Pediatrics in Systemic Autoimmune Diseases [2nd Edition] 9780444635976, 9780444635969

Table of contents :
Content:
Pediatrics in Systemic Autoimmune DiseasesPage i
Handbook of Systemic Autoimmune DiseasesPage ii
Pediatrics in Systemic Autoimmune DiseasesPage iii
CopyrightPage iv
ContentsPages v-xviii
List of ContributorsPages xix-xxi
PrefacePage xxiiiRolando Cimaz, Thomas Lehman
Chapter 1 - Oligoarticular and Polyarticular Juvenile Idiopathic ArthritisPages 1-30P.H. Muller, R. ten Cate
Chapter 2 - Juvenile-Onset SpondyloarthritisPages 31-52R. Burgos-Vargas, S.M.L. Tse
Chapter 3 - Systemic Juvenile Idiopathic ArthritisPages 53-84M. Batthish, R. Schneider
Chapter 4 - Macrophage Activation SyndromePages 85-106A. Ravelli, F. Minoia, S. Davì, A. Martini
Chapter 5 - Assessment Tools in Juvenile Idiopathic ArthritisPages 107-127A. Consolaro, A. Ravelli
Chapter 6 - Childhood UveitisPages 129-144A. Brambilla, G. Simonini
Chapter 7 - Amplified Musculoskeletal Pain SyndromesPages 145-172D.D. Sherry
Chapter 8 - Systemic Lupus Erythematosus: Etiology, Pathogenesis, Clinical Manifestations, and ManagementPages 173-189T. Lehman, F. Nuruzzaman, S. Taber
Chapter 9 - Neonatal Lupus SyndromesPages 191-218A. Brucato, R. Cimaz, V. Ramoni
Chapter 10 - Juvenile DermatomyositisPages 219-233C. Pilkington
Chapter 11 - Localized Scleroderma in ChildrenPages 235-247F. Zulian, F. Sperotto
Chapter 12 - Juvenile Systemic SclerosisPages 249-266I. Foeldvari
Chapter 13 - Autoinflammatory Disorders in ChildrenPages 267-304G. Elizabeth Legger, J. Frenkel
Chapter 14 - Periodic Fever With Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA)Pages 305-313M. Hofer
Chapter 15 - Chronic Recurrent Multifocal Osteomyelitis and Related DisordersPages 315-339P.J. Ferguson
Chapter 16 - Kawasaki DiseasePages 341-359J. Anton, R. Cimaz
Chapter 17 - IgA Vasculitis (Henoch–Schönlein Purpura), Polyarteritis Nodosa, Granulomatous Polyangiitis (Wegener Granulomatosis), and Other VasculitidesPages 361-383S. Ozen, Y. Bilginer
Chapter 18 - Pediatric Antiphospholipid SyndromePages 385-408T. Avčin, R. Cimaz
Chapter 19 - Behçet's DiseasePages 409-426I. Koné-Paut
Chapter 20 - Childhood SarcoidosisPages 427-449C.H. Wouters, C.D. Rose
Chapter 21 - Rheumatic FeverPages 451-464M.T. Terreri, C.A. Len
Chapter 22 - Lyme BorreliosisPages 465-469H.-I. Huppertz, H.J. Girschick
Chapter 23 - Tumor Necrosis Factor Inhibitors in Pediatric RheumatologyPages 471-501V. Gerloni, I. Pontikaki, F. Fantini
Chapter 24 - Other Biological Therapies for Pediatric Rheumatic DiseasesPages 503-525A. Santimov, A.A. Grom
Chapter 25 - Physiotherapy Management of Pediatric Rheumatology ConditionsPages 527-555S. Maillard
IndexPages 557-581

Citation preview

Pediatrics in Systemic Autoimmune Diseases

Handbook of Systemic Autoimmune Diseases Series Editors: F. Atzeni and P. Sarzi-Puttini

Volume 1

The Heart in Systemic Autoimmune Diseases Edited by: Andrea Doria and Paolo Pauletto

Volume 2

Pulmonary Involvement in Systemic Autoimmune Diseases Edited by: Athol U. Wells and Christopher P. Denton

Volume 3

Neurologic Involvement in Systemic Autoimmune Diseases Edited by: Doruk Erkan and Steven R. Levine

Volume 4

Reproductive and Hormonal Aspects of Systemic Autoimmune Diseases Edited by: Michael Lockshin and Ware Branch

Volume 5

The Skin in Systemic Autoimmune Diseases Edited by: Piercarlo Sarzi-Puttini, Andrea Doria, Giampiero Girolomoni and Annegret Kuhn

Volume 6

Pediatrics in Systemic Autoimmune Diseases Edited by: Rolando Cimaz and Thomas Lehman

Volume 7

The Kidney in Systemic Autoimmune Diseases Edited by: Justin C. Mason and Charles D. Pusey

Volume 8

Digestive Involvement in Systemic Autoimmune Diseases Edited by: Josep Font, Manuel Ramos-Casals and Juan Rodes

Volume 9

Endocrine Manifestations of Systemic Autoimmune Diseases Edited by: Sara E. Walker and Luis J. Jara

Volume 10

Antiphospholipid Syndrome in Systemic Autoimmune Diseases Edited by: Ricard Cervera, Joan Carles Reverter and Munther Khamashta

Pediatrics in Systemic Autoimmune Diseases Second Edition

Edited by

Rolando Cimaz A. Meyer Children’s Hospital and University of Florence, Florence, Italy

and Thomas Lehman Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, NY, United States

AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA Copyright r 2016, 2008 Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 978-0-444-63596-9 ISSN: 1571-5078 For Information on all Elsevier publications visit our website at http://www.elsevier.com/

Publisher: Sara Tenney Acquisition Editor: Linda Versteeg-Buschmann Editorial Project Manager: Halima Williams Production Project Manager: Edward Taylor Designer: Victoria Pearson Esser Typeset by MPS Limited, Chennai, India

Contents List of Contributors Preface

1.

Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis

xix xxiii

1

P.H. Muller and R. ten Cate

2.

Introduction Definitions Prevalence/Epidemiology Etiology and Pathogenesis Genetic Predisposition Dendritic Cells Gene Expression Profiling Myeloid-Related Protein 8/14 (S100A8/A9), S100A12 Clinical Manifestations Diagnostic Investigations Differential Diagnosis Treatment Outcome Measures Drugs Used in Children With JIA Future Concerns of Infectious Complications During (Biological) Treatment Concerns of Opportunistic Infections During (Biological) Treatment Concerns of Development of Other Autoimmune Diseases Concerns on Malignancies During Biological Treatment Prognosis References

1 2 3 3 3 7 7 8 8 10 12 15 15 15 17 17 17 17 18 18 19

Juvenile-Onset Spondyloarthritis

31

R. Burgos-Vargas and S.M.L. Tse Introduction Epidemiology Pathogenesis Histopathology

31 31 32 32 v

vi

3.

Contents

Clinical Findings Initial Symptoms and JoSpA Differential Diagnosis Peripheral Arthritis and Enthesitis Features Sacroiliac and Spinal Features Health-Related Quality of Life and Functioning Imaging Studies Clinical Presentation Undifferentiated SpA Juvenile-Onset AS Reactive Arthritis Juvenile-Onset Psoriatic Arthritis Crohn’s Disease and Ulcerative Colitis Ankylosing Tarsitis Therapeutic Recommendations References

34 34 36 37 39 39 41 41 42 42 42 42 43 43 46

Systemic Juvenile Idiopathic Arthritis

53

M. Batthish and R. Schneider

4.

Introduction Prevalence and Epidemiology Pathogenesis of SJIA Common Clinical Manifestations Growth Less Common Clinical Manifestations Macrophage Activation Syndrome Laboratory Investigations Radiologic Investigations Differential Diagnosis Treatment Disease Course, Outcome, and Prognosis Mortality References

53 54 54 56 60 61 63 66 67 68 70 74 75 76

Macrophage Activation Syndrome

85

A. Ravelli, F. Minoia, S. Davı` and A. Martini Introduction Clinical, Laboratory, and Histopathological Features Epidemiology Triggering Factors Nomenclature and Classification Pathogenesis Diagnostic Guidelines Novel Classification Criteria for MAS Complicating SJIA Performance of the New Classification Criteria in MAS Occurring During Biologic Therapy

85 85 87 88 90 91 94 95 98

Contents

5.

vii

Management References

98 100

Assessment Tools in Juvenile Idiopathic Arthritis

107

A. Consolaro and A. Ravelli

6.

107

Introduction The Core Set of Outcome Measures and Definition of Improvement in JIA Disease Activity States The Juvenile Arthritis Disease Activity Score Disease Activity States Based on the JADAS Measures of Physical Function Measures of Health-Related Quality of Life Parent/Patient Acceptable Symptom State A Multidimensional Questionnaire for JIA Parent and Patient-Centered Disease Activity Measures Measures of Damage Conclusions References

107 109 110 114 116 117 120 120 122 122 123 124

Childhood Uveitis

129

A. Brambilla and G. Simonini

7.

Introduction Juvenile Idiopathic Arthritis-Associated Uveitis Type of Arthritis Age and Gender Laboratory Markers Genetic Factors Diagnosis Complications Treatment Corticosteroids Immunosuppressant Agents Methotrexate Other Immunosuppressant Therapies Biologic Response Modifiers Tumor Necrosis Factor Alpha Inhibitors Non anti-TNF-Alpha Biologic Activity Modifiers References

129 131 131 132 132 132 133 133 134 135 136 136 137 137 137 139 140

Amplified Musculoskeletal Pain Syndromes

145

D.D. Sherry Introduction Nomenclature

145 145

viii

Contents

History Criteria Incidence and Prevalence Age, Sex, and Race Etiology and Pathogenesis Clinical Presentation Sleep Measurement of Pain, Dysfunction, and Stress Differential Diagnosis Laboratory Examination Imaging Examinations Pathology Treatment Psychotherapy Physical and Occupational Therapy Transcutaneous Nerve Stimulation Acupuncture Medical Treatment Tricyclic Antidepressants Other Antidepressants Antiepileptics Bisphosphonates Steroids Opioids Ketamine Invasive Procedures Sympathetic Blocks and Sympathectomy Peripheral Nerve Blocks Epidural Infusions Spinal Cord Stimulators Amputation Miscellaneous Therapies A Philosophy of Therapy Course and Outcomes Conclusion References

8.

146 146 146 149 149 151 153 153 154 154 154 156 156 157 158 159 160 160 160 160 161 161 161 161 161 162 162 162 162 162 163 163 163 163 164 164

Systemic Lupus Erythematosus: Etiology, Pathogenesis, 173 Clinical Manifestations, and Management T. Lehman, F. Nuruzzaman and S. Taber Introduction Definition/Classification Epidemiology Genetics Etiology/Pathogenesis

173 174 174 174 175

Contents

9.

ix

Clinical Manifestations and Treatment General Principles Lupus Nephritis Neuropsychiatric Lupus Pulmonary Manifestations Cardiac Manifestations Hematologic Manifestations Systemic Lupus Erythematosus-Related Musculoskeletal Disease Cutaneous Involvement New Developments General Aspects of Management Course and Prognosis Alternate Forms of Lupus: Neonatal, Discoid, Drug-Induced Key Points References

175 175 176 179 180 181 181 182 183 183 184 184 185 185 186

Neonatal Lupus Syndromes

191

A. Brucato, R. Cimaz and V. Ramoni Introduction Anatomical and Pathological Findings Pathogenesis Myocarditis Arrhythmogenesis and Electrophysiological Effects Apoptosis, Transforming Growth Factor-β, Toll-Like Receptor, and the Road to Scar Genetics Other Pathogenetic Mechanisms Evaluation of the Fine Specificities of the Maternal Autoantibody Profile Epidemiology and Definition of Congenital Complete Atrioventricular Block Clinical Features Risk of Delivering a Child With Congenital Complete Heart Block: 1 2% Cardiac Manifestations Skin Rash Neurological Problems and the Possible Role of Fluorinated Corticosteroids Laboratory Abnormalities Prognosis Infants Maternal Risk of Recurrence Obstetric Management of Pregnancy at Risk of Developing Congenital Complete Heart Block Assessment of First-Degree Atrioventricular Block In Utero Fluorinated Steroids and Regression of Second-Degree Atrioventricular Block

191 191 192 192 192 193 194 195 196 196 197 197 198 201 202 203 203 203 204 204 204 205 205

x

Contents

Treatment In Utero Therapy Postnatal Treatment Other Pregnancy Outcomes in Women With Anti-Ro/SSA Antibodies Anti-Ro/SSA-Negative Congenital Heart Block References

10. Juvenile Dermatomyositis

206 206 208 209 209 209 219

C. Pilkington Introduction Incidence of Juvenile Dermatomyositis Juvenile Dermatomyositis Epidemiology Pathogenesis Clinical Manifestations Symptoms at Diagnosis Clinical Signs: Rash Clinical Signs: Calcinosis Clinical Signs: Muscle Weakness General Assessment at Onset Disease Course Diagnostic Investigations Laboratory Tests Radiological Muscle Biopsy Functional Tests Diagnosis Diagnostic Criteria Diagnostic Problems Differential Diagnosis Treatment Evidence Base for Drug Treatment Nonmedical Treatment Recent Developments Key Points Acknowledgments References

11. Localized Scleroderma in Children

219 219 220 220 220 220 221 222 222 223 224 225 225 225 226 226 227 227 227 228 228 228 230 230 231 231 231 235

F. Zulian and F. Sperotto Juvenile Localized Scleroderma Clinical Classification Associated Conditions Epidemiology Etiology and Pathogenesis

235 235 239 240 240

Contents

Extracutaneous Manifestations Laboratory Findings Disease Monitoring Treatment Course of the Disease and Prognosis References

12. Juvenile Systemic Sclerosis

xi 241 242 242 243 244 244 249

I. Foeldvari Introduction Incidence and Prevalence Classification Etiology/Pathogenesis Clinical Manifestations Diagnostic Investigations Radiological Functional Biochemistry/Serology/Immunology Evaluation of the Severity of the Disease Differential Diagnosis Treatment Key Points References

13. Autoinflammatory Disorders in Children

249 249 249 250 251 258 258 258 259 260 260 261 261 262 267

G. Elizabeth Legger and J. Frenkel Abbreviations Introduction Differential Diagnosis Treatment in General Disorders Primarily Affecting IL-1 Family Cytokine Regulation Cryopyrin-Associated Periodic Syndromes Deficiency of IL-1 Receptor Antagonist DITRA NLRC4-Associated Autoinflammatory Syndromes NLRP12-Associated Periodic Syndrome/Familial Cold Autoinflammatory Syndrome 2 Disorders Indirectly Affecting IL-1 Family Cytokine Regulation Hyper IgD Syndrome Familial Mediterranean Fever Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne Syndrome Majeed Syndrome Autosomal Recessive Systemic Juvenile Idiopathic Arthritis

267 268 271 274 274 274 277 278 279 279 280 280 283 286 288 288

xii

Contents

Protein Folding Disorders TNF Receptor-Associated Periodic Syndrome Proteasome-Associated Autoinflammatory Syndrome Interferonopathies STING-Associated Vasculopathy With Onset in Infancy Aicardi Goutieres Syndrome Autoinflammation With Immunodeficiency HOIL-1 Deficiency PLCγ2 Mutations PLCG2-Associated Antibody Deficiency and Immune Dysregulation ADA2 Deficiency Sideroblastic Anemia With Immunodeficiency, Fevers, and Developmental Delay Key Points References

