of the entire body can be useful
for clinicians in this regard [154]. Anti-NXP-2 autobody is common in childhood-­
onset disease and associated with severe calcinosis [57]. Although no standardized
protocol exists, treatment varies by patient. Common agents affecting calcium-­
phosphorus metabolism include bisphosphonates, calcium channel blockers, and
sodium thiosulfate [235, 236] Immunomodulatory therapies—particularly IVIG,
glucocorticoids, and MTX—are increasingly used. Other options include anti-TNF
agents, MMF, calcineurin inhibitors, and tocilizumab [149, 236]. Approximately
40% of patients with calcinosis show no response to biological agent therapies
[199]. Although not considered a first-line treatment option, some clinicians recommend surgical excision of calcinosis if the anatomical location is suitable, if there is
inadequate response to treatment, or if the lesions cause significant pain and limitation of movement [236]. In one review, it was noted that calcium supplements used
for osteoporosis prophylaxis may exacerbate dystrophic calcification, suggesting
dietary intake and supplementation with magnesium and zinc as preferable alternatives [237].
Lung Disease and Management
Respiratory system involvement may present with either a restrictive or obstructive
pattern due to lung parenchymal involvement or weakness of accessory respiratory
muscles. In the early stage of the disease, such involvement is associated with poor
prognosis [68, 154, 238]. Respiratory symptoms at diagnosis may indicate an irreversible course [68]. Impaired pulmonary function and progressive ILD are strongly
linked to anti-MDA5 positivity [239–241]. In this subtype, progressive fibrosis can
develop within 6 months, and findings such as traction bronchiectasis, bronchiolectasis, ground-glass opacities, or reticulation—particularly traction bronchiectasis—
are associated with rapid progression [242]. The level of anti-MDA5 autoantibody
may serve as an indicator of disease activity [149]. Amyopathic DM is another
high-risk group for ILD, where symptoms such as hypoxemia may precede muscle
involvement, with frequent anti-MDA5 positivity [243, 244]. In rapidly progressive
ILD, JAK inhibitors like tofacitinib have shown favorable outcomes in recent case
reports [245, 246].
Tofacitinib is considered for early addition in high-risk ILD cases, particularly in
anti-MDA5–positive, hypoxemic patients with elevated ferritin who are unresponsive to prior therapies [247]. Rituximab and the antifibrotic agent nintedanib have
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also shown efficacy in treatment-resistant cases [184]. Some clinics report improved
prognosis with initial triple therapy combining tofacitinib, rituximab, and plasma
exchange [248]. In advanced stages, lung transplantation has been attempted with
venovenous ECMO support during transition [249, 250]. A 2025 validation study
assessed the 2017 EULAR/ACR criteria for anti-MDA5–positive DM, noting
reduced sensitivity due to exclusion of extra-muscular involvement like ILD and
suggested improved classification if MSA were included [240].
Cardiac Involvement, Cardiovascular Events, and Management
Cardiac involvement may be present at diagnosis or develop later [251]. The
SHARE guidelines recommend that all newly diagnosed patients be evaluated with
ECHO and ECG at diagnosis [154]. Although rare, cardiac involvement in DM is
linked to high morbidity and mortality. A retrospective review reported a cardiac
involvement rate of 9% in DM patients [252]. The most frequently observed events
were non-specific cardiac arrhythmias, impaired myocardial perfusion, and pericardial effusion. In these reviews conducted with JDM and IIM patients with cardiac
involvement, a positive association was found between cardiac manifestations and
the presence of anti-SRP and anti-MDA5 autoantibodies [251, 252].
In a cohort study covering inflammatory myopathies, the rate of cardiovascular
events was found to be 15%, with the most common being ischemic heart disease,
stroke, and venous thromboembolism. Other cardiovascular complications, more
common in adults, include hypertension, atherosclerosis, coronary artery disease,
and metabolic syndrome [251].
When examining the underlying factors, increased body fat ratio, lower muscle
mass, insulin resistance, high serum triglyceride levels, and low HDL cholesterol
levels in these patients have been associated with cardiometabolic risks and
increased cardiovascular disease risk [253]. Monitoring pro-BNP and troponin levels is important for cardiac assessment [252]. Cardiac MRI is among the most sensitive and specific tools for evaluating cardiac involvement [251]. In treatment, a
combination of glucocorticoids and immunosuppressive biological agents is frequently recommended [252]. In severe myocarditis, high-dose steroids with CYC
reduce inflammation and improve cardiac function [254]. Additionally, in milder
cases, MTX, IVIG, and HCQ are used alongside or as alternatives to steroid therapy
[255]. Rituximab is less commonly prescribed [256]. Lack of regular cardiologic
evaluation may lead to missed subclinical involvement and increased heart failure
risk [252]. Management should include cardiovascular screening, risk factor assessment, and early preventive measures such as diet and exercise. While statins are
used, caution is advised due to potential statin-associated myopathies [257].
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Venous Thromboembolism and Management
Venous thromboembolism risk affects the prognosis of patients with DM [179]. Key
contributing factors include abnormal inflammatory responses in vasculopathy,
increased procoagulant activity, and suppressed fibrinolysis. However, exact mechanisms remain unclear due to disease pathogenesis and medication side effects. A
meta-analysis has shown that the risk ratios for deep vein thrombosis and pulmonary embolism are elevated [258]. This complication is more likely to occur within
the first year following diagnosis [180]. Regular glucocorticoid therapy and monitoring of D-dimer levels during the acute phase are recommended to reduce risk.
Prophylaxis against thromboembolism is not routinely recommended but considered individually [259].
Gastrointestinal Involvement and Management
The presence of aspiration, coughing during chewing, nasal speech, and dysphagia
indicates severe disease. GI vasculopathy may cause malabsorption, intestinal
ulceration, abdominal pain, vomiting, constipation, hematemesis, and bloody stool
[68, 154]. GI perforations are life-threatening with high mortality. Anti-NXP-2
autoantibody may be associated with severe GI involvement [260, 261]. Other risk
factors include severe muscle weakness, low BMI, deep skin ulcers, hoarseness, and
low-pitched voice indicating pharyngeal involvement [261]. GI involvement may
occur without severe skin or muscle symptoms [68]. Medical treatments include
high-dose corticosteroids, DMARDs, rituximab, IVIG, CYC, JAK inhibitors, and
plasma exchange [260, 261]. Surgical intervention may be required [68]. There is
currently no standardized treatment protocol for this complication.
Clinical Assessment
Scoring and Assessment of Muscle Strength
Manual Muscle Testing (MMT) One of the most commonly used scoring tools is
manual muscle testing (MMT). In this assessment, the clinician manually evaluates
muscle strength by applying resistance to 24 or more muscle groups. Due to the
lengthy nature of the full examination, a shorter and more practical version, MMT-8,
is more frequently used, particularly in the JDM group. This version includes the
evaluation of approximately eight muscle groups, covering both proximal and distal
muscles. The maximum score for unilateral assessment is 80, while for bilateral
assessment it is 150 [265].
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Functional Capacity Tests and Physical Endurance
Childhood Myositis Assessment Scale (CMAS) This scoring system is used to
evaluate how well patients are able to maintain their daily routines. The maximum
score is 52. It assesses 14 functional activities such as dressing independently,
jumping, sitting and standing up, and climbing stairs. Each activity is scored on a
scale from 0 to 5 [265]. One of its key benefits is that it serves as a guide for evaluating treatment effectiveness. AMAT (adult myopathy assessment tool), which is
more commonly used in adults, evaluates 13 functional activities in terms of time
and performance [265].
Patient-Reported Outcomes
Health Assessment Questionnaire (HAQ) This scale evaluates the extent of difficulty patients encounter in performing daily activities. It is scored from 0 (able to
do without difficulty) to 3 (unable to do) [265]. The Childhood Health Assessment
Questionnaire (CHAQ) is the adapted version designed for pediatric patients [266].
Patient/Parent Visual Analog Scale (VAS) This is a global assessment made by
the patient or parent. Typically, the patient’s perception of disease status does not
align with the clinician’s VAS [68, 265].
Short Form 36 (SF-36) This is a questionnaire that evaluates quality of life and
functioning based on patient-reported information, and its use has been recommended by IMACS to assess treatment response. However, it is strongly discouraged for use in pediatric patients [265].
Child Health Questionnaire (CHQ) This scale is suitable for ages 5–18 and evaluates overall quality of life based on input from both the child and parent. It includes
two summary scores: the Physical Health Summary (PhS) and the Psychosocial
Health Summary (PsS). This questionnaire is supported by PRINTO and IMACS. Its
use in adult patients is not recommended [265, 266].
Composite Disease Activity Measures
Myositis Disease Activity Assessment Tool (MDAAT) This tool evaluates disease
activity across systems such as muscles, skin, and lungs, incorporating both clinician and patient-reported outcomes. It is particularly useful in severe or systemic
myositis [265]. A Norwegian study found that 24% of patients deemed inactive by
PRINTO still showed activity due to persistent extramuscular symptoms,
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highlighting MDAAT’s broader scope [267]. It has two components—MYOACT
and MITAX—assessing seven systems: constitutional, skin, skeletal, GI, pulmonary, cardiac, and muscular. MYOACT uses a 10 cm VAS per system; MITAX
applies a five-level scale [262, 265, 268].
Disease Activity Score (DAS) It is generally used for patients with JDM. The
score evaluates disease activity in terms of skin and muscle involvement. The main
components assessed include the severity of muscle weakness, functional status,
presence of vasculitic findings, and the extent and severity of rashes. The test consists of 19 items with a total score range of 0–20, subdivided into muscle (0–11) and
skin (0–9) scores. It is an important tool for evaluating treatment response. While
endorsed by PRINTO, it does not assess major organ involvement, which may limit
its clinical scope [265, 269].
Total Improvement Score (TIS) Developed in the 2016 ACR-EULAR criteria for
adult DM and PM, TIS uses six weighted core measures: MMT, physician and
patient global assessments, muscle enzymes, physical function, and extramuscular
involvement. Scores range from 0 to 100: 0–19 (no response), 20–29 (minimal),
40–59 (moderate), and ≥60 (major response) [155].
Juvenile DermatoMyositis Activity Index (JDMAI) JDMAI is a DAS-based
score specific to JDM, combining physician and patient global assessment, muscle
strength, and skin activity into a single score ranging from 0 to 40 [269].
Physician Global Visual Analog Scale (PhyGloVAS) This scale is a global scale
based on all available information at the time of examination and assessment; history, physical examination, laboratory results, administered treatments, and response
to therapy are evaluated as a whole. It demonstrates adequate performance for long-­
term monitoring and tracking of changes [68, 265].
Scoring and Assessment of Cutaneous Involvement
Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) CDASI
is a practical scoring tool that separately evaluates skin involvement as activity and
damage in both adult and JDM patients. Activity criteria include erythema, scaling,
and erosion/ulceration, while damage indicators are poikiloderma and calcinosis.
Gottron’s papules, periungual changes, and alopecia are additional clinical findings
that are assessed. Severe disease is defined as a score of 39 or higher [265, 270–272].
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Cutaneous Assessment Tool (CAT) CAT was developed to assess skin changes
associated with juvenile inflammatory myopathies. Later, a shorter version called
aCAT, which takes less time to complete, became more commonly used. In the
original CAT, scoring is based on lesion characteristics, while in aCAT, the criteria
are evaluated as either present or absent. The original CAT provides an activity
score ranging from 0 to 96 and a damage score ranging from 0 to 20. In aCAT, the
activity score ranges from 0 to 17 and the damage score from 0 to 11 [265, 272].
Dermatomyositis Skin Severity Index (DSSI) It is a tool that can be used to
assess skin activity in DM; it does not evaluate damage. The assessment includes
erythema, induration, and scaling in body regions divided into head, trunk, upper
extremities, and lower extremities. Body surface area involvement is also considered in the calculation. The total score ranges from 0 to 72 points. The higher the
score, the more severe the cutaneous disease activity [265].
SkinDAS Within the 20-point Disease Activity Score (DAS), 9 points are allocated
specifically to skin involvement (skinDAS). Scoring is based on the extent and
severity of the skin rash, the presence of vasculitic features, and the presence of
Gottron’s papules [272].
Damage Risk Assessments
Myositis Damage Index (MDI) MDI is used to assess permanent damage in
patients with myositis. However, it cannot determine whether the damage is due to
previous disease activity, treatment complications, or other causes. Findings that
persist for 6 months cannot be clearly interpreted as damage or active disease.
Specific types of damage are assessed across 11 organ systems, and for each system,
damage severity is rated using a 10 cm VAS. The number of questions varies by age
group, and with the addition of optional items, an “Extended Damage Score” can be
generated [265]. It is preferred for evaluating changes in the degree of damage over
the long term.
Newly Developed Scoring Systems
The combined use of multiple measures enhances assessment of disease activity
and damage, leading to developments by PRINTO and EULAR. PROMIS (Patient-­
Reported Outcomes Measurement Information System) includes scales for pain
interference, fatigue, and physical function, and is used in assessing adult patients
with IIM. PROMIS physical function correlates with clinician assessments and
muscle strength; fatigue aligns with quality of life, disease activity, and
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Table 4 Common activity scores for idiopathic inflammatory myopathies
Muscle
strength
MMT
MMT-8
Muscle-DAS
Skin
involvement
CDASI
CAT
Skin-DAS
DSSI
Functional
Composite capacity
MDAAT CMAS
DAS
AMAT
TIS
JDMAI
Patient-dependent
reports
HAQ, CHAQ
Patient VAS
SF36
CHQ
Damage
risk
MDI
Adopted from Refs. [160, 262–264]
MMT Manual Muscle Testing, DAS Disease Activity Score, CDASI Cutaneous Dermatomyositis
Disease Area and Severity Index, CAT Cutaneous Assessment Tool, DSSI Dermatomyositis Skin
Severity Index, MDAAT Myositis Disease Activity Assessment Tool, TIS Total Improvement
Score, JDMAI Juvenile DermatoMyositis Activity Index, CMAS Childhood Myositis Assessment
Scale, AMAT Adult Myopathy Assessment Tool, HAQ Health Assessment Questionnaire, VAS
Visual Analog Scale, SF-36 Short Form 36, CHQ Child Health Questionnaire, MDI Myositis
Damage Index
psychosocial factors; pain interference reflects subjective pain reports, supporting
its routine clinical use [263]. Another scale under active development is the
DM-DSQ (Dermatomyositis Disease Symptom Questionnaire), a patient questionnaire designed to directly assess both muscle and skin symptoms, as well as the
overall impact of disease on general health and quality of life. It may be particularly
useful for evaluating treatment response, facilitating effective communication with
the patient, and tracking quality of life over time [273]. The other composite scale
developed for DM, which assesses both muscle and skin involvement, is DOMS
(Dermatomyositis Outcomes for Muscle and Skin). It incorporates both patient-­
reported outcomes and clinical assessments and suitable for detecting concurrent
changes in muscle- and skin-related symptoms, also helps in evaluating overall disease activity [274] (Table 4).
Inactive Disease and Prognosis
The disease course varies by autoantibodies, age at onset, initial organ involvement, activity level, and treatment adherence [264]. PRINTO’s 2013 guidelines
defined inactive disease as meeting at least three of four criteria: CK ≤ 150 U/L,
CMAS ≥ 48/52, MMT8 ≥ 78/80, or PhyGloVAS ≤ 0.2 [265, 275, 276]. However,
since this definition is largely based on markers reflecting muscle involvement,
concerns have been raised that it may lead to misinterpretation in patients with
skin-­dominant disease. As a result, PRINTO has proposed some revisions to the
criteria [276, 277].
Severe disease onset, elevated initial muscle enzymes, and calcinosis are associated with lower rates of achieving inactive disease [267]. Extramuscular involvement, particularly pulmonary, GI, cardiac symptoms, widespread ulcers, and
Juvenile Dermatomyositis
195
calcinosis, is linked to poor prognosis, prolonged disease, increased morbidity,
complication risks, and may ultimately result in mortality [68]. Anti-NXP-2 autoantibodies are linked to early onset, severe muscle involvement, dysphagia-dysphonia,
and extensive calcinosis, with rare fatal complications such as GI perforation. Anti-­
TIF1γ and anti-MDA5 are associated with predominant skin involvement and ILD,
respectively, while anti-Mi-2 suggests a milder course despite muscle symptoms
[57, 68, 241]. Rare in children, anti-SRP and anti-HMGCR antibodies are associated with necrotizing myopathy and dysphagia, respectively, and anti-synthetase
antibodies are linked to features like mechanic’s hands and lipodystrophy. Muscle
biopsy findings, including fiber necrosis, vasculopathy, and fibrosis, correlate with
disease severity and functional impairment, supporting their diagnostic and prognostic relevance [68, 278] (Table 5).
Table 5 Clinical differences between adult and juvenile dermatomyositis
Feature
Muscle
involvement
Skin
involvement
Cutaneous
ulceration
Calcinosis
Malignancy
association
Lipodystrophy
Adult dermatomyositis
Pronounced and
symmetrical
Gottron’s papules and
heliotrope rash are common
Rare
Interstitial lung
disease
More frequent and severe;
may be associated with
anti-MDA5 and RP-ILD
Myocarditis, arrhythmias,
pericarditis possible
Seronegative, usually mild
Less prominent
Cardiac
involvement
Arthritis
Vasculitis
Serological
autoantibodies
Prognostic
factors
Treatment
response
Rare
Significantly increased
Rare
Juvenile dermatomyositis
Similar findings, but may be subtler at
diagnosis
Similar involvement, may be more prominent
at diagnosis
More frequent and severe, possibly related to
vasculitis
More common
Low
More common, late complication, often
associated with metabolic syndrome
Less common but possible, especially with
anti-MDA5 positivity
Usually mild; subclinical dysfunction may be
detected
More frequent, non-erosive
More common small vessel vasculitis, GI
involvement can be severe
Same autoantibodies may be detected, but
Anti-Mi-2, anti-TIF-1γ,
clinical significance can differ (e.g., anti-­
anti-MDA5, anti-NXP-2
TIF-­1γ associated with malignancy in adults,
not in children)
Presence of malignancy,
Presence of calcinosis, vasculitis, chronic
ILD, autoantibody profile
disease course
Generally responds well, but Usually responds well to immunosuppression,
complications increase risk though long-term complications (e.g.,
calcinosis) may occur
ILD interstitial lung disease, RP-ILD rapidly progressive interstitial lung disease, MDA5 melanoma differentiation-associated protein 5, NXP-2 nuclear matrix protein 2, TIF-1γ transcription
intermediary factor 1 gamma
196
M. O. Erkan et al.
Mortality
With the intensification of immunosuppressive therapies, mortality rates have
decreased to as low as 2% [62, 68]. However, the presence of concomitant ILD can
increase this rate up to 24% [279]. One of the leading causes of mortality is infection. Opportunistic infections, pneumonia, and sepsis, which develop due to immunosuppressive treatments, are the most common. In particular, Pneumocystis
Jirovecii pneumonia is one of the most significant infectious agents in MDA5-­
positive patients [280]. Other factors that increase the risk of death include respiratory failure due to ILD, malignancies, and, less commonly, cardiovascular events
and the presence of other concomitant autoimmune diseases [281]. In a survival
analysis conducted in adult PM and DM patients, it was shown that age at disease
onset, infections, and the presence of malignancy were independent risk factors for
mortality [282].
Novel Treatments
Polymyxin B infusion has recently emerged as a treatment in critically ill patients
[283]. Case-based reports exist, particularly in patients with respiratory failure due
to lung involvement and autoantibody positivity [284]. CD19 CAR T-cell infusion
has also gained a place in the treatment of B-cell-mediated and autoantibody-driven
autoimmune diseases in recent years [285]. In a few treatment-resistant patients
with antisynthetase syndrome, CD19 CAR T-cell infusion has been shown to reduce
CK levels, lung involvement, and other clinical signs, and in one case, drug-free
remission was achieved [286, 287]. Studies evaluating these therapies in refractory
cases are ongoing.
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Vasculitis
Muhammad Ishaq Ghauri and Syeda Urooj Riaz
Introduction
Inflammation of blood vessels in the human body is called vasculitis. A heterogenous collection of disorders that are connected with inflammation of blood vessels
subsequently results in remodeling and scarring. Vasculitis is majorly autoimmune
entity but mainly understood as idiopathic. The inflammation first makes the blood
vessels thick which subsequently results in destruction of vessel walls and downstream tissue ischemia and necrosis. Vasculitis can be accompanied by inflammation of the organs, but inflammation could not necessarily be from vasculitis [1].
Vasculitis can involve any vessel that contains blood—arteries, arterioles, veins,
venules, or capillaries. Vasculitis is a collection of disorders defined by inflammation of blood vessels and can occur in arteries, veins, and capillaries. Inflammation
can lead to vessel wall damage, with resultant compromised blood flow, organ damage, and sometimes-permanent organ loss. The pathogenic mechanisms of vasculitis are multifaceted and involve dysregulation of the immune system, frequently
precipitated by environmental and genetic factors. Depending on the vessel size
involved, vasculitis is divided into three broad categories: large, medium, and small
vessel vasculitis.
This chapter aims to provide an overview of vasculitis, focusing on pathogenesis,
clinical manifestations, and its extensive classification. It outlines the key diagnostic
approaches and current treatment strategies, including both conventional and emerging therapies.
M. I. Ghauri (*) · S. U. Riaz
Jinnah Medical & Dental College, Karachi, Pakistan
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_9
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Epidemiology
Vasculitis is a miscellaneous group of diseases with different epidemiological patterns and causes. Its overall prevalence is low, although some types predominate in
certain ages, sexes, and geographic locations. For instance, giant cell arteritis (GCA)
is the most prevalent adult-onset vasculitis, especially in adults over 50 years of age,
and mostly in people of Northern European ancestry, with a prevalence of 15–30
cases per 100,000 individuals per annum in this group [2]. Takayasu arteritis, on the
other hand, mainly occurs in young women below the age of 40, mainly in Asia and
Latin America. Kawasaki disease, a medium-vessel vasculitis primarily affecting
children under 5, has the highest incidence in Japan—up to 240 cases per 100,000
children [3].
Etiology
In most instances, the etiology is idiopathic, especially in primary vasculitides.
Genetic predisposition is important and is linked to human leukocyte antigen
(HLA). Human leukocyte antigen HLA-B51 is highly linked with Behçet’s disease,
whereas HLA-DRB1 alleles are associated with giant cell arthritis (GCA) [4].
Environmental stimuli like infections, drugs, and toxins can cause secondary vasculitis. Hepatitis B virus is highly linked with polyarteritis nodosa, whereas hepatitis
C is associated with cryoglobulinemic vasculitis [5].
Immune dysregulation is the hallmark of vasculitis pathogenesis. In (ANCA)associated vasculitis, autoantibodies like PR3-ANCA and MPO-ANCA stimulate
neutrophils, causing endothelial damage. In immune complex-mediated vasculitides, immune complex deposition in vessel walls induces complement activation and
inflammation. Knowledge of the epidemiology and etiology of vasculitis is crucial
for diagnosis, risk stratification, and specific treatment plans.
Pathophysiology
The pathogenesis of vasculitis is multifactorial with both genetic and environmental
factors triggering immune-mediated inflammation directed against blood vessel
walls, causing vascular damage, necrosis, and tissue ischemia. The mechanism differ among the various forms of vasculitis, but all have a unifying theme of immune
dysregulation causing vascular inflammation and injury.
In ANCA-associated vasculitis (AAV), which comprises granulomatosis with
polyangiitis (GPA) and microscopic polyangiitis (MPA), the underlying mechanism
is antineutrophil cytoplasmic antibodies (ANCAs) against enzymes like proteinase
3 (PR3) or myeloperoxidase (MPO). These autoantibodies stimulate neutrophils,
resulting in degranulation, release of reactive oxygen species, and consequent endothelial damage [6]. This mechanism is pivotal to small-vessel vasculitides and leads
to capillaritis, glomerulonephritis, and pulmonary hemorrhage.
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215
In immune complex-induced vasculitis, for example, Henoch-Schönlein purpura
or cryoglobulinemic vasculitis, the formation of immune complexes (antigen–antibody complexes) in the vessel walls triggers the classic complement pathway. This
causes neutrophil and macrophage recruitment, leading to inflammation and damage of the vessel wall [7].
Large-vessel vasculitis, including giant cell arteritis and Takayasu arteritis, is
dominated by inflammation mediated by T cells. In both these conditions, the dendritic cells within the adventitia of the vessel present antigens to CD4+ T cells,
which secrete pro-inflammatory cytokines such as interferon-γ and interleukin-6.
This results in granulomatous inflammation, intimal hyperplasia, and occlusion of
the vessel [8].
The pathologic effects of vasculitis are fibrinoid necrosis of the vessel wall,
thrombosis, aneurysm, and impaired tissue perfusion. Scarring may result from prolonged inflammation and subsequent long-term dysfunction of the involved organ.
Comprehension of the pathophysiologic process of vasculitis is required to create
focused therapies and optimize patient outcomes.
Clinical Features
Vasculitides often presents with a prolonged history of intermittent fever accompanied by systemic symptoms, which may affect the skin, gastrointestinal tract, kidneys, nervous system, or musculoskeletal system. Skin-related signs of vasculitis
can be categorized into eight primary types: urticarial papules, macular purpura,
palpable purpura, livedo reticularis, retiform purpura, subcutaneous nodules, tissue
necrosis, and ulcers. Large-vessel vasculitides seldom exhibit skin symptoms,
whereas medium-vessel vasculitides typically manifest as livedo reticularis, retiform purpura, nodules, ulcers, or tissue infarction and necrosis. Small-vessel vasculitides most frequently present with urticarial papules, macular purpura, and
palpable purpura, with the latter being the most common skin sign of both smalland medium-vessel vasculitis. Consequently, individuals with palpable purpura
should be assessed for systemic involvement and antineutrophil cytoplasmic antibody positivity. Although skin biopsies aid in diagnosing vasculitis, further investigations are necessary for precise classification [9].
The eye and its surrounding structures have a rich blood supply, receiving circulation from branches of the internal and external carotid arteries. Various ocular
conditions can arise due to systemic vasculitis, potentially leading to significant
vision loss. The affected structures may include the conjunctiva, cornea, sclera and
episclera, uveal tract, retina, orbit, and optic nerves. Evaluating ocular symptoms of
vasculitis are crucial both for ophthalmologists, who must determine whether an
eye condition is linked to an underlying systemic vasculitis, and for non-­
ophthalmologists diagnosing systemic vasculitis, who need to assess whether the
disease has affected the eyes [10].
Cardiopulmonary involvement is common in systemic vasculitis and plays a
major role in both morbidity and mortality. The symptoms can vary widely, from
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incidental abnormalities on a chest radiograph in an asymptomatic individual to
severe complications like diffuse alveolar hemorrhage or sudden death. Because
initial presentation may resemble isolated pulmonary or cardiac disease, it can be
mistaken for more frequently encountered conditions such as malignancy, infection,
connective tissue disorders, drug toxicity, or embolic events [11].
Although vasculitic neuropathy is uncommon, identifying it is crucial since it is
a treatable condition. It may arise as part of a broader multisystem disease or as an
isolated disorder [12]. The condition results from ischemic injury caused by the
blockage of blood vessels affected by inflammation in the vasa nervorum. The
microvascular network of peripheral nerves has distinct characteristics that influence the disease process. While peripheral nerves are relatively resilient to ischemia—thanks to dual blood supply from extrinsic and intrinsic vascular
systems—and can function under anaerobic conditions, they also have structural
vulnerabilities. Endometrial capillaries in nerves are larger and more widely spaced
than in other tissues, and their smooth muscle layer is underdeveloped, making
them more prone to ischemic damage.
Timely diagnosis and swift intervention for vasculitic lesions in the gastrointestinal (GI) tract are crucial to preventing severe complications. Recent advancements
in our understanding of the gut microbiome are expected to shed light on the GI
tract’s role in autoimmunity [13]. Additionally, various pathological mechanisms
contribute to bowel ischemia as a manifestation of vasculitis in the GI system.
Renal involvement is common in small-vessel vasculitides but rare in large-­
vessel forms [14]. In large-vessel disorders, renal artery stenosis or occlusion may
occasionally occur. In medium-sized artery vasculitis, particularly classical polyarteritis nodosa, branches of the renal arteries are often affected, leading to renal
infarction and renovascular hypertension. In small-vessel vasculitides, antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a significant
cause of rapidly progressive glomerulonephritis. Histopathologically, AAV-related
renal involvement is marked by pauci-immune necrotizing crescentic glomerulonephritis (NCGN). This condition can be associated with granulomatosis with polyangiitis linked to proteinase 3 (PR3-ANCA), microscopic polyangiitis with
myeloperoxidase (MPO-ANCA), or, less commonly, eosinophilic granulomatosis
with polyangiitis, also associated with MPO-ANCA. In most cases, renal-limited
vasculitis (idiopathic NCGN) is linked to MPO-ANCA. Recent advancements in
understanding AAV pathogenesis have facilitated more precise treatment
approaches. Crescentic glomerulonephritis is also observed in IgA vasculitis, characterized by IgA-dominant immune deposits, and in cryoglobulinemic vasculitis,
which involves type II cryoglobulins.
Reduced blood flow to the distal extremities is often the first noticeable sign of
an underlying condition, ranging in severity from a minor inconvenience to critical
ischemia and tissue damage. Digital ischemia presents a significant diagnostic challenge, as delayed identification and treatment can lead to prolonged discomfort and
loss of tissue viability. Due to the urgency of the condition, clinical clues must be
interpreted swiftly to initiate treatment before a definitive diagnosis is established.
Vasculitis
217
Understanding disease mechanisms allows for informed treatment decisions, even
in cases where diagnostic data is incomplete. Since digital ischemia can stem from
different causes—including vasculitic, vasospastic, and thrombotic processes—it is
crucial to differentiate between them for effective management [15]. In recent years,
substantial advancements have been made in understanding the pathophysiology of
vasospasm and vasculopathy, paving the way for promising new treatments for
Raynaud’s phenomenon and digital ischemia.
Nomenclature, Classification, and Subtypes
There have been various nomenclatures used to define vasculitis. American College
of Rheumatology (ACR) presented the classification criteria for vasculitis in 1990
(Table 1) [16]. According to these criteria, vasculitis was classified into primary and
secondary types. Both these types were dependent on the size of vessel involved.
Vasculitis affecting the large arteries includes giant cell arteritis (GCA) and
Takayasu arteritis. Medium vessel vasculitis includes polyarteritis nodosa (PAN)
and Kawasaki disease, while small vessel vasculitis contains granulomatosis with
polyangiitis (GPA) formerly known as Wegener’s granulomatosis (WG), Churg-­
Strauss syndrome now known as eosinophilic granulomatosis with polyangiitis
(EGPS), microscopic polyangiitis (MPA), Henoch-Schönlein purpura, and cryoglobulinemia. Secondary vasculitides encompass vasculitis secondary to
Rheumatoid Arthritis and various infections, e.g., bacterial, viral, and fungal [9].
In 1994, the Chapel Hill Consensus Conference designed a nomenclature classification of vasculitis based on the size of the affected vessel. In 2012, the Chapel
Hill Consensus Conference went for revision of the 1994 classification to provide
more precise classification of vasculitis with illustration of the different forms of
vasculitis encountered in practice considering the nature of the pathology, the vessel
size, and the etiology shown in Fig. 1 [17].
Definitions for vasculitides adopted by the 2012 International Chapel Hill
Consensus Conference on the Nomenclature of Vasculitides (CHCC2012) [17, 18].
Table 1 ACR Classification of vasculitis
Dominant vessel
Large arteries
Medium arteries
Small vessels and
medium arteries
Small vessels
Primary
Secondary
Giant cell arteritis
Aortitis associated with rheumatoid
Takayasu arteritis
arthritis, infections
Classic polyarteritis nodosa Hepatitis B-associated polyarteritis
Kawasaki disease
nodosa
Vasculitis secondary to rheumatoid
Granulomatosis with
arthritis drugs
polyangiitis
Churg-Strauss syndrome
Microscopic polyangiitis
Henoch-Schönlein purpura Drugs, hepatitis C associated,
Cryoglobulinemia
infections
218
Fig. 1 Chapel Hill Consensus Conference 2012
M. I. Ghauri and S. U. Riaz
Vasculitis
219
1. Large-vessel vasculitis (LVV): vasculitis predominantly affecting large arteries
(the aorta and its major branches); however, any size may be affected. It includes
two main subtypes:
(i) Takayasu arteritis (TAK): granulomatous arteritis affecting the aorta and/or
its major branches in patients younger than 50 years. The consensus retained
the eponym “Takayasu” against the proposed non-eponymous term “early-­
onset granulomatous aortitis/arteritis” being more effective than any
alternative.
(ii) Giant cell arteritis (GCA): granulomatous arteritis, usually affecting the
aorta and/or its major branches, with a higher predilection for the branches
of the carotid and vertebral arteries usually in patients older than 50 years
and commonly associated with polymyalgia rheumatic. The disease often
involves the temporal artery with the term “temporal arteritis” being commonly in use; however, not all patients with GCA have temporal artery
involvement.
2. Medium-vessel vasculitis (MVV): vasculitis predominantly affecting medium-­
sized arteries defined as the main visceral arteries and their branches, and any
size artery may be affected by the pathology. Inflammatory aneurysmal dilatations and arterial narrowing are common.
(i) Polyarteritis nodosa (PAN): necrotizing arteritis of the medium or small
arteries or vasculitis in arterioles, capillaries, or venules, not associated with
antineutrophil cytoplasmic antibodies (ANCAs).
(ii) Kawasaki disease (KD): arteritis involving the medium- and small-sized
arteries. The disease occurs in infants and young children presenting with
mucocutaneous lymph node syndrome. Coronary arteritis remains a hallmark being frequently involved, while the aorta and large arteries may get
involved.
3. Small-vessel vasculitis (SVV): vasculitis predominantly affecting small vessels
defined as small intraparenchymal arteries, arterioles, capillaries, and venules.
Similarly, medium arteries and veins may be affected.
(a) ANCA-associated vasculitis (AAV): necrotizing vasculitis, with few or no
immune deposit, that is, pauci-immune necrotizing vasculitis, predominantly affecting the small vessels (i.e., capillaries, venules, arterioles, and
small arteries), usually associated with antibodies to myeloperoxidase
(MPO) or proteinase 3 (PR3) classified as either MPO-ANCA or PR3-­
ANCA, although not all the patients with this form of necrotizing vasculitis
are ANCA positive.
(i) Microscopic polyangiitis (MPA): necrotizing vasculitis, with few or no
immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing pauci-immune arteritis involving small- and medium-sized arteries and necrotizing glomerulonephritis
and pulmonary capillaritis are frequent presentations, while granulomatous inflammation is absent.
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M. I. Ghauri and S. U. Riaz
(ii) Granulomatosis with polyangiitis (Wegener’s) (GPA): necrotizing
granulomatous vasculitis affecting predominantly from small to
medium vessels (e.g., capillaries, venules, arterioles, arteries, and
veins) usually involving the upper and lower respiratory tract.
Necrotizing glomerulonephritis is common.
(iii) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
(EGPA): EGPA is an eosinophil-rich necrotizing granulomatous
inflammation predominantly affecting from small to medium vessels
often involving the respiratory tract and associated with asthma and
eosinophilia. Nasal polyps are common. ANCA is more frequent when
glomerulonephritis is present. The eponym “Churg-Strauss syndrome”
was replaced by “EGPA” in part to achieve nomenclature symmetry
with MPA and GPA.
(b) Immune complex vasculitis: vasculitis predominantly affecting small vessels
(i.e., capillaries, venules, arterioles, and small arteries) with moderate to
marked immune complex deposits within vessel wall. Glomerulonephritis is
frequent.
(c) Antiglomerular basement membrane (anti-GBM) disease: vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM autoantibodies. Lung involvement causes pulmonary
hemorrhage, and renal involvement causes glomerulonephritis with necrosis
and crescents.
(d) Cryoglobulinemic vasculitis (CV): vasculitis with immune deposits affecting small vessels (predominantly capillaries, venules, or arterioles) and
associated with circulating cryoglobulins. Skin, glomeruli, and peripheral
nerves are often involved.
(e) IgA vasculitis (Henoch-Schönlein) (IgAV): vasculitis, with IgA1-dominant
immune deposits, affecting small vessels (predominantly capillaries,
venules, or arterioles). Skin, gastrointestinal tract, and joints are frequently
involved. Glomerulonephritis indistinguishable from IgA nephropathy
may occur.
(f) Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis):
vasculitis affecting small vessels (i.e., capillaries, venules, or arterioles)
manifesting by urticaria and associated with hypocomplementemia and anti-­
C1q antibodies. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation are common presentations.
4. Variable vessel vasculitis (VVV): a form of vasculitis that can affect vessels of
any size (small, medium, and large) and type (arteries, veins, and capillaries).
(i) Behcet’s disease (BD): vasculitis that can affect arteries or veins of variable
calibers, characterized by recurrent oral and/or genital aphthous ulcers and
accompanied by cutaneous, ocular, articular, gastrointestinal, and/or central
nervous system inflammatory lesions. Small vessel vasculitis, thromboangiitis, thrombosis, arteritis, and arterial aneurysms may occur.
Vasculitis
221
(ii) Cogan’s syndrome (CS): Cogan’s syndrome is a form of vasculitis that can
affect vessels of variable sizes. The disease leads to arteritis (affecting small,
medium, or large arteries), aortitis, aortic aneurysms, and aortic and mitral
valvulitis. Clinically presents by ocular inflammatory lesions, including
interstitial keratitis, uveitis, and episcleritis, and inner ear disease, including
sensorineural hearing loss and vestibular dysfunction.
5. Single-organ vasculitis (SOV): vasculitis in arteries or veins of any size in a
single organ that has no features that indicate that it is a limited expression of a
systemic vasculitis. Vasculitis may be unifocal or multifocal/diffuse within the
same organ. Usually defined in terms of the involved organ and vessel type, for
example, cutaneous small vessel vasculitis, testicular arteritis, and central nervous system vasculitis. Some patients originally diagnosed as SOV may develop
additional disease manifestations that warrant redefining the case as one of the
systemic vasculitides, for example, cutaneous arteritis later becoming systemic
polyarteritis nodosa, and so on.
6. Vasculitis associated with systemic disease: vasculitis that is associated with
and/or may be secondary to a systemic disease. The diagnosis should specify the
systemic disease, for example, rheumatoid vasculitis, lupus vasculitis, and so on.
7. Vasculitis associated with probable etiology: vasculitis that is associated with a
probable specific etiology, for example, hydralazine-associated microscopic
polyangiitis, hepatitis B virus-associated vasculitis, hepatitis C virus-associated
cryoglobulinemic vasculitis, and so on.
Differential Diagnoses
Vasculitis has a number of mimics, and therefore, proper assessment of differentials must be evaluated when assessing such patients. Infections like infective
endocarditis, histoplasmosis, and gonococcal infection can mimic vasculitis. As
the management of vasculitis involves the administration of immunosuppressive
medication, it is important to conduct a complete infection screen in all patients
with suspected vasculitis. Coagulopathy such as antiphospholipid syndrome and
thrombotic thrombocytopenic purpura, neoplasms such as atrial myoma, lymphoma, and various drug toxicities such as cocaine and levamisole may have features mimicking vasculitis [19].
Disease Monitoring Tools
Once the diagnosis of a systemic vasculitis is established and therapy is initiated,
there is a need for periodic assessment to evaluate response to treatment or to detect
a disease relapse after achieving remission [20]. Hence, several tools have been
developed to evaluate disease activity, disease extension, prognosis, and damage in
systemic vasculitis. The Birmingham Vasculitis Activity Score (BVAS) is the most
widely used assessment tool for disease activity in vasculitis, and currently, in its
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M. I. Ghauri and S. U. Riaz
third version, the BVAS includes 66 items in 9 different systems. The BVAS is often
used to evaluate small vessel vasculitis and PAN while a specific version of BVAS
was developed for disease activity in GPA [21]. Although not formally validated,
the criteria defined by Kerr et al. are usually used to assess disease activity in
patients with TA. The disease extent index, Takayasu (DEI.TAK), and its new version, the Indian Takayasu arteritis activity index (ITAS), were recently developed to
evaluate active disease in TA [22]. The OMERACT Vasculitis Working Group is
developing a core set of outcome measures in large vessel vasculitis.
The disease extent index (DEI) scores the number of organ and systems involved
in GPA. The DEI is complimentary to BVAS and helps to differentiate whether a
high BVAS is due to severe manifestation in only one organ/system or if it is due to
a multisystem disease [21]. The first version of the five factor score (FFS) was
developed to assess prognosis in patients with PAN, MPA, and EGPA, and it has
been used to guide therapeutic decisions in these diseases [23]. Recently, a new version of the FFS has been developed to include patients with GPA also in the evaluation [24]. The assessment of permanent damage in systemic vasculitis can be done
with the vasculitis damage index (VDI). In this tool, an irreversible scar that lasts
more than 3 months defines permanent damage [21].
Management
The management of the case depends largely on the type of vasculitis, severity,
extent of the disease, and the disease activity. If it is a secondary vasculitis, a search
into the cause of it and a look into the offending antigen be it an infection like hepatitis B or an offending drug is identified and treated along with treatment of vasculitis. The treatment depends on organ involvement, severity of disease, and response
to the drug and side effect profile of a drug.
The approach to treatment for any vasculitis generally includes three components: remission induction, remission maintenance, and monitoring [25].
Glucocorticoids are the first-line treatment for patients with vasculitis used with or
without immunosuppressive agents. The type of vasculitis guides the choice of
immunosuppressive agents. Methotrexate (MTX), azathioprine (AZA), mycophenolate (MMF), cyclophosphamide (CYC), rituximab (RTX), intravenous immunoglobulin, plasma exchange, etc. have all been used in various treatment regimens in
different forms of vasculitis [25]. Once the condition is in remission, slow, downward glucocorticoid titration should commence to maintain control of disease activity and minimize the risks of drug toxicity. Patients and physicians should know the
short-term and long-term toxic side effects of therapeutic agents for monitoring.
Immunomodulatory medications are the mainstay of therapy but are associated with
significant complications such as infection and malignancy. With improved understanding of disease pathogenesis, substantial progress has been made in recent years
to identify more targeted and less toxic treatments for these diseases.
Vasculitis
223
Complication
Complications of vasculitis vary according to the vessel involved. Involvement of
large vessels with vasculitides such as GCA, Takayasu, or Kawasaki may cause
complications such as acute myocardial infarction and stroke, including cranial
artery ischemia such as ophthalmic artery [26]. Mesenteric ischemia, aortic syndromes (such as dissection or intramural hematoma), or critical extremity ischemia
[27]: Fatal complications of small-vessel vasculitis include alveolar hemorrhage,
renal failure, and intestinal ischemia [28]. Aneurysm formation is an established
complication of GCA, polyarteritis nodosa, and Behcet disease [27]. Deep venous
thrombosis and pulmonary embolism are more common in AAV and Behcet disease
than in other vasculitides [29].
Outcome and Prognosis
Long-term survival in patients with vasculitis largely relies on the diagnosis, drug
response, and side effects of drugs. These include the presence of infections as a
complication. In a study evaluating long-term survival in ANCA-associated vasculitis: 1-, 2-, and 5-year survival was 88%, 85%, and 78%, respectively. The mortality
ratio was 2.6 when compared to the general population [30]. Mortality rates are
based on active vasculitic disease as well as therapy complications.
Conclusion
Vasculitis is a chronic systemic disease that needs an interprofessional team for its
treatment. Shared decision-making and communication are the important factors in
a good outcome. Patients, rheumatologists, primary care doctors, nephrologists,
ophthalmologists, pulmonologists, and other specialties, such as pharmacists, would
have to work very closely, in order to obtain remission and enhance the quality of
care and quality of life in such patients.
Nursing will also have a major role in the management of vasculitis cases, from
drug administration to monitoring for disease or drug-related side effects and notifying these to the remainder of the team. The pharmacist will confirm all dosing and
reconcile medications to avoid drug–drug interactions, also notifying the team when
these do exist so a change in therapy can happen proactively. The prescribing/ordering physician would be working in collaboration with the other professions to
enable the interprofessional team model to inform best patient outcomes with few
adverse events.
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Sjögren’s Syndrome
Maria Maslinska
Introduction
Sjögren’s syndrome (SjS)/Sjögren’s disease (SjD) is an autoimmune disease, with
the activation of innate and acquired immune response with the B cell hyperactivation with autoantibodies production, mainly against ribonucleoproteins. The predilection to exocrine glands, especially salivary and lachrymal glands, is a clinical
hallmark of this disease; however, not all patients experience dryness, particularly
in the early stages of the disease. Recurrent episodes of, for example, stones associated with the salivary glands, kidneys or gallbladder, interstitial changes in the lungs
or various neurological symptoms concerning the central and peripheral nervous
system may be the dominant symptoms of the disease. One of the most common
symptoms, however nonspecific, is a chronic fatigue syndrome (CFS).
Among many aspects of a multipicture clinical symptomatology of SjD, the
increased risk of development of lymphomas, mainly of the mucosa-associated
lymphoid tissue (MALT) type, is of particular importance.
The purpose of this chapter is to present the current knowledge about SjD and to
indicate the methods of treatment following the diagnosis of this complex autoimmune disease. With many aspects of SjD still not entirely clear, our understanding
of this perplexing disease may be considered as yet another subject of the “eternal
dissatisfaction” of today’s men (and women) of science.
M. Maslinska (*)
National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
e-mail: klinika.zapaleniastawow@spartanska.pl
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_10
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M. Maslinska
Terminology
In recent years, clinicians involved in autoimmune rheumatic diseases (ARD)
research and the International Sjögren’s community discussed and in 2025 finally
changed the name of this disease from the initial “Sjögren’s syndrome” to “Sjögren’s
disease”. This change was explained by the need to draw attention to the systemic
and organ characteristics of the disease. The term secondary Sjögren’s syndrome
was also withdrawn so as not to give the impression of its lesser significance, unimportance in relation to the disease with which it coexists.
The use of possessive or non-possessive form of the Sjögren’s surname in the
name of the disease was left to the individual or journal preference.