14. Periodic Fever With Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA)

288 288 290 291 292 292 292 292 293 293 293 294 294 295

305

M. Hofer Introduction Clinical Presentation Epidemiology Diagnosis Pathogenesis Treatment Conclusion References

15. Chronic Recurrent Multifocal Osteomyelitis and Related Disorders

305 305 306 307 308 309 311 311

315

P.J. Ferguson Introduction Nomenclature Prevalence and Epidemiology Etiology and Pathogenesis Immune Dysregulation and Possible Triggers Genetics Mendelian Autoinflammatory Bone Disorders Majeed Syndrome (OMIM #609628) Deficiency of the Interleukin-1 Receptor Antagonist (OMIM #612852) Clinical Manifestations of Nonsyndromic Chronic Recurrent Multifocal Osteomyelitis Associated Inflammatory Disorders Diagnostic Testing Differential Diagnosis

315 315 316 316 316 318 318 318 321 322 322 323 326

Contents

Treatment Prognosis References

16. Kawasaki Disease

xiii 327 328 329 341

J. Anton and R. Cimaz Introduction Epidemiology Etiology Pathogenesis Clinical Manifestations Atypical and Incomplete Kawasaki Disease Laboratory Findings Treatment Vaccinations Follow-up Cardiac Imaging Outcome References

341 342 342 344 345 348 349 349 351 351 352 353 354

17. IgA Vasculitis (Henoch Scho¨nlein Purpura), Polyarteritis Nodosa, Granulomatous Polyangiitis (Wegener 361 Granulomatosis), and Other Vasculitides S. Ozen and Y. Bilginer Introduction Classification Common Vasculitides in Children IgA Vasculitis/Henoch Scho¨nlein Purpura Epidemiology Etiology and Pathogenesis Clinical Manifestations Diagnostic Investigations Differential Diagnosis Treatment Polyarteritis Nodosa Epidemiology Etiology and Pathogenesis Diagnostic Investigations Differential Diagnosis Treatment Granulomatous Polyangiitis (Wegener’s Granulomatosis) Epidemiology Etiology and Pathogenesis Clinical Manifestations Diagnostic Investigations

361 362 362 362 362 363 364 365 365 366 367 368 368 369 370 370 371 371 371 372 372

xiv

Contents

Differential Diagnosis Treatment Takayasu Arteritis Epidemiology Clinical and Laboratory Features Treatment Other Rare Vasculitides in Childhood Eosinophilic Granulomatous Polyangiitis (Churg Strauss Syndrome) Hypocomplementemic Urticarial Vasculitis (Anti-C1q Vasculitis) Variable Vessel Vasculitides Single Organ Vasculitides Cutaneous Leukocytoclastic Angiitis Primary Central Nervous System Vasculitis Secondary Vasculitides References

18. Pediatric Antiphospholipid Syndrome

373 374 374 375 375 375 376 376 377 377 377 377 377 378 378 385

ˇ and R. Cimaz T. Avcin Introduction Prevalence of Antiphospholipid Antibodies Healthy Children Systemic Lupus Erythematosus Other Diseases Infections and Vaccinations Epidemiology of Antiphospholipid Syndrome Etiology and Pathogenesis Clinical Manifestations Thromboses Catastrophic Antiphospholipid Syndrome Hematological Manifestations Neurological Manifestations Other Manifestations Neonatal Antiphospholipid Syndrome Diagnostic Investigations Differential Diagnosis Treatment Primary Thrombosis Prophylaxis Secondary Thrombosis Prophylaxis Treatment of Catastrophic Antiphospholipid Syndrome Treatment of Neonatal Antiphospholipid Syndrome References

19. Behc¸et’s Disease

385 385 385 386 387 387 388 389 390 391 391 393 394 395 396 397 398 398 399 399 400 400 401 409

I. Kone´-Paut Definition/Classification Etiology/Pathogenesis

409 410

Contents

Genetics Epidemiology Clinical Manifestations Fever Mucocutaneous Lesions Ocular Lesions Neurological Lesions Articular Features Gastrointestinal Involvement Vascular Involvement Pulmonary Involvement Cardiac Involvement Urinary and Nephrological Involvement Outcome and Prognosis Diagnostic Investigation Differential Diagnosis Aphthosis Periodic Fever Syndromes Neurological Involvement Uveitis Arthritis Treatment Mucocutaneous Lesions Arthritis Severe Manifestations References

20. Childhood Sarcoidosis

xv 411 411 412 412 412 414 415 416 417 417 418 418 418 418 419 419 419 420 420 420 421 421 421 421 422 423

427

C.H. Wouters and C.D. Rose Introduction Definition Nomenclature History Epidemiology Etiology/Pathogenesis Clinical Manifestations Classic Form: Onset Classic Form: Articular Involvement Classic Form: Cutaneous Manifestations Classic Form: Ocular Manifestations Classic Form: Internal Organ Disease Classic Form: Vascular Involvement Classic Form: Late Disease Other Pediatric Granulomatous Inflammatory Disease Variants: Systemic Granulomatosis, Granulomatous Panniculitis, and Granulomatous Osteitis

427 427 427 428 429 429 434 434 435 437 438 439 439 439

439

xvi

Contents

Adult-Type Childhood Sarcoid Arthritis Diagnostic Investigations Routine Laboratory Investigations Pathology Genetic Testing Imaging Differential Diagnosis Arthritis Uveitis Cutaneous Manifestations Vasculitis Treatment and Prognosis Key Points References

21. Rheumatic Fever

440 440 440 441 441 442 442 442 445 445 445 446 447 447 451

M.T. Terreri and C.A. Len Introduction Prevalence Epidemiology Etiology/Pathogenesis Clinical Manifestations Arthritis Carditis Sydenham’s Chorea Subcutaneous Nodules Erythema Marginatum Other Manifestations Diagnosis Laboratory Tests Diagnosis of Rheumatic Carditis Diagnostic Criteria Differential Diagnosis Treatment Key Points References

22. Lyme Borreliosis

451 451 452 452 453 454 454 454 455 455 455 456 456 456 457 458 458 460 460 465

H.-I. Huppertz and H.J. Girschick Introduction Persistent Infection Immunopathological Reactions Autoimmunity Conclusions Key Points References

465 466 466 467 467 468 468

Contents

23. Tumor Necrosis Factor Inhibitors in Pediatric Rheumatology

xvii

471

V. Gerloni, I. Pontikaki and F. Fantini Introduction TNF in the Pathogenesis of JIA Anti-TNFα Therapy in JIA TNFα Blockade in the Treatment of Systemic Onset JIA TNFα Blockade in the Treatment of JIA-Associated Chronic Anterior Uveitis TNFα Blockade in the Treatment of Juvenile Spondyloarthropathies Adverse Events of TNFα Blockade Hyperergic Reactions Cutaneous Manifestations Neuropsychiatric Manifestations Infections TNF Blockade and Vaccines TNF Blockade and Macrophage Activation Syndrome New Onset or Worsening of Autoantibody-Mediated Diseases New Onset of Inflammatory Bowel Diseases Chronic AU Reactivation as AE TNFα-Inhibitors in Juvenile Dermatomyositis TNFα-Inhibitors in Other Pediatric Rheumatic Diseases Conclusions Key Points References

24. Other Biological Therapies for Pediatric Rheumatic Diseases

471 472 473 477 477 478 479 480 480 481 482 483 483 484 485 485 486 487 488 489 490

503

A. Santimov and A.A. Grom Introduction Biologics and Biosimilars General Properties of Biologics Nomenclature Commonly Used Biologics in Pediatric Rheumatic Diseases Proteins That Inhibit Costimulatory Signals Necessary for T-Cell Activation Cytokine Inhibitors Recommended Management of Laboratory Abnormalities IL-1 Inhibiting Biologics General Safety Considerations Active Infections Combination Therapy Vaccinations Surgical Procedures Pregnancy

503 503 504 505 505 505 507 509 509 519 519 519 519 520 520

xviii

Contents

Rare Adverse Events Opportunistic Infections Malignancies New Autoimmunity General Safety Laboratory Monitoring References

25. Physiotherapy Management of Pediatric Rheumatology Conditions

520 520 521 521 521 521

527

S. Maillard Introduction Philosophy of Treatment Principles Assessment Subjective Assessment History of Present Condition Presenting Problems and Symptoms Past Medical History Activities of Daily Living/Function Objective Assessment Assessment of Each Joint, Including Spinal Movements Observation of General Movement and Function Functional Questionnaires (or Some Form of Validated Disease Function Measure) Physiotherapy Management Specific Information for Individual Conditions Main Treatment Goals for All Conditions Muscle Strengthening and Endurance Exercises Pain Inhibits Muscle Function Inflammation Biomechanical Loss of Mobility Disease Activity Muscle Imbalance Training Children’s Muscles Specific Exercise Program Key Points References

Index

527 527 530 530 530 531 532 533 534 535 536 537 537 538 539 539 540 540 540 541 541 541 541 542 551 551

557

List of Contributors J. Anton Pediatric Rheumatology Unit, Hospital Sant Joan de De´u, Universitat de Barcelona, Barcelona, Spain T. Avˇcin Department of Allergology, Rheumatology and Clinical Immunology, Children’s Hospital Ljubljana, University Medical Center, Ljubljana, Slovenia M. Batthish Division of Rheumatology, Department of Pediatrics, McMaster Children’s Hospital, McMaster University, Hamilton, ON, Canada Y. Bilginer Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey A. Brambilla Rheumatology Unit, NEUROFARBA Department, Anna Meyer Children Hospital, University of Florence, Firenze, Italy A. Brucato Department of Internal Medicine, Ospedale Papa Giovanni XXIII (previously named Ospedali Riuniti), Bergamo, Italy R. Burgos-Vargas Rheumatology Department, Hospital General de Mexico and Faculty of Medicine, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico R. Cimaz A. Meyer Children’s Hospital and University of Florence, Florence, Italy A. Consolaro Istituto Giannina Gaslini and Universita` degli Studi di Genova, Genova, Italy S. Davı` Department of Pediatric Sciences, Giannina Gaslini Institute, Genoa, Italy F. Fantini Unit of Pediatric Rheumatology, Chair and Department of Rheumatology, Gaetano Pini Institute, Milan, Italy P.J. Ferguson University of Iowa Carver College of Medicine, Iowa City, IA, United States I. Foeldvari Hamburger Centre of Pediatric and Adolescent Rheumatology, Scho¨n-Klinik-Eilbek, Hamburg, Germany J. Frenkel Department of General Paediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands V. Gerloni Unit of Pediatric Rheumatology, Chair and Department of Rheumatology, Gaetano Pini Institute, Milan, Italy H.J. Girschick Universita¨tskinderklinik Wu¨rzburg, Wu¨rzburg, Germany, Klinik fu¨r Kinder- und Jugendmedizin, Vivantes Netzwerk fu¨r Gesundheit GmbH, Klinikum im Friedrichshain, Berlin, Germany

xix

xx

List of Contributors

A.A. Grom Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States M. Hofer Pediatric Immunology and Rheumatology of Suisse Romande, CHUV, University of Lausanne, Lausanne, Switzerland H.-I. Huppertz Prof.-Hess-Kinderklinik, Klinikum Bremen-Mitte, Bremen, Germany; Universita¨tskinderklinik Go¨ttingen, Go¨ttingen, Germany I. Kone´-Paut Department of Pediatric Rheumatology, National Reference Center for Auto-Inflammatory Disorders, Biceˆtre University Hospital, Le Kremlin Biceˆtre, France G. Elizabeth Legger Department of Paediatric Rheumatology and Immunology, University Medical Centre Groningen, Groningen, The Netherlands T. Lehman Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, NY, United States C.A. Len Pediatric Rheumatology Unit, Department of Pediatrics, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil S. Maillard Great Ormond Street Hospital, London, United Kingdom A. Martini Giannina Gaslini Institute, Genoa, Italy F. Minoia Department of Pediatric Sciences, Giannina Gaslini Institute, Genoa, Italy P.H. Muller Department of Pediatric Rheumatology, Leiden University Medical Center, Leiden, The Netherlands; Department of Pediatric Rheumatology, Sophia Children’s Hospital, Rotterdam, The Netherlands F. Nuruzzaman Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, NY, United States S. Ozen Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey C. Pilkington Great Ormond Street and University College Hospitals, London, United Kingdom; JDRC, Department of Rheumatology, Institute of Child Health, London, United Kingdom I. Pontikaki Unit of Pediatric Rheumatology, Chair and Department of Rheumatology, Gaetano Pini Institute, Milan, Italy V. Ramoni Department of Internal Medicine, Ospedale Papa Giovanni XXIII (previously named Ospedali Riuniti), Bergamo, Italy; I.R.C.C.S Policlinico San Matteo Foundation, Division of Rheumatology, Pavia, Italy A. Ravelli Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Department of Pediatric Sciences, Giannina Gaslini Institute, Genoa, Italy; Istituto Giannina Gaslini and Universita` degli Studi di Genova, Genova, Italy C.D. Rose Thomas Jefferson University, Philadelphia, PA, United States; duPont Children’s Hospital, Wilmington, DE, United States A. Santimov Department of Pediatrics, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russia

List of Contributors

xxi

R. Schneider Division of Rheumatology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada D.D. Sherry The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States G. Simonini Rheumatology Unit, NEUROFARBA Department, Anna Meyer Children Hospital, University of Florence, Firenze, Italy F. Sperotto Pediatric Rheumatology Unit, Department of Pediatrics, University of Padova, Padova, Italy S. Taber Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, NY, United States R. ten Cate Department of Pediatric Rheumatology, Leiden University Medical Center, Leiden, The Netherlands M.T. Terreri Pediatric Rheumatology Unit, Department of Pediatrics, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil S.M.L. Tse Division of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada C.H. Wouters Department of Microbiology and Immunology, University of Leuven, Pediatric Immunology, Leuven, Belgium; Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium F. Zulian Pediatric Rheumatology Unit, Department of Pediatrics, University of Padova, Padova, Italy

Preface Since the first edition of this text there has been steady progress in our understanding of the autoimmune diseases of childhood, and we have therefore added several chapters to this edition. The number and nature of autoinflammatory diseases is becoming increasingly well understood. As the concept expands it is probable that both systemic onset juvenile idiopathic arthritis and chronic recurrent multifocal osteomyelitis will be added to the list of autoinflammatory diseases. Similarly, the expansion of genetic testing has increasingly clarified the error of lumping so many disparate conditions under the nomenclature of juvenile idiopathic arthritis. Not only is nearly every form of arthritis seen in adults recognized in childhood, but in addition there are numerous genetic forms of arthritis that manifest primarily among the pediatric population. The years since the publication of the first edition of this book have seen steadily increasing numbers of pediatric rheumatologists around the world. Many are dedicated solely to serving the children in need of their services, but an increasing number are working in research settings designed to increase our knowledge of the best care for children. Too often we are still dependent on the happenstance that remedies effective for adults with rheumatoid arthritis are effective for children as well. Those studying the autoimmune diseases of children have the opportunity to move to the forefront of clinical research as do those studying the autoinflammatory conditions. We have again gathered the latest insights into the autoimmune diseases of children from a variety of experts around the world. As much as possible these chapters provide insights into the how and why of the diseases, not simply a summary of the relevant references. We hope in these chapters you find both insight and inspiration to move forward to improving the care of children with autoimmune disease. Rolando Cimaz and Thomas Lehman Editors

xxiii

Chapter 1

Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis P.H. Muller1,2 and R. ten Cate1 1

Department of Pediatric Rheumatology, Leiden University Medical Center, Leiden, The Netherlands, 2Department of Pediatric Rheumatology, Sophia Children’s Hospital, Rotterdam, The Netherlands

INTRODUCTION When a child under the age of 16 years has arthritis with a duration exceeding 6 weeks the diagnosis of juvenile idiopathic arthritis (JIA) is probable. Other diseases need to be excluded, especially in the absence of commonly found serological factors such as antinuclear antibodies (ANAs). JIA is a heterogeneous group of diseases and only the category with immunoglobulin M (IgM) rheumatoid factor (RF) is thought to be equivalent to adult rheumatoid arthritis (RA). In the past, several names have been given to chronic arthritis in childhood such as juvenile RA and juvenile chronic arthritis. Since an International League of Associations for Rheumatology work force (last revised in 2007) proposed the name juvenile idiopathic arthritis, this name has been adopted, both in Europe and the United States. Seven categories of JIA are recognized, as shown in Table 1.1 [1]. This classification is currently being questioned. New classification schemes are suggested to incorporate ANA status, age of onset, and symmetry of arthritis [2] but cytokines, genetics, and gene expression profiles might be promising fields to include in future classification [3
8]. Usually children with JIA are first seen by an orthopedic surgeon or a pediatrician and referred to a pediatric rheumatologist in a later stage [9]. As damage to the joints can be prevented by early and adequate medical therapy, permanent postacademic education on the subject of rheumatic diseases in childhood is mandatory in order to obtain early referral of children with a suspicion of inflammatory arthritis.

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00001-3 © 2016 Elsevier B.V. All rights reserved.

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TABLE 1.1 Categories of Juvenile Idiopathic Arthritis (ILAR Classification) G G G G

G G G

Systemic Polyarticular RF-negative Polyarticular RF-positive Oligoarticular G Persistent G Extended Psoriatic arthritis Enthesitis-related arthritis Undifferentiated arthritis G Fits no other category G Fits more than one category

Having (a child with) JIA creates a considerable burden for the child, the family, friends, and school [10] and interventions have been developed to reduce the impact of the disease [11]. The importance of adequate patient and parent information and education is emphasized [12].

Definitions Oligoarticular JIA is defined as arthritis in one to four joints during the first 6 months with exclusion of G

G

G G G

Psoriasis, diagnosed by a dermatologist in at least one first or second grade family member; Human leukocyte antigen-B27 (HLA-B27) associated disease in at least one first or second grade family member; Presence of RF; Arthritis in a boy older than 8 years and HLA-B27 positive; Systemic JIA.

In children with persistent oligoarticular JIA the number of joints involved remains four or less throughout the course of the disease. In extended oligoarticular JIA the arthritis shows extension to polyarthritis after the first 6 months. IgM RF negative polyarticular JIA is defined as arthritis in five or more joints during the first 6 months with negative tests for IgM RF and exclusion of systemic JIA. IgM RF positive polyarticular JIA is defined as arthritis in five or more joints during the first 6 months and presence of the IgM RF on two occasions with an interval of 3 months with the exclusion of systemic JIA.

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PREVALENCE/EPIDEMIOLOGY Joint pain, joint swelling, and morning stiffness are not uncommon in childhood. However, only a minority of children with these symptoms, suggestive of arthritis, are diagnosed with JIA by objective criteria and thorough physical examination performed by an experienced (pediatric) rheumatologist. The exact incidence and prevalence of JIA is unknown. Studies on these topics have shown different results, influenced by the different populations that have been studied as well as ethnicity and environmental factors [13,14]. Also seasonal variation has been described, even in the month of birth [15]. The incidence probably varies from 11 to 35 per 100,000 in the population [16]. Using the American College of Rheumatology criteria, the prevalence of JIA also shows a considerable variability ranging from 15 to 150 per 100,000 [13]. Several studies on the prevalence of JIA have suggested that these figures might underestimate the true prevalence. Close examination of the children under study and restriction to those who are at risk will probably lead to a considerably increase in the prevalence of JIA. A trend toward increasing incidence of JIA is observed, unclear whether due to greater awareness or a real increase in patients [14]. Although JIA can be divided into different categories with different peak incidences of age, it is obvious that despite these differences, generally more girls than boys develop JIA except for the systemic onset type.

ETIOLOGY AND PATHOGENESIS JIA probably has a multifactorial etiology [17]. Genetic predisposition, environmental influences, provoking infections, hormonal factors, and vulnerability in childhood are involved in the development of JIA [18]. The genetic predisposition includes multiple genes that are related to immunity and inflammation.

Genetic Predisposition HLA class I and class II alleles are both associated with an increased risk to develop JIA. The last decade’s research in this field has expanded. It is estimated that genetical factors account for 13% of the risk in JIA [19]. Early-onset oligoarticular JIA in girls is related to the class I antigen HLA-A2. Persistent and extended oligoarticular JIA are associated with class II antigens HLA-DRB1 08 and HLA-DRB1 11, DQA1 04, DQA1 05, and DQB1 04. Enthesitis-related JIA is associated with HLA-B27 (class I) and the class II antigens HLA-DRB1 01 and HLA-DQA1 0101. Systemic-onset JIA is related to HLA-DRB1 11. HLA DR4 is associated with RF-positive disease, like in adult disease [20]. The genetical associations of JIA were recently reviewed by Cobb [21].

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Non-HLA immune regulatory genes are also involved, and the list has expanded in the last years to include PTPN22 [22] STAT4, TRAF-C5 [23], TNF308a, 4q27 [24], DNAM-1 [25], and VTCN1 [26], although not all of them have been independently replicated yet. The genetic predisposition also includes genes that are related to cytokine production [27]. Nowadays, JIA is thought to be triggered by an initial adaptive immune response toward an unknown autoantigen. Right after this event, almost all cells of the immune system start to be involved. T lymphocytes, cytokine production, immune complexes (ICs), and immunodysregulation all lead to inflammation of the joint. Cytokines that are involved in the pathogenesis of nonsystemic JIA are tumor necrosis factor (TNF)-α, IL-1, IL-2, IL-4, IL-6, IL-7, IL-18, and IL2R [28,29]. Concentrations of these cytokines are increased, both in plasma and in the synovial fluid. IL-1α and IL-1β are both particularly involved in oligoarticular and polyarticular JIA and related to disease activity. Increase of IL-1α has been detected in plasma and increase of IL-β in synovial fluid. Soluble TNF-α is also increased in plasma as well as synovial fluid in the more restricted disease types of oligoarticular disease. IL-4 is more prominent in the synovium [30]. IL-17 can induce production of IL-6, MMP-1 and -3, and IL-8 at the synovium, which all can lead to joint damage [31]. During phases of clinical remission, cytokines do not return to a normal healthy-control situation but reflect a condition of compensated inflammation [32]. Bacterial infections not only can cause reactive arthritis, but are also involved in the development of JIA. In children with JIA humoral as well as cellular immune responses against bacterial heat shock proteins (HSPs) have been described. These HSPs are highly conserved proteins of bacterial origin and have been demonstrated in plasma and synovial fluid of JIA patients. T-lymphocyte responses to HSP-60 were demonstrated before remission of JIA and it thus has been speculated that induction of immunotolerance to specific T cells might be beneficial for JIA patients, and nasal administration of HSP-60 might be used as future immunotherapy [33,34]. In 2011 HSP-60 serum concentrations were found to be predictive for disease flare [35]. Complement activation is also involved in the pathogenesis of JIA. Complement components of both the classical pathway (C4) and the alternative pathway (Bb) showed increased levels and correlated with disease activity [36,37]. Mannose-binding lectin (MBL) is a major component of the lectin route of complement activation. An increased frequency of mutations in exon 1 of the MBL2 gene has been demonstrated in RA and JIA patients, indicating a possible role of MBL deficiency in the pathogenesis of JIA [38,39]. The possible role of infection in JIA has also been demonstrated by increased incidence of chronic arthritis in patients with hypogammaglobulinemia, IgA deficiency, and C2 deficiency [40].

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Furthermore, MBL deficiency might lead to defective clearance of ICs and apoptotic cells, as seen in individuals with C1q deficiency. Partial C4 deficiency has also been linked to JIA [41]. Recently the alternative pathway was suspected to be involved in oligoarticular JIA [42]. Circulating immune complexes (CICs) have been demonstrated in JIA. These CICs have been detected in plasma and synovial fluid and revealed complement activation as well as cytokine secretion potential. The CICs correlated with disease activity and systemic features of JIA [36]. The activating capacity of CICs is related to their size. Although often undetectable in plasma of JIA patients, IgM RF is bound to the ICs and concentration of this RF is related to disease activity [43]. Membrane-attack complex bound to CICs correlated significantly with erythrocyte sedimentation rate (ESR), further supporting the notion of complement-mediated tissue injury that is triggered by IC-mediated classical pathway activation [44]. The T-lymphocyte-mediated immune response is important in chronic inflammation. T lymphocytes are the most prominent mononuclear cells in synovial fluid. The T lymphocytes can be differentiated in CD4 (helper/inducer) and CD8 (suppressor/cytotoxic) cells with different functional abilities (Tables 1.2 and 1.3).

TABLE 1.2 Recommended Frequency of Ophthalmological Investigation in Children With Persistent or Extended Oligoarticular Juvenile Idiopathic Arthritis According to the American Academy of Pediatrics (1993) Subtype of Arthritis

Onset of Arthritis (Years of Age) ,7 yearsa

$ 7 yearsb

+ANA

Hc

M

2 ANA

M

M

+ANA

Hc

M

2ANA

M

M

Persistent oligoarticular

Extended oligoarticular

H: high risk = every 3
4 months ophthalmological investigation. M: medium risk = every 6 months ophthalmological investigation. G L: low risk = every 12 months ophthalmological investigation (all other patients with JIA). a All patients are regarded low risk 7 years from onset of arthritis; ophthalmological investigation yearly. b All patients are regarded low risk 4 years from onset of arthritis; ophthalmological investigation yearly. c All patients with high risk are regarded medium risk 4 years from onset of arthritis. G G

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TABLE 1.3 Definitions of Disease Status and Juvenile Arthritis Disease Activity Score Cut-off Values Clinical Condition

Cut-off Value

Clinical remission

1

Minimal disease activity

Oligo 2 Poly 3.8

Acceptable symptom state

Oligo 3 Poly 4.3

Low disease activity

One or no active joints, normal ESR or C-reactive protein, pediatric granulomatous arthritis of overall disease activity score ,3 (0
10), patient/parent GA of overall well-being score ,2 (0
10)

An impaired thymic function, reflected by a decrease in CD4+ T cells, was described in oligoarticular and polyarticular JIA [45]. Recently the same phenomenon of premature aging was observed for CD8+ T cells in JIA patients [46]. The results of different studies on the possible pathogenetic role of CD4+ and CD8+ T lymphocytes have been inconsistent [18]. Increased CD8+ T lymphocytes have been demonstrated in systemic and polyarticular JIA; however, other studies showed decreased CD8+ T lymphocytes, especially in systemic disease [47]. Regulatory T cells (Tregs) first described by Sakaguchi [48] are increasingly thought to play a role in the pathogenesis of (the remitting course of) JIA [49]. These cells are characterized by expression of FOXP3, a transcriptional factor, necessary for the control of inflammation. Recently a review on the emerging role of the Tregs was published [50]. Coexpression of CD25 and FOXP3 in combination with a hypomethylated region within the FOXP3 gene, called the Treg-specific demethylated region, is considered the hallmark of stable Tregs. Recently it was discovered that environment-specific breakdown in FOXP3 stability may threaten the abrogation of inflammation in JIA [51]. Natural (thymic derived) and adaptive Tregs exist, but cannot be discerned as of this writing [50]. It seems that Tregs are heterogeneous and can differ in function. Tregs can be divided by HLA expression (DR+ and DR2) and by cellular markers (naı¨ve or memory). In oligoarticular JIA, at the site of inflammation Tregs of the activated memory phenotype are present. Th17 cells, a subset of the CD4+ effector T cells producing IL-17, are also present at the site of inflammation [52] and have a reciprocal relation to Tregs [53]. Both need TGF beta for induction and the Tregs and Th17 cells

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need to be balanced in a healthy-state situation. Tregs even seem to be able to convert into Th17 cells under certain circumstances [54]. In 2004 it was discovered that in JIA the numbers of Tregs are in fact paradoxically increased in the inflamed joint [55]. Serum Treg numbers, on the other hand, are normal or decreased in O-JIA. In SF of persistent oligoarticular JIA patients the numbers of Tregs are higher than in SF of extended to-be JIA patients. It is hypothesized that the balance between Tregs and Th17 cells is crucial in JIA and that they behave in a reciprocal relationship at the site of inflammation [56]. Possibly are Tregs dysfunctional in JIA? Studies suggest that the Tregs function well (are potent suppressors of inflammation) when taken out of the synovium, suggesting a role for the microenvironment affecting the Tregs in their function.

Dendritic Cells Dendritic cells (DCs) are antigen-presenting cells, necessary for T-cell activation. Evidence for their suspected role in the initiation and perpetuation of inflammation is scarce. Increased numbers of DC in synovial fluid have been described in oligoarticular and polyarticular JIA [57]. B-cell concentration is normal in oligoarticular and polyarticular JIA, however generally increased in patients with systemic JIA. Total levels of IgG might be elevated and a diversity of autoantibodies can be detected in sera of JIA patients. Like IgM rheumatoid-factor JIA, anticyclic citrullinated peptide (CCP) is associated with erosive disease [58]. The pathogenesis of JIA is also influenced by psychological factors. Dysregulation of the autonomic nervous system is related to impaired immunologic response and possible development of autoimmune disease [59].

Gene Expression Profiling Gene expression profiling, also known as transcriptomics, measures the expression level of mRNAs (transcripts) in a cell population at a certain time. In oligoarticular JIA, gene expression profiling on synovial fluid could help predict patients with an extended disease phenotype [60]. In polyarticular JIA, recently it was shown that gene expression was linked to therapeutic outcome at 6 months [61]. Furthermore, in polyarticular JIA, remission could be genomically characterized and differed markedly between methotrexate (MTX) and MTX/etanercept-induced remission. At the therapeutic level gene expression profiles were studied before and after MTX administration to analyze differentially expressed genes. A gene was identified that could contribute to genetic variability in MTX response [6,62,63]. Clinical remission on medication and clinical remission reflect

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states of balanced homeostasis between pro- and anti-inflammatory since gene expression profiling differed between healthy controls and the aforementioned categories [32].

Myeloid-Related Protein 8/14 (S100A8/A9), S100A12 These calcium-binding proteins produced by activated neutrophils and monocytes are present in the serum of patients with both oligoarticular and polyarticular JIA, next to their extreme elevation in active systemic JIA. These danger signals increase before clinical flare is obvious and therefore have predictive value. The serum concentrations of S100A8/A9 and S100A12 are related to the amount of inflammation [64,65]. Levels to predict disease flares have been determined and an ELISA is commercially available [66].