In the International Statistical Classification of Diseases and Related Health
Problems tenth Revision (ICD-10), Sjögren’s syndrome for years was identified as
sicca syndrome with code M35.0 [1]. In the new International Classification of
Diseases 11th Revision (ICD-11), it is classified as belonging to the diseases of the
immune system, a subgroup of acquired immunodeficiencies and a part of “overlap
or undifferentiated non-organ specific systemic autoimmune disease” with codes:
4A43.20 (primary SjS); 4A43.21 (secondary SjS); 4A43.22 paediatric onset Sjögren
syndrome [2]. The additional codes in ICD-11 system can be added to better
describe features of the main disease, e.g. MG30.30 Chronic secondary musculoskeletal pain from persistent inflammation. As it is easy to notice, the ICD-11
nomenclature, despite the current approach, retains the distinction between the primary and secondary forms of SjD.
Sjögren’s disease is classified also as a rare disease; therefore, it is included in
Orphanet nomenclature of rare diseases (ORPHAcodes) with main ORPHA code:
289390 [3].
Genetic Predisposition
HLA Predisposition
Some HLA class II alleles contribute to SD susceptibility—in several studies, association between HLA and SjD was confirmed in patients with anti-SSA/Ro and/or
anti-SSB/La autoantibodies.
The HLA-B8, HLA-DW3, HLA-DR3, and DRw52 genes were recognized as
genetic factors, which presence is responsible for the predisposition to SjD development. The polymorphism of the interferon regulatory factor 5 (IRF 5) gene may also
play a similar role [4].
There were HLA class II phenotypes identified, which support epitope spreading: HLA-DR15 favours anti SS-A synthesis, whereas HLA-DR3 is associated with
both anti SS-A and anti SS-B production. Table 1 presents the genes considered to
be important for the risk of developing SjD [4].
Sjögren’s Syndrome
229
Table 1 The risk genes for SjD development
Interferon signature-associated genes
Interferon regulatory factor 5 (IRF5), signal transducer and activator of transcription 4
(STAT4), interleukin 12A (IL12A) and natural cytotoxicity triggering receptor 3 (NCR3)
B and T cell function-associated genes
B lymphocyte kinase (BLK), B cell activating factor (BAFF), early B cell factor 1(EBF1),
general transcription factor IIi (GTF2I), C-X-C chemokine receptor type 5 (CXCR5), tumour
necrosis factor superfamily member 4 (TNFSF4), TNF-alpha-induced protein 3 (TNFAIP3),
TNFAIP3-interacting protein 1 (TNIP1), lymphotoxin-α (LTA), C-C motif chemokine 11
(CCL11)
Other genes
Serotonin transporter (HTT, solute carrier family 6 member 4; SLC6A4)
Genome-Wide Association Studies
Currently, genome-wide association studies (GWAS), examined mainly in small
cohorts, provide additional information about the number of risk genes that fall
outside the antigen-presenting clusters. In SjD, overexpression/dysregulation of
genes activated by type I interferons (IFNα/β) in salivary glands and peripheral
blood plays a role in the lymphocyte infiltration, autoantibodies production, cell
apoptosis and inflammation [5]. Activation of type I interferons is triggered by several external and internal predisposing factors, mainly viral infections, ultraviolet
radiation, immune complexes, and genetic predisposition. It is worth emphasizing
that IFN I signature is associated with defence/protection against viral infections.
Upregulation of the production of type II interferons (IFNγ), although not dominant in SjD, is associated with lymphoma development in this disease [6, 7]. Mainly
T and NK cells, as well as dendritic cells, macrophages and B cells, produce IFNγ
as a consequence of induction of INF II signature genes. IFNγ promotes antimicrobial protection (host defence), apoptosis, inflammation and tissue damage.
It is possible that a variable imbalance between INF I and INF II types of activation leads to the development of different clinical phenotypes of the disease.
Single-cell RNA sequencing identifies the subsets of IFN gene-enriched monocytes, CD4+ T effector memory and XCL1+ NK cells as potential risk factors of the
development of childhood SjD, especially in cases with recurrent parotitis—the
most common symptom of this disease in children [8]. Researchers found a unique
cluster of monocytes with type I and II IFN-related genes in childhood SjD. An
in vitro study on the regulatory T cell functional assay revealed stable functionality
in childhood SjD, whereas reduced suppression was observed in adult SjD.
Examples of the significant risk loci identified with GWAS are presented in
Table 2.
Knowledge about potentially important genetic susceptibility loci for SjD is constantly expanding, including the identification of new ten Sjögren’s genetic susceptibility loci in the largest GWAS to date of Sjögren’s of European ancestry, nearly
doubling the total number of identified genetic risk loci from 12 to 22 [10]. Further
studies will be necessary to confirm whether the identified genes influence the
pathology of the disease.
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M. Maslinska
Table 2 Significant risk loci identified with GWAS [9]
Gene
HLA-DQB1
HLA-DQA1
HLA-DRB1, HLA-DQA1
HLA-DQB1, HLA-DQA2
IRF5-TNPO3
STAT4
TNFAIP3
SNP
rs115575857
rs116232857
rs9271573
rs9275572
rs3757387
rs10553577
rs5029939
IRF5-TNPO interferon regulatory factor 5–transportin-3, SNP single nucleotide polymorphisms,
STAT-4 signal transducer and activator of transcription (STAT) 4, TNFAIP3 tumour necrosis factor,
alpha-induced protein 3
Epigenetics
Epigenetics is associated with processes influencing gene expression without affecting the actual DNA sequence. These processes include histone modifications, non-­
coding RNA activity and DNA methylation, the last of which is the most thoroughly
studied epigenetic mechanism in SjD. The addition of methyl (CH3) groups at cytosine guanine dinucleotide (CpG) sites in gene promoter regions (hypermethylation)
generally results in repression of gene expression. Conversely, hypomethylation of
DNA is associated with augmented gene expression levels.
Recent studies indicate that disruption of m6A RNA modification in salivary
glands epithelial cells (SGECs) in response to inflammatory factors promotes the
production of dsRNA, which potentially enhances the interferon loop and is important in the pathogenesis of SjD [11].
Transcriptomic studies of SjD SG showed increased expression of genes associated with tissue recruitment and long-term survival of Trm cells (CD8 + CD103+).
A higher incidence rate of CD8 + CD103 + CD69+ cells was confirmed in SjD salivary glands compared to nonspecific sialadenitis (nSS). CD8+CD103+ Trm cells
are associated with, among others, the secretion of granzyme B and interferon γ.
The potential usefulness of intraglandular blockade of CD 103 in SjD in reducing
glandular damage and improving salivary flow was also studied [12].
Similar to GWAS concerning SjD, a large-scale epigenome-wide association
studies (EWAS) were established and currently include ≥100 patients with
pSS. However, some non-HLA variants associated with SD were demonstrated to
be present also in other autoimmune diseases such as systemic lupus erythematosus
(SLE), rheumatoid arthritis (RA) or multiple sclerosis (MS) [6, 13]. Table 3 presents
examples of epigenetic mechanisms influencing gene expression.
Sjögren’s Syndrome
231
Table 3 Examples of epigenetic mechanisms influencing gene expression [6, 13]
DNA modifications
Histone modifications
RNA modifications
Cytosine methylation and hydroxymethylation
Phosphorylation
Methylation
Citrullination
Ubiquitylation
Acetylation
Ribosylation
Simulation
Methylation
Adenosine-to-inosine editing
5-Methyluridine modification
2′-O-methylation
N4-Acetylcytidine
7-Methylguanine
5-Methylcytosine
N6-Methyladenosine
N1-Methyladenosine (m1A)
Outline of the Pathogenesis
The pathogenesis of SjD is still not entirely clear, and the knowledge of factors
responsible for its development is constantly expanding.
Inflammatory response in susceptible individuals, triggered by environmental or
endogenous antigens, constitutes the basis for the initiation of the autoimmune process in SjD. The susceptibility to the SjD development is associated with certain
major histocompatibility complex (MHC) alleles, sex hormone imbalance, extraand intra-environmental factors such as infections, as well as (as discussed in the
previous paragraphs) with genetic and epigenetic factors. Of the environmental factors, viral infections play the most prominent role, especially Epstein–Barr virus
(EBV), human T cell lymphotropic virus type 1 (HTLV-1), cytomegalovirus (CMV)
and hepatitis C virus (HCV) [14, 15].
The infectious agent often activates the process of breaching of the immune tolerance not at the time of the primary infection, but during the reactivation of the
latent form of the pathogen. An example of such a phenomenon is an infection
with EBV.
The development of SjD begins with a damage of the epithelial barrier and the
release of autoantigens from affected epithelial cells. The autoimmune process may
involve both mechanisms of innate and adaptive immunity.
The autoantigens release triggers innate immunity through the activation of epithelial (EC) and dendritic (DC) cells. Dendritic cells are the link between the innate
and adaptive immunity and promote immune defence and maintenance of immune
tolerance. Chemotaxis and migration of DCs are triggered by interactions between
chemokines and their receptors and regulated by multiple intracellular mechanisms.
In response to antigenic stimulation, production of type I and II interferons also
enhances maturation and migration of DCs and production by these cells of IL-12.
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At the next stages of immune response to antigens macrophages, neutrophils, helper
T cells and human B lymphoblastoid cells play an important role in the activation of
natural killer cells (NKCs) and stimulation of Th1 cells.
Both NKCs and Th1 cells stimulate secretion of interferon gamma (INF-γ),
which is responsible for the tissue damage, and secretion of B cell activation factor
(BAFF), produced by both T and B cells. The production of BAFF is also activated
by DCs and strongly stimulated by IFN-α, released by plasmacytoid dendritic cells
(pDCs). Furthermore, the BAFF secretion is stimulated by the activation of innate
response by Toll-like receptors (TLR-9, TLR-7) [16].
The BAFF overproduction causes persistent stimulation of B cells, which causes
the loss of T cell control on B cell production, and leads to the breach of self-­
tolerance by T and B cells. In SjD, the activation of B cells also leads to overproduction of immunoglobulins, predominantly against ribonucleoproteins: anti SS-A, anti
SS-B antibodies and the formation of tertiary lymphatic organs (germinal centres—
GCs). As a consequence of these events, affected tissues (especially the salivary
glands) display the overexpression of cytokines like tumour necrosis factor (TNF),
lymphotoxin-α (LTα; formerly TNF-β), chemokines (CXC; ligand 13, 9, 21). This
process (chronic antigen stimulation → activation by BAFF of the autoreactive
autoantibodies production by B cells → presence of GC-like structures) can lead to
the development of lymphoma. Marginal zone B cell lymphoma (MZBCL) particularly mucosa associated lymphoid tissue (MALT) type has been observed in about
8–10% of SjD patients—40-fold frequency of the MZBCL in the healthy population [17, 18].
Autoantibodies in Sjogren’s Disease
Sjögren’s disease is a model autoimmune disease with autoantibodies production.
However, in current classification criteria, only one set of autoantibodies is
included—anti-Ro/anti SS-A antibodies (without distinguishing between Ro-52
kDA and Ro-60 kDA antibodies); however, a number of other autoantibodies are
associated with this disease (see Table 4).
Antinuclear Antibodies
A basic immunological test for autoantibodies, used in the diagnostics of autoimmune rheumatic diseases (SARDs) including SjD, is the test for the presence of
antinuclear antibodies (ANAs) [19, 20]. These antibodies are found in 80–90% of
patients with SjD. Antinuclear antibodies react with the components of the cell
nucleus and are most often tested with indirect immunofluorescence (IF) on HEp-2
(human epithelial cell) cell line. In SjD, ANAs often occur in higher titers (above
1:320) but may also be detected in lower titers (1:160) and in the concurrent presence of other autoantibodies.
Sjögren’s Syndrome
233
Table 4 Main autoantibodies with importance in SjD [26–28]
Autoantibody
Anti-Ro52 kD
Anti-Ro60 kD
Anti SS-B/La
RF
ACPA
Anti-CENP-B
Novel autoantibodies
Anti-CA6
Anti-PSP
Anti-SP1
Anti-CEP-1
Anti-M3R
Anti α-fodrin antibodies
Autoantibodies binding to
stathmin-4
Anti-ganglioside antibodies
(anti-GM1 IgG, IgM)
Onconeural antibodies
Anti-GW182 antibodies
Clinical findings
Interstitial lung disease
Haematologic changes, photosensitivity, skin involvement,
Raynaud’s phenomena and dryness
Liver (autoimmune disease) PBC
Dryness, hypergammaglobulinaemia and leukopenia
Arthralgia and arthritis
Interstitial lung disease and fibrosis
Dryness and renal tubular acidosis
Dryness
Dryness
Arthritis and renal tubular dysfunction
Autoimmune sialadenitis, leukopenia, diabetes mellitus type 2
Neurologic manifestations, recurrent parotid swelling and
Hashimoto thyroiditis
In IgG3 class polyneuropathy, vasculitis
Possible connection with CNS involvement may be present both
with and without CNS symptoms
Possible connection with CNS involvement may be present both
with and without CNS symptoms
May be present as a paraneoplastic symptom
May be present in pSS and SLE with sensory polyneuropathy
and sensory and motor-sensory ataxic polyneuropathy
RF rheumatoid factor, ACPA anti-citrullinated proteins antibodies, Anti-CA6 Ab anti-carbonic
anhydrase 6 antibodies, Anti-PSP anti-parotid secretory protein antibodies, Anti-SP1 anti-protein
1, Anti-CEP-1 antibodies to citrullinated-enolase peptide1, Anti-CENP-B Ab anti-centromere antibodies (B), Anti-M3R anti-muscarinic 3 receptor, ASMAs anti-smooth muscle antibodies
Antibodies Against Ribonucleoproteins
Anti SS-A/Ro antibodies are associated with small cytoplasmic RNAs [21, 22]. The
antigen for these antibodies includes two different kinds of proteins—Ro60kD and
Ro52kD, each of them having different gene localization: Ro60kD—on chromosome 19 and Ro-52kD on chromosome 11. The SS-A/Ro (60KD + 52KD) complex
is currently known to be present on most cells, including platelets and erythrocytes.
These two proteins, the anti SS-A/Ro antibodies, play a pathogenic role in SjD and
are associated with more severe symptoms, lymphadenopathy, larger salivary glandular infiltrates, characteristic vasculitis and longer duration of the disease [23, 24].
The occurrence of interstitial lung disease (ILD) is associated with anti-Ro52
presence.
Rheumatoid Factor
Rheumatoid factor (RF) is the most common autoantibody in patients with autoimmune rheumatic diseases including SjD and was confirmed in 70–90% of SjD
patients [25]. Rheumatoid factor is directed against antigenic sites of the Fc region
of human IgG.
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M. Maslinska
Presence of RF may occur in various clinical situations, both in case of infectious
and non-infectious disease, such as mononucleosis, tuberculosis, syphilis, leprosy,
malaria, leptospirosis or sarcoidosis. Rheumatoid factor can be also present, in low
serum concentration, in elderly subjects (over 75 years old), and can occur in total
in 1–4% of the general population [26]. In clinical practice, RF is mainly detected
in IgM subclass of immunoglobulins (RF-IgM, classical RF); however, other isotypes of RF (IgG, IgA) are also produced [27].
It has been proven that RF-IgM correlates with more severe course of SjD (lower
Schirmer’s test, higher ESSDAI, leukopenia, higher level of gammaglobulins, ANA
titer, anti SS-A and anti SS-B autoantibodies). Studies suggest that RF-IgA may
indicate more severe bone involvement/inflammation and the extraarticular manifestations of SjD [28].
In Table 4, the main and novel or not full established in SjD autoantibodies are
summarized.
Sjögren’s Disease Development Risk Factors
Several studies and metanalysis identified six risk factors for SjD development:
infection, former or current smoking, female gender, a history of pregnancy, a family history of autoimmune disease of first-degree relatives, polymorphisms of the
IRF5 gene (CGGGG insertion/deletion) and the number of stressful negative life
events >1 [28]. Also, other autoimmune diseases, particularly RA and SLE, can
predispose to SjD development.
Genetically susceptible patients exposed to certain environmental factors can
develop a specific SjD phenotype, e.g. interstitial lung disease associated SjD (ILD-­
SjD), lymphoma associated SjD (L-SjD), dryness associated SjD (D-SjD) depending on constellation of risk factors [28].
Current Classification Criteria
Current classification criteria for diagnosis of SjD were presented and published
simultaneously by EULAR and ACR [29] in 2019 (Table 5). It should be noted that
in the course of establishing a diagnosis, the establishing of the positive score for
the classification criteria must be confronted with the differential diagnosis, taking
into account alternative clinical states, including those constituting exclusion criteria for SjD. Although experts point out that there is high incidence of anti-Ro-52
antibodies in rheumatic autoimmune diseases (RA, SLE, MCTD, etc.) and suggest
focussing on anti-Ro-60 antibodies in SjD cases (what may be difficult due to the
availability of quantitative tests for both of these autoantibodies) [30], the classification criteria rely on the single immunological parameter of anti-Ro, without distinguishing between anti-Ro52 and anti-Ro60 antibodies.
Sjögren’s Syndrome
235
Table 5 EULAR/ACR classification criteria for Sjögren’s syndrome [29]
Feature
Points
Presence of anti-Ro(Ro52/Ro60kDA)/anti SSA antibodies)
3
Immunological part
3
histopathology
Histopathological assessment of minor
salivary glands biopsy (MSGB)* with
mononuclear cells infiltration (1 Focus 50
cells) focus score ≥ 1
≥ 5 pkt
1
van Bijsetveld ocular dye score*** > 4 pkt
1
Ocular stainingscore (OSS)**
Schirmer ’s test****
<5mm/5minute 1
Unstimulated salivary flow < 0.1 ml/min*****
Exclusions
dryness
1
Head and neck radiation
Active HCV infection (PCR confirmation)
AIDS (acquired immune-deficiency syndrome)
Sarcoidosis
diagnosis of IgG4-related disease
Amyloidosis
Graft-versus-host disease (GVH)
Comments to the Elements of Classification Criteria
Establishing a SjD diagnosis is possible with 4 or more points assigned according
to the classification criteria and no exclusion criterium met.
*Histopathological assessment of minor salivary glands biopsy (MSGB) is crucial in the diagnostic of SjD and provides important information for SjD diagnosis
(Fig. 1 and IB) [29]. Results of histopathological assessment have a high diagnostic
value for SjD—specificity (X ± SD = 88.1 ± 11.7) and sensitivity
(X ± SD = 78.8 ± 11.2), with diagnostic confidence in terms of positive predictive
value (X ± SD = 87.6 ± 9.5) and negative predictive value (X ± SD = 79.0 ± 16.9)
[31]. For the purposes of SjD classification criteria, the histopathological assessment is viewed as positive, when at least 1 focus of ≥50 inflammatory cells per
4-mm2 section is present. However, infiltration with mononuclear cells can be present in other diseases such as sarcoidosis, IgG4-RD, human immunodeficiency virus
(HIV) infection, as well as in other viral infections, in which lymphocytes are the
targeted cells (EBV, CMV, HCV) [32]. Therefore, in the case of a strong suspicion
236
a
M. Maslinska
b
Fig. 1 (a) Picture of MSGB (H&E × 100). Focal lymphocytic inflammatory infiltrate—Focus
score 1 (more than 50 inflammatory cells/4 mm2) (Department of Pathological Anatomy, National
Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw). (b) Picture of MSGB
(H&E × 100). Secondary lymph node, germinal centre (red border). (Department of Pathological
Anatomy, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw)
of other than SjD cause of mononuclear infiltrations and sialadenitis, the immunochemistry with cell identification by cluster of differentiation (CD) can be useful. In
one analysis, 54% of anti SS-A/Ro-negative patients had positive histological evaluation which pointed to necessity to MSGB in immunological-negative subjects with
suggestion of SjD symptoms [33].
In the MSGB, it is important to (a) avoid the glandular-free zone in the centre of
the lower lip and (b) optimally obtain at least five glandular lobules for the diagnosis
of SjD [34].
Possible complications of MSGB include, among others: intra- and post-­
operative bleeding, transient or chronic pain, hyper- or hypoesthesia, local inflammation, wound infection, suture dehiscence and cheloid scars. The prevalence of
long-lasting complications was reported in 11–21% of examined patients [34, 35].
**Ocular staining score (OSS) is a method useful to assess conjunctival and
corneal consequences of a dry eye disease (DED) in SjD (Fig. 2) [36]. This examination requires slit lamp and is more difficult to interpret if assessed by a person
without sufficient ophthalmologic experience. Staining with lissamine green allows
assessing conjunctiva; fluorescein staining points to a corneal damage. To fulfil
classification criterion for SjD, OSS should be equal or above 5 for one eye.
***The van Bijsterveld ocular dye score (vBS) uses Lissamine Green (preferred)
or Rose Bengal for conjunctival assessment and fluorescein for corneal assessment,
with maximum of 9 points for one eye (Fig. 3). The scores in assessment: none (0),
sparsely scattered (1), densely scattered (2), confluent spots (3) each for three parts
of a single eye [37].
****Schirmer’s Test
This is a basic test to assess tear production and mainly reflects the secretion of the
aqueous phase of tears. This test is relatively easy to perform, inexpensive, with
moderately reproducible visualization of specific lesions, high reliability of
Sjögren’s Syndrome
237
3
3
3
Patches of confluent staining + 1
Staining in papillary area + 1
Maximum
9
One or more filaments + 1
Max
12
Max 3
Fig. 2 Ocular staining score [36]
3
3
3
Positive ≥4
Maximum
9
Fig. 3 van Bijsterveld ocular dye score [37]
assessment among trained persons, low discomfort for patients. Calibrated strips of
a non-toxic filter paper are used. One free end is placed within a lower eyelid with
eyes gently closed for 5 min. The paper strips are removed from each lower eyelid,
and the amount of wetting of the paper strips is measured. Both eyes are tested at the
same time. It is important to note that before the test artificial tears should not be used.
Other methods of assessment of DED in this disease, not used in the classification criteria, include tear breakup time (T-but), tear film osmolarity measurement,
study of tear components and tears cytological examination.
***** Unstimulated Salivary Flow (USF)
One hour before the performance of this test, the intake of any food or beverage
(water exempted), smoking and chewing gum is prohibited. During USF, the patient
should make as little head movement as possible and swallow before the test begins.
Collection of saliva should take 1–5 min. The final result is presented as a ratio of
the volume of the obtained secretion (mL) per unit of time (1 min) [38].
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M. Maslinska
Salivary flow rate is important not only for SjD diagnosis but also for the management of mouth dryness. For the purposes of mouth dryness management, the
stimulated salivary flow rate (SSFR) test can also be performed. Detection of
hyposalivation (<10 mL/min) in SSFR may be attributed not only to the destruction
of the salivary glands, but also to their inflammation. Differentiating between these
two situations influences the choice of proper symptomatic and pharmacological
treatment [39].
Clinical Presentation
General Symptoms
Chronic fatigue and general weakness are most important of general symptoms in
SjD, which also include myalgia, arthralgia, widespread pain, depressive mood and
anxiety; in some cases, a clinical picture meets classification criteria for fibromyalgia diagnosis as well [40]. Weight loss and fever are not dominant conditions; their
combination with lymphadenopathy requires a broader differential diagnosis in particular; in patients with a longer course of the disease, such symptoms may raise
suspicion of the development of a lymphoproliferative process. Reynaud’s phenomenon may also accompany SjD usually with nonspecific changes in nailfold capillaroscopy; livedo reticularis may occur as well.
Skin Changes
In Sjögren’s disease, skin changes can also be present, such as hypersensitivity to
sunlight, skin dryness (xeroderma), discoid rash, erythema annulare, features of
leukocytoclastic vasculitis with purpura, purpura in the course of symptomatic
cryoglobulinemia and/or urticaria-like lesions. Patients with the presence of cryoglobulins in serum, high concentrations of anti-Ro/SSA and anti-La/SSB autoantibodies are at greater risk of vasculitis and purpura [41].
Exocrine Glands
Exocrine glands are the target of autoimmune process in SjD. Glandular dysfunction may affect not only the salivary or lacrimal glands, but also other glands, e.g.
the glands of the respiratory, digestive and urogenital tract, the exocrine function of
pancreas or gallbladder.
Therefore, patients with SjD often suffer from kidney stones, gallbladder
stones or salivary gland stones. Combination of such clinical features raises a
suspicion of SjD. Patients experience dryness of the mouth and eyes; women suffer additionally from vaginal dryness. However, it should be remembered that
dryness is not an early symptom of SjD—it may be reported even years after the
true onset of the disease.
Sjögren’s Syndrome
239
ry Eye
D
Keratoconjunctivitis sicca (KCS), caused by a decreased tear production or increased
tear film evaporation, is the most frequent cause of complaints concerning the organ
of sight in SjD [42]. It manifests itself with a feeling of dryness described as sandy-­
gritty eye irritation, burning, stinging and feeling of tired eyes. Patients suffer from
pain, eye redness or even decreased vision. Dry eye in SjD is associated mainly with
a decreased production of aqueous phase of the tears. However, irritation of the
eyelids, known as blepharitis or meibomian glands dysfunction (MGD), can also be
present in SjD [43]. Meibomian glands dysfunction additionally promotes evaporation of the tear film. Severe complications of SjD-DED include corneal ulcers, band
keratopathy, cicatrizing conjunctivitis (PCC), eye infections and vision deterioration. Patients quite often complain of contact lens intolerance.
Several environmental factors may themselves cause or influence an existing
DED. These include dust, smoke, dry air, air-condition, long periods of watching
television/computer screen (causing less frequent blinking) or use of contact lenses.
Factors such as certain drugs (antihistamines, β-blockers, diuretics, antispasmodics,
psychotropic), vitamin A deficiency, allergies and menopause can also cause or
intensify dryness. Age may also influence the development and severity of DED
(age-related dry eye—ARDE) with and without SjD.
The incidence of DED varies in autoimmune rheumatic diseases; it can affect
approximately 95% of patients in SjD, 38–47% in RA, 37–79% in systemic sclerosis (SSc) and up to 39% in SLE [44].
Other causes of DED and keratoconjunctivitis, which should be considered in the
differential diagnosis, include sarcoidosis, lymphoma, graft-versus-host disease
(GvHD), acquired autoimmune deficiency (AIDS), diabetes, trachoma (cause chlamydia trachomatis), VII cranial nerve damage, reflex motor block (central damage
of VII cranial nerve), reflex sensory block (trigeminal nerve denervation), refractive
surgery (laser assisted keratomileusis-LASIK; photorefractive keratoplasty—
PRK) [45].
Mouth Dryness
Reduced salivary flow can manifest itself with the disruption of the oral microbiome, a tendency to mucositis, the development of canker sores or dental caries. It
also leads to the inadequate preparation of the consumed food for a further passage
through the gastrointestinal tract. Younger patients, including children, often do not
experience a clear dryness, but functional tests of the salivary glands can demonstrate decreased salivary flow, and mucosal changes, as well as recurrent sialadenitis
or a tendency to develop lithiasis, may raise suspicion of dryness.
Vaginal Dryness
Vaginitis caused by dry vaginal mucosa is often overlooked by doctors, yet it is not
uncommon (patients are hesitant to discuss this issue). The onset of menopause can
further increase the severity of symptoms and discomfort. Dryness can cause soreness or itching around the vagina. It also can cause pain and discomfort during
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M. Maslinska
intercourse (dyspareunia), a need to urinate more frequently and frequent urinary
tract infections [46].
hroat and Upper Respiratory Tract
T
Upper respiratory tract dryness manifests itself with dry throat or nasal passages,
swallowing difficulty, hoarseness or voice change; it results in a need to drink
more often or to use artificial saline. The dry cough, asthma-like symptoms and
prevalence to infections can also be associated with upper respiratory tract epithelium dryness.
Musculoskeletal System
The most common symptom of SjD concerning the musculoskeletal system is joint
pain (arthralgia), myalgia and morning stiffness. Inflammation is usually symmetrical, transient and non-destructive and occurs less frequently than arthralgia. Joint
involvement may precede the SjD diagnosis, as well as the ACPA positivity [47].
However, in presence of ACPA, the monitoring of a possible RA development
should be carried out.
Myalgia and proximal muscle weakness can also occur in SjD, but this is a rarer
symptom. In such cases, histopathological examination may also reveal inflammation; it was found in 72%, while signs of degeneration/regeneration (myositis) were
found in 47% of the patients [48]. Fibromyalgia and fatigue may influence the
arthralgia and myalgia and should be taken into consideration in differential
diagnosis.
Autoimmune diseases such as SjD also influence the bones structure due to a
frequently present low level of vitamin D and inhibition of bone formation. The
level of DKK1 (Dickkopf-related protein 1), a protein which is involved in the
Wnt pathway, is reduced. The disbalance of Nf-κB receptor activating factor
(RANK), its ligand (RANKL) and osteoprotegerin (OPG), all players in bone
formation and drugs (especially glucocorticosteroids) are cause of osteoporosis
and osteomalacia [49, 50].
Lungs and Other Respiratory System Elements
Changes in the mucosa of the upper respiratory tract may cause recurrent infections,
dry cough and symptoms suggesting bronchial hyperresponsiveness. In the case of
the lower respiratory tract, inflammatory changes occur in the interstitial tissue, taking the form of the development of interstitial lung disease, most often of the idiopathic interstitial pneumonia type (NSIP), less frequently of usual interstitial
pneumonia (UIP) and lymphocytic interstitial pneumonia (LIP) (Fig. 4a, b) [51].
Pleural changes are rare and usually not isolated. In severe cases and in rapidly
progressing pulmonary changes, lung tissue destruction may occur, with consequent effects affecting the cardiovascular system (pulmonary hypertension, right
and biventricular failure). Such a condition may require lung or a lung and heart
transplantation.
Sjögren’s Syndrome
a
241
b
Fig. 4 (a) The volume-reduced lungs with features of advanced fibrosing NSIP pattern. Fibrous
interstitial changes (over 20% of the lungs). Redundant thickening of the bronchial walls. The
mediastinal and hilar nodes moderately enlarged. The heart enlarged throughout. The pulmonary
artery trunk dilated 41 mm (Department of Radiology. National Institute of Geriatrics,
Rheumatology and Rehabilitation, Warsaw). (b) Throughout the lungs, scattered clusters of round
and oval thin-walled air spaces varying in size from 4 to 25 mm visible against a background of
ground-glass shadows and reticular changes. LIP. The pleural cavities free of fluid. Mediastinal
and hilar lymph nodes moderately enlarged. Destruction of the lung parenchyma resulting in the
formation of uncountable cystic air spaces, occupying approximately 80% of the lung. (Department
of Radiology. National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw)
Cardiac Involvement
This disease is not directed to cardiovascular system; however, the consequences of
lung involvement, i.e. pulmonary hypertension with secondary heart failure (mainly
right ventricular) as well as the effects of vasculitis or secondary antiphospholipid
syndrome on the vascular system should be taken into account.
Digestive System
Patients with dryness may experience dysphagia resulting from both dryness itself
and oesophageal motility disorders in the case of autonomic neuropathy. The exocrine pancreatic dysfunction with reduced amylase and lipase production may be
present. Chronic gastritis, malabsorption, susceptibility to Helicobacter pylori
infection can also occur, as well as the celiac disease, colitis and gluten sensitivity
were reported [52].
Dysautonomia and small fibre neuropathy (SFN) may cause abnormal oesophageal motility, gastroparesis and intestinal dysmotility. The symptoms such as
abdominal pain, diarrhoea and/or constipation—similar symptoms to irritable
bowel syndrome (IBS) may be present. Gastro-oesophageal reflux disease (GERD)
is common and often more severe in Sjogren’s with symptoms such as heartburn,
chronic cough, chest pain or upper abdominal pain.
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M. Maslinska
Pancreatitis as exocrine gland dysfunction/inflammation may also co-exist with
other features of SjD with symptoms such as upper abdominal pain, nausea, vomiting and fever.
Abnormal liver function tests are quite common in SjD. The overt liver disease
may be observed, such as primary biliary cholangitis (PBC) with anti-mitochondrial
antibodies (AMA-M2) and elevation of alkaline phosphatase serum concentration,
autoimmune hepatitis (AIH) or non-alcoholic fatty liver disease.
Patients with SjD should be screened for celiac disease (CD) especially in the
presence of nausea, abdominal pain, bloating, diarrhoea (or constipation) or unintentional weight loss.
Currently, it is well known that intestinal dysbiosis (abnormal gut microbiome)
and small intestine bacterial overgrowth (SIBO) can also emerge in SjD [53].
Kidneys and Other Urinary Tract Elements
Chronic tubulointerstitial nephritis is the dominant form of involvement of these
organs associated with Sjögren’s syndrome. Most often, it is distal tubular acidosis
(RTA), for which impaired elimination of hydrogen ions (H+) is characteristic. Such
a situation may lead to metabolic acidosis or—in the case of a less severe disorder—
to acidification of urine (after oral acid load) [54]. Symptoms may result from hypokalaemia and less frequently lead to nephrolithiasis and osteomalacia. In SjD,
glomerulonephritis (membranous-proliferative type) with proteinuria or in the
course of cryoglobulinaemic vasculitis may occur. A chronic interstitial cystitis (IC)
is a rare manifestation of SjD, mostly affecting middle-aged women with dysuria,
urinary frequency and suprapubic pain [55].
Nervous System
Central Nervous System
Central nervous system (CNS) involvement in SjD is difficult to determine and
diagnose and may precede the diagnosis of SjD. Symptoms are heterogeneous and
may be focal or diffuse. Diffuse manifestations include memory loss, cognitive dysfunction, impaired concentration and attention (recurrent “subacute encephalopathy”). Focal neurological symptoms include motor/sensory deficits, dysarthria,
cerebellar ataxia or seizures. Spinal cord involvement may occur, typically presenting as transverse myelitis, neurogenic bladder or features of lower motor neuron
disease. Manifestations of CNS involvement also include cranial neuropathies. The
most common cranial neuropathy is trigeminal neuropathy. It usually progresses
quite slowly, with predominant sensory symptoms. It can affect one side, but bilateral involvement of the V nerve has also been described. In some patients, V nerve
neuropathy may coexist with sensory neuropathy or small fibres neuropathy. Cases
of vestibulocochlear nerve involvement and associated sensory deafness are also
Sjögren’s Syndrome
243
described in the literature. Occasionally, these patients also suffer from concomitant
optic neuropathy. In some patients, the oculomotor nerve is damaged. Dysfunction
of the motor branches is significantly less common, with the facial nerve most often
affected. Loss of smell may also occur due to involvement of the I olfactory nerve
[56]. Optic neuritis with vision loss and eye pain may be a precursor to complications of SjD, namely to demyelinating syndrome [57].
The multiple sclerosis-like syndrome (MS-like syndrome) deserves particular
attention; some studies indicate that up to 20% of patients diagnosed with MS actually have SjD with CNS involvement. Neuritis optica spectrum disorders (NMOSDs),
associated with the presence of anti-aquaporin-4 (AQP4) antibodies, may also occur
in pSS and be associated with longitudinal myelitis. Limbic system involvement in
pSS is very rare and poses a significant diagnostic challenge. Cases of limbic
encephalitis have been reported, with patients presenting with a variety of symptoms, including cognitive impairment, mental changes and seizures.
Peripheral Nervous System
Among patients with SjD, the most frequently diagnosed neuropathies were sensory
neuropathies, including small fibre neuropathies, axonal sensorimotor neuropathies,
multifocal mononeuropathies, polyradiculopathies and autonomic neuropathies,
which have been associated with a poorer prognosis [58–60]. Depending on the type
of fibres involved, polyneuropathy is divided into large fibre polyneuropathy with
involvement of myelinated A alpha and A beta fibres, and small fibre neuropathy
with involvement of unmyelinated C fibres and thinly myelinated A delta fibres.
Large fibre neuropathy (LFN) occurs in approximately 15% of patients with SjD,
more frequently in women around 60 years of age. Among patients diagnosed with
LFN, approximately half have distal axonal sensorimotor neuropathy, and another
sensory neuropathy. Motor neuropathy accounts for less than 1% of cases. Symptoms
are usually symmetrical, primarily in the distal lower limbs. Paraesthesia is a common symptom. Physical examination reveals decreased superficial sensation, proprioception and vibration sensation. Sensorimotor neuropathy also presents with
motor disturbances (most often affecting the toe extensors; in some patients,
Achilles tendon reflexes are absent). In distal axonal neuropathy, symptoms vary
depending on the type of fibres involved. A-delta and C-fibre involvement typically
presents with burning, allodynia and pruritus and is worse at night and at rest.
Involvement of large fibres typically manifests as numbness or tingling and, in
severe cases, may result in muscle spasms, atrophy and difficulty moving.
Sensory neuropathies account for approximately 20% of all peripheral neuropathies. They are usually caused by damage to the sensory ganglia [61]. Due to
impaired proprioception in this type of neuropathy, patients most often consult a
doctor with balance disorders.
Small fibre neuropathy (SFN) accounts for approximately 9% of the incidence
of neuropathies in SjD. Brinbaum J et al. [58] observed this neuropathy more frequently in men, and the presence of anti-Ro52-kDa and Ro60-kDa antibodies and
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RF was less frequently confirmed. Small fibre neuropathy affects the nerve endings
responsible for pain and temperature sensation. Symptoms usually appear symmetrically, in distal segments, and progress proximally. The problem primarily
affects the limbs, but in some patients, symptoms may also affect the face, scalp or
trunk [62, 63]. The most common symptoms reported by patients are hypersensitivity to painful stimuli or abnormal sensations. Patients describe the pain as shooting, and temperature sensation is impaired. Some individuals may also experience
autonomic symptoms or restless legs syndrome. Other causes of this neuropathy
should also be taken into account, such as diabetes, toxic factors such as alcohol
and certain medications (bortezomide, metronidazole, isoniazid, antiretroviral drugs).
Mononeuritis multiplex may indicate vasculitis, including changes in the vasa
nervorum. Depending on the nerve involved, physical examination may reveal
motor weakness, muscle atrophy and gait disturbances.
Ataxic sensory neuropathy is associated with asymmetric sensory disturbances.
Some patients experience concomitant autonomic symptoms, such as Adie’s pupil
(denervation of the ciliary sphincter muscle due to destruction of parasympathetic
fibres in the ciliary ganglion), palpitations and orthostatic hypotension. Significant
disability may result from ataxia, balance difficulties and proprioceptive disturbances. Patients with this type of neuropathy have normal muscle strength, but have
notably impaired or absent tendon reflexes and vibration sensation [64].
In SjD, a syndrome similar to Guillain-Barré syndrome (GBS) may occur.
Symptoms are usually symmetrical and begin in the lower extremities, but progress
to the trunk and upper extremities may be extended over time, lasting from several
days to a month. Other symptoms, such as neuropathic pain and cranial neuropathies, may also occur. The occurrence of these symptoms, regardless of the diagnosis of SjD, may be related to a previous infection, stress or trauma.
Psychoimmunology in SjD
Personality
Patient’s personality may also be affected in SjD. One of the studies confirmed that
individuals with SjD presented higher scores of neuroticism and lower scores of
extraversion and openness to experience compared to healthy individuals [65].
Depression was less pronounced than in RA patients, but SjD patients presented
elevated levels of anxiety. Symptoms consistent with brain fog and cognitive disturbances were also described in SjD. Particularly the previously described symptom
of chronic fatigue dominates the descriptions of patients’ complaints and is often
associated with deterioration of concentration or memory.
Depression
Depressed mood or diagnosed clinical depression is attributed to other psycho-­
sociological factors such as chronic fatigue, anxiety and the apprehension about the
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245
consequences of a chronic autoimmune disease. It is also understandable that fear
of developing lymphoma can be a strong factor in anxiety and low mood.
However, the prevalence of depression in SjD patients is comparable to that in
the general population. Patients with SjD and depression experience a poorer prognosis, a significantly reduced quality of life and a higher degree of disability.
Development of depression is influenced by the symptoms of dryness and the resulting problems, as pointed out by Cui et al. [66], such as dry mucous membranes
dysphagia. In addition, drugs used to treat depression (e.g. SSRI) can increase dryness of mucous membranes, which in the case of SjD should be taken into account.
This makes it difficult to assess disease activity, especially using EULAR Sjogren’s
Syndrome Patient Reported Index (ESSPRI) where dryness and chronic fatigue are
important components of the assessment.
Anxiety
As it was already mentioned, anxiety is more prevalent than depression among
patients with SjD. Fear of a chronic, not fully understood disease, with the risk of
lymphoma, in case of young women with SjD—a fear of complications affecting a
foetus during pregnancy or of a disease being inherited by their children, contribute
to the dominance of anxiety in this group of patients. Additionally, chronic fatigue
affects the reception and modifies the sensation of many stimuli [67, 68].
hronic Fatigue and Fibromyalgia
C
There are studies indicating an increased risk of development of SjD in patients
with fibromyalgia (FM), both males and females [69].
In the Gau et al. [69] study, patients aged 20–49 were particularly at risk of
SjD. It seems that the connection between SjD and FM is bidirectional and patients
with SjD develop FM more often than the general population.
The anxiety and chronic fatigue, present in FM, can affect the accuracy of the
assessment of the disease activity in SjD.
Features of FM such as widespread pain, fatigue, cognitive dysfunction (“brain
fog”) and sleep disturbances can also manifest themselves in the context of various
chronic diseases, including SjD. Chronic pain in SjD can be presented as both of
neuropathic and nociplastic type and may also be associated with small fibre neuropathy (SFN) [70].
As shown in FM, chronic pain and psychological factors are associated with
neuroinflammation, which activates immune cells in the central nervous system and
thus affects serum cytokine levels.
Neuroinflammation is a key mechanism in the pathogenesis of fibromyalgia with
systemic activation of T lymphocytes and an imbalance of proinflammatory cytokines such as T helper 17 (Th-17) in patients with fibromyalgia. Also, in SjD, proinflammatory cytokine disorders play an important role with increased activity of
Th-17 cells, with simultaneous expression of interleukin 17 and interferon gamma.
This is associated with chronic inflammation in SjD.
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Reduced activity of the hypothalamic–pituitary–adrenal (HPA) axis is also
important in both diseases; it may have an impact on the development of chronic
fatigue and insomnia.
Sleep Disturbances
In SjD, sleep disturbances are a common problem. Increased prevalence of nocturnal awakenings, obstructive sleep apnea and daytime somnolence were quite often
observed [71]. Polysomnography, psychological test for screening cognitive disfunction, fatigue and anxiety can improve management in SjD. Interventions, such
as cognitive behavioural therapy (CBT) for insomnia and nocturnal humidification
devices, have the potential to improve quality of patient’s life.
Pain in Sjögren’s Disease
The varied symptomatology and involvement of organs and systems, damage to
epithelia and the consequences of these pathological changes are the cause of various pain complaints. Patients with SjD, depending on the dominant symptom, the
most common of which are arthralgia (joint pain), burning and pain of the eyes,
enlargement or pain of the salivary glands, report to various specialists, such as a
rheumatologist, ophthalmologist, otolaryngologist or neurologist. It should be considered that pain is an unspecific symptom which may be caused by several other
pathologies such as osteoarthritis, hypothyroidism, hypercortisolism, vitamin deficiencies, depression or neoplasia [39]. On the other hand, some systemic complications of systemic SjD such as arthritis, hypokalaemia, osteomalacia, lymphoma,
peripheral neuropathy and SFN can be a cause of pain themselves. In SjD local
problems, such as salivary glands enlargement with sialadenitis, enlargement of
lymph nodes may also be a source of pain; such symptoms need be differentiated
from an active infection, while the development of a lymphoma (because of its
increased risk in SjD) has also to be taken into account. In Table 6, pain localization
and main causes in SjD are summarized.
Table 6 Pain localization and main causes in SjD
Localization of pain
Joints
Muscles
Eyes
Oral cavity
Clinical states and comments
Arthralgia with or without non-destructive arthritis
Myalgia, myositis
Feeling of sand under the eyelids—dryness, keratoconjunctivitis,
blepharitis
Increased dryness and changes in the oral microbiota may cause
damage to the mucous membrane (erosions, aphthous),
inflammation of the oral mucosa and chronic periodontitis
(periodontal disease)
(continued)
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247
Table 6 (continued)
Localization of pain
Salivary glands
Head
Vagina
Abdominal pain
Neuropathic and
nociplastic pain (with or
without small fibre
neuropathy), visual and
balance disturbances
Clinical states and comments
Especially in younger patients, salivary gland enlargement with
inflammation, a tendency of saliva thickening and the possibility
of stones occur more often. Salivary gland pain may be short-­
lived and occur after a strong stimulus stimulating the salivary
glands (meal, sour liquid, spicy dish) and during an infection,
most often viral.
Migraine type, chronic fatigue with “brain fog” and headaches
Vaginitis caused by dry mucous and the overlap of menopause
can additionally increase the severity of symptoms and
discomfort. Dryness can cause soreness or itching around the
vagina. It can cause pain and discomfort during intercourse
(dyspareunia), the need to urinate more often and frequent urinary
tract infections
Intestinal dysmotility produces abdominal pain, diarrhoea and/or
constipation, which are often interpreted as irritable bowel
syndrome (IBS)
Polyneuropathy, mononeuropathy multiplex (vasculitis),
fibromyalgia-like symptoms, Guillain-Barré-like symptoms
Table 7 Common autoimmune diseases in the course of SjD
Disease
Interstitial lung disease (ILD)
Primary biliary cholangitis
(PBC)
Autoimmune hepatitis (AIH)
Autoimmune pancreatitis (AIP)
Distal renal tubular acidosis
(RTA)
Sclerosis-multiplex like
syndrome
Guillain-Barré-like syndrome
Cryoglobulinaemia
Autoimmune thyroid disease
(AITD)—Hashimoto disease
Autoantibodies
Anti-Ro52 antibodies
Anti-mitochondrial antibodies (AMA)
Anti-smooth muscle antibodies (ASMA)
Elevated serum gammaglobulins, pancreatic amylase
Anti-carbonic anhydrase VI antibodies
Oligoclonal immunoglobulin G (IgG) bands (OCBs) and
lesional IgG deposition oligoclonal immunoglobulin G
(IgG) bands (OCBs) and lesional IgG deposition are
hallmarks of MS
Antibodies against gangliosides, nodal and paranodal
proteins
Cryoglobulins
Anti-thyroglobulin (anti-TG)—autoimmune thyroiditis
Anti-thyroid peroxidase (anti-TPO)—autoimmune
thyroiditis (AT)
Diseases Associated with SjD
As it is indicated by observations and certain common elements of pathogenesis, a
number of other autoimmune diseases, often associated with inflammation of the
epithelium, may co-occur and may also be an element of SJD. Table 7 includes the
most common autoimmune diseases described in the course of SjD [72].