Clinical Manifestations When taking a history of (parents of) children with JIA pain is usually not a major symptom at onset [67], but the parents of young children may have noticed a regression in the motor phase of their child [68]. An asymmetric pattern is especially alarming. Swelling of the knee or ankle is often noticed by chance when parents are undressing or bathing the child. Other signs at onset can be behavioral problems, limping, or refusal to walk. In older children, especially in those with (IgM RF positive) polyarticular JIA, pain can be a presenting symptom. General malaise, low-grade fever, and fatigue can be present in severely affected children, mostly in those with polyarticular JIA. Morning stiffness and stiffness after spending prolonged time in the same position are common. The onset of JIA may be acute but usually is insidious. At physical examination the general condition of the child should be noticed. They may look anemic and, when suffering from systemic features, ill and in pain. Length and weight should be measured regularly as general growth impairment points at active disease and this may be aggravated by prolonged use of glucocorticoids, which is, in the biological era, becoming less common. In children with IgM RF-positive polyarticular JIA rheumatoid nodules at the extensor surface of the elbows or at the lateral sides of the feet can be found. Asymmetrical diffuse edema of hands or lower leg and ankle in a socklike form can be found in some children with polyarticular JIA [69].This lymphedema is usually nonpitting and not painful. In children with JIA who develop chronic anterior uveitis (CAU) before the onset of arthritis secondary changes in the eyes can be noticed, irregular pupils that do not respond properly to light may reflect the presence of

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synechia. Calcifications of the cornea may be present in the form of band keratopathy. Signs of arthritis are local swelling, increased temperature, pain elicited by movement, and limitation of motion. Local discoloration is very unusual except over the small joints in the hands and feet [70], and when present over a knee or ankle should be a reason for reconsideration of the JIA diagnosis. Establishing arthritis can be difficult, especially in young children with baby fat. An observation by an experienced child physiotherapist and/or the use of ultrasound or MRI with gadolinium enhancement can be helpful. In children with oligoarticular JIA asymmetric swelling of large joints like the knee, ankle, and elbow are most frequent, while in children with polyarticular JIA symmetric involvement of the small joints of the hands and feet is more common. In children with IgM RF swelling around the styloid processus of the ulnar can be prominent. Several complications may develop in children with oligoarticular and polyarticular JIA. Impaired growth and delay of puberty may be the result of disease activity [71] and the (currently outdated) chronic use of glucocorticoids aggravates the impairment of linear growth. Muscle atrophy and leg length discrepancy by accelerated local growth are findings in longstanding asymmetric arthritis [72]. Decreased bone mineral content can be observed in a quarter of children with early onset JIA [73]. Osteopenia can be detected in adolescents with early onset JIA [74]. Cardiac manifestations are rare but may be the cause of significant morbidity, especially valvular disease in RF-positive polyarticular JIA [75]. Parenchymal lung disease is an infrequent finding, but pulmonary function is impaired in some children with JIA [76]. Temporomandibular involvement is common in children with oligoarticular and polyarticular JIA [77,78]. Because of the high prevalence and discrepancy between clinical signs and presence of arthritis in the temporomandibular joint, regular orthodontic evaluation and orthopantomograms are recommended to enable early intervention [78]. Involvement of the temporomandibular joints may lead to impaired opening of the mouth and retrognatia. CAU is reported in up to 10
20% [79,80] of patients with JIA, and is the main secondary disease in JIA. It is associated with the presence of ANA. All children with JIA need to be screened with regular intervals (see Table 1.2) as this type of uveitis is asymptomatic until complications develop. The classic presentation of CAU is an anterior, nongranulomatous, uni- or bilateral uveitis. Slit-lamp examination is necessary to detect the inflammatory cells in the anterior chamber of the eye. It is therefore essential that all children with JIA are seen by an ophthalmologist at regular intervals.

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Early detection and treatment of CAU is of major importance to avoid sight-threatening complications including band keratopathy, synechia, cataract, glaucoma, macular edema, decreased vision, phthisis bulbi, and blindness [81]. Young age of onset (arthritis and uveitis), active uveitis at the time of onset of arthritis, and high uveitis activity at the time of diagnosis is associated with a higher risk of sight-threatening complications. The recommended frequency is listed in Table 1.2. Generally patients with JIA are divided into high- and low-risk groups depending on known risk factors for uveitis. Risk factors are young age of onset, female gender, and oligoarticular onset of JIA. Onset of arthritis usually precedes the onset of uveitis, but uveitis may also start first. The risk of developing uveitis is the highest shortly after onset of arthritis and decreases gradually after the first year [82].

DIAGNOSTIC INVESTIGATIONS In all children with chronic arthritis a full blood count is indicated. In most children with oligoarticular JIA normal hemoglobin levels are found. In some children with oligoarticular JIA with high disease activity and in children with polyarthritis moderate normocytic, hypochromic anemia can be present characteristic of the chronic anemia of inflammation [83]. Anemia and raised platelet count are associated with a less favorable prognosis. In a child with other systemic features like fever, skin rash, and lymph node enlargement other diagnosis like systemic JIA, other autoimmune diseases (such as systemic lupus erythematosus, SLE), or malignancy should be considered. The leukocyte count usually is normal. In children with active disease leukocytosis may be present. During treatment with sulfasalazine or MTX a low leukocyte count may represent drug-induced bone marrow suppression. In a child with possible JIA a low leukocyte count could be the key to another diagnosis; for example, SLE or leukemia. Platelets are within the normal range in most children with oligoarticular and polyarticular JIA, but may be raised in children with high disease activity. The acute phase reactants (ESR, C-reactive protein (CRP) levels) can be normal in children with JIA, but may be raised at onset of the disease and during exacerbations [84]. Blood chemistry is usually not abnormal at onset of JIA. The level of serum urea can increase during the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Liver function tests need to be carefully followed during the use of sulfasalazine and MTX. In the diagnostic phase, broad screening for infectious causes of arthritis is indicated as a variety of microorganisms may induce arthritis

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(see differential diagnosis). The onset of JIA and its exacerbations are frequently preceded by infections [85]. In children with active (poly)arthritis, a raised IgG can be present. In children with oligoarticular JIA the IgA may be low or even absent. During treatment with sulfasalazine the level of IgA may decrease [86]. ANAs are found in about 75% of children with oligoarticular JIA and in 50% of children with polyarticular JIA [8,87]. Their presence is strongly associated with the risk of developing CAU but does not seem to be associated with the severity of the uveitis [80]. A positive ANA is rare in children, but can be a temporary false-positive finding in infections (streptococci, viral). Antibodies to dsDNA are usually not found. When they are detected the child could have SLE. Antibodies to extractable nuclear antigens (antiENA) are rarely present; anti-ENA may indicate other autoimmune diseases such as mixed connective tissue disease (MCTD). Tests for the IgM RF are less frequently positive in children with JIA than in adults with RA. In 5
10% of children with JIA, IgM RF can be detected during the course of the disease. Their presence is associated with onset of disease in girls around 13 years of age with clinical signs as in RA, progressive disease, and early erosions. Anti-CCP antibodies can be detected in the sera of patients with JIA but almost exclusively in the subset of children with IgM RF-positive disease [58]. Serum complement levels usually are within the normal ranges, but may be elevated at onset and during exacerbations of the illness. Analysis of the synovial fluid may provide valuable information in the diagnostic phase of a child with monoarthritis. The number of leukocytes reflects the severity of inflammation. A low leukocyte count (,2 3 109) is unlikely in infectious arthritis and suggests a mechanical disorder of the joint. Gram preparation and culture are indispensable to rule out infection. Polymerase chain reaction (PCR) for Borrelia burgdorferi and Mycobacterium tuberculosis are available. In children with oligoarticular and polyarticular JIA the synovial fluid is yellow with decreased viscosity. The white cell count is usually around 20,000 3 109/L with predominantly polymorphonuclear neutrophils and mononuclear cells. In a child with a chronic monoarthritis without circulating ANA, a synovial biopsy can be necessary to exclude local abnormalities of the synovial membrane when MRI findings are insufficient to make a diagnosis. In children with JIA the histological finding is an aspecific chronic inflammation. For the follow-up of radiological damage by JIA plain X-rays can be used. But in the changing era with early initiation of highly effective therapies there is a need for more sophisticated imaging modalities, more sensitive in detecting preerosive changes. Ultrasound and MRI are suitable to serve that purpose, but have not been validated yet [88
90]. The growing skeleton gives rise to numerous physiological changes over

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time which need to be taken into account during ultrasound and MRI examinations. There is an urgent need for normal values regarding ultrasound and MRI in healthy children. Up to the time of this writing, the exact value of MRI and ultrasound in detecting disease activity in JIA needs to be determined. Ultrasound can be a useful tool, but is not validated yet for detection of synovitis [91]. Subclinical synovitis on ultrasound is present in 3% of JIA patients in clinical remission. Subclinical synovial abnormalities are not related with early flare, in contrast with RA patients [92]. Pediatric scoring systems for MRI have been developed and are validated [88,93,94]. Recently a study showed that MRI is a promising biomarker in measuring therapeutic response [95]. Evidence-based points regarding the role of imaging in JIA are summarized and have been published [96]. At plain X-rays, at onset of the disease, usually only soft tissue swelling and periarticular osteoporosis can be detected. During the course of disease various radiological abnormalities may develop [97]. Ossification centers can develop earlier by increase of blood flow in the involved extremity, resulting in overgrowth but eventually premature closing of the epiphysis may lead to stunting of bone growth. Loss of cartilage can be reflected by narrowing of the joint space. Development of erosions in an early stage can be present in children with IgM RF polyarticular JIA. A radiological scoring system for children with JIA has been developed [98].

DIFFERENTIAL DIAGNOSIS Joint complaints are relatively frequent in childhood, but usually self-limiting and seldom require referral to a hospital. For a correct differential diagnosis, a clear difference must be made between myalgia, arthralgia, arthritis, and possible involvement of the bones. Infectious arthritis as well as reactive arthritis often have an acute onset and will recover with or without medication within approximately 6 weeks. Duration of arthritis of more than 6 weeks is called chronic arthritis. The most frequent cause of chronic arthritis in childhood is JIA. Not only infection or inflammatory diseases can cause complaints of the joints; other possibilities include traumatic, metabolic, hematological, malignant, and even psychogenic causes [99]. Infectious or bacterial arthritis is an acute illness, also called septic arthritis [100]. The child with septic arthritis is often very ill with high fever, and refuses to use the involved joint. One of the most important characteristics is extreme pain. Bacteria can enter the joint either by hematological spread or directly by penetration of the skin. Physical examination should include inspection of the skin to detect a porte d’entre´e, which might lead to identification of the microorganism. Most frequently involved microorganisms

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are Staphylococci and Streptococci. When bacterial arthritis is suspected, puncture of the joint to obtain synovial fluid should be performed for analysis on leukocyte count and bacterial culture. In recent years the occurrence of Kingella kingae as a pathogenic microorganism is increasingly recognized in cases of septic arthritis. This Gram-negative bacterium is the number one causative organism of septic arthritis in the age group 6
36 months [101,102]. It is recommended to have a high index of suspicion in young children presenting with joint inflammation, especially in cases of mildly elevated inflammatory markers [103]. PCR techniques for detection of K. kingae are therefore advocated. K. kingae is generally susceptible to the main antibiotics used in children with osteoarticular infections. The clinical course after treatment initiation is benign. It should be taken into account that osteomyelitis in the vicinity of a joint may give a clinical picture similar to that of infectious arthritis without yielding a positive culture of the synovial fluid [104]. Another microorganism that can cause arthritis is B. burgdorferi [105]. Lyme arthritis is often preceded by erythema migrans, myalgia, and arthralgia, which can be followed by recurrent as well as chronic arthritis [106]. Only in the minority of the patients is a tick bite remembered. After the erythema migrans, arthritis can develop even after months, often starting in one or both knees in episodes. Chronic arthritis occurs in approximately 20% of patients with Lyme arthritis, most frequent as monoarthritis of the knee. Diagnostic tests include PCR of synovial fluid and serology. The presence of anti-Borrelia IgG antibodies is not definite proof of Lyme arthritis because 5% of the adult population have positive IgG antibodies due to asymptomatic infection in the past. Anti-Borrelia IgM antibodies turn positive after approximately 6 weeks and are present for months, whereas IgG antibodies can be detected for years. Lyme arthritis eventually has a relatively good prognosis with complete recovery but a substantial proportion of patients needs more than one course of antibiotics and/or additional treatment with NSAIDs, disease-modifying antirheumatic drugs (DMARDs), intraarticular steroids, or even synovectomy. [107]. Arthritis can also develop after viral infections such as parvovirus, rubella, and hepatitis B, as well as viruses of the herpes group, adenoviruses, and para-myxoviruses [108]. Most of these viral infections will lead to reactive arthritis, and detection of the virus in the synovial fluid is often negative. Viral arthritis generally completely resolves within 6 weeks although chronic duration is possible. Arthritis can develop even after vaccination. Clinical presentation, viral exanthema, and duration of the arthritis are helpful in the diagnosis of possible viral arthritis. Mycoplasma pneumonia is another microorganism that can cause arthritis as well as spondylarthropathy in children [109]. Important symptoms include fever, cough, headache, and myalgia. Approximately 30% of the children with M. pneumonia infection will develop arthritis.

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Reactive arthritis can develop after viral infections, Neisseria meningococci infection, as well as gastroenteritis by Salmonella, Shigellla, Campylobacter, or Yersinia [110]. Reiter’s syndrome is an example of reactive arthritis, associated with HLA-B27, characterized by the triad of arthritis, conjunctivitis, and urethritis [111]. Acute rheumatic fever (ARF) is caused by Group A beta-hemolytic Streptococci (GABHS) [112]. It develops approximately 3 weeks after the GABHS infection, characterized by angina, high fever, illness, and headache. A sore throat is not always present. Arthritis is present in 80% of the patients, often with acute onset, painful polyarticular, migrating from one joint to another, and preferentially involving the large joints of the lower extremities [113]. The diagnosis of ARF is made according to the Jones criteria [114]. Carditis with possible heart failure is an important complication of ARF that occurs in 50% of patients. Mitralis valve and aorta valve stenosis can develop [115]. Other complications include Sydenham’s chorea, subcutaneous noduli, erythema marginatum, and (cutaneous) vasculitis [116]. When carditis is present, prophylactic antibiotic therapy (penicillin) is indicated according to the American Heart Association [117]. Reactive arthritis can develop after an infection with Streptococci without fulfilling the Jones criteria [118,119]. This arthritis is often less severe and not migrating, but with a longer duration. Other Streptococci species in addition to GABHS can cause this form of arthritis [120]. Diagnostic tests include bacterial culture of the throat, nose, and/or ears, as well as antistreptolysin-O-antibody titer and anti-Dnase-B [121,122]. Polyarthritis can be the first clinical sign of other autoimmune diseases like SLE, juvenile dermatomyositis, scleroderma, Sjo¨gren syndrome, MCTD, and systemic vasculitis. Apart from arthralgia, arthritis, and myalgia, these autoimmune diseases are characterized by organ involvement and positive autoantibodies. Hemophilia and sickle cell disease are both hematological disorders with possible involvement of the joint. Vaso-occlusive episodes can be very painful and difficult to distinguish from arthritis [123]. Malignancies like leukemia, lymphoma, Hodgkin disease, osteosarcoma, Ewing sarcoma, as well as neuroblastoma can lead to bone pain, arthralgia, and/or swelling of joints. Nocturnal bone and joint pain is one of the most characteristic clinical signs for malignancy. Differentiation between systemic JIA and malignancy can be difficult when general malaise, fever, anemia, and leukocytosis are present [67,104,124
128]. Another group of diseases that can present with arthritis, as well as arthralgia or myalgia, is the rare group of periodic fever syndromes like familial Mediterranean fever; hyper IgD syndrome; TNF receptor-1 associated periodic syndrome; Muckle-Wells syndrome; and periodic fever, aphtous stomatitis, pharyngitis, and adenitis [129]. These genetic diseases are also known as autoinflammatory disorders.

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Other possible causes of arthritis and arthralgia in childhood include coxitis fugax, Perthes disease, epiphysiolysis, Osgood-Schlatter disease, chondromalacia, hypermobility syndromes, and trauma [130].

TREATMENT The treatment of children with JIA is mostly medical but physiotherapy and other nonpharmacological therapies are also of importance in some patients. Nowadays, children are less frequently referred to a rehabilitation center where therapies can be organized in a multidisciplinary way. In the last two decades an expanding spectrum of effective drugs has become available [131]. The arrival of biologicals has made a significant difference initially to children who were refractory to previously used antirheumatic drugs. But as time progressed biologicals were prescribed earlier to JIA patients [132]. Nowadays the biggest challenges are to select the right JIA patients for treatment with biologicals [133] and to choose the optimal moment to apply them. Furthermore, a concern is how to deal with biosimilars in the treatment of patients with JIA. Long-term safety is guarded by the use of international databases.

Outcome Measures To measure efficacy of medical treatment a definition of improvement [134] has been developed using a core set of outcome variables and a definition of remission (clinically inactive disease, CID) is available [135]. Definitions have followed for clinical remission on (CID on .6 months therapy) and off medication (CID for more than 12 months off therapy) [136]. More recently the juvenile arthritis disease activity score (JADAS) was developed [137], including cut-off values [138]. Increasing evidence [139,140] advocates the early initiation of therapy depending on mild, moderate, or severe disease clinical characteristics. Several guidelines for children with oligoarticular and polyarticular JIA are available and summarized in the paper by Hinze et al. [87]. Illustrative algorithms for children with oligoarticular and polyarticular JIA can be found in the paper by Beukelman [141].

Drugs Used in Children With JIA NSAIDs are effective in suppressing fever and signs of inflammation such as pain and stiffness. Naproxen, ibuprofen, and indomethacine are frequently used. Pseudoporhyria can occur with the propionacid derivatives like naproxen and ibuprofen and induce scarring of sun-exposed areas. Indomethacine can cause headache and malaise in some children.

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As DMARDs hydroxychloroquine, sulfasalazine, MTX, and leflunomide are used. Regular blood checks are advised, especially liver function tests. Retinopathy can occur as an adverse reaction to hydroxychloroquine accumulation. Ophthalmological follow-up is advised every 6 months. Sulfasalazine is effective and safe in children with oligoarticular and polyarticular JIA, but not well tolerated in about one-third of children [142]. Sulfasalazine may induce or worsen low levels of IgA [86]). Nowadays sulfasalazine is mainly reserved for the category of JIA with enthesitis [141]. MTX has gained the position of gold standard for RA and is also very effective in JIA patients [143,144] as monotherapy, but also in combination therapy with biological [145
147]. It is administered once a week as tablets or subcutaneous injection. The use of folic acid can decrease nausea, malaise, and mucosal ulcerations [148]. In some children antiemetics are necessary to alleviate the weekly misery of MTX. During high-dose treatment with MTX, vaccination with live attenuated viruses should be avoided. Further advice on vaccinations in JIA patients is summarized in the European League Against Rheumatism recommendations by Heijstek et al. [149]. Leflunomide is tolerated well by most children with slightly less efficacy as MTX [150]. The use of systemic glucocorticoids should be restricted to life-threatening complications. In some children low-to-medium doses glucocorticoids are used to bridge the interval between start and moment of effectiveness of DMARDs. Glucocorticoids are mainly used as intraarticular injection with good results [151] and no short-term adverse effects on the cartilage. Leakage to the system may induce secondary Cushing syndrome [152]. Triamcinolonhexacetonide has shown to be superior to triamcinolonacetonide judged by the duration of remission [153]. The biologicals have extended the therapeutic arsenal for children with therapy-resistant JIA. To hamper TNF-α both soluble receptors (etanercept) as blocking antibodies (infliximab, adalimumab) are available, but for the use in children only etanercept and adalimumab are registered. The child has to fail on sufficiently high-dose MTX or show unacceptable side effects. About 75% of children with longstanding, resistant, polyarticular course JIA respond to etanercept in a blinded randomized controlled trial [154]. The clinical improvement lasts for over 2 years in the majority of patients [155] without significant adverse events [156]. Since 2008 abatacept, a CTLA4/IgG fusion protein-inhibiting T-cell activation by costimulation blocking, was added to the spectrum of therapeutics. In the original withdrawal trial [157] significantly more flares occurred in the placebo group compared to the abatacept group. It has to be noted that during the initial open-label period approximately 25% did not respond to abatacept, comparable to nonresponse rates as observed in TNF-α blockers.

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Tocilizumab is a humanized, monoclonal, IL-6-receptor antibody, inhibiting IL-6-mediated signaling. Recently the efficacy of tocilizumab in polyarticular course JIA was noted [158]; likewise, in a withdrawal trial design with significantly more flares in the placebo group compared to the tocilizumab group. Tocilizumab for polyarticular course JIA is dosed in 4-week intervals compared to 2-week intervals in systemic JIA. The GO-KIDS trial of golimumab (a human monoclonal antibody that binds both to soluble and transmembrane TNF-α) in polyarticular course JIA has not met its primary and secondary end-points [159], therefore currently preventing golimumab from registration for JIA.

FUTURE In the near future the development of other anticytokine-directed strategies (certolizumab, ustekinumab, tofacitinib) [160] holds great promise for the treatment of children with resistant JIA although the concerns about infections and long-term consequences remain [161].

Concerns of Infectious Complications During (Biological) Treatment Large cohort studies in JIA patients have not revealed increasing numbers of severe infections, requiring hospital admission due to biological treatment [162]. Having JIA without DMARD treatment increased the changes on these complications twofold, which remained twofold with the use of MTX or biologicals irrespective of MTX. Swart et al. reported that additional biologicals increased the chances to severe adverse events and infections compared to MTX only [163].

Concerns of Opportunistic Infections During (Biological) Treatment Opportunistic infections are rare in JIA patients. In almost 14,000 personyears of follow-up a few cases of coccidioides (occurring while not on biological treatment) and Salmonella were mentioned, as well as 32 cases of herpes zoster [164]. An increased incidence rate of herpes zoster in JIA patients on etanercept was confirmed by Nimmrich et al. [165].

Concerns of Development of Other Autoimmune Diseases Under the use of diverse biologicals, cases of other autoimmune diseases like demyelinating disease, inflammatory bowel disease, or the new development of autoantibodies have been documented, which is summarized in the manuscript by Swart et al. [161].

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Concerns on Malignancies During Biological Treatment In 2008 a black-box warning on the use of biologicals in children with JIA was warranted by the FDA. To know the background rate of malignancy in JIA, it is essential to address this issue. Studies on this topic are scarce and difficult due to relative small sample sizes [166,167]. Beukelman demonstrated no increase in malignancies due to use of TNF inhibitors, but in general a small increased rate of incident malignancy in JIA was noted [168]. Large registries are highly needed to gather information on this topic and initiatives to do so are evident both in the United States and Europe [161,169]. Autologous stem cell transplantation was used as an experimental treatment in children with therapy refractory polyarticular and systemic JIA [170] with significant mortality. In recent years less children were candidates for this procedure as a consequence of high effectiveness of biologicals. Complications are less common due to better treatment strategies, therefore diminishing the need for treatment of complications. The experimental use of recombinant human growth hormone restores linear growth and improves body composition in children with glucocorticoid-induced impaired growth and severe osteoporosis (Simon et al., 2003; Grote et al., 2006). The treatment of uveitis consists of topical and systemic drugs. Treatment recommendations for JIA-associated uveitis are summarized in a recent guideline [171]. Topical glucocorticoids are the first choice of treatment and sometimes are combined with mydriatic agents. Subtenon injections of steroids can be used. A large group of patients with uveitis need systemic treatment to achieve adequate disease control. Systemic glucocorticoids are effective, but the use should be minimized because of the harmful effects on bone and growth. Systemic glucocorticoids may also contribute to cataract formation and glaucoma. Intravenous pulses of glucocorticoids (30 mg/kg per dose with a maximum of 1 g) may be effective at lower risk of side effects. MTX and cyclosporin A can be effective and glucocorticoidsparing, but reports about the use of immunosuppressive drugs are scarce (Agle et al., 2003). Other agents that are reported to have some effect in smaller series are mycophenol mofetil, intravenous immunoglobulins, and anti-TNF-α drugs, especially adalimumab. Immunomodulatory therapy started early in the course of uveitis is associated with better visual acuity [181]. Several cases of a flare of uveitis or de novo development of uveitis are reported during the use of etanercept [156,172,173]. The use of abatacept in severe therapy refractory uveitis did not lead to sustained benefit in 21 patients [174].

PROGNOSIS Literature on the outcome of JIA in the prebiological era described ongoing arthritis in almost half of the patients with polyarticular JIA after 10 years [175].

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In addition, oligoarticular-onset JIA was shown to be a severe disease with frequent complications [176]. In 2003 Fantini et al. reported that 75% of their patients with a minimum follow-up of 10 years never reached remission [177]. The course of the disease and outcome depend on the category of JIA and the presence of IgM RF or ANA [178,179]. Patients with ANA-positive JIA seem to constitute a homogeneous subgroup [180] and ocular complications determine visual prognosis in this subgroup [81,181]. The prognosis of IgM RF polyarticular JIA can be compared with that of RA in adults. After introduction of the biologicals, outcome has improved due to earlier initiation of therapy and efficacy of TNF blockers and other biologicals reflected by almost 80% of JIA patients reaching an active joint count of 0 after 2 years in the ReACCh Out cohort [182], although flares still frequently occur [183]. At this moment JIA remains a chronic disease with considerable psychosocial impact that often extends into adulthood [184], although outcome has improved over the years [185
187].

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24. [143] Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and the Cooperative Children’s Study Group. N Engl J Med 1992;326 (16):1043
9. [144] Takken T, Van der Net J, Helders PJ. Methotrexate for treating juvenile idiopathic arthritis. Cochrane Database Syst Rev 2001;(4):CD003129. [145] Horneff G, De BF, Foeldvari I, Girschick HJ, Michels H, Moebius D, et al. Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry. Ann Rheum Dis 2009;68(4):519
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[153] Zulian F, Martini G, Gobber D, Plebani M, Zacchello F, Manners P. Triamcinolone acetonide and hexacetonide intra-articular treatment of symmetrical joints in juvenile idiopathic arthritis: a double-blind trial. Rheumatology (Oxford) 2004;43(10):1288
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9. [155] Lovell DJ, Giannini EH, Reiff A, Jones OY, Schneider R, Olson JC, et al. Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing multicenter, open-label, extended-treatment trial. Arthritis Rheum 2003;48(1):218
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91. [158] Brunner HI, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis 2015;74(6):1110
17. [159] Brunner HI, Ruperto N, Tzaribachev N, Horneff G, Wouters C, Panaviene V, et al. A multi-center, double-blind, randomized-withdrawal trial of subcutaneous golimumab in pediatric patients with active polyarticular course juvenile idiopathic arthritis despite methotrexate therapy: Week 48 Results. Arthritis Rheum 2014;66(Suppl. S3):S191
2 Special Issue: Abstracts from the 2014 Pediatric Rheumatology Symposium [160] Webb K, Wedderburn LR. Advances in the treatment of polyarticular juvenile idiopathic arthritis. Curr Opin Rheumatol 2015;27(5):505
10. [161] Swart JF, de RS, Wulffraat NM. What are the immunological consequences of long-term use of biological therapies for juvenile idiopathic arthritis? Arthritis Res Ther 2013;15(3):213. [162] Beukelman T, Xie F, Chen L, Baddley JW, Delzell E, Grijalva CG, et al. Rates of hospitalized bacterial infection associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 2012. [163] Swart JF, Pistorio A, Bovis F, Alekseeva E, Hofer M, Nielsen S, et al. The addition of one or more biologics to methotrexate in children with Juvenile Idiopathic Arthritis increases the incidence of infections and serious adverse events. The 5882 Pharmachild Cohort. Ann Rheum Dis 2015;74:91 hhttp://dx.doi.org/10.1136/annrheumdis-2015-eular.4397i [164] Beukelman T, Xie F, Baddley JW, Chen L, Delzell E, Grijalva CG, et al. Incidence of selected opportunistic infections among children with juvenile idiopathic arthritis. Arthritis Rheum 2013;65:1384
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[169] Ringold S, Hendrickson A, Abramson L, Beukelman T, Blier PR, Bohnsack J, et al. Novel method to collect medication adverse events in juvenile arthritis: results from the childhood arthritis and rheumatology research alliance enhanced drug safety surveillance project. Arthritis Care Res (Hoboken) 2015;67(4):529
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[185] Oen K, Duffy CM, Tse SM, Ramsey S, Ellsworth J, Chedeville G, et al. Early outcomes and improvement of patients with juvenile idiopathic arthritis enrolled in a Canadian multicenter inception cohort. Arthritis Care Res (Hoboken) 2010;62(4):527
36. [186] Anink J, Prince FH, Dijkstra M, Otten MH, Twilt M, ten CR, et al. Long-term quality of life and functional outcome of patients with juvenile idiopathic arthritis in the biologic era: a longitudinal follow-up study in the Dutch Arthritis and Biologicals in Children Register. Rheumatology (Oxford) 2015;54:1964
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Chapter 2

Juvenile-Onset Spondyloarthritis R. Burgos-Vargas1 and S.M.L. Tse2 1

Rheumatology Department, Hospital General de Mexico and Faculty of Medicine, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico, 2Division of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

INTRODUCTION Juvenile-onset (Jo) spondyloarthritis (SpA) denotes the group of HLAB27 associated rheumatic diseases in children that in the initial years affect the synovium and entheses of peripheral joints and in some patients, the sacroiliac and spinal joints and entheses some years later [1]. Patients with JoSpA are classified in accordance with adult-onset criteria validated in children [2], specifically Amor [3] and European Spondyloarthropathies Study Group [4]. Regarding children’s criteria, JoSpA might include patients with enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA) juvenile idiopathic arthritis (JIA) categories of the International League of Associations for Rheumatology [5]. In contrast to the SpA concept, ERA and PsA categories do not include all children or adolescents with SpA [6]. On the other hand, the Assessment in Spondyloarthritis International Society axial and peripheral classification criteria for SpA [7,8] has not been validated in children and adolescents [9].1

EPIDEMIOLOGY Since most studies have used different definitions for JoSpA, there is no consensus about its true prevalence in the general population. Studies in American and Canadian children show an incidence ranging from 2.1 per 100,000 [10] to 24.0 per 100,000 [11]. The relative frequency of JoSpA/ ERA among children with JIA goes from .10% [12] to 37.4% [13] in different populations. Up to 30 50% of Mexicans, Indians, North Africans, and some Asians have ankylosing spondylitis (AS) onset before the age of 1. In this chapter, we have adopted the acronym JoSpA/ERA to facilitate its comprehension. Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00002-5 © 2016 Elsevier B.V. All rights reserved.

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16 years [14] Finally, up to 85% of HLA-B27 children with JIA may develop chronic SpA [15]. Overall, it seems that JoSpA are more frequently found in specialized departments.

PATHOGENESIS Despite the scarcity of studies in JoSpA, their clinical similarities with adultonset disease suggest the existence of common pathogenic mechanisms. There is familial aggregation of SpA in JoSpA and a strong association with HLA-B27, particularly of juvenile-onset AS and undifferentiated SpA. The HLA-B27 subtypes B 2705 and B 2704 are associated with JoSpA in Mexicans [16] and Han Chinese [17]. The prevalence of HLA-B27 in patients with juvenile-onset PsA and reactive arthritis (ReA) is low. Unfortunately, the role of HLA-B27 in the pathogenesis of SpA is still not completely understood. The widely known “arthritogenic bacteria” hypothesis [18] has lost some credibility. Today most attractive hypotheses, which incriminate HLA-B27 misfolding in the endoplasmic reticulum as well as unfolded protein response [19] and HLA-B27 free heavy-chain and surface homodimer production [20] are not enough to explain the inflammatory and bone osteoproliferative processes that characterize the disease. Besides HLA-B27, other genes in children, specifically the endoplasmic reticulum aminopeptidase 1 and the interleukin-23 receptor (IL-23R) genes have been associated with JoSpA/ERA and PsA, respectively [21]. Interestingly, both genes are implicated in antigen presentation to IL-23R/ TH17 and tumor necrosis factor (TNF)/Th1. Except for ReA, the evidence of microbial infections in the pathogenesis of JoSpA is in general not very strong and consists of the demonstration of humoral or cellular increased responses to some microorganisms [22] or specific bacterial components such as the Streptococcus pyogenes group A cell wall peptidoglycan-polysaccharide [23] and the outer membrane protein of Salmonella typhimurium [24]. More solid findings include the presence of a variety of bacterial DNA in synovial fluid cells [25], toll-like receptors 2 and 4 in peripheral blood and synovial fluid cells [26], and altered microbiota in the stools of patients with JoSpA/ERA [27].