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Lymphoma
Lymphoma affects approx. 5% of SjD patients [73]. Persistent stimulation of lymphatic cells may contribute to the development of lymphoma. Recognized risk factors for lymphoma development in SjD include prolonged disease duration,
cryoglobulinaemia, lymphopenia, decreased serum level of complement C3 and C4
components and the presence of a monoclonal component in serum and/or urine. A
high Focus score (>3), chronic enlargement of the salivary glands and the formation
of germinal centre-like structures may also signal the development of lymphoma. In
2024, Goules et al. [73] demonstrated that ESSDAI ≥5, RF and anticentromere
antibody pattern are main predictors for lymphoma in SjD.
Mortality
Diagnosis at the age over 50 years, ILD-SjD, vasculitis, thrombocytopenia, low
serum level of complement components (C3, C4) and cryoglobulinemia are risk
factors for mortality in SjD [74].
Clinical Phenotypes
Age
The age of a patient can have an impact of the clinical picture of SjD, with two
distinct types of age-dependent phenotypes of SjD being identified, concerning
young and elderly patients.
Juvenile SjD
Childhood onset of SjD (cSjD) is characterized by recurrent or persistent parotitis
and arthralgias, and more severe histopathology results, while symptoms of dryness
are rare. The prevalence of this diagnosis before the age of 18 years is reported at
only 1% of all SjD cases [75]. The majority of children diagnosed with Sjögren
disease did not meet classification criteria for adults [29]. The future challenge for
this group is to develop a more reliable diagnostic approach and more appropriate
diagnostic criteria.
Sjögren’s Disease in Elderly
In elderly patients with SjD, the following can be expected: the presence of autoantibodies (ANA and RF, anti SS-A/Ro and anti SS-B/La antibodies), more severe
dryness also resulting from salivary glands atrophy with less inflammation,
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249
overlapping dryness symptoms (eye, mouth, and vagina) related to age and to the use
of medical drugs, comorbidities (e.g. diabetes) having influence on presented symptoms. In this group of patients, there are also symptoms other than dryness, such as
more severe muscular weakness, sarcopenia, arthralgia and overlapping osteoarthritis, arthritis, autoimmune thyroiditis. Of comorbidities most often cardiovascular
disease, chronic obstructive pulmonary disease (COPD), type 2 diabetes and obesity
occur. The higher risk of malignancy: lymphomas and other cancers is observed [76].
Sex
Another element that may influence clinical course of SjD is sex of a patient. Women
demonstrated more often symptoms of dryness, arthralgia, dental caries. In immunological and laboratory tests: higher ANA titre, anti SS-A/Ro, anti-Ro52,and RF
positivity; higher IgM levels and ESR; as well as higher prevalence of cytopenia and
hypocomplementemia. Symptoms occurring more often in this group include
Raynaud’s phenomenon, fatigue, fibromyalgia, depression and thyroiditis.
Men with SjD demonstrated parotid glands enlargement and more often lung
involvement, including ILD-SjD, higher leukocyte counts, neutrophil counts, haemoglobin levels, C3 levels and C4 levels. In men, there is a higher risk of lymphoma, as well as other malignancies (including multiple myeloma, leukaemia and
solid tumours) development [77].
Useful Additional Tools in Diagnostic SjD Pathway
Ultrasonography
Ultrasonography (US) is a repeatable and non-invasive imaging, particularly useful
in assessing joints, salivary glands, thyroid gland and gallbladder evaluation in SjD.
In arthritis, it can assess of hypertrophy and hyperaemia of the synovial membrane—a typical image for inflammation. It is also the first-line method in the
assessment of the salivary glands image, currently in the semiquantitative method
using SGUS scale according to Hocevar et al. [78] which takes into account the following ultrasound variables of the parotid and submandibular glands (Fig. 5): echogenicity, parenchymal homogeneity, presence of hypoechoic areas, hyperechoic
reflections and posterior border of the glands; according to the total scoring system
of 0–3, the final score ranges from min. 0 to max. 48.
Thanks to US, it is possible to detect not only the changes typical of SjD but also
the development of MALT lymphoma or salivary gland stones. However, this examination was not included in the current classification criteria of SjD diagnosis,
because negative results do not exclude SjD and US present rather low sensitivity
(58.8%) with high specificity (98.7%) [78].
Ultrasonography is also the first-line method in diagnosis of salivary glands
tumours such as Kuttner’s tumour (chronic sclerosing sialadenitis) and Warthin’s
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Fig. 5 The US picture of salivary glands typical for SjD. The submandibular glands normal in
echogenicity, heterogeneous and fibrotic. The right parotid gland shows a few hypoechoic areas;
these areas are significantly more numerous in the left parotid gland we can cut left side with technical parameters. (Department of Radiology. National Institute of Geriatrics, Rheumatology and
Rehabilitation, Warsaw)
tumour (lymphomatous papillary cystadenomas) or Mikulicz’s disease (spectrum
IgG-4 related disease) [79].
Recently, high-frequency US (>20 MHz) of lacrimal glands (LG) with LGUS
has been introduced as a promising tool in comprehensive assessment of SjD
patients with sensitivity 61.5 and specificity 87.5 [80, 81]. As a cut-off in the
OMERACT scoring system, grade ≥2 is considered relevant for scoring pathology
in the lacrimal glands in SjD [81]. Researchers found that LGUS had higher specificity than SGUS and was associated with autoantibodies but not Schirmer’s test.
This is also a method used to assess the migration of lacrimal plugs through lacrimal
canaliculi.
Magnetic Resonance Imaging
Basically magnetic resonance imaging (MRI) is an important tool in SjD assessment of organ involvement especially salivary glands, CNS, bile ducts and pancreas.
In MRI of salivary glands, structural damage and foci/infiltrates that may correspond to MALT lymphoma and is a useful tool to differentiate the salivary glands
tumours such as Kuttner’s tumour, Warthin’s tumour and Mikulicz’s disease
(Fig. 6) [79].
In CNS MRI, white matter hyperintensities (WMH) in the brain are seen in
patients with SjD even without neurological symptoms [82]. This imaging is also
important in diagnosing various changes in the CNS in the case of, among others,
suspected MS or vasculitis limited to CNS.
Magnetic resonance angiography (MRA) allows assess vascular lesions, i.e. stenosis, occlusion, dilatation, aneurysms and vasculitis. In SjD, it can be useful in
cryoglobulinaemic and other types of coexisting vasculitis [83].
Functional MRI (fMRI) a fairly new diagnostic tool be useful for investigating
the brain’s functional organization in SjD, especially with patients with cognitive
Sjögren’s Syndrome
a
251
b
Fig. 6 (a) Picture of salivary glands MR of patients with MALT lymphoma diagnosis confirmation (Department of Radiology. National Institute of Geriatrics, Rheumatology and Rehabilitation,
Warsaw). (b) Heterogeneous parotid salivary glands with steatosis and small cysts. The left parotid
gland is enlarged anteriorly, with a zone of homogeneous, solid structure, decreased signal on
T2-weighted images with homogeneous enhancement and a few small fluid foci. (Department of
Radiology. National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw)
disturbances. The minimal changes in brain activity can be showed during the rest
(rs-fMRI) imaging [84]. Limited access to this type of MRI imaging is the main
limitation.
In some cases, in patients with unexplained cholestasis, the MRI cholangiopancreatography (MRCP) is used to detect the presence of duct involvement, and
contrast-­enhanced MRI or MR cholangiography (MRC) with hepatobiliary contrast
allows detection of morphologic changes while evaluating liver function in the
chronic cholangitides, including PBC, in the course of SjD [85].
Sialography
Classical sialography is one of the first imaging methods used for salivary glands
imaging employing X-ray projections with direct administration of an iodized contrast agent into the salivary ducts (Fig. 7). Currently this method has been replaced
with newer ones—first with CT sialography and more recently with MR—due to
several contraindications (infection, inflammation and allergy to iodine contrast)
and potential complications [86].
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Fig. 7 No tracer accumulation in the salivary glands—activity at background level. Sialographic
curves without response to the stimulating stimulus administered at 15 min. The red line corresponds to the accumulation of the tracer in the thyroid gland. The tracer accumulation is limited in
the salivary glands and, in addition, there is no response to a food stimulus administered at 15 min.
(Courtesy of Leszek Królicki performed at the Department of Nuclear Medicine, University
Clinical Center, Medical University of Warsaw)
Currently, MR sialography is used to assess the ductal system and show morphologic changes of the parotid salivary gland without using any exogenous contrast
agents [87]. Dynamic MR sialography can also be a useful tool to show salivary
gland dysfunction in SjD, but a limited availability of both MR methods and their
price restrict their use.
Scintigraphy
Salivary gland scintigraphy is a noninvasive nuclear imaging technique with radioactive tracer infusion of technetium-99 (99mTc), which allows for the assessment of
a glandular function.
The essence of this test is evaluation of the distribution and speed of elimination
of the radiotracer after secretory stimulation. The sensitivity of this method is 89%
and specificity is only 50% [86, 88]. In some cases, scintigraphy is a method of the
evaluation of the salivary glands disfunction in SjD; however, it is not considered a
tool appropriate for establishing a diagnosis of this disease.
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253
Computed Tomography
Computed tomography (CT) is a widely used imaging method that allows for differential diagnosis of organ changes, especially when ILD-SjD is suspected. High-­
resolution chest CT (HRCT) is in such instances the method of choice, allowing for
initial determination of the type of changes and of their extent. Computed tomography is of great importance in the diagnosis of tumours or bone changes (bone window) in the case of, for example, metastases or fractures. Computed tomography
angiography (CTA) with intravenous injections of special dye allows differentiation
of inflammatory changes of vessels, aneurysms, rupture or injuries of the vascular
wall, abnormal blood vessel formations inside the brain, blood clots, etc. [86, 88].
This is consistent with the broad symptomatology of SjD and the need to differentiate various symptoms.
This method can also replace MRI in the case of contraindications for this imaging. This noninvasive method with relatively short time of imaging duration is very
helpful in diagnosis; however, the main limitation is exposure to X-ray radiation and
allergy to iodine contrast. Although the specific rules on the safety of the use of CT
exceed the scope of this chapter, it should be mentioned that in the case of stable
ILD, it is not recommended to perform CT more often than every 2 years, provided
that the patient is monitored with other tests. Of course, in a case of urgent need, the
restrictions are not crucial.
Positron Emission Tomography–Computed Tomography
Positron emission tomography–computed tomography (PET-CT) can be useful in
assessment of systemic manifestations such as lymphadenopathy, pulmonary
involvement and salivary gland involvement especially in the context of the exclusion of lymphoma as well as in cases of large vessels inflammation, and the coexistence of neoplasms other than lymphoma [89].
Shear Wave Elastography
Shear wave elastography (SWE) of salivary and lacrimal glands is a non-invasive,
quantitative method using sonographic scans and 5–18 MHz transducer. It seems to
be aa additional examination tool to support the diagnosis of pSS; however, there is
no standardized study protocol so far [90].
Assessment of SjD Activity and Damage
Dry eye disease can be assessed by questionnaires focussed on patient-reported
outcome measures (PROMs) such as the Ocular Surface Disease Index (OSDI) and
the Standard Patient Evaluation of Eye Dryness questionnaire (SPEED) [91–93].
The Ocular Surface Disease Index is a good tool for assessing the effectiveness of
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treatment and also provides information on how dry eye affects the patient’s functioning and dry eye-related symptoms.
After analysis of Profile of Fatigue and Discomfort (PROFAD) and Sicca
Symptoms Inventory (SSI), dryness, joint pain, chronic mental and functional
fatigue were identified as the core symptoms of SjD, leading to the development of
the EULAR SS Patient Reported Index (ESSPRI) for assessing disease activity [94].
The ESSDAI is a tool to assess organ involvement in the course of SjD. It consists of 12 domains, including the general symptoms, laboratory tests (as a biologic
domain), organ, joint and skin domains [95]. Each domain contains an assessment
of damage sustained by a given organ according to the degree of activity corresponding to a score from 2 to 12 points, depending on the assessed domain. In the
absence of organ involvement, 0 points are always allocated. The same rule applies
when the symptoms are constant and have not changed for 12 months, because it is
considered that the symptoms are irreversible and we count them as 0 points. In
each domain, we choose the highest number of points obtained, e.g. if the patient
meets the criteria for low disease activity for 3 points, but also for moderate disease
activity for 6 points, finally 6 points are received for this domain (points do not add
up within the domain). The ESSDAI score is the sum of points obtained for all individual domains. The patient can receive a maximum of 123 points. The level of
moderate activity starts from 5 points, and high activity starts from over 14 points
[95]. Treatment gradation refers to the assessment of a disease activity measured by
ESSDAI and is considered effective when a reduction of ≥3 points in the global
ESSDAI score is confirmed. It’s important to remember that not all clinical symptoms are included in the assessment of a disease activity. Some symptoms, such as
Raynaud’s phenomenon, which is not uncommon in SjD, primary pulmonary
hypertension, pleuritis, pericarditis, dysautonomia, interstitial cystitis, and sensorineural hearing loss, are not included in ESSDAI assessment. Therefore, the treatment should also address these “unaccounted for” aspects of the disease, with the
doctor’s experience playing a significant role in the adjustment of a therapy to the
needs of a particular SjD patient.
Sjögren’s syndrome disease damage index (SSDDI) is another tool used to measure damage in this disease. The SSDDI consists of a three-domain assessment:
ocular, oral and systemic. The systemic domain is further divided into following
sub-domains: pulmonary, musculoskeletal, neurological, renal, cardiovascular, gastrointestinal, endocrine and malignancy [96, 97]. The maximum score for each item
is 1, and the index has 27 items in total.
The ESSPRI (EULAR Sjögren’s Syndrome Patient Reported Index) is a numerical scale and is based on three simple questions addressed to the patient regarding
the area of pain in the musculoskeletal area, chronic fatigue and the intensity of
dryness. The patient answers the questions on a scale from the minimum intensity
of symptoms, i.e. 0, to the maximum, i.e. 10, the results are added up. The ESPRI
index correlates well with the activity of the disease [94].
Questions on the ESSPRI scale:
• How severe was the dryness in the last 2 weeks.
• How severe was the fatigue in the last 2 weeks.
Sjögren’s Syndrome
255
Table 8 Selected tools for SjD assessment
Questionnaire
ESSDAI
ESSPRI
Dryness Fatigue
X
X
X
X
ESSDAI
Biological
Pain X (joints) domain
x
X(joint)
SSDDI
OSDI
X
X
X(eye)
SPEED
X
X (eye) X(eye)
Type
Activity
Patient’s questionnaire
PRO
Damage
Patient’s questionnaire
PRO
Patient’s questionnaire
PRO
• How severe was the pain (in joints, muscles of lower and upper limbs) in the last
2 weeks.
In SjD, management additional tools such as the Modified Fatigue Impact Scale
(MFIS) or classification and assessment criteria for fibromyalgia [40] as well as
questionaries concerning detection of chronic pain with neuropathic component
(DN4 questionnaire, LANSS and S-LANSS scoring) can be useful [97, 98]. The
symptoms assessed include among others: dryness, grittiness, scratchiness, irritation, burning, watering, soreness and eye fatigue.
In Table 8, selected useful tools for assessment activity and various aspects of
SjD are presented.
Management in Sjögren’s Disease
Nonpharmacological Treatment
In 2019 the EULAR recommendations for the management of Sjögren’s syndrome
with topical and systemic therapies were published. Recommendations were issued
separately for each of domains affected by SjD; however, when considering the
choice of treatment, it is necessary to assess the clinical picture comprehensively,
assuming the overlap of various symptoms or the simultaneous involvement of different organs/systems [39].
The non-pharmacological treatment constitutes an important part of the therapy,
especially in the case of treatment of symptoms of dry eyes or mouth, FM, chronic
pain or CFS.
Dryness is a crucial symptom in SjD. In some cases a treatment is limited to the
procedures eliminating dryness and to the monitoring of the disease. This happens
when there is no evidence of organ involvement.
Oral Dryness
The use of SWSF test can determine whether initially highly reduced or even eliminated secretion (<0,1 ml/min) can be partially restored under a stimulation (to
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achieve a mild salivary gland disfunction <0.7 ml/min). If secretion reserve still
exists, the stimulation of secretion with sugar-free acidic candies, lozenges, xylitol
and/or mechanical stimulants (sugar-free chewing gum) is recommended.
Accompanying general treatment is also important, i.e. proper hydration, or fluorination of teeth.
Eye Dryness
As the initial line of conduct, the limitation of factors which can exaggerate dryness—e.g. long hours of working with computer, smoking, air-conditioning—should
be advised. The use artificial tears (AT) during the day and lubricant ointment before
sleep is recommended. Agents used as preservatives in medical drops, even those in
moisturizers—among them benzalkonium chloride (BAK) and disodium (EDTA)—
and over-the-counter (OTC) drops with a higher dose of preservatives increase the
symptoms of dryness and thus should be avoided. The main ingredients of AT include
lubricants with a polymeric base or viscosity agents (methylcellulose, hyaluronate),
which protect eye surface, extend the life of the tear film and reduce eye evaporation.
Additionally, improving the function of the Meibomian glands (warm compresses,
blinking with eyelid tightening) allows for a better maintenance of the tear film on
the surface of the eye. The carrying out of blinking exercises is also important in dry
eye management and should be recommended especially for patients with long exposition to work with computer/TV screens. The technique of this exercise is simple:
patient closes the eyes normally (2 s), squeezes the lids together (2 s) and opens them
again. Optimally, this exercise should be repeated nine times a day.
Fatigue and Fibromyalgia
A treatment includes a combination of psychological and behavioural therapy and
self-management approaches (physical exercise, yoga or tai chi). Cognitive behavioral therapies (CBT), mindfulness, biofeedback and hydrotherapy can be helpful,
especially when combined with other types of treatment. Complementary management includes e.g. acupuncture, massage and hypnotherapy.
Arthralgia, Myalgia
Non-pharmacological approach to arthralgia, myalgia or even arthritis is based on
physical exercises (kinesiotherapy) or manual therapy, physical methods (physiotherapy)—application of temperature, magnetic field, relaxation techniques and
techniques that strengthen the musculoskeletal system. Multimodal rehabilitation is
particularly important in pain management. Broadly understood education should
be provided regarding the disease, its treatment and elements important for the
patient in the treatment and monitoring process. Understanding the methods and
goals of a treatment will help keep the patient in therapy and increase the guarantee
of subsequent patient compliance.
Pharmacological Treatment
Although current recommendations were divided into several sections concerning
organs/systems affected by SjD, in determining a proper treatment, it is necessary to
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assess the comprehensive clinical picture of this complex disease. If dryness is a
dominant symptom, a first step of the treatment should be symptomatic, with a use
of topical therapies.
Oral Cavity
It is recommended to perform the measurement of glandular function such as
SWSF, and salivary scintigraphyis before the start of the treatment. In mild and
moderate glandular disfunction (0.1–0.7 ml/min SWSF), initial nonpharmacological stimulation is recommended, with pharmacological stimulation with muscarinic agonists (pilocarpine and cevimeline) constituting a next step of the
therapy. The dose of administered medications (e.g. pilocarpine) should be
increased progressively to a maximum of 15–20 mg/day, while the non-pharmacological stimulation should be stopped. In case of intolerance to muscarinic agonists, the use of mucolytic (bromhexine, N-acetylcysteine) or choleretic
(anetholtrithione) drugs, as well as of electrostimulation, should be considered
[99]. In severe disfunction (<0.1 ml/min despite stimulation), only saliva substitutes can be useful. None of immunosuppressants or antimalarial drugs are effective in the treatment of dry mouth symptoms.
Eye Dryness
Similarly to the assessment of the severity of dry mouth, the OSDI assessment
allows for determining the severity of dry eye symptoms and making therapeutic
decisions. The pharmacological therapy is recommended in case the maximum use
of AT and ointments according to the non-pharmacological recommendation does
not yield desired effects, while the corneal damage using OSS is assessed at the
level of ≥5 and SjD-unrelated ocular processes (i.e. blepharitis, neuropathic pain)
are excluded. A first-line therapy consists of topical non-steroidal anti-inflammatory
drugs (NSAIDs) or glucocorticosteroids (GCs) in a short duration treatment
(2–4 weeks). Prolonging such treatment may cause side effects such as corneal–
scleral melts, perforation, ulceration and severe keratopathy (NSAIDs) or infections, increased intraocular pressure and worsening/development of cataracts (GCs).
Ciclosporin A (CyA) is approved for refractory or severe ocular dryness, especially with corneal damage. It’s important to understand that the patient may experience discomfort and pain during the initial phase of treatment, which indicates the
drug’s effect on ocular surface damage and confirms the appropriateness of this
treatment. This should be explained to the patient; GCs can be used briefly for initial
relief. Treatment with CyA can be used chronically.
As the next stage of treatment, the use of autologous or allogenic serum drops
may be considered in patients who do not respond to the previous therapies or are
intolerant to topical CyA. As the last line of treatment, use of muscarinic agonist
and temporary or permanent occlusion of nasolacrimal channel (plug insertion) is
considered.
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M. Maslinska
Vagina
Not all women with SjD experience vaginal dryness to the same degree, but most
experience it during menopause when estrogen levels decline. Medications that
rehydrate the epithelial cells and maintain vaginal moisture can alleviate these
symptoms. Other medications such as estrogen creams, which can increase capillary blood flow to the vagina and vulva, water-soluble lubricants, probiotic and
hyaluronic acid moisturizers, estradiol-based vaginal inserts and creams containing
vitamin E may be helpful [46, 100].
Skin Involvement
In limited changes of annular erythema (AE) type, the first-line treatment consists
of topical use of GCs. The second line of treatment of such changes, as well as the
therapy of diffuse type HCQ, consists of systemic GCs therapy (0.3 mg/kg/day)
used alternatively to or together with the topical GCs. The second line of treatment
of the diffuse type of AE involves higher doses of GCs (0.5 mg/kg/day).
In cutaneous vasculitis with moderate EESDAI, GCs in medium doses (0.3 mg/
kg/day) are sufficient, but in a case of diffuse purpura, ischemic symptoms/ulcers
and higher ESSDAI, the more aggressive systemic treatment is necessary, which
start from higher doses of GCs (0.5 mg/kg/day). The second line of treatment in
such cases involves oral immunosuppressants such as methotrexate (MTX), leflunomide (LEF), mycophenolate (MMF), azathioprine (AZA) or biologic drug—rituximab (anti-CD20). As a rescue therapy, cyclophosphamide (CYC) and plasma
exchange (PEX) in life-threatening vasculitis should be considered.
Glandular Involvement
In an acute sialadenitis, after exclusion of an infection, a symptomatic treatment
with non-steroidal anti-inflammatory drugs (NSAIDs), carried out for a short period
of 3–5 days, is recommended. The second line of treatment involves systemic
administration of GCs (0.3 mg/kg/day), while in the third one, rituximab or belimumab is a therapeutic option.
Persistent salivary gland enlargement requires exclusion of lymphoma, stones,
other causes of enlargement, e.g. the presence of Kuttner’s tumour or common
benign tumour of salivary gland (tumour mixtus).
Musculoskeletal Pain
Analgesics (mainly NSAIDs) or other pain-modifying agents are used, weighing
potential benefits and side effects. In case of persistent or frequent episodes of musculoskeletal pain, the use of hydroxychloroquine (HCQ) is recommended.
Sjögren’s Syndrome
259
In synovitis with involvement of not more than five joints, HCQ and NSAIDs are
the therapy of choice. In case of a lack of response, exacerbation or expansion of the
number of affected joints HCQ with GCs (low than 0.5 mg/kg/day) is recommended.
The next step of the therapy involves immunosuppressants—synthetic immunosuppressive agents (MTX, LEF, MMF, AZA, CYC), which should be used as GC-sparing
agents. Accompanying diseases and predominant symptoms should be taken into
account when choosing one of them. In arthritis, MTX is usually used. As the rescue
therapy biologics agents, rituximab (anti-CD20 antibody) or abatacept (anti-CTL-4
antibody) should be considered.
Respiratory Tract
In bronchial involvement, the inhalation of GCs and broncho-dilatators is deemed
sufficient. Humidifying the air and avoiding factors that increase dryness and irritation of the bronchial epithelium (air conditioning, dust) is also important. In the
course of ILD–SjD and moderate ESSDAI, GCs (0.5 mg/kg per day) are recommend as a first-line treatment. In case of lack of response to such therapy or when
ESSDAI count is higher, the recommended treatment involves higher doses of GCs
(0.5–1 mg/kg/per day), immunosuppressives, with AZA as well as MMF or CyA
being preferred. Such a treatment is more preferable for LIP and organizing pneumonia (OP) than NSIP or UIP.
Currently, antifibrotic therapy with synthetic drug, nintedanib, is recommended
in a progressive ILD associated with autoimmune diseases including SjD. In life-­
threatening situation (e.g. cryo-vasculitis), CyC or RTX can be considered.
Renal Involvement
In tubular involvement, the correction of metabolic acidosis and potassium level is
necessary in some cases. In glomerulonephritis with moderate ESSDAI, GCs
(0.3 mg/kg/day) and/or immunosuppressants (AZA, MMF, CyA) are recommended.
If there is no improvement or the ESSDAI is high, the high doses of GCs (0.5–1 ­mg/
kg/day), RTX, CyC are used, while in life-threatening cryo-vasculitis, PEX is a
treatment option.
Haematological Disease
Neutropenia below 500 cells or below 1000 cells in patients with recurrent infections is an indication for use of G-CSF and high doses of GCs (0.5–1 mg/kg/day).
High GC doses are also used if there is no response to such treatment or in case of
immune thrombocytopenia (<20,000 cell) or haemolytic anaemia with Hb <8–10 g/
dL. In a severe course of disease with no response for previous treatment and with
worsening anaemia <8 g/dL, the combination therapy with high doses of GCs and
immunoglobulins (iv) or RTX constitutes the second line of treatment, and PEX or/
with CyC the third one.
Lymphoma (90% MALT type), other marginal zone lymphomas (MZL), diffuse
large B cell lymphoma, rare T and NJK cell lymphomas should be treated according
260
M. Maslinska
to haematological therapeutic guidelines. However, in case of low grade of haematological neoplasia, with lymphoma affecting exocrine glands only, without general
symptoms, a “watchful and waiting” approach is also considered in SjD patients.
Disseminated MALT lymphoma or one with concomitant high disease activity
(ESSDAI) is an indication for complex chemotherapy usually with
RTX. Radiotherapy can be necessary in early stages of marginal zone lymphomas,
small lymphocytic lymphoma (SLL) and lymphoplasmacytic lymphoma (LPL).
Decisions on the treatment of a patient with SJD and lymphoma are made by a
haematologist-oncologist.
Central Nervous System
Central nervous system vasculitis or neuromyelitis optica spectrum disorders
(NMOSD) need aggressive treatment with GCs (0.5–1 mg/kg/day), RTX and
PEX. In patients with AQP-4 antibodies, also eculizumab (monoclonal antibody
that inhibits complement C5 activation) can be considered. In cases of lymphocytic
meningitis, after exclusion of the infection, the first stage the treatment is symptomatic; in severe cases, the treatment mentioned above in this paragraph, excluding
eculizumab therapy, can also be administered. Initial patient stabilization is crucial
with intravenous (IV) fluid administration over first 48-hour period. When bacterial
meningitis is suspected, it is imperative to empirically start antibiotic therapy with
choice of drugs depending on patient’s specific age group and potential pathogens,
especially in paediatric cases. It is crucial to obtain cerebrovascular fluid before
antibiotic administration. Multiple sclerosis like syndrome should be treated according to specific MS therapies.
Peripheral Nervous System
Multineuritis should be treated with GCs (0.5 mg–1 mg/kg/dz), with immunosuppressant therapy constituting the next step treatment and RTX used in a case of
cryo-vasculitis. In rescue therapy, CyC or PEX is recommended. In axonal sensory
polyneuropathy, of vasculitis origin, the management is similar as above. In sensory
axonal polyneuropathy, symptomatic treatment with assessment of pain and cardiovascular risk is recommended.
Motor polyneuropathy should be treated with IvIg, methylprednisolone courses
and CyC. Ganglionopathy and CIDP the first-line treatment is the same as in motor
neuropathy. Immunoglobulins (iv) should be introduced as a second-line treatment
along with methylprednisolone pulses. In severe cases, CyC is preferred.
In Table 9, doses of selected drugs are presented.
Sjögren’s Syndrome
261
Table 9 Selected drugs and doses in SjD
Drug
NSAID
CyC
Rituximab (anti-CD-20 antibody)
Belimumab (anti-BlyS/BAFF antibody)
Abatacept (fusion protein composed of the Fc
region of the immunoglobulin IgG1 fused to the
extracellular domain of CTLA-4)
IVIg: intravenous immunoglobulins
Dose/time
Maximum 7–10 days
Pulses 0.5 g/15 day (maximum 6 pulses)
1 g/15 days (two administrations in next
consecutive 15 days) and usually one cycle
every 6 months
10 mg/kg (0, 2 and 4 weeks and then every
4 weeks)
0, 2, 4 weeks and every 4 weeks
10 mg/kg iv
0.4–2 g/kg 5 days
NSAID non-steroidal antiinflammatory drug, CyC cyclophosphamide, CTL-4 Cytotoxic
T-lymphocyte antigen 4
Pregnancy
The most severe complication affecting the foetus during pregnancy of a woman
with SjD with the presence of anti-Ro antibodies is a congenital heart block (CHB)
from first to third degree with life-threatening conditions and risk of hydrops and
death. Trans-placentally transferred maternal anti SS-A/Ro and/or anti SS-B/La
antibodies bind to foetal cardiac conduction cells, causing an inflammatory response
with lymphocytic infiltration resulting in fibrosis and calcification that can lead to a
congenital AV block [100].
As a primary and secondary prevention of such complications, the HCQ is used.
In the case of first- degree CHB, fluorinated GCs and echocardiography control are
recommended. second-degree CHB requires fluorinated GCs for 1 month with IvIg.
In the complete third-degree CHB, fluorinated GCs and IvIg are used as a first-line
treatment, and as a second one, PEX is the treatment of choice [39]. Pacemaker
treatment is associated with a decreased risk of cerebral infarction but increases a
risk of cardiomyopathy/heart failure and infection. The outcome of the preterm foetus with hydrops fetalis due to CHB is unfavourable with high morbidity and mortality. The left ventricular epicardial pacing with a temporary pacemaker and
subsequently, left ventricular epicardial pacing with a permanent pacemaker may be
necessary [101]. Management of these pregnancies is complex and should include
a multidisciplinary approach.
The new EULAR recommendations for the use of antirheumatic drugs in reproduction, pregnancy and lactation: 2024 update was published [102]. They specify
which conventional synthetic disease-modifying drugs (csDMARDs) and other
drugs used in rheumatology are compatible with pregnancy and can be, with a
patient’s agreement, used to control disease during pregnancy and breastfeeding
period. The list includes, among others, AZA, mercaptopurine, HQ and HCQ, colchicine, CyA, sulfasalazine and tacrolimus [102]. In severe maternal disease, methylprednisolone, eculizumab and IvIg can be used when there are no other alternative
treatment options.
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M. Maslinska
Conclusions
To summarize, the SjD management requires a multidisciplinary approach involving various health professionals. A rheumatologist with knowledge of SjD and other
autoimmune diseases should play a role of a “command centre” coordinating this
complex disease management. Such a complicated process, which should include a
full, informed participation of a patient himself and the engagement of the primary
care physician, must rely on good communication between all its participants,
assuring persistence of the treatment.
Due to the rapid development of immunology, genetics and molecular biology
techniques, new findings on the pathogenesis and treatment of Sjögren’s disease can
be extended, including new biologics, the use of CAR-T, bispecific antibodies, and
the use of new possibilities of genetic engineering.
Acknowledgements Thanks to Marta Legatowicz Koprowska, Leszek Królicki, Marek
Chojowski and Krzysztof Maslinski for providing materials and helping with language
proofreading.
Conflict of Interest The author declares no conflict of interest.
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Hashimoto’s Thyroiditis
Syed Khalid Imam
Introduction
Part I: Basic Introduction
Provides foundational knowledge and fundamental concepts necessary to understand thyroid gland’s structure and functions that will help readers understand
pathophysiological mechanism of autoimmune thyroid disorders.
hyroid Glands: Physiological Role in Metabolism and Homeostasis
T
Thyroid gland is a highly vascular endocrine organ and plays a key role in energy
metabolism, growth, and maturation of human body. These effects are mediated by
the thyroid hormones, thyroxine (T4), and triiodothyronine (T3). Thyroid hormones
stimulate diverse metabolic activities in tissues, leading to an increase in basal metabolic rate. One consequence of this activity is to increase body heat production,
which seems to result, at least in part, from increased oxygen consumption and rates
of adenosine triphosphate (ATP) hydrolysis [1].
The thyroid hormones act on nearly every cell in the body. They act to increase
the basal metabolic rate (BMR), affect protein synthesis, help regulate long bone
growth (synergy with growth hormone) and neural maturation, and increase the
body’s sensitivity to catecholamines (such as adrenaline) by permissiveness. The
thyroid hormones are essential to proper development and differentiation of all cells
of the human body. These hormones also regulate protein, fat, and carbohydrate
metabolism, affecting how human cells use energetic compounds. They also stimulate vitamin metabolism. Numerous physiological and pathological stimuli influence thyroid hormone synthesis. Table 1 illustrates thyroid hormone functions in
human body.
S. K. Imam (*)
Sultan Bin Abdulaziz Humanitarian City, Riyadh, Kingdom of Saudi Arabia
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_11
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S. K. Imam
Table 1 Effect of thyroid hormones on various organs and tissues of the body
Organ/tissue
1. Brain
Function of thyroid hormones
Organization and function throughout life
Synaptogenesis, neurogenesis, migration, plasticity, and myelination
Effect cholinergic and serotonergic activities
T3 is the predominant form acting on brain
2. Myocardium Essential for aerobic metabolism and lactic acidosis prevention
Upregulate beta adrenergic receptors and have inotropic and vasodilatory
properties
Effect intracellular homeostasis of ionized calcium
Medical and surgical conditions may decrease T3 and T4 and increase
reverse T3. This phenomenon is called “euthyroid sick syndrome” (ESS)
ESS causes stunned myocardium and may cause cardiogenic shock in
extreme cases.
3. Bone
Important for bone growth and development
Involved in both bone formation and resorption
Excessive thyroid hormone causes increased porosity and decreased cortical
thickness
4. Adipose tissue Important in development and function of brown adipose tissue (BAT) and
(fat)
white adipose tissue (WAT)
In WAT, thyroid hormone regulates basal oxygen consumption, lipogenesis,
lipolysis
TRα-1 gene is the predominantly expressed TR isoform in Ob17 cells
Expression of these genes is modulated by high carbohydrate diet, insulin,
and cAMP
5. Liver
Stimulates enzymes regulating lipogenesis and lipolysis
Regulate expression of important proteins and enzymes involved in
cholesterol metabolism
Deficiency causes hypercholesterolemia with elevated intermediate and LDL
cholesterol
TRβ-1 is the predominant isoform in liver
Regulate gene expression of cellular pathways such as gluconeogenesis,
lipogenesis, insulin signaling, cell proliferation, and apoptosis
6. Pituitary
Regulate transcription of thyrotropin, prolactin mRNA
Regulate TSH synthesis
Thyroid hormone dysregulation causes a significant change in body homeostasis, not only in adults but also in children where it can affect mental and growth
development to a significant level. Therefore, it is important to identify the thyroid
hormone deficiency as early as possible to initiate desired treatment.
hyroid Gland: Basic Anatomy
T
The thyroid gland is a highly vascular butterfly-shaped brownish red organ and is
composed of two cone-like right and left lobes connected via the isthmus. Each lobe
is about 5 cm long, 3 cm wide, and 2 cm thick. The organ is situated on the anterior
side of the neck, lying against and around the larynx and trachea, reaching posteriorly the esophagus and carotid sheath (Fig. 1). It starts cranially at the oblique line
on the thyroid cartilage (just below the laryngeal prominence, or “Adam’s apple”)
and extends inferiorly to approximately the fifth or sixth tracheal ring [2, 3].
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271
Fig. 1 Thyroid gland
anatomy
The thyroid is one of the largest endocrine glands, weighing 2–3 grams in neonates and 18–60 grams in adults, and size is increased in pregnancy. Occasionally,
in 28–55% of population a third pyramidal lobe may be present, also known as
Lalouette’s pyramid. It is of conical shape and extends from the upper part of the
isthmus, up across the thyroid cartilage to the hyoid bone. The pyramidal lobe is a
remnant of the fetal thyroid stalk, or thyroglossal duct [4].
lood Supply and Lymphatic Drainage
B
The thyroid is supplied with arterial blood from the superior thyroid artery, a branch
of the external carotid artery, and the inferior thyroid artery, a branch of the thyrocervical trunk, and sometimes by the thyroid ima artery, branching directly from the
subclavian artery. The venous blood is drained via superior thyroid veins, draining
in the internal jugular vein, and via inferior thyroid veins, draining via the plexus
thyroideus impar in the left brachiocephalic vein. Lymphatic drainage passes
through the lateral deep cervical lymph nodes and the pre- and paratracheal lymph
nodes. The gland is supplied by parasympathetic nerve input from the superior
laryngeal nerve and the recurrent laryngeal nerve. Close examination of a thyroid
gland will reveal one or more small, light-colored nodules on or protruding from its
surface—these are parathyroid glands (meaning “beside the thyroid”). The structure
of a parathyroid gland is distinctly different from a thyroid gland. The cells that
synthesize and secrete parathyroid hormone are arranged in rather dense cords or
nests around abundant capillaries.
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S. K. Imam
Fig. 2 Basic histology of
thyroid gland. (Courtesy of
Dr. Naseem Ahmed,
Department of Pathology,
Dow University of Health
Sciences, Karachi,
Pakistan)
Basic Histology
The microscopic structure of the normal thyroid gland is quite distinctive (Fig. 2).
Thyroid epithelial cells are arranged in spheres called thyroid follicles. Follicles are
filled with colloid, a proteinaceous depot of thyroid hormone precursor. In addition
to thyroid epithelial cells, the thyroid gland houses one other important endocrine
cell, nestled in spaces between thyroid follicles, called as parafollicular or C cells
which secrete the hormone, calcitonin.
Part II: Clinical Introduction
This section connects basic knowledge to clinical practice, emphasizing why
Hashimoto’s thyroiditis is significant.
Dr. Noel Rose stands as a cornerstone of the autoimmune field. In the 1950s at
the University of Buffalo, he demonstrated that the immune system can turn against
the body’s own tissues by identifying autoimmune thyroiditis in animal models,
thus ushering in the modern understanding of autoimmunity. Sir Frank Macfarlane
Burnet, meanwhile, laid the groundwork for contemporary immunology through his
co-development of the clonal selection theory, which elegantly explains how the
immune system discriminates among and mounts defenses against an immense
array of foreign antigens.
Hashimoto’s thyroiditis is part of the spectrum of autoimmune thyroid diseases
(AITDs), characterized by autoimmune destruction by antibody-mediated immune
processes which result in progressive fibrosis of the thyroid gland resulting in thyroid dysfunction [5]. Individuals with Hashimoto’s thyroiditis present with variable
functional status such as euthyroidism, subclinical hypothyroidism, overt hypothyroidism, and occasionally, transient hyperthyroidism.
Hypothyroidism typically develops gradually, initially presenting with subtle
signs and symptoms that may progress over months to years, eventually leading to
more pronounced or overt manifestations. Hashimoto’s thyroiditis (HT) was first
reported in 1912 by Hakaru Hashimoto, a Japanese surgeon working in Berlin, who
described four patients with a chronic disorder of the thyroid gland, termed struma
lymphomatosa, literally means lymphomatous goiter [6]. In 1931, the disorder first
Hashimoto’s Thyroiditis
273
came to be considered a clinical entity, having been described by Allen Graham that
year as an autonomous pathology [7]. In 1956, Roitt et al. found it to be an autoimmune disease of the thyroid gland, following isolation of anti-Tg antibodies from
patients with Hashimoto thyroiditis [8]. It is also reported in the literature as chronic
lymphocytic thyroiditis or chronic autoimmune thyroiditis and was rarely identified
for many years, but an increase in its incidence was noticed since 1940 [9].
Furthermore, the routine use of the fine needle aspiration biopsy (FNAB) and measurement of thyroid autoantibodies have contributed to a significant rise in its frequency. It can occur alone or as part of polyglandular autoimmune syndrome or in
association with other autoimmune disorders.
This chapter presents a comprehensive overview of Hashimoto’s thyroiditis
(HT), encompassing its core concepts, pathophysiology, detailed clinical manifestations, associated conditions, special situations, and recent advancements in research.
It emphasizes emerging therapeutic approaches and highlights the significance of a
holistic management strategy aimed at improving patient outcomes. Ongoing
research into personalized medicine and immunomodulatory therapies offers promising prospects for more targeted and effective interventions in the management of HT.
Epidemiology
Worldwide, the most common cause of hypothyroidism is iodine deficiency.
However, Hashimoto thyroiditis remains the most common cause of spontaneous
hypothyroidism in areas of adequate iodine intake [10]. Hashimoto’s thyroiditis disorder is thought to be the most common cause of primary hypothyroidism in North
America and may affect up to 5% of the United States’ population and found to be
more common in white than black American [11]. Prevalence of Hashimoto’s thyroiditis generally increases with age, which may reflect an increasing loss of tolerance to self-antigen, and this entity is rarely seen in Pacific Islanders [12]. However,
Hashimoto’s thyroiditis can occur at any age, including children, but more incidence peaks in the fifth decade of life, and patients are usually diagnosed between
age 30 and 50 [13]. Women are more commonly affected and female-to-male ratio
is at least 7 to 10:1 [14]. Increase prevalence of Hashimoto’s thyroiditis in women
can be explained by skewed X chromosome inactivation, the role of sex steroids and
fetal microchimerism. The annual incidence of Hashimoto thyroiditis worldwide is
estimated to be 0.3–1.5 cases per 1000 persons [15].
A systemic review and meta-analysis by Xiaojie et al. revealed that the global
prevalence of HT was 7.5%. The prevalence of HT varied across continents, with
the highest rate observed in African adults (14.2%), followed by Oceania (11.0%),
South America and Europe (8.0% each), and North America (7.8%). The lowest
prevalence was recorded in Asian adults at 5.8% [16]. Furthermore, this study found
that Hashimoto’s thyroiditis was four times more common in females than in males.
Differences in prevalence were also noted across economic levels, with the highest
rates observed in low- and middle-income countries [16]. A higher prevalence of
Hashimoto thyroiditis has been observed in certain conditions, such as myasthenia
gravis and systemic sclerosis. While the exact mechanism underlying this
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S. K. Imam
association remains unclear, immune dysfunction—along with genetic, hormonal,
and environmental factors—may contribute to polyautoimmunity [17]. In the pediatric population, this disease exhibits a higher incidence rate, particularly in association with specific chromosomal abnormalities, including Down syndrome,
Turner syndrome, and Klinefelter syndrome [18].
Etiology
Exact cause of autoimmune thyroiditis in not known but the combination of environmental factors, genetic predisposition, and epigenetic factors may play key roles.
nvironmental Risk Factors
E
Development of Hashimoto’s thyroiditis is influenced by number of environmental
factors as mentioned below.
Iodine Excess
Increased iodine intake is associated with higher incidence of autoimmune thyroid
diseases including Hashimoto thyroiditis [19]. Iodine is a necessary microelement
of the diet for the proper functioning of the thyroid gland, including the synthesis of
triiodothyronine (T3) and thyroxine (T4). Iodine is important not only for the synthesis of thyroid hormones but also affects the induction and modulation of thyroid
autoimmunity. Research suggests that an excess of iodine stimulates thymus development and affects the functioning of various immune cells [20]. Possible mechanism of iodine induced thyroiditis includes induction of cytokine and chemokine
production by excess iodine that can recruit immunocompetent cells to the thyroid gland.
Selenium Deficiency
Selenium is a vital micronutrient with diverse effects, including antioxidant and
anti-inflammatory properties. The thyroid gland contains the highest concentration
of selenium per gram of tissue due to its expression of specific selenoproteins. These
selenoproteins, such as glutathione peroxidases and iodothyronine deiodinases,
play a crucial role in thyroid function [21]. Since selenium plays role in modulating
immune functions, therefore, its deficiency may be associated with immune dysfunction [22].
Iron Deficiency
Thyroid peroxidase is a heme-containing enzyme essential for thyroid hormone
production, becoming active upon binding heme. Consequently, iron deficiency
may disrupt thyroid metabolism. However, the link between iron deficiency and
thyroid autoimmunity remains unclear. A systematic review and meta-analysis
assessed the impact of iron deficiency on thyroid function and autoimmunity, revealing a significant increase in the risk of positive thyroid peroxidase and thyroglobulin
antibodies in women of reproductive age [23].
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275
Magnesium Deficiency
Magnesium is one of the most abundant elements in the human body and serves as
a cofactor for over 300 enzymes involved in various biochemical processes. While
reduced serum magnesium levels have been linked to several chronic diseases,
their relationship with Hashimoto’s thyroiditis remains uncertain. A cross-sectional study involving 1257 participants found that low serum magnesium levels
were associated with a higher risk of thyroglobulin antibody positivity, as well as
an increased prevalence of Hashimoto’s thyroiditis and hypothyroidism. However,
no correlation was observed between magnesium levels and thyroid peroxidase
antibodies. Further research is needed to clarify the role of serum magnesium in
thyroid autoimmunity [24].