HISTOPATHOLOGY There is hyperplasia of the lining cells; CD68 expression and CD163+ macrophages in the sublining layer of the knee synovium of patients with JoSpA [28]; and increasing of the vascularity by CD146+ endothelial and CD8-activated cells, TNF-β, interferon-γ, as well as IL-2, IL-4, and IL-6 [29]. Most cells in the synovial membrane express TNF-α receptors p55 and p75. At a certain point during the course of the disease, there is osteocartilaginous proliferation and enthesophytosis at the tendon and ligament

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attachments to bone. In adults, enthesophytes may emerge from inflamed [30 32], but also from noninflamed areas in the spine [33]. Inflammatory mediators and bone lineage proteins seem responsible for such processes [34]. While the former are important in the early stages of the disease, the latter become prominent as the disease progresses. Since enthesophytes may also be found in sites not previously inflamed, it is possible that mechanical stress may be responsible for generating bone proliferation [35]. There are no similar studies in patients with JoSpA/ERA. However, studies involving the feet in patients with tarsitis in both the early inflammatory and chronic ankylosing stages of the disease suggests this is a peripheral model of axial involvement (Fig. 2.1) [36,37]. Interestingly, there are scarce inflammatory cells in the synovium, synovial sheaths, and entheses in tarsitis [37], but in contrast, there is bone differentiation of entheseal cells toward an osteoblastic lineage (Fig. 2.2). Bone islets, embedded within the matrix of the enthesis, suggest a role for mechanic rather than inflammatory process in tarsitis. Remarkably, bone morphogenetic protein signaling [38] and IL-23 on entheseal resident T-cell receptors [39] appear to play a role in the pathogenesis of bone proliferation in animal models.

FIGURE 2.1 Composite images of ankylosing tarsitis in a 16-year-old boy with AS of 9 years’ duration and complete ankylosis of the tarsal bones and grade 2 bilateral sacroiliitis. (A and B) Flat-foot and swelling around the ankle. (C F) Short tau inversion recovery (STIR) MR images showing edema in various tarsal bones, joint spaces (C and D), and soft tissues (E and F) surrounding the tendons of the posterior aspect of the foot on the coronal view (arrows). (G) Complete ankylosis of the tarsal bones and an enthesophyte at the plantar fascia attachment are seen. Modified from Burgos-Vargas R. A case of childhood-onset ankylosing spondylitis: diagnosis and treatment. Nat Clin Pract Rheumatol 2009;5:52 57.

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FIGURE 2.2 (A) Immunohistochemistry photographs of entheseal biopsies in patients with ankylosing tarsitis. Bone lineage proteins—OCN, OPN, and parathyroid hormone-related protein (PTHrP)—are expressed in both the bone (B) and in the entheses (E) with different patterns, with OCN by far the most abundant. Cellular subpopulation detection (CD3, CD4, CD8, CD20, CD68) showed a very isolated staining, suggesting a minimal presence of immune cells. A negative control (NC) is presented as a reference. (B) Expression of osteocalcin (OCN) and osteopontin (OPN) by entheseal fibroblast. (a) Hematoxilin and eosin reference micrograph (40 3 ) of an enthesis. (b) Confocal micrographs of negative control staining sampling both wavelengths. (c) Colocalization confocal micrographs of OPN (red) and OCN (green) in the enthesis showing a stronger expression of OPN in the bone matrix and of OCN in the periosteal bone; both colocalize in the entheseal cells confirming their link to bone lineage. (d) Colocalization confocal micrographs of OCN (green) and fibroblast marker (red) confirming the expression of OCN by entheseal fibroblasts. (e) Colocalization confocal micrographs of OPN (green) and fibroblast marker (red) showing the expression of OPN by entheseal fibroblasts.

CLINICAL FINDINGS JoSpA is recognized by clinical, laboratory tests, radiographic, and other imaging characteristics. Some correspond to inflammatory, potentially reversible changes; others result from structural damage. On the other hand, there are clinical overlaps among JoSpA categories that may result in diagnostic changes throughout the course of the disease.

Initial Symptoms and JoSpA Differential Diagnosis Patients with JoSpA/ERA present to the clinic for the first time with isolated or combined symptoms. Usually, isolated monoarthritis, oligoarthritis, or enthesitis

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FIGURE 2.2 Continued

are more frequently seen than any combination of symptoms or axial symptoms at onset (Box 2.1). Differential diagnoses include trauma, sport and overuse injuries, osteochondrosis, hypermobility syndromes, pigmented villonodular synovitis, septic arthritis, tarsal coalition, mechanical as well as other causes of back pain, and disorders of growth and development. Interestingly, up to onethird of patients with JoSpA participated in heavy sport activities several weeks before symptom onset. In these patients, HLA-B27 might be helpful in JoSpA. Usually, those patients progressing to AS complain of sacroiliac joint or spinal pain within the first 10 years of symptoms, in contrast to the predominant involvement of the spine and sacroiliac joints at onset and peripheral symptoms thereafter found in adults [37 49].

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BOX 2.1 JoSpA Clinical Features at Onset Very common Arthritis Arthritis and enthesitis Common Enthesitis Rare Any combination of arthritis and/or enthesitis with spondylitis and/or sacroiliitis and/or dactylitis and/or uveitis Very rare Sacroiliitis Spondylitis Dactylitis Costochondritis Anterior uveitis Any combination of $ 2 of the following: spondylitis sacroiliitis dactylitis costochondritis

Peripheral Arthritis and Enthesitis Features Arthritis pattern is consistent with unilateral or asymmetric mono- or oligoarthritis involving the knee, ankle, or mid-tarsus (Fig. 2.3) [1]. Less frequently, arthritis affects the metatarsophalangeal (MTP) and interphalangeal joints of the feet, the hips, and rarely the upper extremity joints. Usually, the course of arthritis consists of recurring episodes of oligoarthritis lasting from weeks to months followed by some remission or low disease activity. Yet, there are cases with persistent arthritis and an increasing number of joints involved, including the hips. Enthesitis might not parallel arthritis at onset or during the disease course, but in most cases determines the severity of the disease and ultimately may reduce the physical function and health-related quality of life (HRQoL). The attachments of plantar fascia, Achilles’ tendon, and patellar ligaments are the entheses most frequently involved, followed by the ligament and tendon insertions at the talonavicular joint and base of the fifth metatarsal bone [1,50]. Upper limb entheses such as those on the shoulder and epicondyles as well as those at the iliac bones may also be found. The pattern of lower limb arthritis and/or enthesitis differs very little among

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FIGURE 2.3 Involvement of the feet in patients with JoSpA. (A) Dactylitis of the third digit in a 12-year-old boy with undifferentiated SpA. (B) Diffuse swelling of the tarsal region of an 11-yearold boy with juvenile-onset AS. (C) Tarsal swelling, hyperextension of the digits, and Keratoderma blennorrhagica in a 16-year-old boy with chronic reactive arthritis. (D) Diffuse swelling of the posterior aspect of feet including the ankles, Achilles, and peroneal and tibial posterior tendons in a 12year-old-boy with undifferentiated SpA. Modified from Burgos-Vargas R, Va´zquez-Mellado J. Reactive arthritides. In: Cassidy JT, Petty RE, eds. Textbook of pediatric rheumatology, 5th ed. Philadelphia, PA: Elsevier Saunders, 2005:604 612 and Burgos-Vargas R. The juvenile-onset spondyloarthritides. In: Weisman MH, van der Heijde D, Reveille JD, eds. Ankylosing spondylitis and the spondyloarthropathies. St. Louis, MO: Elsevier Mosby, 2006:94 106.

specific JoSpA entities. For example, the frequency of tarsitis is more commonly seen in patients with AS whereas dactylitis and arthritis of the hands in patients with PsA or ReA is more common. Regarding tarsitis and dactylitis, the involvement of joints and entheses is characteristically accompanied by tenosynovitis as well as bony proliferation. While tarsitis may evolve in ankylosis, dactylitis is more frequently associated with bone destruction and less with bone proliferation. Histopathologic studies of tarsitis in both the early inflammatory and chronic ankylosing stages of the disease show similarities with axial findings (Fig. 2.2) [36,37].

Sacroiliac and Spinal Features Around 10 20% of children with JoSpA have clinical evidence of sacroiliitis or spondylitis at disease onset or during the initial years of disease [51 53]. In general, the initial pattern of these symptoms does not fit very well with those referred by adults with inflammatory back pain (IBP).

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FIGURE 2.4 Grade 3 bilateral sacroiliitis in a 14-year-old boy of 6 years’ disease duration. There is subchondral sclerosis of the iliac bone, joint surface irregularities, which include erosions on both sides, and joint space narrowing of the hips. From Burgos-Vargas R. The juvenileonset spondyloarthritides. In: Weisman MH, van der Heijde D, Reveille JD, eds. Ankylosing spondylitis and the spondyloarthropathies. St. Louis, MO: Elsevier Mosby, 2006:94 106.

Specifically, the combination of insidious onset, alternating gluteal pain, improvement with exercise but not with rest, and nocturnal pain are rarely reported. In fact, most of these children have short-term episodes of gluteal or back pain that frequently extends to the neck. In patients in whom the diagnoses of AS is made, axial symptoms become significant throughout the following 5 10 years, yet radiographic spondylitis may still occur up to 20 years after onset. The exception to that is the description of a small group of patients fulfilling the modified New York criteria for AS within 3 years of disease [54]. They have more severe involvement of peripheral joints and enthesis and all of them had HLA-B27. There is evidence that radiographic sacroiliitis and AS are more frequently seen in boys [15,55], particularly those with HLA-B27 [15,51,52] and age at onset $ 8 years, including early hip involvement [15,55,56] and back pain [53], polyarthritis [54,57], enthesitis [53], polyenthesitis [57], tarsitis [53], and elevated erythrocyte sedimentation rate (ESR) for at least 6 months [55]. Radiographic sacroiliitis (Fig. 2.4) and sacroiliitis and spondylitis detected by MRI (Fig. 2.3) may occur in asymptomatic children or in patients complaining of back symptoms that seldom fulfill IBP criteria. Specifically, the combination of insidious onset, alternating gluteal pain, improvement with exercise but not with rest, and nocturnal pain are rarely reported. In most cases, the relevance of axial symptoms increases with duration and progression of the disease in patients with AS [53].

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Health-Related Quality of Life and Functioning Before the use of TNF-α blockers in the treatment of JoSpA/ERA, only 17% [58] and ,50% [59] of patients were in remission 5 and 10 years after disease onset, respectively. About 50% of patients had active disease 17 years after onset [60], and 60% had functional limitations after 10 years, particularly those with disease activity .5 years [59]. Compared with other JIA categories, patients with JoSpA/ERA had more pain, higher childhood Health Assessment Questionnaire (HAQ) scores, poorer physical health, lower physical functioning, and lower HRQoL [55,61,62]. Treatment failure was associated with familial AS, HLA-DRB1 08, ankle or hip arthritis within the first 6 months of disease, development of sacroiliitis, and persistent ESR within the first 6 months of onset [55]. In juveniles, hip involvement required more joint replacement and in a shorter time than patients with adult-onset AS [42,47]. More patients with juvenile-onset AS had impaired functioning than adult-onset patients [41,43,46 49]. The contrary had been also found: better scores of the Bath AS Functional Index, HAQ, and HRQoL, as well as less fatigue than patients with adult onset AS [45,48]. Nonetheless, as consequence of peripheral involvement, at least juvenile-onset AS seems more severe than AS in adults. Yet, with better medications available today, it is possible to see less severe cases of JoSpA/ERA.

IMAGING STUDIES Radiographic, MRI, and ultrasound with power Doppler studies provide important information about diagnosis and classification, disease progression, and therapeutic efficacy. Radiographic findings include osteopenia, joint space narrowing, and in some cases, ankylosis; such changes are more visible in the hip and midfoot. With the exception of the small joints of the feet and hands, hips, and sacroiliac joints, erosive and destructive changes are rarely seen. MRI studies have been useful in detecting areas of active inflammation and some structural abnormalities (Fig. 2.5). There is a trend to identify subclinical sacroiliitis on MRI in patients with JoSpA/ERA [63,64], but further studies are needed to determine its value as a diagnostic tool and particularly if subclinical sacroiliitis on MRI would be able to drive any specific treatment. T1 and short T1 (tau) inversion recovery (STIR) sequences without gadolinium are usually enough to evaluate the involvement of the joints, entheses, and tendons, particularly for the sacroiliac joints [65]. Yet the use of gadolinium might be recommended for small joints. Whole-body MRI may be valuable for early detection and monitoring of both peripheral and axial disease activity in this population (Fig. 2.6) [66].

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FIGURE 2.5 Short tau inversion recovery (STIR) and T1 MR image sequences of the sacroiliac and spinal joints of an HLA-B27 positive 18-year-old boy with recurrent peripheral arthritis and enthesitis for 7 years and intermittent gluteal and back pain during the last 12 months. (A and B) STIR sequence shows edema of the sacrum and iliac bones. (B and C) T1 sequence showing erosions and fat loss in the area corresponding to the edema found in the STIR sequence. (D F) There is bone edema corresponding to the L4 L5 zygapophyseal joints. From Burgos-Vargas R, Tse SML. Juvenile-onset spondyloarthritis. In Inman RD, Sieper J, eds. Textbook of Axial Spondyloarthritis. Oxford University Press, Oxford (in press).

Ultrasound with power Doppler of the joints and particularly of the entheses, including tendons and bursa, is highly sensitive to detect inflammatory changes including active synovitis and bursitis. Ultrasound may also detect tendon thickening as well as chronic lesions such as enthesophytes, erosions, and cortical irregularities [67 69]. However, ultrasound lacks specificity and might not correlate with clinical examination. In fact, some findings in ultrasound studies showed that JoSpA/ERA patients are similar to those found in healthy children [68].

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FIGURE 2.6 Whole-body short tau inversion recovery (STIR) MRI in a 15-year-old HLAB27 positive adolescent boy with ERA. (A) Abnormal signal within sacroiliac joints especially on the right with high intraarticular signal extending into iliac bone (arrow). The right sacroiliac joint also demonstrates irregularity and sclerosis suggestive of erosive changes. High signal noted at bilateral proximal femoral metaphyses at region of the greater trochanter (arrowheads). High signal also noted in left ischium in addition to bilateral involvement metaphysis and epiphyses of the distal femur, proximal and distal tibia. (B) Corner inflammatory lesions within the vertebral bodies are depicted by the small arrows. From Burgos-Vargas R, Tse SML. Juvenile-onset spondyloarthritis. In Inman RD, Sieper J, eds. Textbook of Axial Spondyloarthritis. Oxford University Press, Oxford (in press).

CLINICAL PRESENTATION Before the 1980s most clinical descriptions referred to juvenile-onset AS and Reiter syndrome; undifferentiated forms became clearly recognized in the early 1980s [70,71]. As mentioned before, there is overlapping between the different categories. In addition, each category may overlap the clinical transition between different categories. Currently, the recognition of early JoSpA forms may result in the introduction of efficacious treatment in the inflammatory stage of the disease.

Undifferentiated SpA Undifferentiated SpA is the most common type of SpA in children and, in a variable proportion of cases, is the earliest form of AS. Previously, this

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group was named HLA-B27 associated SpA and enthesopathy in childhood [70] or seronegative enthesopathy and arthropathy syndrome [71], but now is currently recognized and referred to as ERA [5]. While an unknown proportion of patients achieve disease remission, up to 70 90% of Mexican [51] and Canadian [52], but fewer Italian children [72] fulfill AS criteria approximately 10 years after onset.

Juvenile-Onset AS This term refers to AS starting before the age of 16 years. The diagnosis, according to modified New York criteria [73], is usually made 5 10 years after onset [53,74]. This situation makes AS a rare diagnosis before the age of 16. As mentioned before, back complaints in the pediatric population are uncommon and often do not resemble IBP. Radiographic sacroiliitis is usually found in symptomatic patients (Fig. 2.4). MRI may show acute sacroiliitis in symptomatic patients, but may also appear in asymptomatic patients (Fig. 2.5A).

Reactive Arthritis ReA is restricted to HLA-B27 associated arthritis triggered by Salmonella, Yersinia, Campylobacter, and Shigella, but most patents in a series of cases lack such antigens [75]. Since viable Chlamydia have been found within the joints, the possibility of Chlamydia ReA may represent an infectious arthritis and be more appropriately referred to as “an infectious nonsuppurative arthritis,” which challenges the concept of ReA as a nonseptic arthritis [76].

Juvenile-Onset Psoriatic Arthritis This condition is defined by the concomitant occurrence of arthritis and psoriasis in individuals younger than 16 years of age [77]. Juvenile-onset PsA includes two main patient subpopulations: the first one, not related to SpA, is mainly composed of young girls with polyarthritis involving the hands, dactylitis, and antinuclear antibodies, while the second subpopulation includes more frequently HLA-B27 boys with persistent oligoarthritis, enthesitis, and potentially axial symptoms [78 80]. In JoPsA, arthritis occurs before psoriasis in 50% of cases, psoriasis as the initial manifestation in 40%, and simultaneous occurrence of psoriasis and arthritis in 10%.

Crohn’s Disease and Ulcerative Colitis A total of 18 30% of patients with Crohn’s disease and 15% of those with ulcerative colitis have their first symptoms before the age of 20 [81].

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Peripheral arthritis occurs in 9% and 10 20% of patients with Crohn’s and ulcerative colitis, respectively; 1.7% have arthritis 1 year after the onset of their inflammatory bowel disease (IBD) and 4.2% by 10 years [82]. Most patients have peripheral arthritis with or without axial symptoms. Around 50% of children with arthritis associated with IBD have single or recurrent attacks of lower limb monoarthritis or oligoarthritis for less than 4 weeks [83]; half of such children have simultaneous episodes of arthritis and gut exacerbations [82,83]. This type of arthritis does not resemble that of JoSpA/ ERA, and permanent functional limitations or joint damage do not develop in most patients. In contrast, spondylitis and radiographic sacroiliitis in IBD patients have no relationship with the gut exacerbations and are seen more frequently in older boys who are HLA-B27 positive.

Ankylosing Tarsitis This term refers to a set of clinical and radiographic findings, including inflammatory changes originally described in HLA-B27 associated JoSpA/ ERA [36]. Some of these findings resemble those of the spine and sacroiliac joints in AS. Patients with ankylosing tarsitis have mid-foot swelling associated with perimalleolar and Achilles tendon swelling; decreased mobility of the tarsal, ankle, and MTP joints; pes planus; and hyperextension of the MTP joints (Fig. 2.1). Radiographic, MRI, and ultrasound features were described earlier. Histopathologic findings include slight inflammatory changes along with the formation of bone islets embedded within the enthesis matrix [37]. Ankylosing tarsitis may occur in patients with undifferentiated JoSpA and with AS before radiographic sacroiliitis.

THERAPEUTIC RECOMMENDATIONS The treatment of JoSpA/ERA is aimed to reduce the signs and symptoms of disease activity and improve the quality of life of children and adolescents with JoSpA [84]. The disease is undulant and often has a chronic course extending into adulthood. Until now, there is still no evidence that any treatment might halt disease progression [85]. However, biologic therapies seem the best treatment for these patients. The efficacy of sulfasalazine (SSZ) and methotrexate (MTX) is not fully confirmed. Nonsteroidal anti-inflammatory drugs (NSAIDs) provide symptomatic relief for most patients with mild symptoms, but maybe ineffective in patients with severe disease. At some time, nearly all patients receive SSZ, but its efficacy is limited [86]. MTX is also used, but there is no clear evidence of efficacy. It seems that these drugs may improve psoriasis, anterior uveitis, and Keratoderma blennorrhagica. Oral and intraarticular glucocorticoids in peripheral and even the sacroiliac joints [87] may be beneficial in patients with moderate-to-severe disease activity.

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FIGURE 2.7 MRI improvement of active sacroiliitis induced by the infusion of the tumor necrosis factor alpha-blocker agent infliximab. (A and B—baseline findings) Short tau inversion recovery. (A C) MRI findings at baseline. There is edema extending throughout the sacrum and iliac bones of the left sacroiliac joint. There are also clear irregularities (erosions) along mid-portion of the sacrum articular surface (arrows). (D F) MRI changes observed 14 weeks after the start of infliximab. Although hyperintensive signals (bone edema) have disappeared, erosions and fat deposition suggest the transition to chronic phase.

TNF-α blockers represent the most significant advance in the therapy for JoSpA/ERA, including AS and PsA [88 96]. TNF-α blockers are prescribed in patients with peripheral arthritis and enthesitis not responding to NSAIDs, SSZ, MTX, and glucocorticoid intraarticular injections despite the lack of specific recommendations. The anti-inflammatory effect of etanercept,

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FIGURE 2.8 MRI improvement of active arthritis, enthesitis, and bone edema induced by the infusion of the tumor necrosis factor alpha-blocker agent infliximab. (A and B—baseline findings) Short tau inversion recovery (STIR) MR images of the foot of a 15-year-old boy with ankle swelling and painful heel (Achilles tendon and plantar fascia) for 6 months. Sagittal-lateral views showing synovial fluid effusion in the posterior and anterior aspect of the ankle and the retrocalcaneal bursae and possibly the fat as well as bone edema of the calcaneus, including the attachments of the Achilles tendon and its continuation to the plantar fascia. Synovial fluid effusion of the ankle joint, edema around the posterior peroneal tendon, and extensive edema of the calcaneus in the sagittal-posterior views. Coronal views show the extension of the edema in the calcaneus. (C and D) STIR MR images obtained 8 weeks after starting infliximab showing complete resolution of the calcaneus edema and marked reduction of inflammation in the ankle joint and retrocalcaneal bursae.

infliximab, and adalimumab is clearly seen within the first few weeks of treatment, and their long-term administration provides sustained relief. Efficacy is seen in outcome measures including active joint and enthesitis counts, inflammatory markers (C-reactive protein and ESR), physical function, HRQoL, and adult SpA tools for disease activity. MRI of peripheral and sacroiliac joints may also show significant reduction of inflammation with TNF-α blockers (Figs. 2.7 and 2.8). However, retrospective studies of JoSpA/ERA show that fewer patients than those with other categories of JIA achieve inactive disease, sustained remission, or successful discontinuation of TNF-α blockers [97 99]. In fact, one study showed continued progression of radiographic sacroiliitis in some patients from a group treated with TNF-α blockers for more than 5 years [85]. The selection of TNF-α blockers should be made according to efficacy and safety and on patient preference. Although the US Food and Drug Administration issued a warning highlighting some side effects [100], TNF-α blockers in general have been considered safe and well tolerated.

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Peripheral involvement may affect walking, climbing stairs, the standing position, and other activities. In addition, patients with axial disease may have an important reduction in spinal mobility and chest expansion. Patients should be enrolled in physical and occupational therapy programs in which rest, dynamic splints, and exercises for muscle strength and stretching could be implemented on an individual basis. Additionally, foot orthotics, especially cushions under the heel and plantar (custom-made rather than prefabricated inserts) [101] are recommended for painful enthesitis. Surgical modalities, such as soft tissue release, synovectomy, tendon repair, arthroplasty, and joint replacement, may be indicated in some patients with certain forms of hip, knee, and MTP disease. The impact of JoSpA/ERA in children’s and adolescents’ HRQoL might be very important and often continues as they transition to adulthood. Thus, it is important to consider the psychological, educational, and socioeconomic aspects of the patient’s life. JoSpA may affect the individuals’ social life, including personal and family activities, education, and jobs. Attention to early diagnosis along with appropriate therapeutic strategies and counseling will lead to improved outcomes in children and adolescents with JoSpA/ERA.

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[27] Stoll ML, Kumar R, Morrow CD, et al. Altered microbiota associated with abnormal humoral immune responses to comensal organisms in enthesitis-related arthritis. Arthritis Res Ther 2014;16(6):486. [28] Kruithof E, Van den Bossche V, De Rycke L, et al. Distinct synovial immunopathologic characteristics of juvenile-onset spondylarthritis and other forms of juvenile idiopathic arthritis. Arthritis Rheum 2006;54:2594 604. [29] Grom AA, Murray KJ, Luyrink L, et al. Patterns of expression of tumor necrosis factor alpha, tumor necrosis factor beta, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy. Arthritis Rheum 1996;39:1703 10. [30] Baraliakos X, Listing J, Rudwaleit M, et al. The relationship between inflammation and new bone formation in patients with ankylosing spondylitis. Arthritis Res Ther 2008;10 (5):R104. [31] Maksymowych WP, Chiowchanwisawakit P, Clare T, et al. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis Rheum 2009;60:93 102. [32] van der Heijde D, Machado P, Braun J, et al. MRI inflammation at the vertebral unit only marginally predicts new syndesmophyte formation: a multilevel analysis in patients with ankylosing spondylitis. Ann Rheum Dis 2012;71:369 73. [33] Chiowchanwisawakit P, Lambert RG, Conner-Spady B, et al. Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis. Arthritis Rheum 2011;63:2215 25. [34] Hreggvidsdottir HS, Noordenbos T, Baeten DL. Inflammatory pathways in spondyloarthritis. Mol Immunol 2014;57:28 37. [35] Masi AT. Might axial myofascial properties and biomechanical mechanisms be relevant to ankylosing spondylitis and axial spondyloarthritis? Arthritis Res Ther 2014;16(2):107. [36] Burgos-Vargas R, Granados-Arriola J. Ankylosing spondylitis and related diseases in the Mexican Mestizo. In: Khan MA, editor. Spine: state of the art reviews. Vol 4. Ankylosing spondylitis and related spondyloarthropathies. Philadelphia, PA: Hanley & Belfus; 1990. p. 665. [37] Pacheco-Tena C, Pe´rez-Tamayo R, Pineda C, et al. Bone lineage proteins in the entheses of the midfoot in patients with spondyloarthritis. J Rheumatol 2015;42:630 7. [38] Lories RJ, Derese I, Luyten FP. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest 2005;115:1571 9. [39] Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+CD3+CD4 2 CD8 entheseal resident T cells. Nat Med 2012;18:1069 76. [40] Riley MJ, Ansell BM, Bywaters EG. Radiological manifestations of ankylosing spondylitis according to age at onset. Ann Rheum Dis 1971;30:138 48. [41] Marks SH, Barnett M, Calin A. A case-control study of juvenile- and adult-onset ankylosing spondylitis. J Rheumatol 1982;9:739 41. [42] Calin A, Elswood J. The natural history of juvenile-onset ankylosing spondylitis: a 24-year retrospective case-control study. Br J Rheumatol 1988;27:91 3. [43] Garcia-Morteo O, Maldonado-Cocco JA, Suarez-Almazor ME, Garay E. Ankylosing spondylitis of juvenile onset: comparison with adult onset disease. Scand J Rheumatol 1983;12:246 8. [44] Burgos-Vargas R, Naranjo A, Castillo J, Katona G. Ankylosing spondylitis in the Mexican mestizo: patterns of disease according to age at onset. J Rheumatol 1989;16:186 91.

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[45] Baek HJ, Shin KC, Lee YJ, Kang SW, Lee EB, Yoo CD. Juvenile onset ankylosing spondylitis (JAS) has less severe spinal disease course than adult onset ankylosing spondylitis (AAS): clinical comparison between JAS and AAS in Korea. J Rheumatol 2002;29:1780 5. [46] Stone M, Warren RW, Bruckel J, Cooper D, Cortinovis D, Inman RD. Juvenile onset ankylosing spondylitis is associated with worse functional outcomes than adult-onset ankylosing spondylitis. Arthritis Rheum 2005;53:445 51. [47] Gensler LS, Ward MM, Reveille JD, Learch TJ, Weisman MH, Davis Jr. JC. Clinical, radiographic and functional differences between juvenile-onset and adult-onset ankylosing spondylitis: results from the PSOAS cohort. Ann Rheum Dis 2008;67:233 7. [48] O’Shea FD, Boyle E, Riarh R, Tse SM, Laxer RM, Inman RD. Comparison of clinical and radiographic severity of juvenile-onset versus adult-onset ankylosing spondylitis. Ann Rheum Dis 2009;68:1407 12. [49] Ozgocmen S, Ardicoglu O, Kamanli A, Kaya A, Durmus B, Yildirim K. Pattern of disease onset, diagnostic delay, and clinical features in juvenile onset and adult onset ankylosing spondylitis. J Rheumatol 2009;36:2830 3. [50] Weiss PF, Klink AJ, Behrens EM, et al. Enthesitis in an inception cohort of enthesitisrelated arthritis. Arthritis Care Res (Hoboken) 2011;63:1307 12. [51] Burgos-Vargas R, Clark P. Axial involvement in the seronegative enthesopathy and arthropathy syndrome and its progression to ankylosing spondylitis. J Rheumatol 1989;16:192 7. [52] Cabral DA, Oen KG, Petty RE. SEA syndrome revisited: a long-term followup of children with a syndrome of seronegative enthesopathy and arthropathy. J Rheumatol 1992;19:1282 5. [53] Burgos-Vargas R, Va´zquez-Mellado J. The early clinical recognition of juvenile-onset ankylosing spondylitis and its differentiation from juvenile rheumatoid arthritis. Arthritis Rheum 1995;38:835 44. [54] Burgos-Vargas R, Va´zquez-Mellado J, Cassis N, et al. Genuine ankylosing spondylitis in children: a case-control study of patients with early definite disease according to adult onset criteria. J Rheumatol 1996;23:2140 7. [55] Flatø B, Hoffmann-Vold AM, Reiff A, et al. Long-term outcome and prognostic factors in enthesitis-related arthritis: a case-control study. Arthritis Rheum 2006;54:3573 82. [56] Stoll ML, Bhore R, Dempsey-Robertson M, et al. Spondyloarthritis in a pediatric population: risk factors for sacroiliitis. J Rheumatol 2010;37:2402 8. [57] Pagnini I, Savelli S, Matucci-Cerinic M, et al. Early predictors of juvenile sacroiliitis in enthesitis-related arthritis. J Rheumatol 2010;37:2395 401. [58] Minden K, Kiessling U, Listing J, et al. Prognosis of patients with juvenile chronic arthritis and juvenile spondyloarthropathy. J Rheumatol 2000;27:2256 63. [59] Flato B, Aasland A, Vinje O, et al. Outcome and predictive factors in juvenile rheumatoid arthritis and juvenile spondyloarthropathy. J Rheumatol 1988;25:366 75. [60] Minden K, Niewerth M, Listing J, et al. Long-term outcome in patients with juvenile idiopathic arthritis. Arthritis Rheum 2002;46:2392 401. [61] Flatø B, Lien G, Smerdel-Ramoya A, et al. Juvenile psoriatic arthritis: long-term outcome and differentiation from other subtypes of juvenile idiopathic arthritis. J Rheumatol 2009;36:642 50. [62] Weiss PF, Beukelman T, Schanberg LE, et al. Enthesitis-related arthritis is associated with higher pain intensity and poorer health status in comparison with other categories of juvenile idiopathic arthritis: the Childhood Arthritis and Rheumatology Research Alliance Registry. J Rheumatol 2012;39:2341 51.