Vitamin D Deficiency
Vitamin D also plays an important role in immune homeostasis and its deficiency
can trigger autoimmunity [25]. The role of vitamin D in the development of
Hashimoto’s thyroiditis remains uncertain, though several studies have identified a
link between vitamin D deficiency and the presence of thyroid autoantibodies. An
epidemiological survey demonstrated an association between vitamin D deficiency
and thyroid autoantibody positivity. Additionally, patients with Hashimoto’s thyroiditis exhibited significantly elevated levels of proinflammatory cytokines, including interferon-gamma (IFN-γ) and interleukin-17 (IL-17), secreted by Th1 and
Th17 cells, compared to healthy individuals [26]. A clinical trial conducted by
Nodehi M et al. revealed that administering a weekly dose of 50,000 IU of vitamin
D for 3 months significantly reduced the Th17/Tr1 ratio. These findings suggest that
vitamin D supplementation may help regulate T-cell homeostasis in patients with
Hashimoto’s thyroiditis. Nevertheless, further research is necessary to confirm the
impact of vitamin D treatment on immune function in this patient population [27].
Viral and Bacterial Infections
It is hypothesized that viral infections may contribute to the onset of thyroiditis
through molecular mimicry, which amplifies autoimmune responses. Among the
viruses most strongly implicated in the development of Hashimoto’s thyroiditis,
Epstein–Barr virus (EBV), human parvovirus B19 (PVB19), human herpesvirus 6A
(HHV-6A), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
are considered the most influential [28]. In addition to viral factors, certain bacterial
infections may also play a role in the pathogenesis of Hashimoto’s disease. Notably,
Helicobacter pylori, a Gram-negative bacillus that colonizes the gastric mucosa in
nearly half of the human population, has been identified as a potential contributing
factor. A study by Natale Figura et al. explored the structural homology between
thyroid proteins and Helicobacter pylori antigens, revealing that multiple thyroid
proteins share conserved domains with bacterial antigens. These findings suggest a
significant link between H. pylori infection and Hashimoto’s thyroiditis, likely due
to molecular mimicry and heightened inflammation [29].
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S. K. Imam
Medication
Interferon-α (IFN-α) is a cytokine produced by the host organism in response to
infection. It plays a crucial role in the immune response to infection by stimulating
proinflammatory chemokines and cytokines while also enhancing the cytotoxic
activity of T lymphocytes. Interferon-alpha (IFN-α) is used in the therapy of hepatitis B virus (HBV) and hepatitis C virus (HCV). The classic therapy consisting of
IFN-α and ribavirin in HCV is associated with many side effects of this treatment
including thyroid dysfunctions. Faustino et al. suggested that IFN-α may stimulate
autoimmunity in thyroid diseases. According to this study, IFN-α stimulates Tg production and destruction via the lysosomal-dependent system. Such phenomenon
may lead to the release of potentially immunogenic Tg peptides and stimulate the
autoimmunologic mechanism of thyroid diseases. Furthermore, the authors proposed that IFN-α may influence endoplasmic reticulum (ER) stress in thyrocytes,
potentially triggering apoptosis in thyroid cells [30].
Alteration in Gut Microbiome
The microbiota plays a significant role in maintaining nutritional, metabolic, and
immunologic homeostasis [31]. Evidence suggests that intestinal dysbiosis, bacterial overgrowth, and increased intestinal permeability promote the development of
inflammatory and autoimmune diseases, including Hashimoto’s thyroiditis [32].
Cayres et al. analyzed 40 patients with Hashimoto’s thyroiditis and 53 controls.
They showed an increase in the Bacteroides species and a decrease in Bifidobacterium
in patients with Hashimoto’s thyroiditis [33].
Oxidative Stress
The primary prooxidants include reactive oxygen species (ROS) and reactive nitrogen species (RNS). Maintaining a balance between prooxidants and antioxidants is
crucial for optimal thyroid gland function. Research consistently demonstrates that
patients with Hashimoto’s thyroiditis experience elevated oxidative stress, characterized by increased oxidants and reduced antioxidant levels, regardless of their
thyroid functional status [34]. A study involving 44 newly diagnosed females with
Hashimoto’s thyroiditis and 58 healthy controls revealed significantly lower mean
serum glutathione (GSH) levels in Hashimoto’s patients. As a key antioxidant, GSH
plays a vital role in protecting against oxidative damage. In these patients, GSH
levels showed significant correlations with thyroid peroxidase antibodies and
thyroid-­stimulating hormone (TSH). These findings suggest that GSH deficiency
contributes to oxidative stress and promotes immune intolerance in the progression
of Hashimoto’s thyroiditis [35]. Furthermore, oxidative stress was notably higher in
overweight and obese women with Hashimoto’s thyroiditis compared to those with
a normal body mass index (BMI). Poor dietary habits, particularly low fruit and
vegetable intake were also linked to increased total oxidant status [34].
Chronic Stress and Environmental Factors
The autoimmune process affecting the thyroid gland may also be influenced by various other factors such as stress and environmental conditions. Chronic stress has
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been linked to systemic inflammation, driven by elevated levels of pro-­inflammatory
cytokines, which may contribute to the onset of autoimmune diseases [36].
Therefore, psychological factor may be related to the pathogenesis of Hashimoto’s
thyroiditis and requires more research to determine cause and effect. Notably, there
is a potential link between autoimmune thyroid diseases and climate change.
Populations residing in colder and more extreme climates seem to have a higher
predisposition to autoimmune thyroiditis [37]. This correlation highlights the need
to explore the impact of global warming and shifting weather patterns on the prevalence and development of autoimmune thyroiditis.
Smoking: A Protective Factor?
Tobacco smoke is composed of numerous substances, including nicotine, anatabine,
carbon monoxide, and various carcinogens such as free radicals, aldehydes, and
aromatic hydrocarbons. Interestingly, some studies suggest that smoking may have
a protective effect against the development of Hashimoto’s thyroiditis [38, 39].
Smoking should be recognized as a less apparent protective factor against the development of Hashimoto’s thyroiditis. However, a similar protective effect has not
been established for Graves’ disease; instead, smoking is more commonly linked to
the aggravation of Graves’ ophthalmopathy [40]. There is currently no definitive
evidence on the role of alcohol in the pathogenesis of the disorder, making its impact
a subject of ongoing debate [41].
Genetic Predisposition
Extensive epidemiological evidence, including population-based, family-based, and
twin studies, indicates a significant genetic influence on the development of
Hashimoto’s thyroiditis. The condition tends to cluster within families and is
believed to follow a polygenic inheritance pattern with a complex genetic framework. Immunomodulatory genes are thought to play a crucial role in both predisposition and regulation of the disease’s pathogenesis [42]. Bothra et al. reported that
first-degree relatives of individuals with Hashimoto’s thyroiditis face a nine-fold
higher risk of developing the disease compared to the general population [43]. A
Danish twin study provided epidemiological evidence supporting the genetic susceptibility of Hashimoto’s thyroiditis. The study found a concordance rate of 55%
in monozygotic twins, compared to 0% in dizygotic twins. Additionally, thyroid
autoantibody concordance rates were significantly higher in monozygotic twins
(80%) than in dizygotic twins (40%) [44]. It seems that there is no dominant gene
conferring major susceptibility to the disease. However, an association was described
with human leukocyte antigen (HLA) alleles and with other genes. The human
major histocompatibility (MHC) region, located on chromosome 6p21, consists of
a cluster of genes responsible for encoding HLA glycoproteins and various other
proteins primarily involved in immune function. This MHC locus is categorized
into three gene groups: class I genes, which encode HLA antigens A, B, and C; class
II genes, responsible for HLA-DR, DP, and DQ molecules; and class III genes [45].
Several genes have been implicated in the development of Hashimoto’s thyroiditis,
including those within the human leukocyte antigen (HLA) complex, such as
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S. K. Imam
HLA-A*02:07 and HLA-DRB4, as well as immune regulatory genes (CD14, CD40,
CD25, FoxP3, CTLA-4, IL2R, and PTPN22) and thyroid-specific genes (TSH
receptor and thyroglobulin) [46, 47]. Patients with Hashimoto’s thyroiditis commonly exhibit antibodies targeting various thyroid antigens, most notably anti-­
thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg), with TSH
receptor-blocking antibodies (TBII) detected less frequently. However, approximately 10–15% of patients may test negative for these antibodies. Additional antithyroid antibodies, such as thyroid-stimulating and cytotoxic antibodies, have also
been identified in autoimmune thyroid diseases, including Hashimoto’s thyroiditis
[48]. The condition is strongly associated with other autoimmune diseases, including pernicious anemia, adrenal insufficiency, celiac disease, and type 1 diabetes
mellitus [49].
Ruggeri et al. found that the prevalence of nonthyroidal autoimmune diseases
(NTADs) in Hashimoto’s thyroiditis varies by age. Adults exhibited a higher frequency of NTADs compared to children and adolescents, with multiple autoimmune conditions being more common among adults. Specifically, arthropathies and
connective tissue diseases were more prevalent in adults, while type1 diabetes and
celiac disease were more frequently observed in younger individuals [50].
Epigenetic Factors
Epigenetics explores heritable modifications in gene expression that do not involve
changes to the DNA sequence itself. It can disrupt immune responses, causing the
production of autoantibodies and damage healthy tissues. Therefore, epigenetics
may also play role in pathogenesis of Hashimoto’s thyroiditis by DNA methylation
with the altered expression of immune-related genes, as well as histone and microRNAs (miRNAs) modifications that result in dysregulated immune pathways and
apoptosis.
Pathogenesis
The autoimmune failure of the thyroid unfolds as a complex, multistep process
requiring the convergence of genetic predisposition and environmental triggers
before progressing to overt disease. In the initial phase, antigen-presenting cells
(APCs), particularly dendritic cells and specific macrophage subsets, infiltrate the
thyroid gland [51]. This infiltration is often triggered by environmental factors such
as excessive dietary iodine, selenium deficiency, oxidative stress, vitamin D deficiency, exposure to toxins, or viral infections, etc., which damage thyrocytes and
release thyroid-specific proteins. These proteins act as self-antigens and, upon processing, are presented on the surface of APCs. Subsequently, APCs migrate to the
draining lymph nodes, where they interact with autoreactive T cells, cells that evade
immune tolerance due to dysregulation and B cells. This interaction initiates the
production of thyroid autoantibodies. As the process advances, antigen-producing B
lymphocytes, cytotoxic T cells, and macrophages accumulate in the thyroid,
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279
Fig. 3 Pathogenesis of Hashimoto’s thyroiditis
facilitated by clonal lymphocyte expansion and the formation of lymphoid structures within the gland. T helper type 1 (TH1) cells play a central role in this stage,
releasing regulatory cytokines such as interleukin-12, interferon-γ, and tumor
necrosis factor-α, which further propagate the immune response [52]. In the final
stage, autoreactive T cells, B cells, and thyroid-specific antibodies contribute to the
progressive destruction of thyrocytes through antibody-dependent cytotoxicity,
cytokine-mediated damage, and apoptosis. This culminates in the functional decline
of the thyroid, leading to hypothyroidism and the clinical manifestation of
Hashimoto’s disease (Fig. 3).
Evidence also indicates that both circulating and thyroid-infiltrating Th17 cells
contribute to HT pathology by secreting other proinflammatory cytokines, including IL-17 and IL-22, which are found at elevated levels in affected individuals [53].
Therefore, in the context of thyroid cell injury, cytokines released by infiltrating
lymphocytes play a pivotal role. These cytokines not only mediate immune-driven
damage but also stimulate thyroid cells to produce proinflammatory mediators,
thereby amplifying and sustaining the autoimmune process [37].
Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance
and preventing autoimmune diseases. They can be broadly categorized into natural
or thymic Tregs (CD4+CD25+Foxp3+), which have been found to exhibit abnormalities in Hashimoto’s thyroiditis (HT), and induced Tregs that differentiate in peripheral tissues in response to specific antigens. Notably, an increase in CD4+CD69+Foxp3
Tregs with impaired function has been reported in Hashimoto’s thyroiditis, suggesting a dysregulated immune response [54].
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S. K. Imam
Pathological Variants of Hashimoto’s Thyroiditis
For many years, HT has been characterized as a well-defined clinicopathologic
entity. However, it is now considered a heterogeneous disease, with several subtypes: classic form, fibrous variant, IgG4-related variant, juvenile form (presented
before 18 years of age), Hashitoxicosis, and painless thyroiditis, the latter occurring
either sporadically or in the postpartum period. They share the diagnostic characteristics of HT but have some interesting particularities [55].
The classic variant is the most common and is considered the typical form of
Hashimoto’s thyroiditis (Fig. 4). It is characterized by diffuse lymphocytic infiltration, germinal center formation, and Hurthle cell changes, extensive fibrosis but not
enough to distort the thyroid architecture, and this variant is typically associated
with a diffuse, non-tender goiter. The goiter results from chronic lymphocytic infiltration, follicular destruction, and fibrosis, leading to thyroid enlargement [56].
Key Features of Goiter in the Classic Variant:
• Diffuse, firm, and rubbery thyroid enlargement
• Non-tender on palpation
• May fluctuate in size over time
It can lead to progressive atrophy in later stages, eventually shrinking the gland
and may be considered as an end-stage of the classic variant. Therefore, goitrous
and atrophic form represent variations along a spectrum rather than distinct disease
entities.
a
b
c
Fig. 4 Typical histological findings in patient with Hashimoto’s thyroiditis. (a) Diffuse lymphocytic and plasma cell infiltration, (b) lymphoid follicular formation, (c) follicular basement membrane damage. (Courtesy of Dr. Moustafa Ali Abousarie, Al Borg Diagnostics, Reference Lab Head
unit, Riyadh, Saudi Arabia)
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281
The fibrous variant accounts for 10–13% of HT cases and usually affects older
patients. Its diagnostic criteria were defined by Katz and Vickery in 1974 and
included a marked fibrous replacement of more than one-third of the thyroid parenchyma and changes typical of HT in the remaining tissue and most patients are
hypothyroid at presentation [57].
The IgG4-related variant of HT is a new subtype, first recognized by Li et al. in
2009 [58]. Approximately 30% of Hashimoto’s thyroiditis patients in Japan and the
United States exhibit IgG4-RD involvement of the thyroid, which is associated with
early-onset hypothyroidism and thyroid atrophy. However, the prevalence in Europe
appears to be lower, estimated at around 12% [59]. It may be part of the systemic
IgG4-related disease. The diagnosis of this systemic disorder includes, independently of the affected organ, histological features such as a dense lymphoplasmacytic infiltrate, storiform-type fibrosis and obliterative phlebitis, along with the
demonstration of an increased population of IgG4-positive plasma cells [60]. Cheuk
and Chan considered that it requires an increase in the absolute number of IgG4-­
positive cells of >50 per high power field and a raised IgG4- positive/IgG-positive
ratio of >40% [61]. Deshpande et al. stated that histological data are the mainstay
for diagnosis, since both elevated numbers of IgG4-positive plasma cells and IgG4/
IgG ratios have been described in other inflammatory conditions and malignancies
[62]. Luiz et al. [63] reported that IgG4 variant of HT is characterized by thyroid
inflammation rich in IgG4-positive plasma cells and marked fibrosis.
A high serum IgG4 concentration is often present but approximately 20–30% of
patients with classic histopathological and immunochemical findings of the disease
have normal serum levels [64]. It is usually associated with male gender, rapid progress requiring surgery, more subclinical hypothyroidism, higher levels of thyroid
autoantibodies, and more diffuse low echogenicity on ultrasound, when compared
with the non-IgG4 variant. In 2012, Kakudo et al. studied 105 patients with HT and
classified 28 cases (27%) as IgG4 thyroiditis based on immunohistochemistry [65].
Since this condition seems to be more common than previously thought, author suggests performing the immunostaining in a patient who presents with these typical
clinical features and with lymphoplasmacytic infiltration and marked fibrosis of the
thyroid gland.
The juvenile form of Hashimoto’s thyroiditis (HT) typically manifests before the
age of 18, with an average referral age of 11 years [66].
Although the condition is more common in females, the female-to-male ratio is
lower compared to the adult form. Most affected children present with goiter, yet
they are generally asymptomatic. At diagnosis, thyroid function status varies [67]:
•
•
•
•
•
43% of children are euthyroid (normal thyroid function)
24% exhibit subclinical hypothyroidism
21% have overt hypothyroidism
9% present with overt hyperthyroidism
3% show subclinical hyperthyroidism
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S. K. Imam
The disease course is heterogeneous, often marked by remissions, relapses, and
potential progression to permanent hypothyroidism.
The Hashitoxicosis variant, first described by Fatourechi in 1971 [68], presents
a unique overlap of Graves’ disease-like hyperthyroidism with the histopathological
features of HT. The initial hyperthyroid phase mimics Graves’ disease, characterized by elevated thyroid uptake of radioactive iodine and the presence of thyroid-­
stimulating immunoglobulins (TSI). However, unlike Graves’ disease,
hyperthyroidism in Hashitoxicosis is temporary, eventually transitioning to permanent hypothyroidism within 3–24 months.
Silent thyroiditis variant, also termed painless thyroiditis, is a lymphocytic
inflammation of the thyroid that can occur sporadically or within 1 year postpartum.
The postpartum form, known as postpartum thyroiditis, shares the same clinical
characteristics as silent thyroiditis but is specifically associated with pregnancy. In
populations with higher dietary iodine intake, painless thyroiditis is observed more
frequently [69].
This condition follows a triphasic progression, beginning with thyrotoxicosis,
followed by hypothyroidism, and ultimately leading to recovery. Postpartum thyroiditis affects approximately 8% of pregnancies [70], though prevalence varies
depending on population demographics and the frequency of follow-up.
ashimoto’s Thyroiditis and Type 2 Polyglandular
H
Autoimmune Syndrome: Pathogenesis
and Genetic Susceptibility
Polyglandular autoimmune syndrome (PAS) refers to the coexistence of at least two
endocrine autoimmune disorders within a single patient. The most recognized forms
include PAS type 1 (PAS-1), PAS type 2 (PAS-2), and X-linked immune dysregulation, polyendocrinopathy, and enteropathy (IPEX) syndrome. Among these, PAS-2
is the most prevalent polygenic variant, characterized by lymphocytic infiltration
leading to organ-specific autoimmune destruction. This process is driven by a complex interplay of multiple genetic loci and environmental factors [71].
Historical Perspective of Polyglandular Autoimmune Syndrome
The association between Addison’s disease and chronic lymphocytic thyroiditis was
first described by Schmidt, leading to the designation of Schmidt syndrome [72].
Later, Carpenter expanded this understanding by identifying the frequent coexistence of type 1 diabetes mellitus (T1DM) with Schmidt syndrome. In a review of
142 cases, he introduced the term Carpenter syndrome, denoting the triad of
Addison’s disease, autoimmune thyroid disease, and T1DM [73].
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283
Genetic Susceptibility in PAS-2
The major histocompatibility complex (MHC) genes play a crucial role in organ-­
specific autoimmunity in PAS-2. Notably, the HLA-DR3 and HLA-DR4 haplotypes, along with the class II HLA alleles DQ2 and DQ8, have been associated with
increased susceptibility to the syndrome. Beyond HLA-related influences, non-­
HLA genes have also been implicated in PAS-2 pathogenesis. These include: CD25
(interleukin-2 receptor), cytotoxic T-lymphocyte protein 4 (CTLA-4), protein tyrosine phosphatase, non-receptor type 22 (PTPN22).
Diagnostic Criteria and Clinical Spectrum of PAS-2
A diagnosis of PAS-2 requires the presence of at least two of the following three
endocrine disorders in the same patient:
• Primary adrenal insufficiency (Addison’s disease)
• Autoimmune thyroid disease (manifesting as Graves’ disease or Hashimoto’s
thyroiditis)
• Type 1 diabetes mellitus (T1DM)
In addition to these core features, PAS-2 can present with various endocrine and
non-endocrine autoimmune conditions [71], including:
• Endocrine manifestations: primary hypogonadism
• Neuromuscular disorders: myasthenia gravis, stiff-person syndrome,
Parkinson’s disease
• Gastrointestinal conditions: celiac disease, pernicious anemia
• Dermatological findings: alopecia, vitiligo, dermatitis herpetiformis
• Hematological disorders: idiopathic thrombocytopenia
• Cardiac involvement: idiopathic heart block, serositis
• Immunodeficiencies: IgA deficiency
• Pituitary involvement: hypophysitis
Clinical Features of Hashimoto’s Thyroiditis
Hashimoto’s thyroiditis (HT) manifests with both local and systemic symptoms, as
well as features specific to different forms of the disease. Clinical manifestations of
HT are variable and commonly include diffuse or nodular goiter with euthyroidism,
subclinical hypothyroidism, which shows a combination of elevated serum TSH
concentrations and normal free T4 and T3 concentrations, and permanent
hypothyroidism.
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S. K. Imam
Local Manifestation
The disease typically presents as a painless, diffuse, and gradually progressive
enlargement of the thyroid gland [55]. The goiter is often firm, symmetrical, and
may involve enlargement of the pyramidal lobe, while well-defined nodules are
uncommon. In rare cases, patients may experience pain, tenderness, or symptoms
associated with neck compression, such as dyspnea or dysphagia, particularly in
instances of rapid thyroid swelling [74]. The thyroid gland may also remain
unchanged for several years, and some individuals neither develop goiter nor exhibit
glandular atrophy [75].
The following local symptoms and signs of HT, as reported in the literature, arise
due to pressure on cervical structures near the thyroid gland [76]:
•
•
•
•
•
•
•
•
Neck pain (0.02–16%)
Voice changes (7–30%)
Throat discomfort (20–35%)
Dyspnea (12.5–50%)
Dysphagia (29–33%)
Sleep apnea (prevalence not available)
Enlarged cervical lymph nodes (63–88.5%)
Neck enlargement (prevalence not available)
Systemic Manifestation
A majority of individuals with Hashimoto thyroiditis are euthyroid with normal
thyroid function tests. About 20–30% of individuals with Hashimoto thyroiditis
develop hypothyroidism [77].
In Hashimoto’s thyroiditis, hypothyroidism typically develops gradually with
signs and symptoms progressing over months to years and are consequences of
thyroid hormone deficiency in target tissues and exhibit a wide spectrum of severity.
In some cases, patients may initially experience transient hyperthyroidism, known
as Hashitoxicosis [67], results from release of T4 and T3 from thyrocyte destruction
and this early presentation can sometimes be mistaken for Graves’ disease. The
course of the disease varies depending on the rate of progression and the severity of
hypothyroidism, and a history of other autoimmune conditions may be present.
Hypothyroidism in HT can affect all organ systems. The presence and severity of
clinical manifestations are usually dependent on the degree of hormone deficiency.
Two mechanisms explain most of the symptoms and signs: the generalized slowing
of metabolic processes and the accumulation of glycosaminoglycans in the interstitial space of many tissues [78].
A detailed account of the systemic manifestations of hypothyroidism is provided
below, with a summary of manifestations in Table 2.
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285
Table 2 Systemic manifestations of Hashimoto’s thyroiditis
Skin and
appendages
Cardiovascular
Respiratory
Gastrointestinal
Symptoms
Dry skin and hair
Delayed wound
healing
Easy bruising
Hair fall
Thickened and
brittle nails
Reduced exercise
tolerance
Dyspnea
Angina
Hoarseness of
voice
Obstructive sleep
apnea
Dyspnea
Heartburn
Dyspepsia
Anorexia
Weight gain
Constipation
Neurologic
In children:
(cretinism)
Mental
retardation
In adults:
Headache
Memory
impairment
Lack of
concentration
Hearing loss
Vertigo
Tinnitus
Confusion
Altered level of
sensorium
Seizures
Psychosis
Hashimoto’s
encephalopathy
Signs
Pallor
Yellowish tint
Queen Anne’s sign
Absent eyebrows (Queen
Anne’s sign)
Bradycardia
Diastolic hypertension
Narrow pulse pressure
Signs of pericardial
effusion
Pronged PR interval
Pronged QT interval
Low voltage
Alteration in ST segment
Flattened or inverted T
waves
Signs of bilateral pleural
effusion
Macroglossia
Fecal impaction
Megacolon
Ileus
Signs of ascites
Laboratory/radiology
findings
Increase homocysteine
Increase creatinine
kinase
Elevated total and
LDL-Cholesterol
Pericardial effusion
Carbon dioxide (CO2)
retention
Pleural effusion
Elevated aspartate
aminotransferase
Elevated lactate
dehydrogenase
Elevated
carcinoembryonic
antigen
Low vitamin B12
Tremor
Rigidity
Spasticity of the trunk and
proximal extremities
Strabismus
Sensorineural hearing loss
Delayed relaxation of deep
tendon reflexes
Carpal tunnel syndrome
Cerebellar ataxia
Myoclonus
Tremor
Hyperreflexia
(continued)
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S. K. Imam
Table 2 (continued)
Psychiatric
Musculoskeletal
Children
In adults:
Hematopoietic
Endocrine/
reproductive
Eye involvement
Symptoms
Signs
Depression
Psychosis
Hallucination
Cognitive
impairment
Somnolence
Delayed closure of the
Growth
fontanelles
retardation
Short stature
Dwarfism
Generalized muscular
Arthralgias
Joint stiffness and hypertrophy and weakness
effusions
Muscle weakness
Cramps
Pallor
Easy bruising
Epistaxis
Gum bleeding
Menorrhagia
Goiter
Galactorrhea
Delayed puberty
Decreased libido
Erectile
dysfunction
Ovulatory failure
Infertility
Miscarriage
Menstrual
irregularity
Menorrhagia
Bilateral proptosis, eyelid
swelling, conjunctival
injection
Laboratory/radiology
findings
Epiphyseal dysgenesis
Delayed bone age
Elevated creatinine
phosphokinase
Decreased urinary
excretion of calcium
Macro or microcytic
anemia
Deficiency of von
Willebrand factor
Increased prolactin
Decreased growth
hormone
Skin and Appendages
A mucinous nonpitting edema known as myxedema can be found around the eyes
given a puffy or moonlike appearance, on the dorsum of the hands and feet, and in
the supraclavicular fossa. This is explained by the accumulation of hyaluronic acid
and other glycosaminoglycans in the dermis. The secretions of the sweat and sebaceous glands are reduced, leading to dryness of the skin. The skin is pale and cool
because of cutaneous vasoconstriction and/or anemia. Some patients may have
hypercarotenemia, which gives the skin a yellow tint. Wounds heal slowly. Easy
bruising can also occur due to an increase in capillary fragility [79, 80]. Head and
body hair is dry and brittle, lacks shine, and tends to fall out. Hair may be lost from
the lateral margins of the eyebrows (Queen Anne’s sign), although this is not a specific feature. Eyebrows can totally disappear. The nails are thickened, brittle, and
grow slowly.
Hashimoto’s Thyroiditis
287
Cardiovascular
The cardiac output is decreased due to a reduction in both stroke volume and heart
rate, which can explain the symptoms of reduced exercise tolerance and dyspnea.
Peripheral vascular resistance is increased. These hemodynamic alterations cause
narrowing of pulse pressure, diastolic hypertension (10–25% of patients) and a
decrease in blood flow to organs [81, 82]. In most tissues, the reduction in blood
flow is proportional to the decrease in oxygen consumption and therefore angina is
an infrequent symptom [83]. When present, it is usually explained by an underlying
coronary heart disease (CHD). Serum levels of homocysteine [84, 85] and creatine
kinase (CK) may be increased in hypothyroidism [86]. Dyslipidemia can be found
in more than 90% of patients, usually presenting as elevations of total and low-­
density lipoprotein (LDL) cholesterol [87]. These findings may contribute to an
increased risk of atherosclerosis. An electrocardiogram can show sinus bradycardia,
low voltage, prolongation of the PR interval, alterations of the ST segment, prolonged QT interval and flattened or inverted T waves [79, 80]. Torsade de pointes
can rarely occur [88]. Echocardiographic evaluation may reveal pericardial effusion
and asymmetric septal hypertrophy or other abnormalities, and rarely, patients can
develop congestive heart failure [89–91].
Respiratory
Pleural effusions can be present and may contribute to dyspnea. In severe hypothyroidism, alveolar hypoventilation and carbon dioxide retention may occur, contributing to the development of myxedema coma [92, 93]. The voice is husky
(hoarseness), low-pitched, and coarse. The speech is slow and slurred [80].
Obstructive sleep apnea is common because of macroglossia [94, 95].
Gastrointestinal
Appetite is usually reduced (anorexia). Modest weight gain can occur due to the
decreased metabolic rate and retention of fluid in tissues. Contrary to popular belief,
hypothyroidism is not related to an increase of fat and obesity [96]. Dysphagia or
heartburn may be due to disordered esophageal motility, whereas dyspepsia, nausea,
or vomiting are related to delayed gastric emptying [97]. Decreased gut motility and
decreased food intake result in constipation [98]. The latter may lead to fecal impaction, megacolon, and ileus [99]. The rate of intestinal absorption is decreased and
intestinal transit time is prolonged [100]. Ascites is rarely found [101]. Gallbladder
motility is decreased in hypothyroid patients [102]. In addition, measurements of
serum aspartate aminotransferase, lactate dehydrogenase, and carcinoembryonic
antigen may be elevated, and pernicious anemia can be present [103–105].
Neurologic
Thyroid hormones are crucial for the development of the central nervous system.
Congenital hypothyroidism is related to severe and irreversible neurologic abnormalities if left untreated. It can be associated with hypoplasia of cortical neurons,
retarded myelination, and altered cell migration and differentiation [106, 107].
Manifestations include mental retardation, impaired motor development such as
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S. K. Imam
tremor, rigidity and spasticity of the trunk and proximal extremities, and also strabismus and sensorineural hearing loss [108]. Hypothyroidism occurring in adult life
is characterized by less severe neurologic manifestations. Headaches can be identified in 30% of hypothyroid patients [109]. Carpal tunnel syndrome is present in
29–38% of cases due to compression of the median nerve by deposits of glycosaminoglycans [110, 111]. Body movements are slow and cerebellar ataxia may be identified [112]. The occurrence of delayed relaxation of deep tendon reflexes may be
related to peripheral neuropathy [113]. Hearing loss, vertigo, and tinnitus are frequent [114]. These changes are caused by myxedematous infiltration of the tongue
and larynx. Loss of initiative, memory and calculation defects, reduced attention
span, and poor concentration may be present. Irritability is decreased and apathy
can occur.
Hashimoto’s encephalopathy is a rare manifestation of HT [115]. Patients most
often have an acute or subacute onset of confusion with alteration of consciousness
and other neurologic signs, such as seizures, myoclonus, tremor, hyperreflexia, and
psychosis [116]. The diagnosis is usually performed by the presence of these clinical manifestations in patients with elevated thyroid antibodies [117].
Psychiatric
Psychiatric disorders are common and usually manifest as depression. However,
some patients may present with psychosis and hallucinations (myxedema madness)
[118]. An association between Alzheimer’s disease and hypothyroidism was
reported but an etiologic relationship has not been established [119, 120]. The
pathogenesis of cognitive dysfunction in hypothyroidism is unknown. It may be
related to a decrease in cerebral blood flow and a reduction in glucose metabolism [121].
Musculoskeletal
Thyroid hormones are essential for normal growth and skeletal development.
Thyroid hormone deficiency in infants results in growth failure and dwarfism in
which the limbs are disproportionately short in relation to the trunk. Epiphyseal
dysgenesis is a typical finding that can be identified in radiologic exams. Ossification
centers appear late and bone age is retarded in relation to chronologic age [122].
Delayed closure of the fontanelles is also found. In older children, hypothyroidism
can cause short stature [123]. Adults may complain of arthralgias, joint stiffness,
and effusions [124]. Muscular symptoms can be identified in about 80% of patients,
namely muscle weakness and cramps [110]. Rarely, a combination of generalized
muscular hypertrophy and weakness may be found, which is referred as Kocher-­
Debre-­Semelaigne syndrome in children [125, 126] and Hofmann’s syndrome in
adults [127]. CK levels are sometimes high and patients may develop rhabdomyolysis [128]. Serum calcium levels are usually normal but may be elevated [129].
Serum phosphorus concentration is normal. Urinary excretion of calcium is
decreased.
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289
Renal
Renal blood flow is decreased due to the reduction of cardiac output and blood volume. The glomerular filtration rate is also low [130]. Other effects of hypothyroidism include impaired sodium reabsorption and renal ability to dilute urine. As a
result, increased serum creatinine and hyponatremia can occur [131].
Hematopoietic
The red blood cell mass is decreased. Mild anemia may be found in one-third of
patients [132], and it is usually normocytic and normochromic. Less commonly, a
macrocytic form in the context of pernicious anemia or folate deficiency may occur
[133]. Menorrhagia and the defective absorption of iron resulting from achlorhydria
can contribute to a microcytic and hypochromic anemia. White blood cell and platelet counts are usually normal. Hypothyroid patients have a higher risk of bleeding
mainly due to acquired von Willebrand’s syndrome [134, 135]. Some symptoms
such as epistaxis, gum bleeding, menorrhagia, and easy bruising may be present.
Endocrine
In primary hypothyroidism, the increase in TSH levels stimulates the thyroid gland
and results in the development of a goiter. Untreated primary hypothyroidism can
also cause hyperplasia of the thyrotrophs and pituitary gland enlargement [136],
which may result in hypopituitarism and visual field defects [137, 138]. About
39–63% of patients have increased serum prolactin levels due to the increased TRH
secretion. Elevated prolactin can result in suppressed gonadotropin secretion and
diminished responsiveness to GnRH, leading to anovulatory cycles, menstrual
irregularities, galactorrhea, and infertility [139, 140]. Growth hormone secretion is
decreased in hypothyroidism [141]. Serum aldosterone and cortisol levels are often
normal in hypothyroid patients, but the turnover rates are decreased. Plasma renin
activity is also reduced [142]. Individuals may have an elevated plasma noradrenaline level, whereas the adrenaline concentration is usually normal and a decreased
adrenergic response is often found [143, 144].
Reproductive
Thyroid hormones influence sexual development and reproductive function.
Untreated infantile hypothyroidism results in sexual immaturity, whereas juvenile
hypothyroidism causes a delay in the onset of puberty. However, it may also induce
precocious puberty, which can be explained by the action of elevated levels of TSH
on the follicle-stimulating hormone receptor [145]. In adult women, hypothyroidism may be associated with diminished libido and failure of ovulation [146].
Irregular menstrual cycles are present in more than 20% of women, especially oligomenorrhea and menorrhagia [147]. Fertility may be reduced and both miscarriage
and adverse neonatal outcomes can occur [148]. However, most women with
untreated hypothyroidism have uneventful pregnancies and give birth to normal
infants [149]. Hypothyroidism in adult men may cause decreased libido, erectile
dysfunction, delayed ejaculation, and defects in spermatogenesis [150, 151].
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Eye Involvement
Thyroid eye disease affects up to 6% of individuals with Hashimoto’s thyroiditis.
Approximately 15% of patients with Hashimoto’s thyroiditis have TSH receptor
antibodies (TSHR Ab), with the majority being of the blocking type. In a small
subset of cases, TSHR-stimulating antibodies may be present, leading to ocular
involvement [152].
Energy Metabolism
Energy metabolism is decreased in hypothyroidism leading to cold intolerance and
contributing to a lower energy expenditure, oxygen consumption, and utilization of
substrates. Both the synthesis and the degradation of protein are decreased, but
nitrogen balance is usually positive. Permeability of capillaries to protein is
increased, which explains the high levels of protein in effusions [79]. Hypothyroidism
is usually associated with normal plasma glucose levels, whereas plasma insulin can
be increased [153]. A lower glucose uptake in muscles and adipose tissue was
reported [154]. In patients with preexisting diabetes mellitus who develop hypothyroidism, insulin requirements may be reduced possibly due to the decreased insulin
degradation [155]. Both the synthesis and the degradation of lipid are reduced in
hypothyroidism. As previously noted, hypothyroidism is associated with dyslipidemia usually presenting as elevations of total and LDL cholesterol [87].
Link Between Hashimoto’s Thyroiditis and Cancer
The association between Hashimoto’s thyroiditis (HT) and thyroid cancer remains
a topic of debate. This potential link was first reported by Dailey et al. in 1955 [156].
Some studies suggest that patients with HT have a threefold increased risk of developing papillary thyroid carcinoma (PTC) compared to those without HT [157].
However, other researchers argue that the evidence supporting a causal relationship
between these conditions is inconsistent [158]. Notably, thyroid cancer in patients
with coexisting HT may present with a less aggressive course and a more favorable
prognosis [159]. For further details, see prognosis and morbidity in Hashimoto’s
thyroiditis as mentioned below.
Investigations
Currently, there are no specific guidelines from the American Thyroid Association
(ATA) or the European Thyroid Association (ETA) that detail diagnostic criteria
exclusively for Hashimoto’s thyroiditis, and the diagnostic criteria for Hashimoto’s
thyroiditis (HT) are based on a combination of clinical, biochemical, and imaging
findings, as well as histopathology when necessary. The diagnosis is primarily clinical and supported by laboratory tests and is typically diagnosed in patients
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presenting with a diffuse goiter alongside at least one biochemical or histological
marker, such as positive thyroid peroxidase antibodies (TPOAb), positive thyroglobulin antibodies (TgAb), or lymphocytic infiltration of the thyroid gland.
However, in some cases, goiter may be absent, and the presence of thyroid autoantibodies in serum can be sufficient for diagnosis [160].
Following investigations are helpful in diagnosing HT and its related
complications.
Thyroid Function Tests
Thyroid-Stimulating Hormone (TSH): In the presence of clinical symptoms and
suggestive physical findings, serum TSH measurement is essential for diagnosing
primary hypothyroidism. TSH is the most sensitive marker of thyroid function and
is consistently elevated in Hashimoto’s thyroiditis and other causes of primary
hypothyroidism [161, 162]. In subclinical hypothyroidism, TSH is elevated while
total or free T4 remains within the reference range. The rise in TSH occurs as the
pituitary gland compensates for the failing thyroid gland. However, TSH levels may
not be reliable in conditions such as central hypothyroidism and nonthyroidal illness, where clinical findings and other thyroid function tests become critical for
diagnosis. Some patients may have transient hyperthyroidism (“Hashitoxicosis”) in
early stages due to thyroid destruction.
Free Thyroxine (FT4): Measurement of free T4 is crucial in cases where TSH
interpretation is challenging. A low FT4 in conjunction with an elevated TSH confirms the diagnosis of primary hypothyroidism.
Free Triiodothyronine (FT3): T3 levels generally remain within the normal
range, even in advanced hypothyroidism. Measurement of T3 is not particularly
useful for diagnosing hypothyroidism [163]. Notably, T3 levels can be low in up to
70% of hospitalized patients without thyroid dysfunction, as seen in nonthyroidal
illness syndrome.
Thyroid Autoantibodies
The most reliable marker for predicting progression to overt hypothyroidism is an
elevated TSH level with the presence of thyroid autoantibodies. Anti-TPO antibodies are detected in 95% of patients with Hashimoto’s thyroiditis, while anti-Tg antibodies are present in 60–80% of cases, making them less specific for diagnosis
[164, 165]. However, anti-TPO antibodies can also be found in other autoimmune
diseases without thyroid dysfunction, and their presence alone does not always
necessitate treatment. TSH receptor antibodies (TSHR Ab) exist in stimulating,
blocking, or neutral forms [166]. In Hashimoto’s thyroiditis, blocking antibodies
predominate, though stimulating antibodies may rarely be detected.
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Additional Thyroid Evaluations
Ultrasound: Although ultrasonographic features of Hashimoto’s thyroiditis are
often present, thyroid ultrasound generally is not required for diagnosis. It is primarily useful for evaluating thyroid size, echotexture, and the presence of nodules [167].
Ultrasound aids in assessing malignancy risk, particularly when nodules exhibit:
•
•
•
•
Irregular margins
Poorly defined halo
Microcalcifications
Increased vascularity on Doppler imaging
Additionally, ultrasound helps in guiding fine-needle aspiration (FNA) of suspicious or small nodules.
Fine-Needle Aspiration Biopsy (FNAB): It is performed on dominant or suspicious thyroid nodules to rule out malignancy or thyroid lymphoma, especially in
rapidly enlarging goiters [168].
Histological Findings: Histopathological examination is definitive for
Hashimoto’s thyroiditis (Fig. 4) and characterized by following features:
•
•
•
•
Diffuse lymphocytic and plasma cell infiltration
Lymphoid follicle formation
Follicular basement membrane damage
Thyroid parenchymal atrophy
Correlation with positive thyroid autoantibodies (anti-TPO, anti-Tg) further supports the diagnosis.
Iodine Uptake and Scan: Radioactive iodine uptake (RAIU) and thyroid scanning are generally not required for diagnosing Hashimoto’s thyroiditis. However,
these studies are useful in differentiating hot vs. cold nodules, where a cold nodule
may suggest a higher risk of malignancy, warranting fine-needle aspiration.
Evaluation of Complications in Hashimoto’s Thyroiditis
In certain patients with Hashimoto’s thyroiditis (HT), further investigations may be
warranted to assess potential complications of hypothyroidism when clinically
indicated.
1. Complete Blood Count (CBC): Anemia is observed in 30–40% of patients with
hypothyroidism, primarily due to reduced erythropoiesis [132]. Approximately
15% exhibits iron deficiency anemia, characterized by microcytosis and hypochromia. While anemia may present as normocytic normochromic, macrocytic
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293
anemia is the most prevalent morphological abnormality, potentially linked to
vitamin B12 and folate insufficiency [133].
2. Lipid Profile: Hypothyroidism is associated with elevated total cholesterol, LDL,
and triglycerides [87].
3. Renal Function: Reduced glomerular filtration rate, renal plasma flow, and free
water clearance can contribute to hyponatremia [130, 131].
4. Creatine Kinase (CK) and Aldolase: CK levels, particularly the MM isoenzyme
from skeletal muscle, and aldolase enzyme are often elevated in severe hypothyroidism [128].
5. Prolactin Levels: Prolactin may be elevated in primary hypothyroidism, likely
due to TRH-induced stimulation of lactotrophs and reduced prolactin clearance.
6. Serum Iron Levels: Assessment of serum iron levels may be necessary in patients
presenting with clinical signs of iron deficiency or gastrointestinal symptoms,
given the higher prevalence of celiac disease and atrophic gastritis in individuals
with HT [23, 71].
7. Vitamin D Levels: Vitamin D evaluation is recommended due to the increased
prevalence of HT in patients with vitamin D deficiency [25].
8. Imaging and Cardiac Assessment [79, 80, 88, 89]:
• Chest radiograph: May reveal small pleural or pericardial effusions.
• Electrocardiogram (ECG): May display low-voltage QRS complexes, nonspecific ST-wave changes, premature ventricular contractions, and in some
cases, QT prolongation with torsades de pointes and ventricular tachycardia.
• Echocardiogram: May detect pericardial effusion in severe cases of
Hashimoto’s thyroiditis.
Treatment of Hashimoto’s Thyroiditis
Euthyroid Hashimoto’s Thyroiditis
Euthyroid Hashimoto’s thyroiditis (HT) is diagnosed based on the presence of thyroid peroxidase antibodies (TPO Abs) and/or characteristic sonographic findings of
the thyroid gland, while serum TSH and T4 levels remain within the normal range.
The risk of developing hypothyroidism increases by 5% every year and the individuals at risk require annual TSH monitoring to assess the potential development
of hypothyroidism and to optimize management, particularly before conception and
during pregnancy [169].
Subclinical Hypothyroidism in Hashimoto’s Thyroiditis
Treatment initiation is generally recommended for patients with subclinical hypothyroidism when serum TSH levels reach 10 mIU/mL or higher, as this threshold
has been linked to an increased risk of cardiovascular events and mortality. In
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younger and middle-aged individuals who exhibit symptoms of hypothyroidism,
treatment may be considered even at lower TSH levels [170, 171].
Meta-analyses suggest that individuals with TSH levels ranging from 7 to 9.9
mIU/mL may have an elevated risk of fatal stroke and coronary heart disease mortality, prompting some experts to advocate for a lower threshold for treatment initiation in both younger and older individuals. In such cases, levothyroxine (LT4)
therapy may be considered when TSH levels exceed 7 mIU/mL [171–173].
Table 3 illustrates recommendations of levothyroxine replacement in subclinical
hypothyroidism associated with HT.
Overt Hypothyroidism in Hashimoto’s Thyroiditis
Patients diagnosed with overt hypothyroidism should receive thyroid hormone
replacement therapy. Studies have shown that levothyroxine treatment significantly
reduces the risk of myocardial infarction, stroke, atrial fibrillation, heart failure, and
cardiovascular mortality, as well as all-cause mortality when compared to untreated
individuals [174, 175].
The primary goal of therapy is to replicate normal thyroid physiology. The
appropriate LT4 dosage depends on residual endogenous thyroid function and
patient weight, particularly lean body mass. The healthy thyroid gland is estimated
to produce 85–100 mcg of T4 and 5–6.5 mcg of T3 per day, with an additional 26.5
mcg of T3 generated from peripheral T4-to-T3 conversion by type 1 and type 2
deiodinases. Based on this physiology, the recommended initial LT4 dose typically
ranges between 1.4 and 1.8 mcg/kg body weight in patients with preserved degree
of endogenous thyroid function [170, 176, 177].
Dose Adjustment and Monitoring
Upon initiation of LT4 therapy, dose adjustments should be guided by TSH targets,
ensuring alignment with age-appropriate reference ranges. In patients with short-­
bowel syndrome and malabsorption, increased doses of levothyroxine are required
to maintain a euthyroid state. The free T4 and TSH levels are within reference
ranges in the biochemically euthyroid state, with the TSH level in the lower half of
the reference range [163].
Longitudinal studies indicate that a significant proportion of patients experience
over- or undertreatment. In a large cohort study involving over 162,000 patients
monitored for 23 years, 11.6% of patients had TSH levels below 0.4 mIU/mL (suggesting overtreatment), while 32.4% had TSH levels above 4.0 mIU/mL (suggesting
undertreatment) [178]. Another study reported 19.8% of patients were overtreated,
whereas 17.4% were undertreated over a 5-year period [179]. Overtreatment was
associated with longer therapy duration, whereas undertreatment was more common among male patients and may also be influenced by ethnic and socioeconomic
disparities [180].
The optimal timeframe for evaluating LT4 dose adjustments is 6–8 weeks after
therapy initiation or dose modification, allowing sufficient time for the
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295
Table 3 Recommendation of levothyroxine treatment in subclinical hypothyroidism in HT
TSH
level
miu/ml Age < 65
Age > 65
Treat with levothyroxine to reduce the risk Treat with levothyroxine to reduce the
≥10
of progression to overt hypothyroidism and risk of progression to overt
hypothyroidism and mortality associated
mortality associated with heart failure,
with heart failure, stroke, and ischemic
stroke, and ischemic heart disease
heart disease
Consider treatment with levothyroxine to
7–9.9
Treat with levothyroxine to reduce
reduce mortality associated with heart
mortality associated with heart failure,
failure, stroke, and ischemic heart
stroke, and ischemic heart disease
disease
4.5–6.9 Annual follow-up TSH measurement in
Treatment not recommended
asymptomatic patients
Consider therapy for the following groups
of patients:
Positive TPO-Abs
Progressively increasing TSH levels
Goiter
A plan for pregnancy
Symptoms of hypothyroidism
Hyperlipidemia
hypothalamic-­
pituitary-­
thyroid axis to re-establish homeostasis. Although TSH
exhibits diurnal variation, this fluctuation is not significant enough to necessitate
testing at a specific time of day. Once the optimal LT4 dosage is determined, TSH
monitoring at 3–6 months is recommended, followed by annual evaluations in most
patients [170, 181].
However, achieving biochemical euthyroidism (normal TSH) does not always
correlate with an improvement in quality of life. Some researchers advocate for
assessing additional biomarkers of thyroid hormone action at the tissue level,
including sex hormone-binding globulin (SHBG), osteocalcin, cholesterol, creatine
kinase, ferritin, and N-telopeptides etc., to ensure comprehensive thyroid hormone
optimization [170].
Combination Therapy: Levothyroxine (LT4) and Liothyronine (T3)
For patients experiencing persistent symptoms despite LT4 therapy, combination
therapy with levothyroxine (T4) and liothyronine (T3) has been considered to more
closely mimic natural thyroid hormone physiology. However, a review of nine controlled clinical trials found that only one study demonstrated a significant improvement in mood, quality of life, and cognitive performance with combination therapy
compared to LT4 monotherapy [182].
Given the lack of conclusive evidence supporting the superiority of combination
therapy, levothyroxine monotherapy remains the preferred treatment for hypothyroidism. Further studies are required to establish definitive guidelines for the routine
use of LT4 and T3 combination therapy.
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Levothyroxine (LT4) Dosage Recommendations
• Patients younger than 60 years: 1.5–1.8 mcg/kg per day
• Patients aged 60 years or older, or with known/suspected heart disease: 12.5–50
mcg per day [183].
Administration Guidelines
• Take levothyroxine orally once daily
• Administer 30–60 minutes before meals
• Avoid concomitant intake of calcium carbonate, ferrous sulfate, proton pump
inhibitors, bile acid sequestrants, or ion exchange resins, as these can impair
absorption
• Maintain a 4-hour gap between LT4 and interfering substances
Complications Associated with Levothyroxine Overreplacement Include the
Following:
• Increased heart rate
• Increased cardiac wall thickness
• Increased contractility
The above problems increase the risk of cardiac arrhythmias (especially atrial
fibrillation), particularly in the elderly population.
• Accelerated bone loss
• Reduction in bone mineral density
• Osteoporosis
iet, Vitamin, and Mineral Supplementation in Hashimoto’s
D
Thyroiditis
Role of Diet in Autoimmune Modulation
The concept of an autoimmune diet focuses on gut healing and reducing the severity
of autoimmune responses [184]. A small study involving 40 female participants
demonstrated beneficial effects on thyroid function, with reductions in thyroid peroxidase (TPO) and thyroglobulin antibodies, following a Mediterranean and gluten-­
free diet [185].
Individuals with Hashimoto’s thyroiditis should avoid foods high in iodine, as
excessive iodine intake may trigger thyroid autoimmunity in genetically predisposed individuals. However, further research is necessary before incorporating
these dietary interventions into established guidelines.
Vitamin D Supplementation
The role of vitamin D deficiency in the pathogenesis of Hashimoto’s thyroiditis and
thyroid dysfunction has been extensively studied. Higher anti-TPO antibody levels
have been observed in vitamin D-deficient patients. Studies indicate that oral
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vitamin D3 supplementation (1200–4000 IU daily for 4 months) significantly
reduces serum anti-TPO antibody levels in these patients [186].
Selenium Supplementation
Systematic reviews and meta-analyses suggest that selenium supplementation provides modest benefits in managing Hashimoto’s thyroiditis, particularly in individuals not on thyroid hormone replacement, leading to improved thyroid function and
reduced thyroid antibody levels [187]. A daily selenium dose of 50–100 μg is considered beneficial and safe, particularly in selenium-deficient regions [188]. A study
of 412 individuals further demonstrated that selenium supplementation (200 μg/
day) enhanced quality of life in patients receiving levothyroxine for hypothyroidism
due to Hashimoto’s thyroiditis [189].
Iron Supplementation
Iron status is an important factor in thyroid health. Research indicates that each unit
increase in iron levels is associated with a 43% reduction in the risk of Hashimoto’s
thyroiditis among women of reproductive age [190].
Surgical Treatment
Surgical intervention for Hashimoto’s thyroiditis has traditionally been reserved for
patients experiencing pain, compressive symptoms due to goiter, or the presence of
coexisting malignant thyroid nodules or lymphoma. Preoperative evaluation should
include a barium swallow study, pulmonary function tests (including flow-volume
loops), and a neck computed tomography (CT) scan [191]. It is important to note
that antithyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) antibody
levels are not reliable indicators for assessing the surgical outcome, as findings on
their post-surgical decline have been inconsistent—one study reported no significant reduction, while another demonstrated a notable decrease in antibody titers
[192, 193].
Prognosis and Morbidity in Hashimoto’s Thyroiditis
With early diagnosis, prompt initiation of levothyroxine replacement therapy, comprehensive patient follow-up, and management of associated complications, the
prognosis of Hashimoto’s thyroiditis (HT) is excellent, allowing patients to lead a
normal life. However, untreated myxedema coma carries a poor prognosis with a
high mortality rate.
Morbidity associated with HT primarily results from:
• Failure to diagnose hypothyroidism in a timely manner.
• Inadequate L-thyroxine replacement therapy or suboptimal dosing.
• Non-adherence to medication by the patient.
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• Additionally, untreated hypothyroidism is linked to an increased prevalence of
lipid disorders, which may elevate the risk of coronary artery disease and its
associated morbidity.
Hashimoto’s Thyroiditis and Thyroid Cancer Risk
• As mentioned earlier, the potential link between Hashimoto’s thyroiditis and thyroid cancer remains controversial, with studies presenting inconsistent evidence
regarding a causal relationship. A meta-analysis examining cytological and pathological specimens from HT patients concluded that this association is supported
by low-to-moderate quality evidence [194].
• It is important to highlight that thyroid cancers associated with Hashimoto’s thyroiditis (HT) do not appear to exhibit greater aggressiveness compared to papillary thyroid carcinomas (PTCs) occurring without HT. In fact, a study by Liang
et al. suggested that patients with both HT and PTC might experience a more
favorable prognosis than those diagnosed with PTC alone [195].
These patients tend to exhibit:
• Smaller tumor sizes
• Less advanced TNM staging
• Lower rates of lymph node metastasis
Association with Thyroid Lymphoma
In contrast, non-Hodgkin primary thyroid lymphoma shows a strong association
with HT, with affected individuals having a 60-fold increased risk compared to the
general population [196]. Diffuse large B cell lymphoma (DLBCL), which accounts
for 50–70% of cases, and mucosa-associated lymphoid tissue (MALT) lymphoma,
which accounts for 10–50% of cases, are the most prevalent histotypes [197]. A
rapidly enlarging thyroid gland or localized pain should raise suspicion for lymphoma. Establishing a definitive diagnosis of thyroid lymphoma is critical, as it
significantly alters the treatment approach. Unlike other malignant thyroid nodules,
which are typically managed with surgical intervention, thyroid lymphoma requires
targeted chemotherapy as the primary treatment strategy.
Special Condition in Hashimoto’s Thyroiditis
Hashitoxicosis
Hashitoxicosis typically manifests in the early stages of autoimmune hypothyroidism. It arises due to the release of stored thyroxine (T4) and triiodothyronine (T3)
into circulation, leading to transient symptoms of thyroid hormone excess.
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299
Clinical Presentation
Patients generally exhibit mild to moderate hyperthyroidism. On thyroid palpation,
a firm, non-tender goiter may be detected. Notably, the painful and tender goiter
characteristic of subacute thyroiditis, as well as a history of preceding viral infection is absent. Unlike the diffusely enlarged, lobulated, and bruit-associated goiter
seen in classical Graves’ disease, the goiter in Hashitoxicosis tends to be small,
diffuse, and firm. However, clinical features alone are not definitive for diagnosis [198].
Differentiation from Other Thyrotoxic Variants of Hashimoto’s Thyroiditis
Hashitoxicosis should be distinguished from other autoimmune thyroiditis variants
(refer to Sect. “Pathological Variants of Hashimoto’s Thyroiditis” above) associated
with transient thyrotoxicosis, such as silent thyroiditis and postpartum thyroiditis.
These conditions typically involve a self-­limiting hyperthyroid phase lasting about
a month, followed by a hypothyroid phase lasting 2–6 months, with eventual recovery to euthyroidism. However, some patients—particularly multiparous women
with postpartum thyroiditis—may progress to permanent hypothyroidism [55].
Laboratory and Imaging Findings [199]
• Thyroid function tests reveal elevated T4 and/or T3 levels with suppressed TSH.
• Anti-thyroid peroxidase (anti-TPO) antibody titers are typically high in
Hashitoxicosis and thyroglobulin levels may be elevated, consistent with other
destructive thyroid disorders.
• TSH-receptor antibodies may be positive in approximately 6% of Hashimoto’s
thyroiditis cases, making it unreliable in differentiating Hashitoxicosis from
Graves’ disease.
• Thyroid ultrasound with Doppler imaging is a valuable diagnostic tool. In
Graves’ disease, color Doppler typically shows a highly vascular “inferno” pattern, whereas Hashitoxicosis presents with normal or slightly increased
vascularity.
• Thyroid scintigraphy findings can vary, with normal or even increased uptake in
some cases.
Management Approach
Since Hashitoxicosis results from thyroid inflammation rather than true hyperfunction, treatment is primarily supportive. β-blockers are commonly used to alleviate
symptoms, while anti-thyroid medications are generally unnecessary. The condition
typically resolves within 3–24 months, often leading to permanent
hypothyroidism.
If the diagnosis of transient thyrotoxicosis due to autoimmune thyroiditis remains
uncertain—particularly if Graves’ disease is suspected—a short course of anti-­
thyroid drugs may be considered. However, close monitoring with periodic thyroid
function testing is essential to prevent the development of hypothyroidism [198].
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Myxedema Coma
Hashimoto’s thyroiditis is the most common cause of primary hypothyroidism, and
if left untreated or triggered by a stressor, it can lead to severe hypothyroidism,
culminating in myxedema coma, a rare, life-threatening condition that arises when
adaptive mechanisms fail to maintain homeostasis [200]. Despite its name, most
patients are not truly comatose, but rather present with a profound and decompensated state of hypothyroidism.
Common Precipitating Factors
Myxedema coma often develops in response to an acute trigger in individuals with
pre-existing or undiagnosed thyroid dysfunction. The most common settings
include:
•
•
•
•
Infections: Pneumonia, sepsis, etc.
Cardiovascular events: Stroke, congestive heart failure
Gastrointestinal bleeding
Medications: Narcotics, sedatives, anesthetic agents, antidepressants, tranquilizers (all of which depress respiratory drive)
• Undiagnosed, long-standing hypothyroidism
• Abrupt discontinuation of levothyroxine therapy
• Failure to initiate thyroid hormone replacement following:
– Radioactive iodine therapy for Graves’ disease
– Total thyroidectomy
Seasonal and Demographic Trends
Myxedema coma frequently occurs during winter or in extreme cold weather, most
commonly affecting elderly women with chronic hypothyroidism [201]. Hospitalized
patients are often found to have a history of sedative medication use, which can
exacerbate respiratory depression and cognitive decline.
Clinical Presentation
Patients typically exhibit a constellation of neurological, cardiovascular, respiratory, and metabolic abnormalities [202], including:
• Neurological: Altered mental status (lethargy, confusion, psychosis, coma),
delayed deep tendon reflexes
• Cardiovascular: Bradycardia, hypotension
• Respiratory: Hypoventilation, hypercapnia, hypoxemia
• Metabolic: Hypothermia, hyponatremia, anemia, hypoglycemia
• Dermatologic: Diffuse non-pitting edema
• Endocrine findings: Elevated TSH, undetectable free T4 levels, and low cortisol
and high adrenocorticotropic hormone (ACTH), if concomitant with primary
adrenal insufficiency.
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301
Management
Early recognition and immediate intervention are critical to improving survival outcomes, as mortality remains high (25–60%) [203]. Treatment is best carried out in
an intensive care setting and includes the following measures [202]:
• Respiratory support: Mechanical ventilation for hypoventilation and carbon
dioxide retention
• Hemodynamic monitoring and Swan-Ganz catheter for assessing cardiovascular status
• Continuous electrocardiographic (ECG) monitoring of arrythmias
• Temperature management: Gradual rewarming to prevent excessive vasodilation, which may worsen hypotension and lead to vascular collapse
• Adrenal insufficiency consideration: Empirical hydrocortisone therapy (100 mg
IV every 8 hours) until adrenal insufficiency is ruled out
• Infection control with appropriate antibiotics-take blood cultures before initiating antibiotic.
• Supportive care for cardiovascular events and metabolic derangements
• Fluid balance: Fluid restriction, with or without hypertonic saline and loop
diuretics (e.g., furosemide), to manage hyponatremia
• Nutritional support: Due to decreased gastrointestinal motility, oral feeding
should be delayed until the patient is alert, extubated, and exhibits normal bowel
function.
Thyroid Hormone Replacement Therapy
Given the rarity of myxedema coma, no randomized trials exist to determine the
optimal thyroid hormone regimen [202, 204, 205]. However, common approaches
include:
Levothyroxine (T4) Monotherapy
• Initial intravenous (IV) bolus of 200–400 mcg (4 mcg/kg)
• Maintenance dose: 50–100 mcg/day IV
Combination therapy with intravenous T4 and T3 is recommended if there is no
response within 24 hours:
Initial dose:
• T4 200–300 mcg IV
• T3 10–25 mcg IV
Maintenance doses:
• T3 maintenance: 2.5–10 mcg IV every 8 hours
• T4 maintenance dose: 50–100 mcg/day IV
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Intravenous T3 and T4 are discontinued once clinical improvement occurs, and
oral LT4 monotherapy is continued. Lower intravenous dosages of T4 and T3 should
be considered in older adults and patients with a history of cardiovascular disease.
Monitoring and Follow-up
Serum FT4 and T3 levels should be measured every 1–2 days and samples should
be collected at least 1 hour after dosing [170, 204] as this allows for accurate measurement of the hormone levels after the medication has been absorbed and distributed. Since treatment guidelines remain non-standardized, individualized therapy
should be tailored based on the patient’s age, comorbidities, and cardiovascular status.
Pregnancy and Hashimoto’s Thyroiditis
Thyroid disorders are the second most prevalent endocrinological conditions and
the estimated prevalence of hypothyroidism during pregnancy is 0.3–0.5% for overt
hypothyroidism and 2–3% for subclinical hypothyroidism. Hashimoto’s thyroiditis
is recognized as the most common cause of hypothyroidism during pregnancy [206].
hysiological Changes in Thyroid Function During Pregnancy
P
Pregnancy significantly affects thyroid gland function. In iodine-sufficient regions,
the thyroid gland enlarges by approximately 10%, whereas in iodine-deficient areas,
it may increase by 20–40%. The production of thyroxine (T4) and triiodothyronine
(T3) rises by 50%, accompanied by a 50% increase in daily iodine requirements. In
iodine-deficient women, these physiological adaptations can lead to hypothyroidism in later pregnancy, despite euthyroidism in the first trimester.
Total T4 and T3 levels are typically elevated during pregnancy due to estrogen-­
induced sialylation of thyroxine-binding globulin (TBG), which reduces its hepatic
clearance and enhances its binding capacity. Additionally, a transient decline in
serum TSH levels is observed at the end of the first trimester, driven by elevated
human chorionic gonadotropin (hCG) levels, a phenomenon often misinterpreted as
hyperthyroidism [207].
Pregnancy also increases the requirement for levothyroxine, attributed to elevated TBG, heightened fetal utilization, and enhanced thyroxine metabolism by the
fetoplacental unit. This increased need typically emerges within the first 8 weeks of
gestation and persists throughout pregnancy, reverting to pre-pregnancy levels
6–8 weeks postpartum.
hyroid Function and Fetal Development
T
By 10–12 weeks of gestation, the fetal thyroid begins concentrating iodine, with
pituitary TSH regulating its function by approximately 20 weeks. Fetal serum levels
of TSH, TBG, FT4, and FT3 progressively increase, reaching adult-equivalent levels by around 36 weeks [208].
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303
While TSH does not cross the placenta, small amounts of maternal T4 and T3 do.
In neonates with congenital hypothyroidism, transplacental passage of maternal
thyroid hormones is sufficient to mitigate overt hypothyroid symptoms at birth,
maintaining umbilical cord thyroid hormone levels at 25–50% of normal [209].
hyroid Dysfunction in Hashimoto’s Thyroiditis
T
and Pregnancy Outcomes
Untreated maternal hypothyroidism is associated with increased maternal and fetal
complications. Pregnant women who are TPO antibody (TPOAb) positive have a
higher incidence of fetal loss, with TPOAb prevalence estimated at 5–14%, and
thyroglobulin antibodies (TgAbs) found in 3–18% [210].
Thyroid autoimmunity, as indicated by these antibodies, is linked to a two- to
fourfold increase in recurrent miscarriages and a two- to threefold higher risk of
preterm birth [211–213]. The precise mechanisms remain unclear, but some
researchers suggest that TPOAbs may serve as markers for additional autoimmune
conditions affecting the placenta and fetal development.
A study by Negro et al. demonstrated that euthyroid Caucasian women with
positive anti-TPO antibodies who received levothyroxine (LT4) during the first trimester had lower miscarriage and preterm delivery rates, comparable to those without thyroid antibodies [214].
Additionally, LT4 therapy has been shown to improve in vitro fertilization success rates in TPOAb-positive women with TSH level above 2.5 mIU/mL. Therefore,
treatment is recommended for pregnant women with TPOAbs when their TSH falls
between 2.5 and 4 mIU/mL [213]. A meta-analysis of 19 cohort studies involving
47,045 pregnant women revealed that subclinical hypothyroidism nearly tripled the
risk of preterm birth, while isolated hypothyroxinemia increased preterm birth risk
by 1.5 times [215].
Overt hypothyroidism was further associated with a higher prevalence of gestational hypertension (including preeclampsia and eclampsia), gestational diabetes,
placental abruption, postpartum hemorrhage, preterm delivery, low birth weight,
neonatal intensive care unit (NICU) admissions, fetal loss, and neurodevelopmental
impairments in offspring [216–218]. Table 4 summarizes feto-maternal
complications.
Table 4 Feto-maternal complications in Hashimoto’s thyroiditis
Maternal complications
Increased risk of spontaneous abortion
Eclampsia
Pre-eclampsia
Abruptio placentae
Postpartum hemorrhage
Gestational diabetes
Anemia
Fetal complications
Low birth weight
Preterm delivery
Impaired cognitive development
Increased NICU admission
Fetal mortality
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S. K. Imam
reatment of Hypothyroidism in Hashimoto’s Thyroiditis
T
During Pregnancy
Pre-existing Hypothyroidism
Levothyroxine is the standard treatment for maternal hypothyroidism. Women on
LT4 before conception typically require a 30–50% increase in dosage during early
pregnancy, which generally translates to taking two additional doses per week
[169]. During pregnancy, the estimated full replacement dose of LT4 is 2–2.4 μg/kg/
day. In cases of severe hypothyroidism, an initial dose twice the anticipated maintenance dose may be given to rapidly replenish extrathyroidal thyroxine stores before
tapering to the maintenance level. The degree of dose adjustment depends on the
etiology of hypothyroidism, with patients who have undergone radioiodine ablation
or extensive thyroidectomy requiring larger dose increments than those with
Hashimoto’s thyroiditis, who typically retain some functional thyroid tissue.
Levothyroxine should not be taken concurrently with iron or calcium-containing
supplements. Following delivery, the LT4 dose can be reduced to pre-pregnancy
levels, with TSH re-evaluation at 6 weeks postpartum.
Newly Diagnosed Hypothyroidism in Pregnancy
In a study of 77 pregnant women with newly diagnosed hypothyroidism (64 with
subclinical and 13 with overt hypothyroidism), Abalovich et al. determined optimal
LT4 dosages for achieving euthyroidism [219]:
• Subclinical hypothyroidism (TSH ≤ 4.2 mIU/L): 1.2 μg/kg/day
• Subclinical hypothyroidism (TSH > 4.2–10 mIU/L): 1.42 μg/kg/day
• Overt hypothyroidism: 2.33 μg/kg/day
These dosages successfully restored euthyroidism in 89% of patients with subclinical hypothyroidism and 77% of those with overt hypothyroidism and are recommended for newly diagnosed cases during pregnancy. As mentioned earlier, LT4
therapy is advised for pregnant women with TPOAbs if TSH level is between 2.5
and 4 mIU/mL.
Since iodine deficiency remains a major cause of neonatal neurodevelopmental
impairment, pregnant and lactating women should consume an average of 250 μg of
iodine daily.
Follow-up and Monitoring of Thyroid Function
Pregnant women with hypothyroidism should be monitored through TSH and free
T4 assessments at 4–8 week intervals, with subsequent evaluations every 6–8 weeks
as needed [220, 221].
Hashimoto’s Thyroiditis
305
Target TSH levels should be:
• First trimester: <2.5 mIU/L
• Second trimester: <3.0 mIU/L
• Third trimester: <3.5 mIU/L
Trimester-specific reference ranges for free T4 (FT4) include:
• First trimester: 0.26–1.92 ng/dL (3.7–23.4 pmol/L)
• Second trimester: 0.59–1.56 ng/dL (7.4–18.9 pmol/L)
• Third trimester: 0.65–1.25 ng/dL (8.3–15.6 pmol/L)
Preconception Counseling
Women with hypothyroidism should receive preconception counseling to emphasize the importance of achieving euthyroidism prior to conception. Uncontrolled
hypothyroidism is associated with reduced fertility and increased miscarriage risk.
Additionally, prompt monitoring upon pregnancy confirmation is crucial, as many
patients exhibit TSH elevations by the first prenatal visit. Euthyroid women on stable LT4 therapy should increase their weekly dose by two additional tablets as soon
as pregnancy is suspected or confirmed via a home pregnancy test.
Latest Advancement and Research in Hashimoto’s Thyroiditis
Stem Cell Therapy
Mesenchymal stem cells (MSCs) are being explored for their potential to regenerate
damaged thyroid tissues and modulate immune responses. Studies suggest that
MSCs can differentiate into thyroid follicular cells, potentially restoring thyroid
function and hormone production. Additionally, MSCs’ anti-inflammatory properties may help inhibit the autoimmune response characteristic of Hashimoto’s thyroiditis [222].
Metformin Treatment
Traditionally used for type 2 diabetes, metformin has shown promise in reducing
thyroid autoantibodies, such as thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb), in patients with Hashimoto’s thyroiditis. This reduction
may alleviate disease severity and improve patient outcomes [223].
Nutritional Supplementation
Selenium supplementation has been found to significantly reduce thyroid-­associated
autoantibody levels, suggesting a beneficial role in managing Hashimoto’s thyroiditis [224].
306
S. K. Imam
Sustained Release T3
New preparations of sustained release T3 is under clinical trials and may add to our
armamentarium for HT therapy once necessary efficacy trials are completed
[225, 226].
Conclusion
Hashimoto thyroiditis (HT), now recognized as the most prevalent autoimmune disorder, was first described over a century ago as a lymphocytic infiltration of the
thyroid, primarily affecting women. Over time, several clinicopathological variants
have been included under this umbrella term. The disorder exhibits a strong familial
predisposition, with its pathogenesis driven by a complex interplay of genetic, epigenetic, and environmental factors. While HT often progresses to hypothyroidism,
its initial presentation can vary, with some patients remaining euthyroid or even
experiencing transient hyperthyroidism. Diagnosis of HT relies on detecting circulating thyroid antibodies (thyroperoxidase and thyroglobulin) and identifying
reduced echogenicity on thyroid ultrasonography in a clinically suspected patient.
Thyroxine replacement remains the cornerstone of treatment to maintain euthyroid
status, while surgical intervention is reserved for cases involving significant goiter-­
induced compression or suspected malignancy.
Effective management of HT requires a multidisciplinary approach, emphasizing
patient education, adherence to treatment, and regular thyroid function monitoring.
Healthcare professionals play a crucial role in providing lifelong support, with physicians ensuring optimal hormone replacement, pharmacists advising on medication
interactions and proper levothyroxine administration, and gynecologists addressing
reproductive concerns, particularly during pregnancy, to prevent fetal and maternal
complications.
Future therapeutic advancements hold promise for HT management. Stem cell-­
based regenerative therapies are being explored as potential interventions to restore
thyroid function by replacing cells damaged by autoimmune processes. Additionally,
novel sustained-release T3 preparations are currently undergoing clinical trials and
may provide new treatment options once efficacy and safety evaluations are completed. With continuous research and a patient-centered approach, the long-term
care of HT patients can be significantly improved, ensuring better outcomes and
quality of life.
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Graves’ Disease
Ali Asghar and Saima Askari
Introduction
Graves’ disease (GD) is the most frequent cause of hyperthyroidism and a classic
example of an organ-specific autoimmune disorder that mainly targets the thyroid
gland. It occurs when the body’s immune system produces antibodies—known as
thyroid-stimulating immunoglobulins (TSIs)—that mistakenly bind to and activate
the thyroid-stimulating hormone receptor (TSHR). This leads to uncontrolled thyroid hormone production and enlargement of the thyroid gland, a process known as
glandular hyperplasia [1].
First described in the nineteenth century, Graves’ disease remains the leading
cause of thyrotoxicosis around the world. It affects approximately 1–2% of the population, with women between the ages of 30 and 50 being most commonly
affected [2, 3].
People with Graves’ disease may notice symptoms that mainly reflect the body’s
increased metabolic state, such as tachycardia, weight loss, heat intolerance, and
tremors, among many others. A diffusely enlarged thyroid (goiter) is a hallmark
feature of this disease, often accompanied by Graves’ ophthalmopathy (GO)—an
inflammatory eye condition affecting nearly half of all patients affected by GD [4].
GO, also known as Grave’s eye disease, typically presents with bulging eyes (proptosis), periorbital puffiness, and double vision [5]. Skin changes, though less common, may also occur.
A. Asghar (*)
Liaquat National Hospital and Medical College, Karachi, Pakistan
e-mail: drasghar@gmail.com
S. Askari
Baqai Institute of Diabetology and Endocrinology, Baqai Medical University,
Karachi, Pakistan
e-mail: saimaaskari@bide.edu.pk
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_12
317
318
A. Asghar and S. Askari
At the root of the condition is a loss of immune tolerance, where the body produces antibodies that mimic TSH and keep the thyroid chronically overactive [6].
The development of Graves’ disease is not due to a single factor but rather the interplay between genetic predisposition and environmental influences, such as excessive iodine intake, smoking, and certain infections [7].
Graves’ disease can present with varying degrees of severity, from mild or even
silent hyperthyroidism to full-blown thyrotoxicosis, and in rare cases, a life-­
threatening condition known as thyroid storm. Early recognition and prompt treatment of the disease are crucial to prevent long-term complications and improve
quality of life [8].
This chapter comprehensively reviews the current understanding of Graves’ disease, especially focusing on prevalence, clinical features, diagnostic approaches,
therapeutic options, and recent advances in research that may shape future management strategies.
Epidemiology
Graves’ disease (GD) is a global health issue, with a prevalence ranging from 0.5%
to 2% in the general population, making it the leading cause of hyperthyroidism
worldwide [1]. It disproportionately affects women, with a female-to-male ratio of
approximately 5–10:1 [2]. The peak incidence occurs between the third and fifth
decades of life, though it may manifest at any age [3].
Global and Regional Prevalence
The prevalence of GD varies significantly based on geographic location, largely
influenced by iodine intake and genetic predisposition [4]. In iodine-sufficient areas
such as North America, Europe, and East Asia, the prevalence is relatively higher,
while iodine-deficient regions, including parts of sub-Saharan Africa and Southeast
Asia, report lower rates [5]. Iodine supplementation programs, while beneficial for
correcting deficiency, may transiently increase the incidence of autoimmune thyroid
diseases, including GD [6].
Incidence Trends
Recent epidemiological studies suggest a rising trend in autoimmune thyroid diseases, including GD, particularly in developed countries [7]. This may reflect
increased awareness, better diagnostic access, and environmental changes. A
population-­based Danish study reported an incidence of GD at approximately 80
cases per 100,000 women annually [8]. A similar trend has been observed in Japan
and South Korea, although with slightly lower absolute numbers [9].
Graves’ Disease
319
Ethnic and Genetic Differences
Ethnic variation plays a crucial role in the expression and prevalence of
GD. Caucasian and East Asian populations tend to have higher prevalence rates
compared to African and Latin American populations [10]. Genetic susceptibility
loci such as human leukocyte antigen—DR3 (HLA-DR3), cytotoxic T-lymphocyte-­
associated protein 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type
22 (PTPN22)—have been implicated in the pathogenesis and are more common in
these ethnic groups [11]. Twin studies suggest a heritability of approximately
70–80%, supporting a strong genetic component [12].
Sex Differences
The marked female predominance in GD is consistent across populations and
reflects the general trend in autoimmune diseases. Estrogen is thought to enhance
immune reactivity, possibly by affecting T-cell function and cytokine production
[13]. This might partly explain the higher incidence in women, especially during the
reproductive years.
Environmental Risk Factors
Numerous environmental triggers have been associated with the onset of GD in
genetically susceptible individuals. These include:
Iodine intake: Sudden changes in iodine intake may trigger autoimmunity [14].
Smoking: Strongly associated with the development and severity of Graves’ ophthalmopathy [15].
Stressful life events: Psychological stress has been proposed as a trigger, although
causal links are hard to establish [15].
Infections: Certain viral infections may initiate thyroid autoimmunity, but evidence
remains limited [16].
Drugs: Immune checkpoint inhibitors and interferon-alpha have been linked to the
onset of autoimmune thyroid disease, including GD [17].
Pediatric Graves’ Disease
Although rare, GD does occur in children and adolescents, comprising 1–5% of all
thyroid disorders in pediatric populations [18]. These cases often present with more
severe disease and require long-term management. There is a rising trend in pediatric autoimmune diseases globally, and GD mirrors this shift [19].
320
Table 1 Key
Epidemiological features of
Graves’ disease
A. Asghar and S. Askari
Feature
Prevalence
Peak incidence age
Female:Male ratio
Higher risk ethnicities
Environmental risk
factors
Pediatric proportion
Postpartum association
Description
0.5–2% globally
30–50 years
5–10:1
Caucasian, East Asian
Smoking, iodine intake, stress,
infections
1–5% of all thyroid disorders in
children
Increased risk of onset or relapse
Postpartum and Perimenopausal Considerations
The postpartum period is a recognized window for immune dysregulation. Women
may experience either new-onset GD or exacerbation of existing disease during this
phase [20]. This is attributed to the rebound of the immune system following the
relative immunosuppression of pregnancy, which can trigger autoimmune thyroid
activity. Similarly, hormonal shifts during perimenopause may unmask latent autoimmunity, contributing to the development or flare of autoimmune thyroid disorders
[21]. Table 1 shows key epidemiological features of GD.
Pathophysiology of Graves’ Disease
Graves’ disease (GD) is the most common cause of hyperthyroidism and represents
a classic model of organ-specific autoimmunity. It involves a dysregulated immune
response directed against the thyroid-stimulating hormone receptor (TSHR), leading to increased thyroid hormone production, thyroid growth, and frequently, extrathyroidal manifestations such as Graves’ orbitopathy (GO). The disease is driven by
a combination of genetic predisposition, environmental triggers, hormonal factors,
and immune dysregulation. The pathophysiology is complex, involving both
humoral and cellular immune responses and intricate interactions between the thyroid gland and the immune system [22].
Autoantibodies and the Role of TSH Receptor Antibodies
The underlying cause of GD is the presence of autoantibodies that are directed
against the TSHR. These thyroid-stimulating immunoglobulins (TSI) bind to the
TSHR on thyroid follicular cells, mimicking the action of TSH but without feedback inhibition, resulting in persistent stimulation of thyroid hormone synthesis and
release [23]. Unlike blocking or neutral antibodies seen in other autoimmune thyroid conditions, the stimulating TRAb (TSI) leads to thyrotoxicosis and diffuse thyroid enlargement [24].
Graves’ Disease
321
TSHR is a G-protein-coupled receptor, and TSI-induced activation leads to
enhanced cyclic adenosine monophosphate (cAMP) production, stimulating genes
involved in thyroglobulin production, iodine uptake via sodium/iodide symporter
(NIS), and thyroid hormone synthesis. These antibodies are also involved in extrathyroidal manifestations, especially thyroid eye disease/orbitopathy, where they
bind to TSHR expressed on orbital fibroblast [25].
Genetic and Epigenetic Factors
Family and twin studies demonstrate a strong genetic predisposition to Graves’ disease. Concordance rates in monozygotic twins range from approximately 17–36%,
significantly higher than in dizygotic twins (2–7%), supporting a heritable component. Heritability estimates suggest that genetic factors account for 60–80% of disease susceptibility, with environmental and epigenetic influences contributing to the
remainder [26–28]. Key susceptibility genes include:
• HLA-DR3: Strongly associated with GD in Caucasian populations.
• CTLA-4: Involved in T-cell costimulatory inhibition, with polymorphisms reducing regulatory control.
• PTPN22: Encodes a phosphatase that downregulates T-cell activation.
• Cluster of differentiation 40 (CD40) and interleukin 2 receptor alpha (IL2RA):
Modulate T-cell and B-cell interactions [29].
Epigenetic changes such as deoxyribonucleic acid (DNA) methylation, histone
acetylation, and non-coding ribonucleic acids (RNAs) also modulate gene expression in thyroid and immune cells, further influencing disease risk [30]. Environmental
triggers can induce epigenetic reprogramming, possibly explaining why only some
genetically predisposed individuals develop disease.
Loss of Central and Peripheral Immune Tolerance
Central tolerance defects during thymic T-cell development allow escape of autoreactive T cells. In the periphery, impaired regulatory T cell (Treg) function contributes to a breakdown in immune surveillance. GD patients often exhibit reduced
numbers and functional activity of Tregs, alongside an expansion of proinflammatory T helper 1 (Th1) and T helper 17 (Th17) cells [31]. These cells secrete
interferon-γ (IFN-γ) and interleukin-17 (IL-17), enhancing antigen presentation and
thyroid cell destruction or hyperfunction.
The thyroid gland itself participates in this immune dysregulation by expressing
major histocompatibility complex (MHC) class II molecules (normally restricted to
antigen-presenting cells), allowing it to present autoantigens and sustain autoimmune attack [32].
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Cytokine Imbalance and Proinflammatory Milieu
GD is associated with a skewed cytokine environment that favors inflammation.
Key cytokines include:
• IL-6: Promotes B-cell activation and antibody production.
• TNF-α and IFN-γ: Contribute to thyroid epithelial cell apoptosis and
inflammation.
• IL-17: Produced by Th17 cells, promotes fibroblast activation and neutrophil
recruitment [33].
This environment enhances autoantibody production, promotes lymphocytic
thyroid infiltration, and facilitates the extrathyroidal manifestations of GD.
B-Cell Dysregulation and Autoantibody Production
B cells are central to GD pathogenesis—not only through antibody secretion but
also via cytokine production and antigen presentation. Autoreactive B cells, upon
activation by autoreactive T helper cells, differentiate into plasma cells producing
TRAb. BAFF (B-cell activating factor) levels are elevated in GD and correlate with
disease severity. These cells may escape normal tolerance checkpoints and accumulate in the thyroid and orbit [34].
Graves’ Orbitopathy (GO) and Extrathyroidal TSHR Expression
A unique feature of GD is Graves’ orbitopathy, seen in ~25–50% of patients. GO is
characterized by inflammation, tissue expansion, and remodeling within the orbit.
This results from TSHR and insulin-like growth factor-1 receptor (IGF-1R) expression on orbital fibroblasts and preadipocytes [35]. TRAb and IGF-1R antibodies
stimulate these fibroblasts to:
• Differentiate into adipocytes.
• Produce glycosaminoglycans (GAGs) like hyaluronan, causing edema.
• Secrete proinflammatory cytokines (IL-1β, IL-6, TNF-α).
These changes cause exophthalmos, diplopia, and in severe cases, optic
neuropathy.
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323
Environmental Triggers
Various environmental factors can act as disease triggers in genetically susceptible
individuals, for example:
• Iodine excess: Can increase thyroid immunogenicity and antigen expression.
• Smoking: Increases risk of GO and worsens thyroid autoimmunity via oxidative
stress and hypoxia pathways [36].
• Stress and infections: Reactivate immune pathways possibly contribute to epitope spreading and immune activation.
• Radiation and certain drugs: These include interferon-α and alemtuzumab [37].
Hormonal Influences
Graves’ disease disproportionately affects women, suggesting hormonal modulation. Estrogens enhance humoral immunity, promote B-cell survival, and can reduce
Treg efficiency, all favoring autoimmunity [38]. Progesterone, in contrast, generally
has immunosuppressive effects [39].
Disease flares are common in periods of hormonal transition:
• Postpartum period: Associated with immune rebound and reactivation of latent
autoimmunity [29].
• Perimenopause: Shifts in estrogen levels may expose latent thyroid autoimmunity [30].
Table 2 summarizes salient factors contributing to the pathogenesis of GD.
Table 2 Pathophysiological mechanisms in Graves’ disease
Mechanism
Autoantibodies
Genetic susceptibility
Epigenetics
T-cell dysregulation
B-cell dysregulation
Cytokine imbalance
Environmental triggers
Orbital fibroblast
activation
Hormonal influence
Key elements
TSI/TRAb activate TSHR → ↑T3/T4, goiter, GO
HLA-DR3, CTLA-4, PTPN22, CD40
DNA methylation, miRNA, histone modification
↑Th1/Th17, ↓Treg; cytokine overproduction
↑Autoantibody-producing plasma cells, ↑BAFF
↑IL-6, IL-17, TNF-α, IFN-γ
Smoking, iodine, stress, infections
TSHR and IGF-1R activation → ↑GAG, adipogenesis,
inflammation in orbit
Estrogens promote, androgens suppress, immune activation
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Clinical Manifestations of Graves’ Disease
Graves’ disease (GD) is an autoimmune disorder characterized primarily by hyperthyroidism due to circulating thyroid-stimulating hormone receptor antibodies (TRAb).
These antibodies persistently activate the thyroid gland without negative feedback.
The clinical presentation of GD is broad and complex, including thyroidal symptoms
caused by excessive thyroid hormone production, extrathyroidal autoimmune manifestations, and systemic involvement across multiple organ systems. Recognizing the
diversity and subtlety of these manifestations is of paramount important for early
diagnosis, appropriate monitoring, and optimal management of patients.
Thyroidal Manifestations
The hallmark of GD is thyrotoxicosis; excessive circulating thyroid hormones
resulting from the overstimulation of the thyroid gland by TRAb [40]. However, the
spectrum ranges from subclinical disease to overt hyperthyroidism and rarely thyroid storm.
Overt Hyperthyroidism
In the majority of GD patients, the hyperfunctioning thyroid produces abnormally
high amounts of thyroxine (T4) and triiodothyronine (T3), leading to increased
basal metabolic rate and multisystem effects.
• Weight Loss with Increased Appetite: Despite a hypermetabolic state causing
significant caloric expenditure, patients typically have an increased appetite.
Weight loss results from catabolism exceeding intake.
• Heat Intolerance and Hyperhidrosis: Elevated metabolism produces excess heat;
patients report intolerance to warm environments and excessive sweating [41].
• Cardiovascular Symptoms: Increased β-adrenergic sensitivity leads to sinus
tachycardia, palpitations, widened pulse pressure, and occasionally arrhythmias
such as atrial fibrillation. Elderly patients are especially susceptible to atrial
fibrillation, which can precipitate stroke and heart failure [42].
• Neuromuscular Symptoms: A fine, high-frequency tremor of the outstretched
hands is common. Proximal muscle weakness and fatigue (thyrotoxic myopathy)
impair activities such as climbing stairs or lifting objects [43].
• Neuropsychiatric Manifestations: Anxiety, irritability, emotional lability, and
insomnia are frequent complaints. Severe cases can manifest with thyrotoxic
psychosis [44].
• Gastrointestinal Hyperactivity: Increased gut motility often causes frequent
bowel movements or diarrhea [45].
• Menstrual Disturbances: Oligomenorrhea or amenorrhea may occur due to
effects on the hypothalamic-pituitary-gonadal axis [46].
• Hair and Skin Changes: Diffuse hair thinning, brittle nails, and warm, moist skin
with increased blood flow are typical [47].
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325
Diffuse Goiter
A diffuse, symmetric enlargement of the thyroid gland is a hallmark of GD and
results from follicular cell hyperplasia and hypertrophy stimulated by TRAb [48].
• The goiter is typically smooth and soft; however, sometimes it may feel rubbery
due to increased vascularity.
• A thyroid bruit, audible on auscultation, reflecting hyperdynamic blood
circulation.
• The gland size may range from barely palpable to large, occasionally causing
compressive symptoms like dysphagia or airway obstruction, though this is
uncommon.
• The size of the goiter does not necessarily correlate with the severity of
hyperthyroidism.
ubclinical Hyperthyroidism [49]
S
Subclinical hyperthyroidism (SCH) is increasingly recognized as an important clinical entity in GD and is defined biochemically by:
• Suppressed or low serum TSH levels below the lower limit of normal.
• Normal free T4 and free T3 concentrations.
SCH is often asymptomatic but represents a continuum on the spectrum of thyroid hormone excess. It may precede overt hyperthyroidism or represent a mild
form of GD, especially in early disease or partial TRAb activity.
Epidemiology and Etiology
• SCH is more common in older adults and populations with sufficient or excess
iodine intake.
• In GD, SCH results from low-level stimulation of the thyroid gland by TRAb
that is insufficient to raise circulating T3 and T4 but enough to suppress pituitary
TSH secretion.
Clinical Features
• Mostly patients are asymptomatic or have mild, nonspecific symptoms such as
palpitations, mild tremor, or slight heat intolerance.
• Some may report subtle neuropsychiatric symptoms like anxiety or irritability.
Risks and Complications
• SCH carries significant risks, especially in elderly people, including:
– Increased incidence of atrial fibrillation and associated thromboembolic events.
– Accelerated bone loss leading to osteoporosis and increased fracture risk, particularly in postmenopausal women.
• Therefore, periodic monitoring and consideration of treatment in at-risk groups
is recommended.
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atural History and Management
N
• SCH may persist indefinitely, revert to euthyroidism, or progress to overt hyperthyroidism [50].
• Elevated TRAb titers, goiter size, and clinical risk factors predict progression [51].
• Treatment decisions depend on age, symptom burden, cardiovascular risk, and
bone health considerations [8].
Extrathyroidal Manifestations
Autoimmune processes in GD extend beyond the thyroid gland, affecting orbital
and dermal tissues uniquely.
raves’ Orbitopathy (Thyroid Eye Disease)
G
GO is the most common extrathyroidal manifestation of GD, occurring in 25–50%
of patients [52].
• Pathophysiology: Autoimmune targeting of orbital fibroblasts expressing TSHR
and IGF-1 receptors induces inflammation, adipocyte proliferation, and glycosaminoglycan deposition, leading to orbital tissue expansion.
• Clinical Presentation:
– Exophthalmos (Proptosis): Forward displacement of the eyeballs is the cardinal sign.
– Periorbital Edema and Conjunctival Injection: Swelling and redness of eyelids and conjunctiva are common.
– Eyelid Retraction: Frequent, causing increased scleral show and exposure
keratopathy.
– Diplopia: Due to extraocular muscle inflammation and fibrosis restricting eye
movements.
– Orbital Pain or Pressure: Especially in the active inflammatory phase.
– Optic Neuropathy: Rare but serious, caused by optic nerve compression
requiring urgent intervention.
• Smoking increases both the risk and severity of GO substantially.
• GO may precede, coincide with, or follow the onset of thyrotoxicosis by months
to years.
hyroid Dermopathy (Pretibial Myxedema) [53]
T
A rare skin manifestation characterized by:
• Non-pitting, localized thickening and induration of the skin over the anterior
lower legs.
• The skin appears erythematous or hyperpigmented with an orange-peel texture.
• Pathogenesis involves immune-mediated activation of dermal fibroblasts producing excess glycosaminoglycans.
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327
• Usually occurs in patients with GO but can be isolated.
• Generally chronic but benign and rarely disabling.
hyroid Acropachy [54]
T
The rarest extrathyroidal manifestation, presenting with:
• Soft tissue swelling of the hands and feet.
• Digital clubbing and periosteal new bone formation visible on radiographs.
• Almost always associated with severe GO and dermopathy.
Systemic Manifestations
The systemic effects of GD arise from thyroid hormone excess, impacting multiple
organ systems.
ardiovascular System [51]
C
Cardiovascular involvement significantly contributes to morbidity and mortality in GD.
• Sinus Tachycardia: Nearly universal; caused by increased adrenergic tone.
• Atrial Fibrillation (AF): Particularly prevalent in patients over 60 years, with
incidence rates up to 15%. AF increases stroke and heart failure risk and often
resolves with euthyroidism restoration.
• High-Output Heart Failure: Occurs due to persistent tachycardia and reduced
systemic vascular resistance.
• Hypertension: Predominantly systolic.
• Palpitations and Angina: Symptoms related to increased myocardial oxygen
demand; angina may unmask underlying coronary artery disease.
Early cardiac evaluation and rhythm control are critical, especially in elderly
patients.
eurological and Psychiatric Manifestations [53]
N
• Anxiety and Nervousness: Among the earliest symptoms, driven by central nervous system (CNS) hyperexcitability.
• Tremor: A fine, rapid tremor of the hands and fingers.
• Insomnia and Restlessness: Common complaints.
• Emotional Lability and Depression: Can develop in chronic cases.
• Thyrotoxic Psychosis: Rare and severe, manifesting with hallucinations or
delirium.
Musculoskeletal Effects
• Thyrotoxic Myopathy: Symmetric, proximal muscle weakness and atrophy
resulting in functional impairment [55].
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A. Asghar and S. Askari
• Osteoporosis: Excess thyroid hormone accelerates bone resorption, decreasing
bone mineral density and predisposing to fractures [56].
• Thyrotoxic Periodic Paralysis: Episodic muscle weakness caused by hypokalemia, more common in Asian males [57].
astrointestinal Manifestations [54]
G
• Increased appetite with concomitant weight loss.
• Frequent bowel movements or diarrhea due to hypermotility.
Reproductive System
• Menstrual Irregularities: Oligomenorrhea or amenorrhea occurs due to
hypothalamic-­pituitary-gonadal axis disruption [55].
• Infertility: Thyrotoxicosis adversely affects fertility in both women and men. In
women, it can disrupt menstrual cycles, lead to anovulation, and impair implantation, while in men it may reduce sperm count and motility [58].
• Pregnancy Complications: Increased risks of miscarriage, preterm labor, and
fetal thyrotoxicosis due to transplacental antibody transfer [59].
ediatric Graves’ Disease [18]
P
Although less frequent than in adults, pediatric GD presents similarly but requires
special considerations:
•
•
•
•
May cause growth delay due to metabolic disturbance.
Behavioral symptoms including hyperactivity or emotional changes.
Early puberty onset has occasionally been reported.
Early diagnosis and treatment are essential to prevent developmental
complications.
eonatal Graves’ Disease [60]
N
Neonates born to mothers with elevated TRAb can develop transient
thyrotoxicosis:
• Presents with irritability, tachycardia, poor feeding, and failure to thrive.
• Usually resolves spontaneously as maternal antibodies wane.
• Requires close monitoring and sometimes pharmacologic intervention. Table 3
provides a summary of clinical manifestations in GD.
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329
Table 3 Summary of clinical features of Graves’ disease
Category
Thyroidal
Subclinical
hyperthyroidism
Extrathyroidal
Cardiovascular
Neurological/
psychiatric
Musculoskeletal
Gastrointestinal
Reproductive
Pediatric/neonatal
Clinical features
Diffuse goiter, thyroid bruit,
hyperthyroid symptoms (weight loss,
palpitations, tremor)
Low/suppressed TSH, normal free T4/
T3; often asymptomatic or mild
symptoms
Graves’ orbitopathy: Proptosis,
diplopia, eyelid retraction
Pretibial myxedema: Localized skin
thickening
Thyroid acropachy: Digital clubbing,
soft tissue swelling
Tachycardia, atrial fibrillation, heart
failure, systolic hypertension
Anxiety, tremor, insomnia, thyrotoxic
psychosis
Proximal muscle weakness,
osteoporosis, periodic paralysis
Diarrhea, increased appetite
Menstrual irregularities, infertility,
pregnancy complications
Growth delay, behavioral changes
(pediatric); transient neonatal
thyrotoxicosis
Comments
Size may vary; bruit due to
hypervascularity
Risk of progression to overt
hyperthyroidism; CV and bone
risks
25–50% of patients; smoking
worsens severity
Rare; usually chronic and benign
Very rare; severe phenotype
Major morbidity, especially in
the elderly
Reflect CNS hyperactivity
Important to monitor bone health
Reflects hypermetabolism
Affects fertility and fetal
outcomes
Requires early detection and
management
iagnosis: Laboratory and Imaging Evaluation
D
of Graves’ Disease
Accurate diagnosis of Graves’ disease (GD), an autoimmune hyperthyroid disorder,
relies heavily on a systematic and comprehensive evaluation integrating biochemical, immunological, and imaging modalities. Early and precise diagnosis is essential to guide therapy, prognosticate disease course, and monitor treatment response.
This section elaborates on the detailed laboratory and imaging workup pivotal to
establishing the diagnosis and assessing disease severity.
Laboratory Evaluation [61]
hyroid Function Tests (TFTs)
T
The biochemical hallmark of GD is elevated thyroid hormone levels secondary to
TSH receptor stimulation by autoantibodies.
• Serum TSH:
The initial and most sensitive screening test. In GD, TSH is markedly suppressed,
typically <0.01 mIU/L, due to negative feedback on the hypothalamic-pituitary
330
•
•
•
•
A. Asghar and S. Askari
axis by increased circulating thyroid hormones. Persistently suppressed TSH in
conjunction with clinical symptoms mandates further evaluation [62].
Free Thyroxine (Free T4):
Measures the unbound, biologically active form of thyroxine. Elevated free T4
levels confirm thyrotoxicosis. Free T4 assays employ equilibrium dialysis or
ultrafiltration methods to reduce interference from thyroid-binding proteins.
Free Triiodothyronine (Free T3):
Free T3 often rises earlier than free T4 and is a sensitive indicator, especially in
early or mild GD. In some cases, T3 toxicosis predominates, where free T3 is
elevated while free T4 remains normal. This is attributed to increased conversion
of T4 to T3 in the thyroid and peripheral tissues stimulated by TSH receptor
antibodies.
Total T4 and T3:
Less commonly used today due to variability caused by alterations in thyroid-­
binding globulin (TBG) levels (e.g., pregnancy, estrogen therapy). Free hormone
measurements are preferred.
Thyroid Hormone Binding Ratio:
This older test is largely obsolete, replaced by more precise free hormone assays.
Thyroid Autoantibodies
Autoantibody profiling is indispensable for confirming the autoimmune etiology.
• TSH Receptor Antibodies (TRAb): [63]
The pathognomonic antibodies in GD stimulate TRAb, which mimic TSH and
induce unregulated thyroid hormone synthesis and release.
– Assays detect stimulating (TSAb), blocking, or neutral antibodies.
– Third-generation competitive binding immunoassays and bioassays quantify
TRAb levels with high specificity and sensitivity (>95%).
– Quantitative TRAb measurement correlates with disease severity and risk of
relapse post-treatment, guiding prognosis.
– Positive TRAb is diagnostic for GD, even in cases with atypical thyroid function tests (e.g., euthyroid Graves’ orbitopathy).
• Thyroid Peroxidase Antibodies (TPOAb): [64]
Commonly positive in autoimmune thyroid disease but not specific for GD. Found
in 70–80% of GD patients but also in Hashimoto’s thyroiditis and healthy
individuals.
• Thyroglobulin Antibodies (TgAb): [65]
Less frequently elevated, mainly assist in differentiating autoimmune
thyroiditis.
dditional Laboratory Markers
A
• Serum Thyroglobulin:
Elevated in GD reflecting increased thyroid hormone synthesis and glandular
turnover. Useful to rule out exogenous thyroid hormone intake, as thyroglobulin
will be low or undetectable in factitious thyrotoxicosis [66].
Graves’ Disease
331
• Inflammatory Markers (ESR, CRP): [67]
Usually normal in GD; elevated values suggest thyroiditis.
• Serum Calcium and Alkaline Phosphatase: [68]
Thyrotoxicosis-induced bone turnover increases serum calcium and bone-­
specific alkaline phosphatase, relevant in evaluating systemic complications.
Imaging Evaluation
Imaging modalities provide critical anatomical and functional information that
complements laboratory findings and guides management decisions.
hyroid Ultrasonography with Doppler Flow Studies [69]
T
Ultrasonography is a readily available, non-invasive technique to characterize thyroid morphology and vascularity.
• Morphologic Features:
GD typically presents as a diffusely enlarged thyroid gland with smooth contours. The echotexture is usually hypoechoic or heterogeneous due to lymphocytic infiltration and follicular hyperplasia.
• Vascularity (Doppler Studies):
The “thyroid inferno” pattern, a striking increase in intrathyroidal blood flow on
color Doppler, is highly characteristic of GD, caused by hypervascularity from
arteriolar dilatation and increased metabolic demand.
• Diagnostic Value:
High sensitivity in detecting diffuse gland involvement, differentiating from
nodular thyroid diseases. It also assists in identifying nodules that may require
fine-needle aspiration.
• Monitoring:
Doppler flow parameters correlate with disease activity and respond dynamically
to treatment, providing a non-invasive biomarker for remission or relapse.
adionuclide Thyroid Scintigraphy [70]
R
Scintigraphy using iodine-123 (I-123) or technetium-99 m pertechnetate (Tc-99 m)
is the functional imaging gold standard.
• Mechanism:
I-123 is actively taken up and organified by thyroid follicular cells, reflecting
iodine trapping and hormone synthesis. Tc-99 m pertechnetate concentrates in
the gland but is not organified, serving as an iodine analog.
• Typical Findings in GD:
– Uniformly increased and symmetrically distributed uptake across the thyroid lobes.
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A. Asghar and S. Askari
– Elevated quantitative uptake values: >30% for iodine at 24 h (normal 10–30%),
and >4% for technetium (normal 1–4%).
– Rapid washout consistent with increased turnover.
• Diagnostic Utility:
This diffuse pattern with elevated uptake definitively distinguishes GD from thyroiditis (low uptake due to follicular damage) and toxic adenomas (focal
increased uptake).
• Clinical Implications:
Quantitative uptake helps estimate iodine turnover, which can influence dosing
for radioactive iodine therapy.
• Limitations:
Contraindicated in pregnancy and breastfeeding.
rbital Imaging—Computerized Tomography (CT) and Magnetic
O
Resonance Imaging (MRI) [71]
In patients exhibiting Graves’ orbitopathy (GO), imaging of the orbit assesses disease severity and guides therapeutic decisions.
• Pathognomonic Imaging Findings:
– Enlargement of extraocular muscles, primarily of the muscle bellies, sparing
the tendinous insertions.
– Increased orbital fat volume and inflammation.
– Possible optic nerve compression, proptosis, and orbital edema.
• Modalities:
– Computed Tomography (CT): Excellent spatial resolution for bone and soft
tissue anatomy. Preferred for assessing bony orbital walls and muscle
enlargement.
– Magnetic Resonance Imaging (MRI): Superior soft tissue contrast; useful for
detecting active inflammation and edema.
• Clinical Relevance:
Imaging helps differentiate active inflammation from fibrotic changes, influencing immunosuppressive therapy choices and surgical planning.
ther Emerging Imaging Techniques
O
• Shear Wave Elastography: [72]
Assesses tissue stiffness and may differentiate GD from thyroiditis or malignancy.
• PET/CT Imaging: [73]
Investigational role in refractory cases; uptake patterns may reflect inflammatory
activity.
Integration of Laboratory and Imaging Findings in Diagnosis
The diagnosis of GD integrates clinical presentation with confirmatory laboratory
and imaging data:
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333
Table 4 Differential diagnosis of thyrotoxicosis: laboratory and imaging clues
Condition
Graves’ disease
TSH
Free T4/T3
Suppressed Elevated
Toxic
multinodular
goiter
Toxic adenoma
Suppressed Elevated
Subacute
thyroiditis
Factitious
thyrotoxicosis
Suppressed Elevated
Suppressed Elevated
(transient)
Suppressed Elevated
TRAb
Positive
Radionuclide
uptake
Diffuse, high
Ultrasound/Doppler
Diffuse
enlargement,
hypervascular
Negative Patchy, nodular Multiple nodules
uptake
with variable flow
Negative Focal increased Single nodule with
uptake
increased flow
Negative Low uptake
Diffuse hypoechoic,
low vascularity
Negative Low uptake
Normal gland
• Laboratory:
The combination of suppressed TSH, elevated free T4 and/or free T3, and positive TRAb provides definitive diagnosis.
• Imaging:
Radionuclide scan showing diffuse increased uptake supports diagnosis, especially when autoantibody tests are inconclusive. Thyroid ultrasound adds morphological detail and assesses vascularity.
• When to Consider Additional Testing:
In cases of atypical presentation (e.g., euthyroid GO), isolated T3 toxicosis, or
suspected thyroiditis, antibody assays and imaging are crucial to clarify diagnosis. Table 4 provides laboratory and imaging features which help in differential
diagnosis of GD.
Special Populations and Diagnostic Challenges
Pregnancy [74]
• Limitations:
Radionuclide scans contraindicated due to fetal radiation risk.
• Diagnostic Strategy:
Rely on TFTs and TRAb levels. TRAb measurement is critical for predicting
neonatal thyrotoxicosis risk.
ediatric Graves’ Disease [75]
P
• Often presents with higher TRAb titers.
• Ultrasonography is useful to monitor gland changes due to concerns about radiation exposure. Table 5 shows how to employ a diagnostic approach to GD.
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A. Asghar and S. Askari
Table 5 Comprehensive diagnostic approach for Graves’ disease
Test/modality
TSH
Purpose
Screening
Free T4 and Free
T3
TRAb
Confirm thyroid
hormone excess
Autoimmune
confirmation
Autoimmune thyroid
disease support
Morphology and
vascularity
TPOAb and
TgAb
Thyroid
ultrasound +
Doppler
Radionuclide
scintigraphy
Functional thyroid
activity
Orbital CT/MRI
Assess Graves’
orbitopathy severity
Serum
thyroglobulin
Differentiate
endogenous hormone
production
Diagnostic findings
indicative of GD
Suppressed
Elevated (Free T3 may
be elevated earlier)
Positive
Often positive but
nonspecific
Diffuse
hypoechogenicity and
hypervascularity
Diffuse increased uptake
Extraocular muscle
enlargement, fat
expansion
Elevated
Clinical utility
Initial and sensitive
screening
Confirms biochemical
hyperthyroidism
Diagnostic and
prognostic marker
Helps differentiate
autoimmune conditions
Non-invasive
assessment, excludes
nodules
Gold standard for
differentiating
hyperthyroidism
Guides management of
GO
Excludes factitious
thyrotoxicosis
Management and Follow-Up of Graves’ Disease
Graves’ disease (GD) management aims to control thyrotoxicosis, address autoimmune manifestations, particularly ophthalmopathy, and prevent complications. The
three primary treatment options include antithyroid drugs (ATDs), radioactive
iodine (RAI) therapy, and thyroidectomy. Treatment choice depends on patient factors, disease severity, comorbidities, and preferences [8].
General Principles of Management
• Goals of therapy: Normalize thyroid hormone levels, prevent recurrence, alleviate symptoms, and manage extrathyroidal manifestations [76].
• Multidisciplinary approach: An interdisciplinary approach involving endocrinologists, ophthalmologists, nuclear medicine specialists, and surgeons is essential for optimal care.
• Patient-centered decision-making: Age, reproductive plans, goiter size, severity
of orbitopathy, comorbid conditions, and personal preferences guide treatment
selection [8].
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335
Antithyroid Drugs (ATDs) [8]
ATDs are often the first-line treatment, especially in mild or moderate cases, or as a
bridge to definitive therapy.
Mechanism of Action
Methimazole (MMI) and propylthiouracil (PTU) inhibit thyroid peroxidase to
reduce hormone synthesis. PTU also inhibits peripheral conversion of T4 to T3.
Indications
First-line in mild to moderate GD, children, adolescents, and pregnant women
(especially first trimester—PTU). It is also suitable for patients unwilling or unsuitable for definitive therapy.
Dosing and Monitoring
Initial dosing includes MMI at 10–30 mg/day and PTU at 100–150 mg thrice daily.
Doses are adjusted based on T4 and T3 levels every 4–6 weeks. Maintenance doses
typically range from 2.5 to 10 mg/day of MMI. TSH often remains suppressed for
months despite biochemical euthyroidism.
Duration and Remission
Treatment duration is typically 12–18 months, with remission rates of 30–50%,
particularly favorable in patients with low TRAb titers and small goiter size. TRAb
levels at the end of therapy help predict relapse.
ide Effects and Monitoring
S
Adverse effects include minor issues such as rash, arthralgia, and gastrointestinal
discomfort. Serious risks include agranulocytosis (0.2–0.5%) and hepatotoxicity
(especially with PTU). Baseline CBC and liver function tests are recommended,
with prompt evaluation of sore throat, fever, or jaundice during treatment.
Radioactive Iodine (RAI) Therapy [77]
RAI therapy is a definitive, non-invasive treatment that ablates thyroid tissue via
beta radiation from I-131.
Indications
It is indicated in adults with recurrent GD, those with poor adherence to ATDs, or
those preferring a permanent solution. RAI is contraindicated in pregnancy, lactation, and in patients with active moderate-to-severe orbitopathy.
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A. Asghar and S. Askari
Dosing
Administered orally; typical doses 10–30 mCi.
Uptake depends on thyroid size and iodine status.
Outcomes and Monitoring
Euthyroidism or hypothyroidism typically develops within 6–12 weeks and hypothyroidism develops in >80%, requiring lifelong levothyroxine. Post-treatment
TFTs should be monitored every 4–6 weeks until stabilization.
Orbitopathy Considerations
RAI may exacerbate ophthalmopathy, particularly in smokers or those with high
TRAb titers. Prophylactic corticosteroids, such as prednisone 0.4–0.5 mg/kg/day
tapered over 2–3 months, can mitigate this risk.
Safety
Patients should avoid pregnancy for at least six months post-RAI. Despite radiation
exposure, with standard precautions, there is minimal risk to family members.
Thyroid Surgery [8, 78]
Total thyroidectomy offers rapid and definitive management, particularly in cases
with large goiters, suspected malignancy, or pregnancy during the second trimester.
It is also preferred when other modalities fail or are contraindicated.
Preoperative Preparation
Preoperative preparation includes achieving euthyroidism with ATDs and beta-­
blockers. Potassium iodide (Lugol’s solution) is administered for 7–10 days preoperatively to reduce gland vascularity.
Outcomes and Monitoring
Hyperthyroidism resolves immediately postoperatively, but lifelong levothyroxine
replacement is necessary. Calcium levels should be monitored post-op to assess for
hypoparathyroidism.
Complications
Potential complications include transient hypocalcemia (20%), permanent hypocalcemia (<2%), recurrent laryngeal nerve injury (1–2%), and wound-related issues
such as hematoma or infection. Despite these risks, surgery provides a definitive and
rapid resolution.
Graves’ Disease
337
Adjunctive and Symptomatic Treatment
Beta-blockers, such as propranolol (20–40 mg three times daily) or atenolol
(25–50 mg once daily), provide symptomatic relief from adrenergic excess.
Cholestyramine may be used in severe thyrotoxicosis or thyrotoxic storm scenarios
to enhance thyroid hormone clearance.
Management in Special Populations
Pregnancy Pregnancy necessitates PTU use in the first trimester due to hepatotoxicity risks with MMI, which may be resumed in the second and third trimesters. FT4
levels should be maintained in the upper normal range, with monthly monitoring.
RAI is contraindicated [67].
Children/Adolescents In children and adolescents, ATDs are preferred. Surgery
or RAI may be considered in non-responders or relapsing cases.
Graves’ Orbitopathy [8] In patients with Graves’ orbitopathy (GO), mild GO
allows any treatment modality. Moderate-to-severe GO warrants avoidance of RAI
and consideration of surgery or ATDs.
Follow-Up and Monitoring [8]
Initial follow-up includes TFTs every 4–6 weeks. TRAb levels help guide decisions
about discontinuing ATDs. Following definitive therapy, regular screening for hypothyroidism is essential. Ophthalmic assessments should be conducted in patients
with orbitopathy. Table 6 outlines comparison of different treatment strategies in GD.
Long-Term Considerations and Quality of Life
Long-term management includes patient education on signs and symptoms of thyroid dysfunction, encouragement of smoking cessation (especially important in
GO), and regular monitoring for levothyroxine compliance [79].
Bone mineral density should be assessed in postmenopausal women or patients
with prolonged thyrotoxicosis [80]. Attention to psychosocial aspects, including
anxiety and quality of life, enhances comprehensive care [81] (Fig. 1).
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A. Asghar and S. Askari
Table 6 Comparison of treatment modalities for Graves’ disease
Feature
Mechanism
Drugs/method
First line in
Antithyroid drugs
(ATDs)
Inhibits thyroid
hormone synthesis
Methimazole,
Propylthiouracil
Young, mild disease,
pregnancy, GO
Onset of action
4–6 weeks
Remission rate
30–50%
Risk of
hypothyroidism
Adverse effects
Low-moderate
(10–30%)
Agranulocytosis,
hepatotoxicity, rash
TFTs, complete blood
count (CBC), liver
function tests (LFTs)
Non-invasive,
reversible, useful in
pregnancy
Hepatic disease, history
of agranulocytosis
Relapse risk, daily
compliance needed
Monitoring
Advantages
Contraindications
Limitations
Radioactive iodine
(RAI)
Destroys thyroid
tissue via
β-radiation
I-131, orally
(10–30 mCi)
Older patients,
recurrence,
intolerance to ATD
6–12 weeks
Permanent
hypothyroidism
expected
High (>80%)
Worsening GO,
hypothyroidism
TFTs every
4–6 weeks
Definitive,
non-surgical
Surgery (total
thyroidectomy)
Removes the thyroid gland
entirely
Surgical excision (usually
total thyroidectomy)
Large goiters, malignancy
suspicion, pregnant (second
trimester)
Immediate (requires pre-op
euthyroid state)
Permanent hypothyroidism
expected
100% (requires lifelong
levothyroxine)
Hypoparathyroidism, nerve
injury, bleeding
Calcium, TFTs
Definitive, rapid resolution,
avoids RAI
Pregnancy, lactation Unfit for surgery
Delayed effect,
contraindicated in
pregnancy
Surgical risks,
hospitalization
Fig. 1 Decision-making flowchart for the management of Graves’ disease
Graves’ Disease
339
ecent Advances and Future Directions in Pathophysiology,
R
Diagnosis, and Management of Graves’ Disease and Thyroid
Eye Disease
Graves’ disease (GD) and thyroid eye disease (TED) represent autoimmune conditions with evolving understanding and management. Traditional paradigms have
relied on suppressing thyroid hormone production or eliminating thyroid tissue.
However, recent scientific progress has highlighted novel molecular mechanisms,
refined diagnostic tools, and expanded therapeutic options, especially targeting
immunological and cellular pathways.
Advances in Pathophysiology
Historically, GD has been understood as a TSH receptor antibody (TRAb)-mediated
autoimmune disease. However, newer studies underscore a broader autoantibody
milieu, implicating the insulin-like growth factor-1 receptor (IGF-1R) as a key co-­
conspirator in both thyroidal and orbital autoimmunity. The interaction between
IGF-1R and TSHR on orbital fibroblasts leads to cytokine release, adipogenesis,
and hyaluronan production—central events in TED pathogenesis [1].
High-throughput genomic and proteomic studies have revealed several non-HLA
genes associated with GD susceptibility, including CTLA-4, PTPN22, and CD40,
and epigenetic modifications such as DNA methylation changes are now being
explored for their regulatory role in disease expression. The role of Th17 cells and
IL-17 in disease amplification further reflects the complexity of the immune
response beyond the traditional Th1/Th2 paradigm [82].
Another exciting area involves the gut-thyroid axis. Altered gut microbiota composition in GD patients suggests a potential immunomodulatory role for the microbiome, possibly impacting autoantibody generation or thyroid hormone metabolism
[4]. Future strategies may involve microbiota modulation [83].
Innovations in Diagnosis
The diagnosis of GD still relies on clinical features, thyroid function tests, and
TRAb detection. However, advancements in immunoassays have improved the sensitivity and specificity of TRAb measurement. The third-generation TRAb assays
can now differentiate stimulating from blocking antibodies, aiding diagnostic and
prognostic precision [84].
Imaging modalities have also seen refinements. Orbital imaging in TED using
high-resolution MRI with fat suppression or diffusion-weighted imaging offers
superior soft tissue characterization and helps differentiate active from fibrotic disease [85]. Artificial intelligence (AI) algorithms integrated into ultrasound imaging
and facial recognition technologies are under development to quantify TED severity
objectively and monitor response to therapy [86].
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A. Asghar and S. Askari
Positron emission tomography (PET) tracers like gallium68-dodecanetetraacetic acid-Tyr3-octreotate (68Ga-DOTATATE), initially developed for neuroendocrine tumors, have been explored in TED to image activated orbital fibroblasts
expressing somatostatin receptors, potentially helping in early detection of inflammatory activity [87].
Emerging Therapies in GD
While antithyroid drugs, RAI, and surgery remain the foundation, the limitations of
recurrence, hypothyroidism, or surgical risks have stimulated the development of
novel therapies.
Teprotumumab, a monoclonal antibody targeting IGF-1R, marks a paradigm
shift in TED treatment. Initially approved by the FDA for active TED, it has shown
dramatic improvement in proptosis, diplopia, and quality of life metrics [88]. Its
efficacy supports the IGF-1R–TSHR signaling pathway’s centrality in disease
pathophysiology. Ongoing trials are evaluating its role in chronic or recurrent TED.
Another agent, rituximab, an anti-CD20 monoclonal antibody, has shown mixed
results in TED but may have niche applications, especially in steroid-refractory
cases [89]. Research into tocilizumab (anti-IL-6) and mycophenolate mofetil suggests immunomodulatory benefit, though head-to-head trials are awaited [90].
In GD, small-molecule TSHR antagonists are under development. These molecules inhibit the receptor’s activation by TRAb, potentially offering targeted, reversible disease control without ablating the thyroid [91].
Also under evaluation are immune tolerance-inducing vaccines, such as
ATX-GD-59, which delivers peptides mimicking TSHR to modulate autoreactive T
cells. Early-phase studies show potential in reducing TRAb levels and preserving
thyroid function [92].
Advances in TED Management
Steroids remain the first-line treatment for moderate-to-severe active TED. However,
poor tolerability and relapse upon withdrawal highlight the need for alternatives.
Teprotumumab is now considered superior to steroids in many patients due to sustained proptosis reduction and functional improvement [89].
Surgical management, including orbital decompression, remains necessary in
advanced disease. Recent innovations in surgical technique, including image-guided
navigation and minimally invasive approaches, reduce complications and improve
cosmetic outcomes [93].
There is growing interest in precision medicine, where TED treatment is guided
by specific biomarkers (e.g., TRAb subtype, cytokine profiles) or genetic susceptibility markers. This approach may reduce overtreatment and tailor interventions to
disease phase and activity.
Graves’ Disease
341
Future Directions
1. Biomarker Discovery and Stratification: Advances in proteomics and metabolomics are anticipated to identify disease activity and remission markers, enabling
early intervention and better prediction of relapse [94].
2. Gene Editing and Tolerance Restoration: Clustered Regularly Interspaced Short
Palindromic Repeats and CRISPR-associated protein 9 (CRISPR/Cas9) technologies are being explored in autoimmune conditions to correct immune dysregulation, though application in GD is at a conceptual stage.
3. Microbiome-Targeted Therapies: Probiotic or fecal transplant strategies to
restore gut eubiosis in GD are in experimental phases. If successful, they may
offer adjunctive, non-invasive immunomodulation [92].
4. Telemedicine and Artificial Intelligence (AI)-Driven Management: Machine
learning models can now predict GD relapse based on laboratory and clinical
inputs. Smartphone-based orbital photographs and wearable devices may support remote TED monitoring, especially valuable in under-resourced settings [94].
5. Combination Therapies: Future therapeutic regimens may combine ATDs with
immunomodulators or biologics to induce sustained remission with fewer side
effects.
Summary
Graves’ disease (GD) is a prototypical autoimmune thyroid disorder and a leading
cause of hyperthyroidism worldwide. It is characterized by the production of
thyroid-­stimulating immunoglobulins (TSI) that bind to and activate the thyroid
(TSH) receptor, causing thyroid hormone overproduction and, in many cases, extrathyroidal involvement, especially Graves’ orbitopathy (GO). This condition predominantly affects women and typically arises between the ages of 20 and 50. A
comprehensive understanding of its pathophysiology, clinical features, diagnosis,
and management is essential for effective care.
The pathogenesis of Graves’ disease involves a complex interplay of genetic,
environmental, and immunological factors. Genetic predisposition includes associations with HLA-DR3, CTLA-4, and other immune-regulatory genes. Environmental
triggers such as stress, smoking, infections, and iodine excess can precipitate disease onset in genetically susceptible individuals. Immunologically, aberrant activation of T and B cells, breakdown of central and peripheral tolerance, and the
production of autoantibodies lead to thyroidal hyperfunction and tissue inflammation.
Graves’ orbitopathy, the most recognized extrathyroidal manifestation, results
from autoimmune targeting of orbital fibroblasts expressing both TSH receptor
and insulin-like growth factor-1 receptor (IGF-1R). This leads to orbital inflammation, edema, adipogenesis, and fibrosis, causing symptoms such as proptosis,
diplopia, and, in severe cases, vision loss. Smoking remains a strong risk factor
and disease modifier.
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A. Asghar and S. Askari
Diagnosis is established based on clinical symptoms of thyrotoxicosis, such as
weight loss, heat intolerance, tremors, and palpitations and amenorrhea in females,
alongside biochemical confirmation of suppressed TSH and elevated free T4 and/or
T3. The presence of TRAb is diagnostic, and imaging modality such as radioactive
iodine uptake scans may aid in differentiation from other causes of hyperthyroidism. Orbital imaging, including MRI or CT, is indicated in patients with eye
symptoms.
Management strategies are tailored to the individual’s age, comorbidities, disease severity, goiter size, and patient preference. The three main therapeutic
options are:
• Antithyroid drugs (ATDs)—such as methimazole and propylthiouracil—are first-­
line in mild to moderate cases, children, and pregnant women. They inhibit thyroid hormone synthesis and offer a non-invasive approach with remission
possible after 12–18 months in selected patients.
• Radioactive iodine (RAI) therapy—a definitive, non-surgical option that ablates
thyroid tissue using I-131. It is contraindicated in pregnancy, lactation, and active
moderate-to-severe GO. Patients often require lifelong levothyroxine replacement after RAI.
• Thyroidectomy—indicated in cases of large goiters, suspected malignancy, or in
patients who are pregnant (second trimester), non-responsive, or intolerant to
other treatments. It offers immediate resolution but carries surgical risks such as
hypoparathyroidism and recurrent laryngeal nerve injury.
Graves’ orbitopathy requires careful evaluation and may necessitate referral to
an ophthalmologist. Mild GO can be observed or managed conservatively. In
moderate-­to-severe active cases, intravenous glucocorticoids, orbital radiation, or
biologic therapies such as teprotumumab are recommended. Smoking cessation is a
critical part of management and improves response to therapy.
Follow-up and monitoring include regular thyroid function tests (TFTs) every
4–6 weeks during active treatment and periodically after definitive therapy. TRAb
levels may predict relapse post-ATD therapy. After surgery or RAI, patients must be
monitored lifelong for hypothyroidism and adjusted for levothyroxine replacement.
In patients with GO, periodic ophthalmic evaluation is essential.
Special populations require individualized care. In pregnancy, PTU is preferred
in the first trimester due to teratogenicity concerns with methimazole. Children and
adolescents are often started on ATDs, with surgery or RAI reserved for relapsed or
refractory cases. Elderly patients or those with cardiac comorbidities require careful
control of thyrotoxicosis to prevent atrial fibrillation and heart failure.
In recent years, significant advances have transformed the understanding and
treatment of GD and GO. On the diagnostic front, high-sensitivity immunoassays,
novel imaging techniques, and AI-driven tools are improving early detection and
disease stratification. Therapeutically, monoclonal antibodies targeting IGF-1R,
such as teprotumumab, and small molecule TSHR antagonists are promising new
agents offering mechanism-specific intervention.
Graves’ Disease
343
Future directions include the development of antigen-specific immunotherapies,
modulators of immune tolerance, and gut microbiome-targeted therapies, aiming
not only for disease control but for immune modulation and potential cure. Further
research into epigenetic mechanisms, long non-coding RNAs, and personalized
medicine approaches is expected to refine prognosis and guide individualized
therapy.
Quality of life remains a key concern in GD, influenced by both physical symptoms and psychological distress. Addressing fatigue, anxiety, and cosmetic concerns, especially in GO, is integral to holistic care. Long-term monitoring for
osteopenia, cardiovascular risks, and medication adherence is necessary to prevent
complications.
Conclusion
Graves’ disease is a complex but manageable autoimmune disorder with expanding
diagnostic and therapeutic frontiers. A patient-centered, multidisciplinary approach,
incorporating recent scientific advances, is essential for optimal outcomes.
Continued research promises a future of more targeted, less toxic, and potentially
curative therapies for both GD and its extrathyroidal manifestations.
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Type 1 Diabetes Mellitus
Syeda Nazish Azim
Introduction
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by
immune-mediated destruction of pancreatic beta cells, leading to absolute insulin
deficiency, necessitating lifelong insulin therapy. The discovery of insulin in the
early twentieth century was a landmark achievement transforming T1DM from a
uniformly fatal condition to a manageable chronic illness [1]. Despite this breakthrough and subsequent advancements in management, T1DM continues to pose
significant challenges to the affected individuals and the healthcare system worldwide [1]. T1DM is among the most common chronic diseases in children and adolescents. Its global incidence is rising, particularly in low- and middle-income
countries (LMICs), demanding improved understanding of the disease, enhanced
management strategies, and equitable access to care [1].
Modern management approach to T1DM has a growing emphasis on disease
modifying therapies, immunological monitoring, and early-stage screening.
Particularly, immunotherapy and genetic risk stratification offers hope to delay or
even prevent disease onset in high-risk individuals [2].
This chapter provides an understanding of type 1 diabetes mellitus, including its
epidemiology, pathogenesis, clinical presentation, diagnostic criteria, evidence-­
based management, and new advancement and technologies, with a focus on optimizing long-term glycemic control, preventing complications, and improving
quality of life.
S. N. Azim (*)
Sindh Institute of Child Health and Neonatology, Karachi, Pakistan
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_13
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Epidemiology
T1DM accounts for approximately 10% of all diabetes cases across age groups,
affecting about 1.8 million children and young adults under 20 years of age globally, with over 95,000 new cases diagnosed annually [3]. The incidence of T1DM is
increasing globally with an estimated annual growth rate between 2% and 5%. The
disease affects all ethnicities and geographical regions, though with significant variations in incidence and prevalence. While incidence rates are generally higher in
high-income countries, with the highest rates observed in Scandinavian countries
like Finland and Sweden, exceeding 60 cases per 100,000 children annually, the
most rapid increases are now seen in some LMICs, indicating a shift in the global
epidemiology of the disease [1].
T1DM can present at any age. However, there are typically two peak ages of
onset observed, one between 5 and 7 years of age and another around puberty [4].
The first peak may be related to the increased exposure to infections at the beginning of the school life, while the second peak may arise due to production of growth
hormone and sex steroids during the pubertal spurt [5].
Unlike most other autoimmune disorders, T1DM affects girls and boys with
almost equal frequency, with a modest predilection toward male in some ethnicities.
There also appears to be a seasonal variation with most new cases occurring in winter and fall, potentially linked to increased viral exposures [5].
Risk Factors
The development of T1DM is multifactorial, with a complex interplay of genetic
predisposition and environmental factors, potentially modulated by hormonal influences, leading to an autoimmune cascade that results in gradual destruction of pancreatic beta cells [6].
Genetic Predisposition
Genetic factors play a significant role in the development of T1DM, as evident by
its familial clustering. First-degree relatives of individuals with T1DM have a
considerably higher lifetime risk of developing the disease. Siblings have an estimated 8% risk, which is 15-folds higher than that for the general population. The
lifetime risk for children of a parent with T1DM is around 5%, with a 2–4% risk
if the mother has T1DM and a 6–7% risk if the father is affected. The risk dramatically increases to around 30% if both parents are affected. Monozygotic twins
have a concordance rate of 65% compared to 6–10% in dizygotic twins. However,
it is important to recognize that approximately 85% of newly diagnosed T1DM
cases lack a positive family history, indicating the involvement of other etiologic
factors [6].
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351
Genetic susceptibility to T1DM is linked to multiple risk loci, with the human
leucocyte antigen (HLA) complex on the chromosome 6p21 conferring the strongest genetic susceptibly. Specifically, the HLA-DR3-DR2 and HLA-DR4-DR8 haplotypes are strongly associated with increased risk, while HLA-DQ6 appears to be
protective. Genome-Wide Association Studies (GWASS) have identified more than
50 non-HLA genes such as CTLA-4, cytotoxic T-lymphocyte-associated protein 4
(CTLA-4), protein tyrosine phosphatase non-receptor type (22PTPN22), and interleukin-­2 receptor subunit alpha (IL2RA) that contribute to T1DM risk [6].
Environmental Modulators
While no singular environmental factor has been definitively implicated, a confluence of factors is being considered [6].
Viruses, particularly Enteroviruses, have been consistently investigated for their
potential role in triggering autoimmunity in genetically susceptible individuals
through mechanisms like molecular mimicry and bystander activation [7].
Dietary exposures during infancy and early childhood, like early introduction of
cow milk protein, gluten, and low vitamin D levels, have been investigated as potential contributors, although evidence remains inconclusive. Conversely, prolonged
breastfeeding has been suggested as a protective factor, though its direct impact on
T1DM prevention is still under investigation [6].
Research suggests a link between alterations in the gut microbiome and T1DM,
though a direct cause-effect relationship has not been established. Compared to the
healthy population, patients with T1DM have a less diverse gut microbiome with a
low population of bacteria that produce butyrate. Butyrate, a short-chain fatty acid
with a possible anti-inflammatory effect, is believed to be important in maintaining
the integrity of the intestinal lining [6].
Perinatal factors, including maternal age, pre-eclampsia, caesarean delivery, and
increased birth weight, have also been associated with increased susceptibility.
However, the mechanism leading to altered autoimmunity remains unclear [5].
The hygiene hypothesis, suggesting that reduced early childhood exposure to
infections might increase the risk of autoimmunity, remains a topic of discussion [5].
Hormonal Influences
Puberty is a well-recognized period of increased risk of development as well as
accelerated disease progression, likely due to the physiologic insulin resistance
driven by growth hormone and sex steroids. Adolescents may progress to clinical
disease more rapidly compared to younger children [5].
The precise mechanism by which these genetic and environmental factors converge to initiate and propagate pancreatic beta cells autoimmunity is not fully
understood. Emerging areas like epigenetics offer potential insights into how environmental cues might modulate gene expression in susceptible individuals.
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Understanding the temporal dynamics and synergistic effects of these risk factors is
crucial in developing predictive models and potentially preventive strategies [6].
Pathogenesis and the Natural History of T1DM
T1DM develops in genetically susceptible hosts when various environmental triggers interact to initiate an autoimmune response. This response targets and gradually destroys the pancreatic beta cells within islets of Langerhans, eventually
resulting in insulin deficiency as a critical mass of the pancreatic beta cells are
lost [5].
The immunological mechanisms leading to destruction of beta cells are complex
and involve both cellular and humoral immunity. The process begins with the loss
of immune tolerance against beta-cell antigens, resulting in activation of autoreactive CD4+ and CD8+ T-cells. These autoreactive T cells, after infiltrating the pancreatic islets, recognize specific antigens such as insulin, glutamic acid decarboxylase
65(GAD-65), insulinoma-associated antigen-2 (IA-2), and zinc transporter 8
(ZnT-8) and initiate cytotoxic responses, which include the release of pro-­
inflammatory cytokines such as interferon gamma (IFN-ϒ), tumor necrosis factor
alpha (TNF-a), interleukin-1 beta (IL- 1b) and direct killing through perforin/ granzyme pathways [6, 9].
A key factor in the pathogenesis of T1DM is the disruption of the normal balance
between the pro-inflammatory T-effector cells and the regulatory T cells (Tregs).
The impaired number and/or function of Tregs allow autoreactive T cells to escape
control and destroy pancreatic beta cells [6, 8].
The B lymphocytes also play a critical role through antigen presentation and
production of islet- specific autoantibodies, including those against insulin, e.g.,
insulin autoantibodies (IAA), glutamic acid decarboxylase (GAD-65), insulinoma-­
associated antigen-2 (IA-2), and zinc transporter-8 (ZnT8). These autoantibodies
are important markers of the autoimmune process and can be detected years before
the onset of symptoms. While their precise contribution to pancreatic beta cells
destruction is still being investigated, they serve as valuable diagnostic and predictive tools. The likelihood of developing clinical disease increases dramatically with
the increasing number of detectable autoantibodies. The 10-year progression rate to
T1DM is 15% in children with one autoantibody, 70% in those with two, and 90%
in those with three autoantibodies [4, 6].
Stages
The development of T1DM progresses in a predictable sequence at variable rates. A
staging model of T1DM, reflecting the natural progression of autoimmunity, has
been described in the International Society for Pediatric and Adolescent Diabetes
(ISPAD) 2024 guidelines [10].
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Stage 1: Autoimmunity/Normoglycemia/ Pre-symptomatic T1DM:
The first stage is characterized by the onset of autoimmunity as evident by the presence of two or more islet cells autoantibodies. However, the individual remains
euglycemic and hence asymptomatic.
Stage 2: Autoimmunity/Dysglycemia/ Pre-symptomatic T1DM:
As disease progresses, glucose intolerance develops due to loss of significant pancreatic beta-ell numbers. However, the patient remains asymptomatic.
Stage 3: Autoimmunity/Dysglycemia/Symptomatic T1DM:
This stage is characterized by the onset of clinical disease where individuals start
manifesting symptoms of hyperglycemia. Some patients may experience a transient phase of remission, often referred to as the honeymoon phase, due to residual insulin production from the remaining pancreatic beta cells. This phase
usually occurs within weeks of onset of clinical disease and may last 6 to
12 months, until the progressive loss of pancreatic beta cells is complete.
Stage 4: Established disease with or without complications.
This stage encompasses individuals with established disease. It may be complicated
by acute metabolic events (e.g., DKA), or long-term microvascular and macrovascular complications, depending on glycemic control and disease duration.
Clinical Manifestation
The hallmark clinical features of T1DM are a result of absolute insulin deficiency.
The clinical presentation may range from a relatively gradual onset of the classic
symptoms of hyperglycemia to rapid and severe presentation with diabetic ketoacidosis (DKA) [11].
A small proportion of children and adolescents may be diagnosed in the pre-­
symptomatic stage either with an incidental finding of hyperglycemia or when present with seemingly unrelated complaints such as vulvovaginal candidiasis [11].
Classic Symptoms
The triad of classic “poly” symptoms is often the initial clinical indicator of the
disease [11].
• Polyuria: The increased frequency of urination occurs when the blood glucose
levels surpass the renal threshold (typically around 200 mg/dL). The excess glucose in the renal tubules acts as an osmotic diuretic, resulting in increased urinary output. In children, this may manifest as new onset of nocturnal diuresis in
a previously dry child [11].
• Polydipsia: Excessive thirst is a physiological response to fluid loss resulting
from polyuria. Children may ask for drinks, especially sugary beverages which
may exacerbate hyperglycemia [11].
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• Polyphagia: Despite hyperglycemia, the lack of insulin impairs cellular glucose
uptake, causing intracellular energy deprivation. This stimulates hunger, leading
to an increased food intake. Nevertheless, the cells remain energy-deprived and
start breaking proteins and fats to generate energy resulting in weight loss [11].
Besides the classic triad, other symptoms may include fatigue, weakness, blurred
vision, and mood changes [11].
Diabetic Ketoacidosis
Approximately 30% of individuals with newly diagnosed T1DM present with DKA,
an acute life-threatening condition characterized by severe insulin deficiency along
with excess counter-regulatory hormones, as described in Fig. 1. Risk factors for
DKA presentation diagnosis include young age, particularly under 2 years, ethnic
minority status, and lower socioeconomic or parental education levels [2].
Absolute Insulin Deficiency
Stress, Infection or
Insufficient Insulin
Increased Counter-Regulatory Hormones
↑ Lipolysis
- Glucagon
- Growth Hormone
- Cortisol
- Catecholamines
↓ Glucose Utilization
↑ Protiolysis
↓ Protein synthesis
↑ Gluconeogenesis
↑ Free Fatty Acids
Hyperglycemia
↑ Ketogenesis
Glucosuria
Acidosis
Loss of water & electrolytes
Dehydration
↑ Lactate
Fig. 1 Pathophysiology of DKA [12]
↑ Glycogenolysis
Type 1 Diabetes Mellitus
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These patients typically exhibit the classic symptoms of diabetes, polydipsia,
polyphagia, polyuria, and weight loss, which tend to worsen as the disease progresses. With the development of acidosis, appetite often decreases, and symptoms
such as nausea, vomiting, and abdominal pain become more predominant. In
response to the increasing ketoacidosis, patients develop deep, labored breathing
(Kussmaul breathing) as a compensatory mechanism to wash out excess acid as
acetone in the breath, giving it a fruity odor [11].
If left untreated, the combined effects of hyperosmolality and acidosis can lead
to progressive deterioration in mental status. Hence, prompt recognition and management of DKA is necessary to prevent serious complications (such as cerebral
edema) and mortality [11].
Diagnosis
The diagnosis of T1DM in children and adolescents typically involves evaluating
clinical symptoms and confirming hyperglycemia through laboratory investigations
[1, 13]. Table 1 outlines the diagnostic criteria for all form of diabetes, as described
by the American Diabetes Association (ADA) and World Health Organization
(WHO) [11].
Once diabetes is confirmed, it is essential to determine the specific type. To distinguish T1DM from other forms, testing for islet cells autoantibodies is often performed. These include antibodies to:
•
•
•
•
Insulin (IAA)
Insulinoma-associated antigen-2 (IA-2)
Glutamic acid decarboxylase (GAD-65)
Zinc transporter-8 (ZnT8)
The presence of one or more of these autoantibodies, in the context of clinical
presentation, strongly supports the diagnosis of T1DM [4].
Table 1 Criteria for the diagnosis of diabetes mellitus
HbA1C ≥ 6.5%, where the test is performed using a method that is National GlycoHemoglobin
Standardization Program (NGHS) certified and standardized to the Diabetes Complications &
Control Trial Assay (DCCTA)
OR
Fasting plasma glucose ≥126 mg/dL; fasting is defined as no caloric intake for at least 8 h
OR
2-h glucose tolerance test reading ≥200 mg/dL; the test is performed as described by WHO,
using a glucose load equivalent to 1.75 g/kg to a maximum of 75 g anhydrous glucose
OR
Random plasma glucose ≥200 mg/dL in a patient with classical symptoms of hyperglycemia
Data from: American Diabetes Association [2]
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C-peptide levels can serve as an additional tool to support the diagnosis of
T1DM. As a by-product of endogenous insulin production, its levels are usually low
or undetectable in T1DM, reflecting the reduced or absent pancreatic beta-cell function [4].
Complications
Despite advancements in management, T1DM remains associated with acute and
chronic complications that contribute significantly to morbidity and mortality if not
managed properly. These complications reflect the systemic effects of chronic
hyperglycemia, metabolic dysregulation, and autoimmune processes [12].
The Diabetes Control and Complications Trial (DCCT) and its long-term follow­up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study,
definitively established that intensive glycemic control significantly reduces the risk
of developing and progressing these complications [13].
Acute Complications
Diabetes Ketoacidosis
Diabetes ketoacidosis (DKA) is a life-threatening emergency resulting from severe
insulin deficiency. While DKA can occur at the time of diagnosis, it can also happen
in individuals with established T1DM due to missed insulin doses, illness, infection,
or insulin pump malfunction [2].
It is characterized by a triad of hyperglycemia, ketosis, and acidosis. It results
from significant or absolute deficiency of insulin coupled with increased levels of
counter-regulatory hormones, catecholamines, cortisol, growth hormone, and glucagon. The insulin deficit disrupts glucose utilization and decreased peripheral glucose uptake, while increased gluconeogenesis and glycogenolysis by the actions of
counter-regulatory hormones lead to marked hyperglycemia. Simultaneously, the
increase in lipolysis mobilizes free fatty acids that are converted to ketone bodies in
the liver. Osmotic diuresis from hyperglycemia leads to dehydration and electrolytes loss, further exacerbated by vomiting often seen in severe ketosis. The resulting dehydration causes renal impairment, reducing ketone clearance, thereby
perpetuating the cycle of acidosis and hyperglycemia [12].
The biochemical criteria for the diagnosis of DKA, according to ISPAD, are [12]:
• Hyperglycemia—blood glucose ≥200 mg/dL
• Venous pH < 7.3 or serum bicarbonate < 18 mmol/L
• Ketonemia—blood beta-hydroxy butyrate ≥3 mmol/L or moderate to large
ketonuria
Type 1 Diabetes Mellitus
357
The severity of DKA is categorized based on the severity of acidosis [12]:
• Mild DKA—venous pH < 7.3 or serum bicarbonate < 18 mmol/L
• Moderate DKA—venous pH < 7.2 or serum bicarbonate < 10 mmol/L
• Severe DKA—venous pH < 7.1 or serum bicarbonate < 5 mmol/L
The cornerstone of DKA management, as outlined in Fig. 2, involves the following three components:
• Restoration of circulatory volume and electrolyte balance
• Correction of hyperglycemia using insulin therapy
• Identification and treatment of precipitating factors
Prompt recognition and structured management are critical. Close monitoring is
essential to avoid complications, such as cerebral edema—the most feared consequence of DKA in children and adolescents [2].
Hypoglycemia
Hypoglycemia represents a frequent and potentially serious complication in individuals with T1DM, particularly in pediatric patients undergoing intensive insulin
therapy [2]. Although technological advances have improved glucose monitoring
and insulin delivery, hypoglycemia remains a key barrier to optimal glycemic control and remains a source of anxiety for patients and their families [6].
Hypoglycemia is defined as plasma glucose level ≤ 70 mg/dL. The incidence of
mild, symptomatic episodes is common, while severe hypoglycemia—characterized by the need for external assistance due to altered mental or physical function—
remains a critical concern, with reported rates of 1.1 to 1.5 episodes per patient-year
in children receiving intensive insulin therapy [2].
Common precipitating factors include missed meals, incorrect insulin dosing,
physical activity, and changes in insulin absorption kinetics. Infants and young children are particularly vulnerable due to unpredictable food intake and physical activity, immature counter-regulatory mechanisms, and limited ability to communicate
symptoms or access treatment independently [2].
Hypoglycemia normally triggers a counter-regulatory response that includes
suppression of endogenous insulin, increased glucagon secretion, and catecholamine release. The first two responses are lost early during the course of disease.
Over time, repeated hypoglycemia blunts the catecholamine response, leading to
impaired awareness of hypoglycemia and hypoglycemia-associated autonomic failure. This state of diminished symptom perception and inadequate hormonal response
increase the risk of recurrent and severe episodes [14].
Symptoms of hypoglycemia arise from both autonomic and neuroglycopenic
responses. Early symptoms, including a sensation of hunger, tremors, palpitations,
irritability, sweating and pallor, are largely mediated by catecholamine release. As
blood glucose levels fall further, neuroglycopenic symptoms predominate, manifesting as behavioral changes such as aggression and confusion, followed by drowsiness,
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DKA Diagnosis Confimed: Hyperglycemia+Ketonemia+Acidosis
Shock
Moderate to Severe
Dehydration-not in Shock
Resuscitate:
-Maintain Airway & Breathng
- Circultion- 10-20 ml/kg 0.9% Saline
over 30-60 min, repeat until
circulation is restored.
- 10-20 ml 0.9% Saline over 1-2 hours
Mild Dehydration
Tolerating orally
- Start SC Insulin
- Continue oral hydration
- Calculate fluid requirement
- Correct fluid deficit over 24-48 hours
- Add KCl 40 mmol/L
No improvemnt
Start regular insulin infusion at 0.05 to 0.1 Units/kg/hr starting after 1 hour after fluids initaited
Monitor
Hourly blood glucose, input & output,neurological status, 2-4 hourly electrolytes, cardiac monitoring
Acidosis not improving
Blood glucose ≤ 300 mg/dL Or
Blood glucose fall ≥ 90mg/dL per
hour
Signs of Neurological
deterioation
- Haedache
-Irritability
- Slowing heart rate
Re-evaluate
- IV Fluid Calclations
-Reduced conscious level
- Change IVF to 0.45% - 0.9%
saline, add Dextrose (5-12.5%)
-Specific neurological signs
- Insulin delivery & dose
- Consider sepsis
Improved
Cliically well, tolerating orally, ketoacidoss
has resolve
Transition to SC insulin
Fig. 2 Overview of DKA management [12]
Exclude hypoglycemia;
Consider Cerebral Edema
Type 1 Diabetes Mellitus
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seizures, and, in severe cases, coma or death. Young children may display nonspecific symptoms such as fussiness or lethargy, complicating recognition [14].
For conscious individuals with blood glucose ≤70 mg/dL, 15 grams of rapid-­
acting carbohydrate (e.g., glucose tablets, juice) is the preferred treatment. Blood
glucose should be rechecked after 15 min, and the process repeated if necessary.
Once blood glucose is above 100 mg/dL, a snack or adjustment in insulin dose may
prevent recurrence. Glucagon is used for severe hypoglycemia, when oral carbohydrate intake is not possible. Available options include:
• Intramuscular/subcutaneous glucagon, 0.5 mg for children <20 kg and 1 mg
for ≥20 kg
• Nasal glucagon, 3 mg for patients >4 years of age
• Mini-dose glucagon, 10 μg per year of age (up to 150 μg)
Caregivers should be trained in the use of glucagon and always have access to
it [15].
Severe hypoglycemia can result in transient neurological symptoms or long-term
cognitive deficits, particularly in the very young children. Prolonged episodes may
produce focal neurological signs. Although permanent damage is uncommon, the
psychological impact of severe episodes can lead to reluctance in adherence to tight
glycemic control [4].
Patients and caregivers must be educated in recognizing early symptoms, common triggers, and appropriate management. Reviewing hypoglycemic patterns at
each visit and educating school staff and other caregivers is essential [15].
Dawn Phenomenon and Somogyi Effect
The dawn phenomenon is a physiological increase in early morning blood glucose,
typically due to nocturnal surges in counter-regulatory hormones—especially
growth hormone and cortisol—that enhance insulin resistance. Since individuals
with T1DM lack compensatory endogenous insulin release, this rise in hormones
leads to fasting hyperglycemia, necessitating careful basal insulin adjustment [5].
The Somogyi effect, on the other hand, represents a hypothetical rebound hyperglycemia following unrecognized nocturnal hypoglycemia. Counter-regulatory hormones, particularly glucagon and epinephrine, drive hepatic glucose release in
response to low blood glucose levels. While once commonly cited, this phenomenon is now believed to be relatively uncommon [11].
The Somogyi effect is frequently mistaken for the dawn phenomenon, a natural
early-morning rise in blood sugar caused by hormonal shifts. However, a key distinction is that the Somogyi effect follows a period of low blood sugar (hypoglycemia), whereas the dawn phenomenon does not. Accurate diagnosis requires careful
blood glucose monitoring. Measuring blood sugar levels around 2 or 3 a.m. can help
detect whether nighttime hypoglycemia is present, indicating the Somogyi effect.
Management strategies include modifying the timing or dosage of basal insulin,
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preventing overnight hypoglycemia, and ensuring bedtime carbohydrate intake
when appropriate [11].
Chronic Complications
Chronic complications of T1DM typically develop over several years and are primarily related to the damaging effects of long-term hyperglycemia on blood vessels.
These can be broadly categorized into microvascular and macrovascular complications. The risk of these complications increases with the duration of diabetes and is
largely influenced by the presence of co-morbidities, like hypertension and dyslipidemia, and genetic predisposition. Table 2 summarizes the recommended screening schedule for these complications [15].
Table 2 Screening guidelines for complications and associated conditions [15]
Condition
Thyroid
disease
Celiac
disease
Initial test
At diagnosis
At diagnosis
Hypertension At diagnosis
Frequency
Every 1–2 years, or
sooner if symptoms
Within 2 years and again
at 5 years or sooner if
symptoms or first-degree
relative with Celiac
disease
Each visit
Dyslipidemia At diagnosis if age ≥2 years, once Annually if abnormal,
else every 3 yearly
glucose control is established. If
normal subsequent screening
between 9 and 11 years of age
Annually
Nephropathy At puberty or ≥10 years of age,
whichever is earlier if
T1DM > 5 years
Neuropathy
Retinopathy
At puberty or ≥10 years of age,
whichever is earlier if
T1DM > 5 years
At puberty or ≥11 years of age,
whichever is earlier if T1DM
>3–5 years
Annually
Every 2–4 year
Test
TSH, thyroid
antibodies
Anti TTG-Ig A
and IgG
BP ≥90% for
age, sex, height
on 3 separate
occasions
Fasting lipid
profile
Early morning
urine albumin or
spot urine
albumin-to-­
creatinine ratio
Detailed foot
exam
Dilated eye
exam
TSH Thyroid stimulating hormone, Anti TTG-Ig A and IgG anti-tissue transglutaminase antibodies
of IgA and IgG
Type 1 Diabetes Mellitus
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Microvascular Complications
1. Diabetic Retinopathy
Diabetic retinopathy (DR) causes progressive vision loss and is the leading cause
of new blindness in adults aged 20–74 years. DR is classified into two main categories: non-proliferative diabetic retinopathy and proliferative diabetic retinopathy [14].
The ADA recommends that children and adolescents with T1DM, screening for
DR should begin 3–5 years after diagnosis, once the child is ≥11 years of age or has
entered puberty, whichever occurs first. Subsequent assessments are typically done
every 2 years, or annually if abnormalities are detected or risk factors increase [15].
2. Diabetic Nephropathy
Diabetic nephropathy (DN) is one of the most common and severe complications
of T1DM, typically developing 5–15 years after diagnosis. DN affects 20–40% of
individuals with diabetes and is the leading cause of end-stage renal disease.
Albuminuria is the hallmark of DN and reflects glomerular injury. Screening is vital
as DN is often asymptomatic until advanced stages. Annual urine albumin-to-­
creatinine ratio (ACR) is recommended starting at 10 years of age or onset of
puberty, or after 5 years of diagnosis, whichever comes first [15].
3. Diabetic Neuropathy
Diabetic neuropathy encompasses a spectrum of nerve disorders in diabetes,
with distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathy
(DAN) being the most common. DPN typically presents in a stockings-gloves pattern affecting extremities leading to symptoms like pain, numbness, tingling, and
loss of sensations, while DAN can involve cardiovascular, gastrointestinal, genitourinary, and sudomotor systems. In children and adolescents with T1DM, yearly
comprehensive foot examination should begin at 10 years of age or puberty or
5 years after diagnosis, whichever comes first [15].
Macrovascular Complications
Cardiovascular diseases (CVD) include coronary artery disease, cerebrovascular
disease, and peripheral vascular disease. In individuals with T1DM, pathophysiological mechanisms involve chronic hyperglycemia-induced endothelial injury and
vascular inflammation, leading to atherosclerosis. Although macrovascular complications rarely manifest during childhood and adolescence, subclinical CVD is often
detected in youth in studies evaluating carotid intima media thickness [5].
The ADA advises monitoring blood pressure at every visit, while a fasting lipid
profile should be done in children 10 years of age or older, once glycemic control
has been established [15].
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ther Associated Conditions
O
Several autoimmune diseases have a higher prevalence among individuals with
T1DM compared to the general population. Autoimmune thyroid disease is among
the most prevalent, with up to 25% of children and adolescents with T1DM exhibiting thyroid antibodies and clinical hypothyroidism developing in approximately
15–20% [4].
Celiac disease is diagnosed in 4–10% of pediatric patients with T1DM compared
to ~1% in the general population [4].
Addison disease, while less common, affects an estimated prevalence of 0.5–1%
in this population and can lead to considerable morbidity if not promptly recognized [4].
Other autoimmune conditions, like autoimmune hepatitis and autoimmune gastritis, are rare but should be considered in the appropriate clinical context [4].
Clinical guidelines recommend screening for autoimmune comorbidities soon
after the diagnosis of T1DM and periodically, thereafter, with the frequency and
extent of testing guided by symptoms, risk factors, and initial findings [15].
Management
Goals of Therapy: The primary goals of the management of T1DM in children and
adolescents are [11]:
•
•
•
•
•
Optimize glycemic control
Prevent acute complications
Minimize the risk of long-term complications
Promote normal growth and development
Support psycho-social well-being
Insulin Therapy
The mainstay of management in T1DM is insulin therapy. Since individuals with
T1DM have absolute insulin deficiency, replacement with exogenous insulin is
essential for survival and metabolic control. Insulin therapy has undergone a remarkable evolution, from the initial extraction of animal insulin to the development of
insulin analogs and advance delivery systems [16].
Goals of Insulin Therapy
Insulin replacement should be initiated as soon as possible after diagnosis with the
immediate goal to correct any metabolic decompensation (like DKA) and begin the
process of establishing and maintaining euglycemia [17].
The primary aim is to mimic physiological insulin action as closely as possible
to achieve optimal metabolic control. This is important not only in preventing acute
complications, like DKA and hypoglycemia, but also in reducing the long-term risk
Type 1 Diabetes Mellitus
363
of development of micro- and macro-vascular complications. Furthermore, therapy
should support normal growth and development in children and adolescents while
minimizing the burden of disease on their daily lives [17].
Recent guidelines from ISPAD and ADA provide specific targets to guide insulin
therapy. These include:
1. Glycemic Targets:
1. HbA1C: A target of 6.5% is recommended if it can be achieved safely without significant hypoglycemia. For many a more lenient target of 7% would be
more appropriate to balance glycemic control with safety and feasibility [18].
2. Time in Range (TIR): The goal is to spend 70% of the time with glucose
levels between 70 and 180 mg/dL. More stringent targets will be appropriate
for some, while less stringent targets will be necessary for some, particularly
the younger children or those with frequent hypoglycemia [18].
3. Glucose Targets:
(a) Pre-meal capillary glucose 80–130 mg/dL
(b) Post-meal (2 h) capillary glucose less than 180 mg/dL
2. Minimizing Hypoglycemia:
A critical goal in the management of T1DM is to reduce the frequency and
severity of hypoglycemia. It can impair neurocognitive development, particularly in young children, and is a significant source of anxiety and stress to
patients and families [17].
3. Supporting Normal Growth and Development: Adequate insulin replacement is
essential for normal growth and development in children with T1DM. Persistent
under-insulinization may lead to poor growth and delayed puberty [17].
4. Improving Quality of Life: The management plan should be designed to integrate
smoothly into the daily lives of the patient and their families, with the goal to
minimize disruption to schooling and other social engagements [17].
These goals are dynamic and should be individualized based on the child’s age,
developmental stage, duration of diabetes, the presence of comorbidities, and the
family’s capacity to manage the therapy [15].
Types of Insulin
A variety of insulin preparations are available, differing primarily in their pharmacokinetic and can be broadly categorized into mealtime and basal insulin, as
described in Table 3 [17].
1. Mealtime insulins: These are designed to cover glucose loads following meals.
This group includes:
I. Regular (short-acting) insulin: This has a slower onset and prolonged peak
compared to the newer analogs, necessitating administration at least 30 min
before mealtime. The slower onset and longer duration can increase the risk
of post-prandial hypoglycemia as well as late hypoglycemia. While historically, it was the mainstay for prandial insulin coverage, in current practice,
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Table 3 Insulin analogs’ action profile
Bolus or prandial insulin
Ultra rapid acting
Fast-acting insulin aspart
Fast-acting insulin lispro
Rapid acting
Insulin aspart
Insulin glulisine
Insulin lispro
Short acting
Regular human insulin
Basal insulin
Intermediate acting
NPH insulin
Long acting
Insulin glargine
Insulin deltimir
Insulin degludec
Onset of action
Peak effect
Duration
15–20 min
15–17 min
1.5–2.2 h
2–3 h
5–7 h
5–7 h
15 min
12–30 min
15–30 min
1–3 h
1.5 h
1–2 h
3–5 h
5.3 h
5h
30–60 min
2–4 h
5–8 h
2–4 h
4–12 h
12–24 h
2–4 h
1–2 h
30–90 min
None
None
None
22–24 h
20–24 h
48 h
Data from Cengiz et al. [17]
its clinical use is mainly confined to specific situations, like intravenous
insulin infusion during hospitalizations [17].
II. Rapid-acting insulin analogs are the preferred choice for meal-time boluses
due to the rapid onset and short duration of action, closely resembling the
physiologic insulin response to food intake [17].
III. Ultra rapid-acting insulins: Newer formulations of aspart and lispro are
engineered for even faster absorption, potentially beneficial for controlling
post-meal glucose spikes and to be used with insulin pumps and automated
insulin delivery devices [13].
2. Basal Insulins: These provide background coverage to regulate blood glucose
levels between meals and overnight. This category includes:
I. Intermediate-acting insulin: NPH is an older, intermediate-acting insulin formulation with a longer duration but less predictable peak and hence a higher
risk of hypoglycemia. Due to this, it’s no longer preferred to be used in the
pediatric population [17].
II. Long-acting insulins: The long-acting analogs (such as glargine and detemir)
and ultra-long-acting analogs (such as degludec) offer stable and prolonged
action without a pronounced peak, reducing the risk of hypoglycemia and
making them a better choice for basal coverage [13].
3. Pre-mixed Insulins: The pre-mixed insulins contain a combination of rapid- or
short-acting insulin and intermediate insulin in various proportions. These are
used in the fixed dose regimens. While they simplify the injection routine, they
offer less flexibility in adjusting basal and bolus doses individually and hence are
not a preferred choice in the pediatric population where tailoring doses to meals
and activity is often required [17].
Type 1 Diabetes Mellitus
365
I nsulin Regimens and Delivery Systems
The two most commonly used insulin regimens include the basal-bolus regimen and
the fixed-dosed regimen. Insulin can be administered through several methods, and
the two primary approaches are the multiple daily injections (MDI) and the continuous subcutaneous insulin infusion (CSII), commonly known as insulin pumps [17].
1. Multiple Daily Injections (MDI) involve administering insulin via subcutaneous
injection several times a day. These are relatively low cost compared to insulin
pumps, do not require an indwelling catheter, and allow for the use of different
insulin types for basal and bolus needs. However, MDI requires multiple injections daily and can be less precise compared to insulin pumps for insulin delivery [13].
I. Basal Bolus Regimen: This is the most common MDI approach and aims to
mimic physiological insulin secretion. This includes:
(a) Basal insulin—a long-acting insulin given 1–2 times a day to provide
background insulin coverage to maintain blood glucose levels between
meals and overnight.
(b) Bolus insulin—a rapid-acting insulin administered with each meal to
manage the glucose load. The dose of basal insulin is calculated based on
the amount of carbohydrate in the meal and the pre-meal blood glucose
level. Additional bolus doses of rapid-acting insulin can also be used to
correct high blood glucose levels between meals [17].
II. Fixed-Dose Regimen: This regimen consists of two injections daily of a mixture of rapid−/short- and intermediate-acting insulin. The limited flexibility
of the fixed-dose regimen presents significant challenges to align insulin
delivery with the day-to-day variability in dietary intake and physical activity
in children and adolescents. However, it may be considered temporarily in
cases with suboptimal compliance to reduce injection burden and support
engagement with treatment [17].
2. Continuous Subcutaneous Insulin Infusion (CSII) or Insulin Pump uses a small,
computerized device that delivers insulin from the reservoir through a small cannula inserted under the skin. The CSII offers precise insulin delivery without the
need for multiple injections. However, these systems are expensive and require
education for significant patient and caregiver regarding the management of
device malfunctions, infusion site issues, and troubleshooting [19].
I. Basal insulin delivery—The pump delivers a programmed basal rate of insulin throughout the day.
II. Bolus insulin delivery—The user programs the pump to deliver a bolus dose
of insulin, based on the meal contents and the pre-meal blood glucose.
Correction boluses can also be administered when needed.
III. Integration with continuous glucose monitoring (CGM)—The newer generation pumps are now integrated with the CGM system. This allows for
features like real-time glucose monitoring with alerts for high and low glucose levels, and in more advanced systems, automated adjustments of insulin delivery (hybrid closed-loop systems) [19].
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I nsulin Dosing and Adjustments in Special Circumstances
Precise insulin dosing is critical for optimal glycemic control. Insulin dosing is
highly individualized based on age, weight, activity level, carbohydrate intake, and
insulin sensitivity. It requires frequent adjustments based on monitoring with the
goal of maintaining glycemic control while minimizing the risk of hypoglycemia [17].
• The initial total daily dose (TDD) of insulin may vary from 0.4 to 1.2 units/kg/
day based on several factors including age, pubertal stage, and presence or
absence of DKA at diagnosis.
• Basal insulin accounts for 30–50% of the TDD and is usually given as a long-­
acting insulin in one to two divided doses.
• A bolus dose of rapid-acting insulin is given before every meal and snack. This
dose is calculated based on the anticipated carbohydrate amount to be ingested
and the pre-meal blood glucose level, using the insulin to carbohydrate ratio
(ICR) and the insulin sensitivity factor (ISF), also referred as correction factor
(CF) [11].
– The insulin to carbohydrate ratio (ICR) represents the units of insulin required
to cover a certain amount of carbohydrates. The “500 rule” is used to calculate
the ICR by dividing 500 by the estimated TDD [11].
– The insulin sensitivity factor (ISF) or correction factor (CF) reflects how
much 1 unit of insulin is expected to lower blood glucose. The “1800 rule” is
used to calculate the CF by dividing 1800 by the estimated TDD [11].
– CF can also be used to control hyperglycemia between meals.
Sick-Day Management
Acute illness in individuals with T1DM presents an increased risk of metabolic
decompensation. Physiologic stress during infections or other illnesses results in the
release of counter-regulatory hormones that antagonize insulin actions, promote
gluconeogenesis and ketogenesis, and elevate blood glucose levels. If unrecognized
or inadequately managed, even common viral illnesses can rapidly progress into
serious metabolic emergencies [11].
The core principle of diabetic sick-day management is to maintain insulin administration, monitor glucose and ketone levels frequently, and ensure adequate hydration. An outline of sick-day management is given in Table 4 [17].
A structured sick-day plan with clear guidance on when and how to administer
supplemental insulin, how to interpret ketone and glucose results, and when to seek
help are central to safe diabetes management during illness [17].
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Table 4 Diabetes sick-day rules and medical red flags [11]
Management steps:
1. Check blood glucose every 3–4 h
2. Administer correction doses of rapid-acting insulin every 3–4 h, as needed
3. Monitor ketones (in urine/blood) every 3–4 h
4. Encourage fluid intake ≈ 30 ml/year of age/hour
5. Adjust fluid type based on blood glucose level:
>200 mg/dL: give sugar-free fluids
140–200 mg/dL: give a mix of sugar-free and sugar-containing fluids
<140 mg/dL: give sugar-containing fluids
Seek immediate medical attention if:
Persistent vomiting
Moderate-to-large ketones
Rapid breathing or signs of respiratory distress
Drowsiness or altered mental status
Inability to carry out sick-day plan
Glycemic Monitoring and Goals
Regular glucose monitoring is essential for effective management. The dynamic
insulin needs during growth, puberty, illness, physical activity, and psychosocial
stressors necessitate frequent and reliable glucose assessment.
elf-monitoring of Blood Glucose (SMBG)
S
SMBG using finger-prick capillary testing has long served as the primary modality
for glucose monitoring. The recommended frequency includes measurements
before meals, at bedtime, and during any periods of suspected hypoglycemia, illness, or physical activity. Despite its utility, SMBG has its inherent drawbacks such
as pain, inconvenience, and episodic glucose data resulting in inability to detect
trends or nighttime hypoglycemia [20].
ontinuous Glucose Monitoring (CGM)
C
Advancement in diabetes technology has shifted the paradigm toward CGM systems. These devices assess interstitial glucose every few minutes, generating real-­
time profiles that provide a more dynamic view of glucose control than SMBG
alone. CGM can be used in real time (rtCGM) or intermittently scanned format
(isCGM) [20].
CGM enables trend analysis and predictive alerts, thereby enhancing preemptive
decision-making by families and clinicians. Moreover, data from CGM has shifted
glycemic management goals from sole reliance on HbA1C to a more nuanced
appraisal of glucose patterns. Table 5 summarizes the key parameters of CGM.
When CGM is integrated with insulin pumps, it allows automated insulin adjustments based on real-time glucose trends. These systems have been shown to improve
glycemic control and hence are strongly recommended in children and
adolescents.
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Table 5 CGM monitoring parameters and goals [18]
Time in range (TIR): Percentage of time glucose is within 70–180 mg/dL; the recommended
target is >70%
Time below range (TBR): Percentage of time glucose is <70 mg/dL, which should be <4% with
<1% below 54 mg/dL
Time above rage (TAB): Percentage of time glucose is >180 mg/dL: should constitute <25%
Glucose management indicator (GMI): An estimate of HbA1C derived from CGM data
Glycemic variability: ideal coefficient of variations should be <36%
While CGM adoption is increasing, barriers remain, including device cost,
access inequality, user fatigue, and occasional skin irritation or sensor adhesion
issues. Successful implementation requires structured education, consistent data
review, and support from the diabetes care team [20].
Adjunctive Medical Therapy
While insulin remains the cornerstone therapy for individuals with T1DM, adjunctive non-insulin pharmacological agents have emerged as potential options to
improve metabolic outcomes and reduce treatment burden. Table 6 provides an
overview of some of these agents. Each of these agents target different aspects of
glucose regulation and energy metabolism. However, their role in pediatric diabetes
care remains limited due to regulatory restrictions, side effect profiles, and lack of
robust long-term evidence. Until larger, controlled pediatric trials are available, the
use of these agents should remain cautious, individualized, and closely monitoredalways complementing, not replacing, intensive insulin therapy.
Nutrition Therapy
Nutritional therapy is a crucial part of T1DM management, aiming to optimize glycemic control, promote normal growth, and prevent complications. Key principles
of medical nutrition therapy include:
• Individualized meal planning: Effective nutritional management requires a
highly tailored approach, considering patient’s familial dietary patterns, cultural
and religious influences, daily schedules, physical activity levels, and the cognitive and self- management capabilities of the patient and caregivers [15].
Consistent mealtimes also help in maintaining optimal glycemic control, reducing the risk of hypoglycemia at the same time [5]. Regular assessments by a
registered dietitian are essential to accommodate changes in food availability,
preferences, and developmental needs.
• Macronutrients Composition: A common misconception in the management of
T1DM is the belief that restricting caloric intake or eliminating certain foods is
necessary. This belief often stems from dietary approaches used in type 2
Type 1 Diabetes Mellitus
369
Table 6 Adjunctive therapies in T1DM [17]
Agent
Pramlintide
(Amylin
analog)
SGLT-2
inhibitors
Metformin
GLP-1
receptor
agonists
Mechanism of
action
Slows gastric
emptying
Suppresses
glucagon
Enhances satiety
Decreases
hepatic
Glucose
production
Promote renal
glucose
excretion
Benefits
Modest
HbA1C
reduction
↓ postprandial
glucose
↓ weight
↓ insulin dose
↓ HbA1C
↑TIR
↓ Insulin dose
↓ weight
Improves insulin ↓ weight
sensitivity
↓ insulin
Decreases
requirement
hepatic glucose Improves lipid
output
profile
Increase insulin ↓ weight
secretion
↓ insulin dose
Suppress
Modest ↓ in
glucagon
HbA1C
Delay gastric
emptying
Promote satiety
Limitations
High cost
Risk of
hypoglycemia
Administered as
pre-meal SC
injections
Regulatory status
FDA approved
(adults)
Not EMA or
pediatrics
↑ risk of euglycemic
DKA
↑ urogenital
infections
Minimal effect on
HbA1C
Gastrointestinal side
effects
Not approved for
T1DM
EMA label
withdrawn
Approved for
T2DM and PCOS
>10 years of age
Off-label use in
T1DM
Approved for
T2DM and obesity
>10 years of age
Gastrointestinal side
effects
diabetes or historical insulin regimens that employ fixed insulin doses, necessitating strict meal patterns. Current recommendations emphasize that individuals
with T1DM should follow a healthy, balanced diet comparable to that recommended for the general population. A commonly acceptable macronutrients distribution is approximately 50% of calories from carbohydrates, 30% from
proteins, and 20% from fats, limiting saturated and trans-fats [17].
• Carbohydrate choices should emphasize complex carbohydrates that are rich in
dietary fibers and exhibit a low glycemic index, while minimizing intake of
added sugars.
• Carbohydrate Counting: Accurate carbohydrate counting is important to match
prandial insulin doses with the carbohydrate intake, enabling better postprandial
glycemic control. While precision is helpful, minor deviations (within 10 grams
or 15% of carbohydrate amount) are generally well tolerated [5]. For patients
with limited numeracy skills, prandial insulin dosing can be effectively guided
by consistent meal patterns and experiential knowledge.
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Physical Activity and Exercise
Regular physical activity is essential for the physical, emotional, and social well-­
being of children and adolescents with T1DM.
Current recommendations encourage children and adolescents with T1DM to
engage in at least 60 min of moderate-to-vigorous intensity aerobic activity daily,
with muscles and bone- strengthening exercises at least 3 days per week [15].
However, exercise presents unique glycemic challenges. The interplay of exogenous insulin and the exercise-induced hormonal responses, such as increases in insulin
sensitivity and counter-regulatory hormones, can lead to both hypoglycemia (during
and hours after exercise) and hyperglycemia, particularly with high-­intensity anaerobic
activity [4]. To minimize glycemic excursions during physical activity, patients and
their families should be counselled on the key strategies outlined in Table 7.
Despite these challenges, regular physical activity should be encouraged and
supported as an integral part of T1D management.
Psycho-social Support
The psycho-social impact of T1DM is substantial, affecting not only the child but
the entire family. In addition to the physiological burden of the disease, the demands
of daily glucose monitoring, insulin administration, dietary management, and the
constant vigilance required to prevent complications can contribute significantly to
psychosocial stress [15].
Children and adolescents with T1DM are at increased risk of developing psychological co-morbidities, particularly depression, anxiety, and eating disorders, when
compared to their peers without diabetes. The initial phase following the diagnosis
can be particularly challenging, requiring families to make major lifestyle adjustments. Adolescents may experience phases of denial, non-acceptance, or treatment
of fatigue leading to suboptimal adherence to therapy [5].
Family involvement is central to effective T1DM management. Supportive, communicative family environments that foster shared responsibility and age-­appropriate
autonomy are associated with better metabolic outcomes and psychological well-­
being. Family-based interventions, such as goal setting, self-monitoring, positive
reinforcement, and collaborative problem-solving, have demonstrated efficacy in
improving both psychological adaptation and glycemic control [2].
Table 7 Blood glucose management during physical activity [2]
Perform frequent glucose monitoring before, during, and after exercise
A pre-exercise blood glucose target range of 90–250 mg/dL is generally considered safe
Adjust insulin dosing, preferably by reducing prandial or basal insulin, rather than increasing
carbohydrate intake
Ensure ready access to rapid-acting carbohydrates to treat hypoglycemia
Avoid strenuous exercise when glucose levels are markedly high and ketones are present, as
this may precipitate ketoacidosis due to increased counter-regulatory hormones
Type 1 Diabetes Mellitus
371
Routine psychosocial screening should be an integral part of diabetes care. A
multidisciplinary approach, incorporating diabetes educators, psychologists, social
workers and psychiatrists, is essential. Psychosocial support should include counselling, structured education programs, peer support, and access to mental health
services when needed. These interventions should be developmentally appropriate
and culturally sensitive to ensure optimal engagement and effectiveness.
Technologies in T1DM Management
The care of children and adolescents with T1DM has evolved rapidly in recent
years, driven by advancements in diabetes technology. These tools have significantly enhanced the precision of glucose monitoring and insulin delivery, enabling
tighter glycemic control while minimizing the risk of hypoglycemia.
1. Continuous Glucose Monitoring (CGM):
These systems have transformed glucose surveillance from isolated point-in-­
time measurements to comprehensive glucose profiling, improving decision-­
making for patients and healthcare providers alike [20].
2. Insulin Pump Therapy (Continuous Subcutaneous Insulin Infusion—CSII):
Insulin pump delivers rapid-acting insulin via a programmable device, allowing adjustable basal rates and bolus dosing to match physiological needs. Modern
pumps integrate bolus calculators, infusion history logs, and wireless communication with CGM systems [19].
3. Automated Insulin Delivery (AID) Systems:
These are often referred to as a hybrid-closed-loop system or artificial pancreas. These systems combine a CGM, an insulin pump, and a sophisticated
control algorithm that automatically adjusts basal insulin delivery based on glucose trends.
Most currently available systems are hybrid in nature, requiring manual input
for mealtime boluses but automated basal insulin adjustments. Current guidelines recommend offering AID systems to eligible children and adolescents,
highlighting their safety and efficacy across all age groups [19].
4. Smart Insulin Pens and Connected Devices:
These represent an important innovation for patients using MDI. These
devices digitally record insulin doses, timings, and injection history, transmitting
data to mobile platforms for analysis. These systems offer features like dose
reminders, missed dose alerts, bolus calculators, and other decision support
tools [19].
5. Mobile Health and Diabetes Apps:
Mobile health technologies play a supportive role in diabetes self-­management.
These apps assist with carbohydrate counting, dose calculations, data logging,
and remote monitoring. Many integrate with CFM or smart pen data, offering a
unified interface for analysis and feedback [16].
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Telemedicine platforms, particularly accelerated during the COVID-19 pandemic, have improved access to specialized care and education for families,
regardless of geographic location.
6. Emerging and Investigational Technologies:
Emerging technologies such as dual-hormone closed-loop systems (delivering insulin and glucagon), implantable CGMs, and wearable non-invasive sensors are currently under clinical evaluation. Advances in algorithm learning,
personalized machine learning models, and artificial intelligence (AI)-driven
decision support tools promise even more individualized and adaptive diabetes
care in the near future [19].
Disease-Modifying Therapies
In recent years, research has increasingly focused on disease-modifying therapies
(DMTs) that aim to preserve residual beta cell function and potentially alter the
disease trajectory. These therapies broadly fall into two categories: non-antigen-­
based immunotherapies and antigen-specific strategies [21].
Non-antigen-Based Immunotherapy
These therapies target key immune pathways responsible for pancreatic islets
inflammation and destruction. Teplizumab, an anti-CD3 monoclonal antibody, is
the first FDA-approved agent that has shown promise in delaying progression from
the pre-symptomatic stage. Similarly, Rituximab (anti-CD20) and TNF-a inhibitors
like Etanercept and Golimumab have demonstrated short-term benefits in preserving C-peptide secretion and reducing insulin requirements when administered soon
after diagnosis. Other candidates, like Janus kinase (JAK) inhibitors and co-­
stimulatory blockade agents, are undergoing clinical evaluation with variable outcomes [21].
Antigen-Specific Approaches
These strategies aim to induce immune tolerance to beta-cell antigens such as insulin and GAD-65. Despite theoretical promise, clinical trials with a vaccine formulation combining the protein glutamic acid decarboxylase 65 with aluminum
hydroxide (GAD alum), oral/ nasal insulin, and proinsulin-based vaccines have generally failed to demonstrate sustained beta-cell preservation or metabolic improvement [21].
Pancreatic Replacement Therapies
This approach aims to restore endogenous insulin production by reintroducing functional beta cells, with the aim to reduce or eliminate the need for exogenous insulin
and improve long-term metabolic outcomes.
Type 1 Diabetes Mellitus
373
• Pancreatic Islet Cells Transplantation: It involves the infusion of pancreatic
islets isolated from deceased donors into the portal vein of a recipient. Some
recipients achieve partial-to-complete insulin independence, particularly in the
short term. However, the benefits are often temporarily limited by donor scarcity,
immune rejection, and complications associated with chronic immunosuppression [5].
• Stem Cell-Derived Pancreatic Beta-Cell Replacement: Pluripotent stem cells,
either embryonic or induced, can be differentiated into insulin-producing beta-­
like cells. Studies have demonstrated the ability of these cells to restore normoglycemia in animal models of T1DM. Clinical trials are underway to evaluate
their safety and efficacy in humans [5].
Encapsulation technology aims to protect these transplanted cells from immune
attack without the need for systemic immunosuppression. Various bioengineered
devices, such as microencapsulation capsules and semi-permeable membranes,
are being explored to create an immune-privileged environment [21].
• Pancreatic Organoids and Tissue Engineering: Emerging techniques involve
generating organoids from progenitor cells or patient-derived stem cells. These
organoids mimic the 3D architecture and function of the pancreas. Although still
experimental, this approach may offer individualized therapy, with reduced
immunological complications, especially if autologous cells are used [6].
These innovative therapies mark a fundamental transition in the management of
T1DM from passive insulin replacement to active beta-cell restoration and protection, holding the potential to alter the disease course or provide a functional
cure [5].
Conclusion
T1DM in children and adolescents is a lifelong autoimmune condition with profound clinical, psychological, and societal implications. Despite remarkable progress in understanding its pathogenesis and advances in management, the disease
continues to present complex challenges due to its early onset, lifelong trajectory,
and continuous demand for precise and adaptive care.
While exogenous insulin therapy remains the cornerstone of therapy, the growing understanding of pathogenesis has significantly enhanced both diagnostic accuracy and therapeutic precision. In recent years, T1DM management has been
revolutionized by advances in diabetes technology. Continuous glucose monitoring
systems, sensor augmented insulin pumps, and automated insulin delivery platforms have dramatically improved glycemic control, reduced the risk of acute and
chronic complications, and promoted greater patient autonomy and quality of life.
However, optimal management of T1DM extends beyond technology. A comprehensive patient-centered approach, emphasizing individualized nutritional strategies, regular physical activity, robust psychosocial support, and continuous diabetes
education, is vital. In pediatric populations, this also involves empowering families,
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addressing developmental transitions, and integrating care across school, home, and
healthcare environments.
Looking ahead, the future of T1DM care lies not only in enhanced disease management but also in the possibility of modifying disease progression itself. Advances
in immunomodulatory therapies, targeted at preserving residual pancreatic beta-cell
function, promise delaying or even halting the autoimmune process. At the same
time, regenerative medicine and pancreatic beta-cell replacement strategies are
being actively explored.
Yet, ensuring these advancements benefit all populations requires a commitment
to equity in access and implementation. The disparities in access to even basic diabetes care across the globe, particularly in LMICs, threaten to widen the gap in
health outcomes. Ensuring that innovations reach all populations will require global
collaboration and sustainable policy frameworks.
In conclusion, T1DM in children and adolescents exemplifies the challenges of
managing a lifelong autoimmune disease in a dynamically changing clinical landscape. While insulin replacement remains foundational, the integration of emerging
therapies, technological advances, and personalized care strategies is redefining
what is possible. With continued research, inclusive implementation, and integrated
care delivery, the vision of transforming T1DM from a lifelong burden into a more
manageable, potentially modifiable, and ultimately curable condition is becoming
an increasingly attainable goal.
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Addison’s Disease
Bhagwan Das, Tehseen Fatima, and Aisha Sheikh
Introduction
Addison’s disease is named in honor of Dr. Thomas Addison, who initially described
it in 1855 [1]. It is a rare autoimmune disease of the adrenal glands characterized by
immune-mediated destruction of bilateral adrenal glands and deficiency in the production of endocrine hormones by the adrenal cortex, including aldosterone, cortisol, and androgens.
The most common manifestation of Addison’s disease is the gradual onset of
hormonal deficiency symptoms, and due to the nonspecificity of symptoms, diagnosis is often delayed [2]. Several cases are diagnosed to be adrenal insufficient after
their first presentation in an emergency as an adrenal crisis. An adrenal crisis is a
medical emergency; a high index of suspicion, along with a low threshold for testing, is necessary for timely identification. The diagnosis is usually made by demonstrating low serum cortisol and aldosterone levels, elevated renin levels, and a
failure of cortisol response after corticotropin administration. Disease management
focuses on optimum hormone replacement, patient education regarding sick days,
and preventing adrenal crises.
This chapter aims to elucidate the underlying pathophysiology, including autoimmune destruction of the adrenal cortex, infections, and other less common etiologies. It aims to describe the clinical manifestations, ranging from nonspecific
symptoms, such as fatigue and weight loss, to life-threatening adrenal crises.
Furthermore, the chapter explores diagnostic strategies, including hormonal assays
B. Das (*)
Aster Sanad Hospital, Riyadh, Saudi Arabia
T. Fatima
Russells Hall Hospital, Dudley, West Midlands, UK
A. Sheikh
Aga Khan University Hospital, Karachi, Pakistan
e-mail: aisha.sheikh@aku.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_14
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and imaging studies, as well as evidence-based approaches to both acute and long-­
term management. Emphasis will be placed on patient education, stress-dose steroid
protocols, and the importance of timely recognition and treatment to prevent morbidity and mortality.
Epidemiology
Addison’s disease was historically thought of as a rare condition with a prevalence
of around 40–70 cases per million [3], but recent data from Europe reported increasing incidence and prevalence [4, 5]. Studies from Iceland show a prevalence of 22.1
per 100,000 population, whereas in Norway, it was 144 per million [6]. The incidence is approximately 4/100,000 people annually [6]. Addison’s disease is more
common in women, which usually manifests between the ages of 30 and 50 [5, 7, 8].
Risk Factors
Autoimmune adrenal insufficiency (AAI) may be familial or nonfamilial. It is more
likely familial when it occurs with other organs or endocrine gland disorders.
Likewise, having a family history of Addison’s disease or other autoimmune conditions, like autoimmune polyendocrinopathy syndromes (APS), increases the risk [9].
Research has indicated that AAI is linked to some major histocompatibility complex (MHC) genotypes, including DR3-DQ2 and DR4-DQ8 [4, 10–12]. Furthermore,
it has been demonstrated that individual susceptibility to AAI is increased by polymorphisms in cytotoxic T-lymphocyte antigen 4 (CTLA4), protein tyrosine phosphatase, non-receptor type 22 (PTPN22), class II transactivator (CIITA), and C-type
lectin domain family 16, member A (CLEC16A), which are similarly linked to
other autoimmune illnesses [12].
Pathophysiology
The adrenal cortex consists of three distinct zones.
The outer zone, known as the zona glomerulosa, secretes mineralocorticoids,
including aldosterone. The middle zone is the zona fasciculata, which secretes glucocorticoids like cortisol, while the inner zone is the zona reticularis, which secretes
androgens such as dehydroepiandrosterone (DHEA) [13].
The adrenal medulla secretes two hormones, epinephrine and norepinephrine.
Cortisol is the body’s primary stress hormone; its secretion is governed by the
hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus secretes
corticotropin-­releasing hormone (CRH), prompting the anterior pituitary gland to
release adrenocorticotropic hormone (ACTH), which stimulates the adrenal cortex
to produce cortisol [14]. The secretion of ACTH and CRH is suppressed by
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sufficient cortisol through a negative feedback mechanism (Fig. 1). The HPA axis
generally adheres to the circadian rhythm and releases cortisol in response to stress.
Cortisol increases blood glucose levels by increasing gluconeogenesis and
decreasing glycogen synthesis in the liver, inhibiting cellular glucose uptake, and
suppressing endogenous insulin secretion [15]. It also increases heart rate and blood
pressure and suppresses inflammation [16]. Its deficiency causes carbohydrate, fat,
and protein metabolism disturbances, leading to hypoglycemia and weight loss.
Aldosterone regulates blood pressure and the balance of salt and water in the
body by enhancing sodium and water reabsorption into the bloodstream and promoting potassium excretion via the kidneys [16]. Its deficiency results in a low
serum sodium concentration and a high potassium concentration. Urinary salt and
water loss cause volume depletion and hypotension and may lead to shock.
It is believed that both humoral and cell-mediated immunity play a role in
destroying the adrenal cortex as autoreactive circulating CD8+ and CD4+ T lymphocytes against 21-hydroxylase have been found in the patients along with autoantibodies [17, 18].
In Addison’s disease, steroidogenic enzymes in the adrenal cortex are identified
as self-antigens [19], and the autoimmune process slowly damages all three zones
of the adrenal cortex. This process is characterized by lymphocyte infiltration of the
adrenal parenchyma, followed by adrenal gland fibrosis and atrophy [20].
Fig. 1 Hypothalamic-­
pituitary-­adrenal axis
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Most patients have positive adrenal cortex antibodies (ACA) at diagnosis. The
cumulative disease risk in ACA-positive patients is 48.5% [21]. Anti-21-hydroxylase
antibodies were found in 86–95% [4, 20, 22], with some studies reporting antibody
positivity as high as 100% [8].
Antibodies could be detected several months to years before biochemical and
clinical evidence of the disease. A study following individuals with positive Anti-21-­
hydroxylase revealed that about 30% progressed to clinically overt adrenal insufficiency during five years follow-up [21].
Adrenal Insufficiency and Its Types
Adrenal insufficiency (AI) is a condition in which adrenal steroidogenesis is wholly
or partially compromised due to a defect in the HPA axis.
Primary adrenal insufficiency (PAI) refers to conditions where adrenocortical hormone production is impaired due to damage to the adrenal cortex.
Secondary adrenal insufficiency (SAI) is characterized by inadequate production of
ACTH from the pituitary gland, leading to a reduction in adrenal steroid
synthesis.
Tertiary adrenal insufficiency (TAI) refers to conditions in which inadequate CRH
from the hypothalamus causes decreased adrenal steroid production; this usually
occurs because of prolonged exogenous steroid therapy.
Causes of Adrenal Insufficiency
Addison’s disease is the predominant cause of PAI in the Western world, accounting
for approximately 70–80% of cases [2, 23]. It is characterized by autoimmune-­
induced adrenalitis [24]. This may occur in isolation or as part of one of the autoimmune polyglandular syndrome (APS), APS Type 1 or APS Type 2 [25]. Other causes
of PAI include various infections, malignancies, infiltrative diseases, and medications. Table 1 provides a comprehensive summary of multiple causes of PAI [6,
26, 27].
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Table 1 Causes of primary AI
A, Autoimmune:
Isolated AI
APS (type 1 and 2)
B, Infections:
Tuberculosis
Bacterial (Neisseria meningitides, Haemophilus influenza, Pseudomonas aeruginosa)
Fungi (histoplasmosis, pneumocystis jirovecii, blastomycosis)
Viruses (human immunodeficiency virus, herpes simplex, cytomegalovirus)
Syphilis
C, Malignancy:
Primary adrenal tumor
Metastasis (lungs, breast, stomach, colon)
Adrenal lymphoma
D, Hemorrhage or infarction:
Waterhouse-Friderichsen syndrome
Anti-phospholipid antibody syndrome
Disseminated intravascular coagulation
Trauma
Anticoagulant therapy
E, Infiltrative:
Hemochromatosis
Amyloidosis
Histiocytosis
F, Iatrogenic:
Bilateral adrenalectomy
F, Medication:
Ketoconazole, Itraconazole, fluconazole, Osilodrostat, Rifamin, Etomidate, Mitotane,
Metyrapone, immune checkpoint inhibitors
G, Other:
Congenital adrenal hyperplasia
Adrenoleukodystrophy
Congenital lipoid adrenal hyperplasia
Clinical Manifestations
The disease onset is variable, ranging from an insidious to a more acute presentation. An adrenal crisis precipitated by intercurrent illness is often the first presentation. The degree and rate of damage to the adrenal cortex will usually dictate
presentation.
Clinical features usually do not manifest until about 90% of the adrenal cortex is
lost [13].
Symptoms can be vague complaints like weight loss, fatigue, lethargy, and dizziness. Loss of the negative feedback effect on ACTH leads to high circulating levels
of ACTH, which causes pigmentation due to stimulation of skin melanocortin 1
receptors (MC1R) [28]. Pigmentation is often seen on palmar creases, buccal
mucosa, high-friction skin areas like elbows and knees, and scars acquired after the
onset of adrenal insufficiency [29].
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Gastrointestinal symptoms could be nausea, vomiting, abdominal pain, and diarrhea. Hypoglycemia is rare.
Mineralocorticoid deficiency causes reduced sodium absorption and decreased
renal potassium excretion, resulting in hyponatremia, hyperkalemia, and postural
hypotension [30].
Androgen deficiency manifests as reduced libido and decreased axillary and
pubic hair.
When to Suspect Adrenal Insufficiency
Patients presenting with unexplained symptoms such as hypovolemia, hypotension
refractory to standard treatment with fluids, and unexplained electrolyte imbalances
such as hyponatremia, hyperkalemia, or hypoglycemia should be tested for adrenal
insufficiency [26].
Complications
An adrenal crisis, also known as Addisonian crisis, is an acute emergency that, if not
promptly treated, may be life-threatening.
The symptoms may be nonspecific, such as nausea, vomiting, abdominal pain,
lethargy, fatigue, delirium, syncope, hypotension, and shock.
Abdominal pain can be variable, from mild, vague pain to severe enough to
mimic a surgical acute abdomen. Electrolyte abnormalities include hyponatremia,
hyperkalemia, hypoglycemia, and hypercalcemia.
In cases without a prior diagnosis of AI, a high level of suspicion is key to prompt
diagnosis and management of the condition. Most importantly, treatment should not
be postponed while awaiting the diagnostic results.
Investigations
1. General:
• Hyponatremia
• Hyperkalemia
• Hypoglycemia
• Normocytic normochromic anemia
• Mild hypercalcemia
• ESR may or may not be elevated
2. Disease Specific:
(i) A morning 8 AM serum cortisol level of >14.5 (>400 nmol/L) effectively
excludes any HPA axis dysfunction [31].
(ii) ACTH Stimulation/Short Synacthen Test.
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In cases with an 8 AM morning serum cortisol level between 4 and 14.5 μg/dL,
the cosyntropin stimulation test/ACTH stimulation test/short synacthen test is the
recommended dynamic test [31].
The cosyntropin test can be performed at any time of day; ideally, it should be
performed at 9:00 AM. A baseline serum cortisol level is collected, and then 250 μg
of Cosyntropin is administered IV/IM. After 30 and/or 60 min of Cosyntropin
administration, serum samples are collected for cortisol levels. Failure to achieve
cortisol level ≥ 500 nmol/L (≥18 μg/dl) post synacthen indicates adrenal insufficiency. Due to significant variation among different assays used for cortisol measurement, the cut-off for a normal or failed response must be assay-specific [26, 32].
In situations where a cosyntropin stimulation test is not practicable, a baseline
serum cortisol level of less than 4 μg/dL (110 nmol/L) paired with a blood ACTH
level that is much higher than the typical reference range (often >100 pg/ml) provides a diagnosis of PAI without the need for dynamic testing [26]. Similarly, the
basal serum level of dehydroepiandrosterone-sulfate (DHEAS) >65 μg/dL
(>1700 nmol/L) confirms an intact HPA axis without any further stimulation testing
[31, 33].
Differentiating Between Primary and Secondary Adrenal Insufficiency
To differentiate between PAI and SAI, simultaneous measurement of plasma ACTH
should be done. Ideally, the ACTH sample should be taken simultaneously along
with the baseline cortisol sample in the cosyntropin test or paired with the 8 AM
cortisol sample. A plasma ACTH above twice the upper limit of the standard reference range would reflect an adrenal cause of AI [26].
Simultaneous plasma aldosterone and renin measurements should be undertaken
to diagnose mineralocorticoid deficiency in PAI; aldosterone levels would be normal in SAI [26].
Further testing should be done to determine the etiology in patients with confirmed AI.
3. Antibodies:
Diagnostic workup for the cause includes a validated assay for 21-Hydroxylase
(21OH) antibodies [26].
4. Imaging:
Adrenal imaging is not usually required for the diagnosis. However, in
tuberculosis-­endemic areas where antibodies are reported negative, a CT of the
abdomen may show calcified atrophic adrenals secondary to tuberculosis adrenalitis. In addition, it can help to look for any infiltration, hemorrhage, or malignancy [34].
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Screening for Other Related Autoimmune Diseases
Addison’s disease can occur in isolation or as part of one of the APS [8, 25].
APS type 1:
• Also called autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED).
• It is an autosomal recessive condition.
• It results from a mutation in the autoimmune regulator (AIRE) gene, which is
located on chromosome 21p22.3.
• It is characterized by at least 2 out of 3 of PAI, hypoparathyroidism, and chronic
mucocutaneous candidiasis [13].
• It may be associated with primary gonadal failure, hypothyroidism, and occasionally type 1 diabetes mellitus (T1DM).
APS type 2:
• Polygenic inheritance.
• Characterized by at least two out of three from PAI, autoimmune hypothyroid,
and T1DM [13].
• There can be associated pernicious anemia, premature ovarian insufficiency, vitiligo, alopecia, and immune thrombocytopenic purpura [25].
• PAI, along with autoimmune hypothyroidism, is called Schmidt syndrome.
• PAI, along with T1DM, is called Carpenter syndrome.
Management
All patients diagnosed with Addison’s disease necessitate glucocorticoid and mineralocorticoid supplementation [26].
Glucocorticoid Replacement
Current guidelines recommend hydrocortisone as the steroid of choice for replacement [26]. The entire daily dose of hydrocortisone (15–25 mg) should be prescribed
orally in two to three divided doses.
A two-dose or three-dose regime can be used, depending on the individual
patient’s profile and preferences. The highest dose is given upon awakening in the
morning.
In a two-dose regimen, the second dose is administered in the early afternoon. In
a three-dose regimen, the second and third doses are administered during lunch and
in the afternoon.
In cases where multiple daily doses are not appropriate or compliance is an issue,
Prednisolone 3–5 mg/day is an alternative.
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Dexamethasone is not recommended due to difficulties with dose titration, long
half-life, and risk of developing cushingoid features.
In addition to the above conventional replacement options, novel therapeutic
options like plenadren (once-daily modified-release hydrocortisone formulation),
chronocort (twice-daily modified-release hydrocortisone formulation), and hydrocortisone infusion pumps are being introduced to keep glucocorticoid replacement
as close as possible to the body’s circadian rhythm, decrease side effects, and
improve quality of life [35, 36].
Mineralocorticoid Replacement
Fludrocortisone at a starting dose of 50–100 mcg can help with postural symptoms [26].
DHEA Replacement
Unlike glucocorticoids and mineralocorticoids, replacement of adrenal androgen is
not part of standard treatment [37].
In women experiencing low libido and low energy levels despite being on optimal replacement of glucocorticoid and mineralocorticoid, a trial of DHEA for six
months is recommended [26].
Symptoms are to be reviewed at six months; DHEA should be discontinued if
there is no improvement [26].
Limited studies have reported improved overall well-being, mood, and fatigue
[7, 38, 39]. More research is needed regarding long-term benefits, risks, and safety.
Monitoring of Treatment
Periodic clinical assessments and continued follow-up are required to monitor treatment. Routine hormone testing to check for adequate replacement is not
recommended.
The development of cushingoid features, weight gain, and insomnia indicates
glucocorticoid excess. Nausea, weight loss, poor appetite, lethargy, and hyperpigmentation signify insufficient glucocorticoid dosing.
In selected populations, like cases with suspected malabsorption, monitoring
cortisol levels through serum or salivary day curve assessments may assist in guiding dosing.
Additionally, routine ACTH measurement should not be used to adjust glucocorticoid dosage, as it can be misleading and may result in over-replacement.
The absence of postural hypotension and normal electrolytes is a reliable marker
of adequate mineralocorticoid replacement [26].
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Patient Education
Glucocorticoid requirement increases during periods of stress. Prevention of adrenal crisis requires that patients receive complete education regarding sick day rules
and the management of steroids in specific stressful situations.
Patients should always carry with them a steroid emergency card and be encouraged to wear a medical alert necklace or bracelet mentioning: “Adrenal insufficiency—dependent on steroids!” [26].
Complete education needs to be provided regarding sick day rules, how to double or triple their usual steroid dose while they are feeling ill, and that in situations
where they are too unwell to take oral steroids, they need to take them as an injection and urgently seek medical attention.
Every patient needs an emergency kit containing a 100 mg vial of hydrocortisone, water for injection, a 2 mL syringe, and needles.
Symptoms of adrenal crisis should be discussed with patients so they can identify impending crisis early and get medical attention along with self-administration
and injection of hydrocortisone. This should be taught to the patient, parents, or
partner [40].
They should have emergency contact numbers to call the specialist endocrine
team in emergencies.
All information should be revised with the patient at least during annual follow­up visits or more frequently if needed.
The prescription should include sufficient hydrocortisone to cover sick days. The
expiry date on the emergency kit needs to be checked regularly to ensure it is up
to date.
Sick Day Rules
Stress doses of glucocorticoids are required in case of febrile illness or any illness
requiring bed rest [41].
It is advisable to double the dosage of steroids for any infection requiring antibiotic therapy or before a small outpatient surgery, including dental procedures.
Hydrocortisone replacement doses must be increased to double (if temperature >38 °C) or triple (if temperature >39 °C) until recovery, typically a couple of
days [26].
In case of vomiting, fasting, surgery, trauma, or severe illness, either intravenous
or intramuscular hydrocortisone should be administered.
When undergoing major surgery under general anesthesia, childbirth, major
trauma, or preexisting conditions necessitating intensive care, hydrocortisone 50 mg
every six hours IM or IV should be given. Alternatively, continuous IV infusion of
hydrocortisone 200 mg/24 h can be given.
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Adrenal Crisis Management
Immediate treatment comprises a stat dose of parenteral hydrocortisone 100 mg,
followed by 200 mg in the next 24 h, either as six-hourly injections in divided doses
or continuous IV infusion. Parenteral hydrocortisone is continued until oral intake
is well-established and tolerated.
Once oral intake is established, double replacement doses of hydrocortisone are
recommended until the patient is clinically well.
Generous fluid resuscitation is needed to correct fluid and sodium loss. Treatment
of underlying precipitants (e.g., infection) is crucial. Monitoring and correction of
electrolytes should be done as indicated.
Hydrocortisone has significant mineralocorticoid activity (40 mg of hydrocortisone is equivalent to 100 mcg of fludrocortisone). Fludrocortisone replacement is
not needed when taking higher doses of hydrocortisone above 50 mg/day.
Fludrocortisone can be recommenced once the dose has been reduced to below
50 mg/day.
In case hydrocortisone is unavailable, prednisolone can be used as an alternative.
Dexamethasone should be reserved for situations where no other glucocorticoid is
available.
Conclusion
Addison’s disease is a rare autoimmune disease of the adrenal cortex that can be
potentially fatal if untreated. Its prevalence has increased since its initial identification. A heightened level of suspicion is essential for diagnosis, particularly in those
with a personal or familial history of other autoimmune conditions. A vital part of
management revolves around screening for the associated conditions and optimum
replacement of deficient hormones. Patient and family education regarding the disease is essential to prevent acute adrenal crises.
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Coeliac Disease
Syed Tariq Khalil
Introduction
The word coeliac comes from the Greek koiliakos, simply meaning “abdominal,”
derived from koilia (“belly”). The term later evolved through Latin (coeliacus) into
the modern name, coeliac disease. Coeliac disease is an immune-mediated disorder
triggered by gluten and other prolamins, primarily affecting the small intestine.
While it often presents with gastrointestinal symptoms such as diarrhea, malabsorption, and weight loss, it may also manifest through extraintestinal complications or
be identified incidentally through family screening, even in asymptomatic individuals [1]. Coeliac disease was first described in modern medical literature in 1888, but
it was not till early 1950 that gluten was implicated as the primary trigger [2].
This chapter provides an overview of celiac disease, including its epidemiology,
pathophysiology, clinical manifestations, diagnostic criteria, and management
strategies.
Epidemiology
Coeliac disease is often recognized as the most common among individuals of
Caucasian descent, with estimates indicating it affects up to 2% of specific European
populations [3]. However, emerging evidence challenges this assumption. A study
from China suggests that adult coeliac disease may be more common in East Asia
than previously thought [4]. In a prospective cross-sectional survey, up to 2% of
young Chinese tested positive for serum assay of coeliac disease [5]. Coeliac disease has also been identified among Canadian immigrants from regions including
China, Japan, and South Asia, particularly the Punjab region of India [6].
S. T. Khalil (*)
Advocate Christ Medical Center, Oak Lawn, IL, USA
e-mail: Syedtariq.khalil@aah.org
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_15
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S. T. Khalil
Risk Factors
Consistent with other autoimmune diseases, the development of coeliac disease
necessitates both a genetic predisposition and an environmental trigger. The genetic
link was suspected due to the higher risk observed in first-degree relatives of affected
individuals and high concordance rates of over 70% in monozygotic twins and
30–40% in human leukocyte antigen (HLA) identical siblings [7].
Coeliac disease is strongly associated with specific HLA class II genes, particularly HLA-DQ2 and HLA-DQ8. Approximately 90% of individuals with coeliac
disease carry the HLA-DQ2 haplotype, and most of the remaining cases carry
HLA-DQ8. These genes encode molecules that present gluten-derived peptides to T
cells, triggering the inappropriate immune response characteristic of the disease [8].
Although HLA-DR3 and HLA-DR4 are associated with various immune-mediated
diseases, they are not responsible for coeliac disease but are often found in linkage
disequilibrium with HLA-DQ2 and HLA-DQ8. This indicates they are frequently
inherited together, and the presence of DR3 and DR4 can indicate a higher risk for
coeliac disease [9].
Thirty to forty percent of individuals of Caucasian descent carry these risk haplotypes, though the majority does not go on to develop the disease. Thus, while the
HLA-DQ2/DQ8 gene variants are essential for the development of coeliac disease,
they alone are not enough; non-HLA genetic factors also play a role in increasing
the risk of coeliac disease [10]. Several studies have identified at least 39 non-HLA
loci that also predispose to coeliac disease [11].
Pathophysiology
The pathophysiology of coeliac disease involves a complex interplay between
genetic, environmental, and immunological factors. Gluten is the most significant
environmental factor in the pathogenesis of coeliac disease, triggering both innate
and adaptive immunity. The pathogenesis of coeliac disease requires two critical
immunological events: first, the activation of gluten-specific inflammatory CD4
helper (TH1) response and second, targeted cytotoxicity against intestinal epithelial
cells mediated by activated T cell receptors (TCR) αβ [12]. Gliadin is the key component of gluten that is not completely digestible by intestinal enzymes [13]. In a
healthy population, gliadin in the intestinal lumen cannot enter epithelial cells
because of tight junctions. In a genetically susceptible person, gliadin binds to chemokine receptor 3 (CXCR3) CXXR3 on epithelial cells to initiate an increase in
intestinal permeability through the release of Zonulin, which enables the paracellular passage of gliadin from the lumen to the gut mucosa [14]. Once gliadin is in
the lamina propria, it is deamidated by tissue transglutaminase (tTG), which is then
presented to the T-helper cell by antigen-presenting cells [15]. However, professional antigen-presenting cells, such as dendritic cells, B cells, and plasma cells,
express major histocompatibility molecule (MHC) molecules coded by HLA-DQ2/
DQ8 alleles. Still, some studies have implicated the role of intestinal epithelial cells
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(IEC) as antigen-presenting cells [16]. The activated T cell secretes cytokines such
as interferon-gamma, which activate myofibroblasts to release matrix metalloproteinases, leading to a remodeling of the mucosa [17].
Cytokines, particularly interferon-gamma, influence HLA-DQ expression. When
interferon gamma is produced locally during an infection, it can increase HLA DQ
expression on antigen-presenting cells. This enhanced expression facilitates the presentation of gluten peptides, which may play a role in triggering or intensifying a
gluten-specific T-cell response involved in celiac disease [18]. The proinflammatory
cytokine interleukin 15 (IL-15) is produced by intestinal epithelial cells (IECs) and
antigen-presenting cells (APCs) in response to stimuli such as gluten exposure. It
plays a pivotal role in regulating intraepithelial lymphocytes (IELs).​Upon gluten
stimulation, IECs and APCs upregulate the expression of IL-15 which then acts in a
paracrine manner to influence neighboring immune cells. IL-15 is critical for the
development, activation, and survival of IELs. It promotes the proliferation and
cytotoxic function of these lymphocytes, contributing to the maintenance of intestinal immune homeostasis [19].
In celiac disease, the aberrant expression of IL-15 leads to the activation of
intraepithelial lymphocytes (IELs), resulting in epithelial cell damage and villous
atrophy. Neutralizing IL-15 has been shown to inhibit tissue-damaging immune
responses in the intestinal mucosa of untreated celiac patients, highlighting its central role in disease pathogenesis [20]. When activated, T helper 2 (Th2) cells secrete
cytokines that promote B cell activation and differentiation. These B cells then
mature into plasma cells that produce antibodies against gliadin and tissue transglutaminase (tTG). These anti-gliadins and anti-tTG antibodies can interact with extracellular tTG, potentially contributing to epithelial damage in the small intestine [21].
The previously believed factors, such as mode of delivery, timing of gluten introduction, and breastfeeding, are not supported by evidence in the context of coeliac
disease [22]. Although various studies have supported the hypothesis of a positive
association between several viruses, vaccines, and the use of several drugs in developing coeliac disease, no causal relationship has been established.
In recent decades, considerable research has focused on the interaction between
the gut microbiota and host factors in the pathogenesis and progression of coeliac
disease. Although there is promising evidence suggesting a link, it has not been
established as a cause.
Clinical Presentation
Clinically, coeliac disease is divided into classic, non-classic, asymptomatic, latent,
and refractory [23]. The classic form typically appears within the first two years of
life, shortly after the introduction of solid foods in the diet, and is commonly present
with chronic diarrhea, weight loss, and failure to thrive. The non-classical form of
coeliac disease often presents later in life, typically during late childhood or even in
the second or third decade of life. The presentation can be subtle gastrointestinal
symptoms like constipation, bloating, or extraintestinal symptoms like delayed
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puberty, skin rashes, iron deficiency anemia, infertility, anxiety, depression, osteopenia, headaches, and signs of peripheral neuropathy. These nonspecific symptoms
can make diagnosis challenging, often leading to delays unless serologic testing is
performed [24].
Asymptomatic coeliac disease refers to individuals who test positive for coeliac-­
specific antibodies and show characteristic intestinal damage on biopsy but do not
exhibit any apparent symptoms. Often identified through screening, particularly
among individuals with a family history or associated autoimmune conditions, these
individuals may feel completely healthy at the time of diagnosis. However, despite
the absence of symptoms, they are still at risk for complications such as osteoporosis, infertility, nutritional deficiencies, and, in rare cases, intestinal lymphoma. For
this reason, a strict gluten-free diet is recommended to prevent long-term health
consequences, even when the disease is clinically silent [25].
Latent coeliac disease refers to individuals who have a genetic predisposition to
coeliac disease, typically carrying HLA-DQ2 or HLA-DQ8 alleles, and may also
test positive for coeliac-specific antibodies but currently exhibit a normal small
intestinal mucosa on biopsy and have little to no symptoms. Unlike active coeliac
disease, there is no villous atrophy at the time of assessment, though these individuals remain at risk for developing mucosal damage in the future. Management typically involves careful monitoring with periodic serological and clinical evaluation
rather than immediately initiating a gluten-free diet unless signs of progression appear.
Refractory coeliac is persistent clinical and histological changes despite a gluten-­
free diet for 6–12 months. Refractory coeliac disease (RCD) is classified into two
types based on the immunophenotype of intraepithelial lymphocytes (IELs). A normal IEL phenotype characterizes type 1 RCD and typically has a more favorable
prognosis, often responding to nutritional support and immunosuppressive therapy.
In contrast, Type 2 RCD involves an abnormal, clonal IEL phenotype and is associated with a significantly poorer prognosis due to its potential progression to
enteropathy-­associated T-cell lymphoma (EATL); that’s why accurate differentiation between the two types is essential for appropriate management and monitoring [26].
Complications
Coeliac disease is an inflammatory condition in which continued exposure to gluten
leads to persistent inflammation of the small intestine. Chronic inflammation can
lead to malabsorption and deficiencies in essential nutrients, ultimately affecting
other bodily systems. Common deficiencies seen in coeliac disease are iron, vitamin
D, calcium, vitamin B12, folic acid, and zinc. Less common are copper, vitamin B6,
magnesium, and selenium [27].
Bones are commonly affected in untreated or inadequately managed coeliac disease, with reduced bone mineral density (BMD) of varying severity observed in
Coeliac Disease
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approximately 20–40% of adults and up to 16% of children [28–30]. The low bone
mineral density was also observed in patients with asymptomatic celiac disease [31].
Coeliac disease affects bone health primarily due to malabsorption of essential
nutrients. This occurs because of immune-mediated damage to the small intestinal
villi, which impairs the absorption of calcium and vitamin D [32]. The resulting
hypocalcemia triggers secondary hyperparathyroidism, a compensatory response in
which parathyroid hormone levels rise to maintain calcium balance. However, this
leads to increased bone resorption, further reducing bone mineral density. Bone loss
in celiac disease is related to secondary hyperparathyroidism [33]. In addition, the
chronic inflammation associated with coeliac disease can directly interfere with
bone remodeling, compounding the risk of osteopenia and osteoporosis.
Proinflammatory cytokines like tumor necrosis factor-alpha (TNF-α), IL-1β, and
IL-6 are elevated in coeliac disease, which promotes osteoclast differentiation and
activity, leading to increased bone resorption [34].
Women with coeliac disease have an increased risk of miscarriages, intrauterine
growth restrictions, low birth weight neonates, and preterm deliveries. These complications improve with a gluten-free diet [35]. Most of the complications are secondary to nutritional deficiencies. Still, coeliac disease-related autoantibodies may
compromise placental function directly by interfering with placental tissue transglutaminase activity and disruption of endometrial angiogenesis [36].
Patients with coeliac disease are at higher risk for skin conditions like eczema,
psoriasis, urticaria, vitiligo, and alopecia areata [37]. One of the most common
extraintestinal manifestations of coeliac disease is dermatitis herpetiformis. It is
characterized by the intense, itchy, symmetrical distribution of small vesicles and
papules on the extensor surface of elbows and knees, as well as the scalp and buttocks. It is an autoimmune disease characterized by granular immunoglobulin deposition in the skin. It is more common in males in the third to fourth decade of life.
Mucosal involvement is rare but can present with vesicles and erosions in the oral
mucosa or tongue [38]. Dental anomalies, such as grooves, defective enamel color,
and delayed eruptions, can also be observed in patients with coeliac disease, as well
as in dermatitis herpetiformis [39].
Neurological issues are common in patients with coeliac disease. CDs have been
linked to various neurological and psychiatric disorders, including cerebellar ataxia,
peripheral neuropathy, epilepsy, dementia, depression, and in children with attention deficit hyperactivity disorder, learning disabilities, and tic disorders [40]. Some
studies have reported up to 50% of patients with peripheral neuropathy [41]. Most
commonly presents with peripheral sensory neuropathy, but sometimes may present
with acute inflammatory demyelinating polyneuropathy, mononeuritis multiplex,
pure motor neuropathy, autonomic dysfunction, and Guillain-Barré syndrome [42].
Lactose intolerance is commonly associated with coeliac disease in up to 10% of
patients and is most likely secondary to immune-mediated damage to intestinal
mucosa [43].
Hypersplenism is often an unrecognized complication of coeliac disease. The
incidence is higher in untreated cases, 43.7%, and up to 88% in refractory coeliac
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disease [44]. Although the actual cause is unknown, it may be secondary to persistent immune activation or some autoimmune process [45].
Associated Autoimmune Diseases
Coeliac disease is associated with a higher risk of autoimmune diseases. The most
common associations are type 1 diabetes mellitus, autoimmune thyroiditis like
Hashimoto’s and Graves’, autoimmune hepatitis, autoimmune hepatitis, primary
biliary cholangitis, Sjögren syndrome, and Addison’s disease [46]. Autoimmune
diseases are estimated to affect up to 15% of patients with coeliac disease, and this
may be because of shared genetic factors [47].
Celiac Disease and Risk of Malignancy
Patients with coeliac disease have an increased risk of certain types of cancer, primarily undiagnosed or poorly controlled cases. The most common is enteropathy
associated with T cell lymphoma, which is a rare but aggressive malignancy that is
seen in type 2 refractory coeliac disease. Small bowel adenocarcinoma is most
likely related to chronic mucosal damage and inflammation. Coeliac disease is also
associated with non-Hodgkin lymphomas and squamous cell carcinoma of the
esophagus and oropharynx due to long-term immune activation and nutrient deficiencies. Though rare, hepatocellular carcinoma is seen in patients with coeliac disease, especially in patients with autoimmune liver diseases [48]. Strict adherence to
a gluten-free diet reduces the risks, emphasizing the importance of early detection
and lifelong dietary compliance [49].
Investigations
1. Serologic Testing
It is essential to have clinical suspicion due to nonspecific gastrointestinal and
extraintestinal symptoms, including screening first-degree relatives of individuals
with coeliac disease and patients with autoimmune diseases. Initial screening
involves serologic testing. The first line is anti-tissue transglutaminase antibodies
(tTG-IgA), followed by more specific endomysial antibodies (EMA-IgA). It is also
imperative to rule out IgA deficiency, which may cause a false negative tTG-­
IgA [50].
2. Small Intestinal Biopsy
It is the gold standard for diagnosing coeliac disease based on the Marsh-­
Oberhuber classification, a standardized histological grading system used to assess
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Table 1 Marsh-Oberhuber histological grading system for coeliac disease
Marsh
grade
Description
Marsh 0
Normal intestinal mucosa with healthy villi and no abnormalities
Marsh 1
Increased intraepithelial lymphocytes (IELs) with normal villous architecture
Marsh 2
Increased IELs and crypt hyperplasia; villi remain structurally intact
Marsh 3 encompasses all the previous features, along with varying degrees of villous atrophy
Marsh
All the previous features plus partial villous atrophy
3a
Marsh
All the previous features plus subtotal villous atrophy
3b
Marsh
All the previous features plus total villous atrophy
3c
Total villous atrophy with hypoplastic, often atrophic mucosa; seen in long-­
Marsh 4
standing or refractory coeliac disease
the extent of mucosal damage in individuals affected by the condition. The original
system ranged from 0 to 4, and a score of 3 or higher suggested a diagnosis of coeliac disease, but it has been modified over time [51].
Marsh-Oberhuber histological grading system is defined in Table 1.
According to the updated guidelines from the European Society for Pediatric
Gastroenterology, Hepatology and Nutrition (ESPGHAN), a small intestinal biopsy
is no longer mandatory to diagnose coeliac disease in all cases. In certain pediatric
patients, particularly those with strongly positive serological markers, such as high
levels of anti-tissue transglutaminase (tTG) antibodies (typically more than 10 times
the upper limit of normal) along with positive endomysial antibodies (EMA), a
diagnosis can be made without the need for biopsy. A small bowel biopsy is still
recommended in some instances, particularly when the diagnosis isn’t straightforward. This includes individuals with atypical symptoms, negative or borderline
blood test results, coexisting medical conditions, or situations where there is general
uncertainty about the diagnosis. The goal is to avoid unnecessary invasive procedures while still ensuring an accurate diagnosis, especially in patients with
borderline-­positive serology, IgA deficiency, or unusual clinical presentations [52].
Management
The management of coeliac disease is a strict, lifelong gluten-free diet, which allows
the intestine to heal and symptoms to improve. However, sticking to this diet can be
challenging, as gluten is found not only in obvious sources like bread and pasta but
also in many processed foods and everyday products. This makes patient education
critical. People with coeliac disease need to learn how to read food labels carefully,
be mindful of cross-contamination, and recognize that gluten can be hidden in
things like sauces, salad dressings, processed meats, and even some medications or
supplements.
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To track the effectiveness of the gluten-free diet, it is recommended to follow up
with serial serological testing. A decrease in antibody levels, especially anti-tissue
transglutaminase (anti-TTG) IgA, typically indicates compliance.
In addition, management involves correcting nutritional deficiencies, such as
iron, calcium, folate, and fat-soluble vitamins, and carefully monitoring for associated complications, including autoimmune disorders, osteoporosis, and an increased
risk of intestinal malignancies, particularly enteropathy-associated T-cell lymphoma
(EATL) and small bowel adenocarcinoma. Coeliac disease with hyposplenism
increases the risk of infections, particularly from encapsulated bacteria such as
Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae type B, and
Neisseria meningitidis (meningococcus). As a result, vaccination against these
pathogens is strongly recommended.
Management of refractory coeliac disease (RCD) requires careful and individualized planning, as some patients may need total parenteral nutrition (TPN) due to
severe malabsorption and malnutrition. In addition to nutritional support, immunosuppressive therapy is often necessary, particularly in type II RCD, which carries a
higher risk of progression to enteropathy-associated T-cell lymphoma (EATL).
Treatment options may include corticosteroids (e.g., prednisolone or budesonide),
azathioprine, and cyclophosphamide. In more resistant or aggressive cases, biologic
and immune-modifying agents such as infliximab (a TNF-α inhibitor) and alemtuzumab (a monoclonal antibody targeting CD52) may be considered. These therapies
require specialist supervision due to the risk of significant side effects and the need
for closer and frequent monitoring.
Conclusion
Coeliac disease is a lifelong condition, but with proper care, it can be well managed.
The primary treatment is a strict gluten-free diet, which helps the gut heal and
reduces the risk of long-term complications. It’s also essential to correct any nutritional deficiencies that may have developed and to maintain regular follow-up
appointments. This is especially important because coeliac disease can sometimes
be linked to other health conditions, so ongoing monitoring helps catch any issues
early. While rare, some individuals may experience more complex forms of the
disease that require additional medical treatment. With good support, awareness,
and care, most people with coeliac disease can lead healthy, fulfilling lives.
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Inflammatory Bowel Disease
Faisal Ziauddin
Introduction
Inflammatory bowel disease (IBD) is a chronic inflammatory condition with a
remitting and relapsing course, significantly impacting patients’ quality of life. It
consists of two primary subtypes: Crohn’s disease (CD) and ulcerative colitis (UC).
Crohn’s disease can affect any part of the gastrointestinal (GI) tract, from the mouth
to the anus, with the terminal ileum and colon being the most commonly involved
sites. In contrast, in ulcerative colitis, inflammation typically starts in the rectum
and extends proximally in a continuous manner, involving part or the entire colon.
Unlike Crohn’s disease, which is characterized by transmural inflammation that
affects all layers of the bowel wall, ulcerative colitis affects only the mucosal and
submucosal layers [1]. This fundamental difference explains the distinct complications seen in each disease, such as fistulae and strictures in Crohn’s disease, while
UC more commonly leads to superficial ulceration and bleeding.
In at least 10% of patients, overlapping features make it difficult to differentiate
between the two disorders at initial presentation, a category often referred to as
indeterminate colitis. The pathogenesis of IBD is multifactorial, involving a complex interplay of genetic predisposition, immune system dysregulation, and various
environmental factors including diet, smoking, and alterations in gut microbiota.
Besides the GI tract, both Crohn’s disease and Ulcerative colitis are associated with
numerous extra intestinal manifestations, affecting organs such as the skin, joints,
eyes, and hepatobiliary system. Recognizing these diverse presentations is crucial
for comprehensive patient management and improving long-term outcomes.
This chapter provides an overview of inflammatory bowel disease (IBD), focusing on its epidemiology, pathogenesis, clinical features, diagnosis, and management. It covers both Crohn’s disease and ulcerative colitis, highlighting key
differences, complications, and extraintestinal manifestations. The chapter also
F. Ziauddin (*)
Ziauddin University, Karachi, Pakistan
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2026
S. K. Imam, S. I. Ahmad (eds.), Autoimmune Diseases,
https://doi.org/10.1007/978-3-032-12937-6_16
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outlines current treatment approaches, offering evidence-based guidance for effective patient care.
Epidemiology
IBD affects millions of people worldwide, with varying prevalence rates depending
on geographic location, age, and genetic factors. It is most commonly diagnosed in
individuals aged 15 to 30 years, although it can occur at any age. Crohn’s disease is
more common in females than males and has a bimodal age distribution, with either
presenting between 20 and 40 years or later in life between 60 and 80 years [2]. The
incidence of IBD has been steadily rising over the past few decades, with recent
studies indicating an increasing trend in the younger age group. IBD, especially
Crohn’s disease, is highly prevalent in Northern European and North American
countries, which may be due to a westernized environment and lifestyles. Nine to 20
cases are reported among every 100,000 persons per year [3]. The prevalence of
ulcerative colitis is more common in the Mediterranean and Eastern Europe.
Pathophysiology
The exact cause of inflammatory bowel disease (IBD) remains unclear, with multiple contributing factors proposed, though none are universally present in all patients.
Current understanding suggests a dysregulated immune response to gut microbiota
in genetically susceptible individuals, triggered by environmental factors. Twin
studies have shown concordance rates of 35% for Crohn’s disease (CD) and 16% for
ulcerative colitis (UC), supporting a genetic component. Mutations in the CARD15
gene on chromosome 16 have been identified as risk factors, particularly for
CD. This gene plays a key role in immune recognition of pathogens and regulation
of the gut microbiome. These mutations may impair monocyte recognition of intestinal flora, leading to defective innate immune responses and persistent inflammation. In CD, increased intestinal permeability allows luminal antigens such as
bacteria and food to activate mucosal macrophages, which produce interleukins 12
and 18. These cytokines recruit Th1 helper cells that release interferon-gamma and
tumor necrosis factor-alpha (TNF-α), resulting in leukocyte recruitment and sustained mucosal inflammation.
Environmental triggers: Although not fully understood, various environmental
factors such as diet, infections, antibiotic use, smoking, and exposure to pollution
have been implicated in the development of IBD.
Western diets, with high-fat, high-sugar, and low-fiber foods, have been associated with an increased risk of IBD. Diets rich in animal fats and processed foods
may promote inflammation through their effects on the gut microbiota and immune
system [4, 5].
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Some ongoing studies suggest that the use of probiotics (beneficial bacteria) and
prebiotics (food that promotes the growth of beneficial bacteria) may help improve
gut health and reduce inflammation in IBD patients [6].
Some literature suggests that certain viral or bacterial infections can provoke
immune responses which in turn initiate or worsen IBD symptoms. For example,
enteric infections (those involving the digestive tract) can lead to changes in the gut
microbiota, potentially triggering an inflammatory response in the intestines.
Smoking is particularly associated with the exacerbation of Crohn’s disease,
whereas it seems to have a protective effect in ulcerative colitis [7].
The gut microbiome plays a crucial role in immune modulation and maintaining
intestinal barrier integrity. Disruptions in the microbiome may contribute to the
pathogenesis of IBD by promoting chronic inflammation.
The chronic inflammation associated with IBD leads to tissue damage, ulceration, and, in some cases, fibrosis. In Crohn’s disease, all layers of the bowel wall
are involved, leading to complications such as fistulas, strictures, and abscesses. In
ulcerative colitis, the inflammation is generally confined to the mucosa and submucosa of the colon, potentially causing bleeding and colonic perforation in severe
cases [8].
Types of Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) primarily consists of three main types: Crohn’s
disease, ulcerative colitis, and indeterminate colitis. While these diseases share
common features, such as chronic inflammation and immune system dysfunction,
they differ in their location, extent of inflammation, and clinical manifestations.
1. Crohn’s Disease
Crohn’s disease (CD) results in transmural ulceration of any portion of the gastrointestinal tract from mouth to anus. Most common site of involvement is the
ileocecal region (45%), followed by colon (25%), terminal ileum (20%), extensive
small bowel (5%), gastroduodenal and perianal (5%) each [2]. It may be categorized
on the basis of severity (mild, moderate, or severe) and location. CD also is classified by phenotype as inflammatory, structuring, or penetrating [1]. The inflammation is patchy with healthy tissue between affected areas, i.e., “skip lesions.”
Transmural inflammation leads to complications such as strictures, fistulas, and
abscesses. During the later phase of the disease, the mucosa will reveal a cobblestone appearance due to the linear ulcers between the normal mucosa. Strictures
may result in bowel obstruction, whereas fistulas may result in abnormal communications between different parts of bowels or with other organs, such as the bladder,
vagina, or skin. The clinical presentation can be variable depending upon the site
and predominant pathology of that site.
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Major symptoms include:
• Diarrhea (can be bloody with colonic involvement, or steatorrhea in small bowel
disease).
• Abdominal pain.
• Weight loss.
• Constitutional symptoms such as malaise, anorexia, nausea, vomiting, and a low-­
grade fever.
• 15% of patients have no gastrointestinal symptoms at all.
Patients having ileocecal and terminal ileum involvement present with pain and/
or tender mass in right iliac fossa with or without diarrhea and weight loss. It can at
times present as an emergency with acute right iliac fossa pain mimicking acute
appendicitis. Crohn’s colitis presents with symptoms such as diarrhea (mucous/
blood), sense of urgency, and occasionally abdominal pain/malaise similar to ulcerative colitis but with less blood in diarrhea. Patients with extensive small bowel
involvement present with typical pain, diarrhea, and weight loss in addition to features of malabsorption (e.g., steatorrhea) and anemia. Anal and perianal complications like fissure, hemorrhoids, skin tags, perianal or ischiorectal abscess, and
anorectal fistulae are common. Undernutrition results from factors such as reduced
food intake, malabsorption, and increased protein loss from inflamed bowel. Short
bowel syndrome develops when extensive bowel resection leads to excessive malabsorption of fluids, electrolytes, and nutrients. There is an increased risk of colorectal carcinoma with Crohn’s disease and a small increase in risk of rarer small
intestinal and anal cancers occurring in sites of prolonged inflammation.
There are many systemic associations and complications of CD affecting the
liver, biliary tree, joints, skin, and eyes.
Arthritis is both peripheral and axial. Ankylosing spondylitis affects about 5% of
patients with Crohn’s colitis. The patient presents with back pain and stiffness, and
it can occur years before the CD.
Erythema nodosum occurs in 8% of Crohn’s colitis patients when disease is
active. Hot, red tender nodules appear on the arms and legs and subside after a
few days.
Pyoderma gangrenosum occurs in 2% of CD patients, starting as a small pustule,
then developing into a painful, enlarging ulcer, most commonly on the leg.
Sclerosing cholangitis occurs in a small proportion of patients. The pathogenesis
is unknown, and the condition is characterized by an inflammatory obliterative
fibrosis of the biliary tree. It progresses slowly, eventually requiring liver
transplantation.
Episcleritis and uveitis affect the eyes and are also seen in other autoimmune
conditions [9].
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2. Ulcerative Colitis
Chronic inflammatory disease is characterized by mucosal inflammation starting
distally in the rectum, with continuous extension proximally for a variable distance,
often with an abrupt demarcation between inflamed and non-inflamed mucosa. It is
the most common form of inflammatory bowel disease worldwide. It varies in
severity, ranging from mild inflammation to more severe forms that cause significant tissue damage and complications. Ulcerative colitis usually presents with
bloody diarrhea, abdominal cramps, rectal bleeding, weight loss, and fever. Urgency
(the sudden, compelling need to have a bowel movement) and tenesmus (a sensation
of incomplete evacuation or rectal discomfort) are common. Tenesmus often leads
to a feeling of straining to pass stool, even when the bowel is empty. The disease is
often associated with periods of flare-ups, followed by periods of remission.
Extraintestinal manifestations include arthritis, skin lesions (e.g., pyoderma gangrenosum), and eye inflammation (e.g., episcleritis or uveitis). Liver disease, such
as primary sclerosing cholangitis (PSC), is also commonly associated with ulcerative colitis.
Severe, long-standing ulcerative colitis can result in toxic megacolon, a life-­
threatening condition characterized by rapid colon dilation and perforation. There is
also an increased risk of developing colorectal cancer in individuals with long-­
standing disease [10].
3. Indeterminate Colitis
Indeterminate colitis is a term used when the diagnosis of IBD cannot be definitively classified as either Crohn’s disease or ulcerative colitis due to overlapping
clinical, endoscopic, and histological features [11–14]. Indeterminate colitis may
present with features such as discontinuous inflammation or involvement of both
the colon and small intestine. The inflammation may not show clear patterns typical
of Crohn’s disease or ulcerative colitis, making it difficult to classify definitively.
Treatment for indeterminate colitis generally follows the same approach as that
for both Crohn’s disease and ulcerative colitis, with therapies aimed at controlling
inflammation and inducing remission. However, long-term monitoring may be necessary to determine the eventual diagnosis and ensure appropriate management.
Some individuals with indeterminate colitis will eventually develop characteristics
of Crohn’s disease or ulcerative colitis, while others may remain classified as
indeterminate.
Common Complications of IBD
Intestinal obstruction is common in Crohn’s disease as chronic inflammation and
fibrosis can lead to strictures.
Toxic megacolon is a severe, life-threatening complication of ulcerative colitis
and can lead to perforation, sepsis, and shock. It requires immediate medical intervention, including corticosteroids or surgery [13, 15].
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Colon cancer risk is increased in individuals with long-standing IBD, particularly those with ulcerative colitis. The risk is higher in those who have had the disease for more than 8–10 years or who have extensive colonic involvement. Regular
screening with colonoscopy is recommended for such patients.
Fistulas and abscesses complicate Crohn’s disease and so does malnutrition
leading to vitamin and mineral deficiencies such as vitamin B12, iron, and folate.
Chronic symptoms, frequent hospitalizations, and the unpredictability of flare-­
ups result in anxiety, depression, and social isolation. These psychological issues
can also exacerbate physical symptoms and impair overall well-being.
Diagnostic Approaches
The diagnosis of IBD is based on a combination of clinical evaluation, laboratory
tests, imaging techniques, and endoscopic and histological examinations. Patients
with a first-degree relative with IBD have a significantly higher risk of developing
the disease themselves, particularly if the relative has early-onset IBD. Differential
diagnosis includes irritable bowel syndrome (IBS), gastrointestinal infections,
colorectal cancer, and diverticular disease.
1. Laboratory Tests
Laboratory tests are needed to confirming the diagnosis, evaluating disease activity, and assessing for complications, such as anemia or infection.
Anemia is often a significant feature in both Crohn’s disease and ulcerative colitis, as chronic disease can lead to iron deficiency. CRP and ESR are nonspecific
markers of inflammation that may be elevated during active disease and can be useful in monitoring disease activity. Fecal calprotectin and lactoferrin both are released
by activated neutrophils in the gastrointestinal tract during inflammation. Elevated
levels of fecal calprotectin or lactoferrin can be used to differentiate IBD from other
conditions like IBS, which typically do not result in elevated levels of these markers.
Anti-Saccharomyces cerevisiae antibodies (ASCA) are more commonly found
in patients with Crohn’s disease, whereas perinuclear anti-neutrophil cytoplasmic
antibodies (pANCA) are more commonly found in ulcerative colitis. However,
these tests are not definitive and are not routinely used in clinical practice.
Liver function tests can help detect hepatobiliary complications associated with
IBD, such as primary sclerosing cholangitis (PSC).
Stool cultures Clostridium difficile toxin assays are sent in acute settings, especially if the patient has recently traveled or has a history of antibiotic use.
2. Imaging Techniques
Imaging techniques are essential for assessing the extent and severity of disease
and detecting complications such as strictures, fistulas, or abscesses.
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Abdominal X-ray can be useful in assessing complications like toxic megaco