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[63] Bollow M, Biedermann T, Kannenberg J, et al. Use of dynamic magnetic resonance imaging to detect sacroiliitis in HLA-B27 positive and negative children with juvenile arthritides. J Rheumatol 1998;25:556 64. [64] Weiss PF, Colbert RA. Radiography versus magnetic resonance imaging (MRI) in juvenile spondyloarthritis: Is the MR image everything? J Rheumatol 2014;41:832 3. [65] Weiss PF, Xiao R, Biko DM, et al. Detection of inflammatory Sacroiliitis in children with magnetic resonance imaging: Is gadolinium contrast enhancement necessary? Arthritis Rheumatol, 67. 2015. p. 2250 6. [66] Aquino MR, Tse SM, Gupta S, et al. Whole-body MRI of juvenile spondyloarthritis: protocols and pictorial review of characteristic patterns. Pediatr Radiol 2015;45:754 62. [67] Jousse-Joulin S, Breton S, Cangemi C, et al. Ultrasonography for detecting enthesitis in juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011;63:849 55. [68] Aydin SZ, Tan AL, Hodsgon R, et al. Comparison of ultrasonography and magnetic resonance imaging for the assessment of clinically defined knee enthesitis in spondyloarthritis. Clin Exp Rheumatol 2013;31:933 6. [69] Weiss PF, Chauvin NA, Klink AJ, et al. Detection of enthesitis in children with enthesitis-related arthritis: dolorimetry compared to ultrasonography. Arthritis Rheumatol 2014;66:218 27. [70] Jacobs JC, Johnston AD, Berdon WE. HLA-B27 associated spondyloarthritis and enthesopathy in childhood: clinical, pathologic and radiographic observations in 58 patients. J Pediatr 1982;100:521 8. [71] Rosenberg AM, Petty RE. A syndrome of seronegative enthesopathy and arthropathy in children. Arthritis Rheum 1982;25:1041 7. [72] Olivieri I, Cutro MS, D’Angelo S, et al. Low frequency of axial involvement in southern Italian Caucasian children with HLA-B27 positive juvenile onset undifferentiated spondyloarthritis. Clin Exp Rheumatol 2012;30:290 6. [73] van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361 8. [74] Schaller JG, Bitnum S, Wedgwood RJ. Ankylosing spondylitis with childhood onset. J Pediatr 1969;74:505 16. [75] Stamato T, Laxer RM, de Freitas C, et al. Prevalence of cardiac manifestations of juvenile ankylosing spondylitis. Am J Cardiol 1995;75:744 6. [76] Burgos-Vargas R, Va´zquez-Mellado J. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn L, editors. Reactive arthritides. seventh ed. Philadelphia, PA: Elsevier Saunders; 2015. p. 704 12. [77] Shore A, Ansell BM. Juvenile psoriatic arthritis—an analysis of 60 cases. J Pediatr 1982;100:529 35. [78] Southwood TR, Petty RE, Malleson PN, et al. Psoriatic arthritis in children. Arthritis Rheum 1989;32:1014 21. [79] Hamilton ML, Gladman DD, Shore A, et al. Juvenile psoriatic arthritis and HLA antigens. Ann Rheum Dis 1990;49:694 7. [80] Stoll ML, Zurakowski D, Nigrovic LE, et al. Patients with juvenile psoriatic arthritis comprise two distinct populations. Arthritis Rheum 2006;54:3564 72. [81] Burbige EJ, Huang SH, Bayless TM. Clinical manifestations of Crohn’s disease in children and adolescents. Pediatrics 1975;55:866 71. [82] Jose FA, Garnett EA, Vittinghoff E, et al. Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2009;15:63 8.

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[83] Lindsley C, Schaller JG. Arthritis associated with inflammatory bowel disease in children. J Pediatr 1974;84:16 20. [84] Tse SM, Burgos-Vargas R, Colbert RA. Juvenile spondyloarthritis treatment recommendations. Am J Med Sci 2012;343:367 70. [85] Hugle B, Burgos-Vargas R, Inman RD, et al. Long-term outcome of anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondyloarthritis. Clin Exp Rheumatol 2014;32:424 31. [86] Burgos-Vargas R, Va´zquez-Mellado J, Pacheco-Tena C, et al. A 26-week randomised, double-blind, placebo-controlled exploratory study of sulfasalazine in juvenile onset spondyloarthropathies. Ann Rheum Dis 2002;61:941 2. [87] Fritz J, Tzaribachev N, Thomas C, et al. Evaluation of MR imaging guided steroid injection of the sacroiliac joints for the treatment of children with refractory enthesitis-related arthritis. Eur Radiol 2011;21:1050 7. [88] Henrickson M, Reiff A. Prolonged efficacy of etanercept in refractory enthesitis-related arthritis. J Rheumatol 2004;31:2055 61. [89] Tse SM, Burgos-Vargas R, Laxer RM. Anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondylarthropathy. Arthritis Rheum 2005;52:2103 8. [90] Burgos-Vargas R, Casasola-Vargas JC, Gutierrez-Suarez R, et al. An open, observational, extension study of a three-month, randomized, placebo-controlled trial to assess the longterm efficacy and safety of infliximab in juvenile-onset spondyloarthritis (Jo-SPa) [abstract 1103]. Arthritis Rheum 2008;58(Suppl.):S578. [91] Sulpice M, Deslandre CJ, Quartier P. Efficacy and safety of TNF-alpha antagonist therapy in patients with juvenile spondyloarthropathies. Joint Bone Spine 2009;76:24 7. [92] Otten MH, Prince FH, Ten Cate R, et al. Tumour necrosis factor (TNF)-blocking agents in juvenile psoriatic arthritis: Are they effective? Ann Rheum Dis 2011;70:337 40. [93] Otten MH, Prince FH, Twilt M, et al. Tumor necrosis factor-blocking agents for children with enthesitis-related arthritis—data from the Dutch Arthritis and Biologicals in Children Register, 1999 2010. J Rheumatol 2011;38:2258 63. [94] Horneff G, Fitter S, Foeldvari I, et al. Double-blind, placebo-controlled randomized trial with adalimumab for treatment of juvenile onset ankylosing spondylitis (JoAS): significant short term improvement. Arthritis Res Ther 2012;14:R230. [95] Horneff G, Burgos-Vargas R, Constantin T, et al. Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the Clipper study. Ann Rheum Dis 2014;73:1114 22. [96] Burgos-Vargas R, Tse SM, Horneff G, et al. A randomized, double-blind, placebocontrolled, multicenter study of adalimumab in pediatric patients with enthesitis-related arthritis. Arthritis Care Res (Hoboken) 2015; http://dx.doi.org/10.1002/acr.22657. [Epub ahead of print] [97] Donnithorne KJ, Cron RQ, Beukelman T. Attainment of inactive disease status following initiation of TNF-α inhibitor therapy for juvenile idiopathic arthritis: enthesitis-related arthritis predicts persistent active disease. J Rheumatol 2011;38:2675 81. [98] Boiu S, Marniga E, Bader-Meunier B, et al. Functional status in severe juvenile idiopathic arthritis in the biologic treatment era: an assessment in a French paediatric rheumatology referral centre. Rheumatology (Oxford) 2012;51:1285 92. [99] Oen K, Tucker L, Huber AM, et al. Predictors of early inactive disease in a juvenile idiopathic arthritis cohort: results of a Canadian multicenter, prospective inception cohort study. Arthritis Rheum 2009;61:1077 86.

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[100] Beukelman T, Haynes K, Curtis JR, et al. Safety assessment of biological therapeutics collaboration. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 2012;64:1263 71. [101] Powell M, Seid M, Szer IS. Efficacy of custom foot orthotics in improving pain and functional status in children with juvenile idiopathic arthritis: a randomized trial. J Rheumatol 2005;32:943 50.

Chapter 3

Systemic Juvenile Idiopathic Arthritis M. Batthish1 and R. Schneider2 1

Division of Rheumatology, Department of Pediatrics, McMaster Children’s Hospital, McMaster University, Hamilton, ON, Canada, 2Division of Rheumatology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

INTRODUCTION The unique systemic features of systemic juvenile idiopathic arthritis (sJIA), the association with macrophage activation syndrome (MAS), the relatively poor response to traditional treatment modalities, and poor outcome for a significant proportion of patients have always intrigued investigators and clinicians. Some have questioned whether sJIA should really be classified as a form of juvenile idiopathic arthritis (JIA) at all, and current understanding of the immunopathogenesis of the disease suggests that it should be considered an autoinflammatory disease. Increased attention to the disease pathogenesis over the past decade has finally started to yield tangible results with the introduction of novel treatments with biologic agents targeting interleukin (IL)-1 and IL-6. The International League of Associations for Rheumatology (ILAR) classification criteria for systemic arthritis have been widely accepted. In addition to arthritis in any number of joints, these criteria include fever for at least 2 weeks (documented to be quotidian for 3 days) and at least one of the following features: evanescent, erythematous rash, generalized lymphadenopathy, serositis, and hepatomegaly or splenomegaly [1]. However, in one study, only 30% of patients with a clinical diagnosis of sJIA fulfilled the ILAR criteria at presentation [2]. These patients often did not have the classic quotidian fever pattern as described in the ILAR criteria or did not have arthritis at presentation [2], suggesting that it may be inappropriate to use strict ILAR classification as diagnostic criteria for sJIA.

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00003-7 © 2016 Elsevier B.V. All rights reserved.

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PREVALENCE AND EPIDEMIOLOGY sJIA makes up 10 20% of most North American and European series of children with JIA, while in parts of Asia it may account for closer to 20 50% of JIA cases [3,4]. Age of onset is broad but peaks between 1 and 5 years of age [2]. Boys and girls appear to be affected equally. One population study in Norway established that the prevalence of sJIA was approximately 0.6 per 100,000/year [5]. Several investigators have looked at seasonal onset, with some suggesting that onset in the winter months might be less common [6], but no consistent seasonal pattern has been found [7]. Although the clinical features may suggest potential infectious causes of the disease, this hypothesis has not been supported in the literature.

PATHOGENESIS OF SJIA Unlike the other subtypes of JIA, no strong associations between major histocompatibility complex (MHC) class II alleles and sJIA have been found. The only exception is in a population of patients with erosive arthritis who were found to have an association with the HLA-DR4 allele [8]. Furthermore, cases of sJIA do not cluster in families. There is growing evidence to support the notion that sJIA stems from a dysregulation of the innate immune system. As a result, the characteristic clinical and laboratory features of sJIA are associated with a distinctive cytokine profile. IL-1β and IL-6 play a central role in the perpetuation of the inflammatory process in sJIA, on the basis of several studies that demonstrate that specific blockade of these cytokines results in rapid abrogation of the major clinical and laboratory features of the disease [9 13]. A number of studies support the role of IL-6 in producing both the extraarticular systemic manifestations of the disease as well as synovial inflammation [14]. Circulating IL-6 levels are markedly elevated in sJIA, rise with the peak of fever, and fall with its defervescence, a temporal association that has not been demonstrated with IL-1β or tumor necrosis factor (TNF)-α. IL6 levels are also markedly elevated in synovial fluid and circulating levels are highly correlated with the extent and severity of arthritis. IL-6 combined with the IL-6 receptor (IL-6R) is a hepatocyte-stimulating factor and induces production of a variety of acute phase proteins including C-reactive protein (CRP), serum amyloid A, and fibrinogen. Circulating IL-6 levels are significantly correlated with high CRP levels and with the elevated platelet counts typically seen with active disease. IL-6 increases ferritin expression and hepatic uptake of iron, resulting in a reticuloendothelial block with impaired availability of iron for effective erythropoiesis and the characteristic hypochromic, microcytic anemia.

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Genetic studies suggest that a single nucleotide polymorphism in the promoter region of the IL-6 gene may be associated with overproduction of IL-6 in sJIA [15]. Of two genotypes identified, the 174GG genotype is associated with higher levels of IL-6 production and the 174CC genotype with lower IL-6 production. The low responder genotype is less commonly seen in sJIA, especially in those children whose disease began before 6 years of age. A subsequent study confirmed that the 174G allele of the IL-6 gene confers susceptibility to sJIA [16]. Furthermore, a gene expression study examining the profiles of patients with active sJIA compared to healthy controls demonstrated increased expression of IL-6 in blood monocytes [17]. Although IL-1β levels have not been shown to parallel the fever peaks in sJIA, it is a highly active cytokine that can cause fever, elevated neutrophil and platelet counts, and an increase in circulating IL-6, which may then induce hepatic production of acute phase proteins and thrombocytosis [18]. Circulating levels of this cytokine may not be highly correlated with disease manifestations. However, IL-1 has been shown to stimulate the destruction of cartilage and bone [19]. IL-1 receptor levels have been demonstrated to peak within an hour of the fever peak and may also account for relatively low circulating IL-1. A series of experiments has suggested that IL-1 dysregulation is central to the pathogenesis of sJIA [9]. Serum from patients with sJIA added to peripheral blood mononuclear cells (PBMCs) of healthy donors resulted in upregulated expression of a variety of cytokine genes, including IL-1α and IL-1β. Activation of sJIA patients’ PBMCs resulted in increased production of IL-1β. Furthermore, gene expression studies have revealed an IL-1-driven signature in PBMCs from patients with untreated, new-onset sJIA [20]. The blockade of IL-1 activity by administration of an IL-1 receptor antagonist (IL-1Ra) has provided convincing evidence for the role of IL-1 in sJIA. The IL-1Ra, anakinra, resulted in the rapid resolution of fever, neutrophilia, and thrombocytosis and rapid improvement in erythrocyte sedimentation rate (ESR), anemia, and arthritis in most sJIA patients [21,22]. Gene expression profiling has provided evidence for the role of multiple proinflammatory cytokines in sJIA, including IL-1, IL-6, and IL-18. Gene expression studies have also demonstrated that the changes in gene expression profiles from PBMCs in sJIA return to normal with anti-IL-1 therapy [9,11,23]. IL-18 is potent stimulator of production of proinflammatory cytokines by T lymphocytes, natural killer (NK) cells, and macrophages, and extremely high levels of IL-18 have been reported in adult-onset Still’s disease [24] and sJIA [25]. IL-18 levels, in serum and synovial fluid, have been shown to be increased in all subtypes of active JIA; however, these levels were much higher in children with sJIA [26]. Recently, a study demonstrated an IL-6-predominant and IL-18-predominant disease pattern in sJIA [27]. Patients with higher IL-6 levels tended to have a greater number of active joints, while those with higher IL-18 levels were more likely to develop

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MAS. It is known that elevated levels of serum IL-18 are significantly associated with hyperferritinemia, hepatosplenomegaly, and serositis and may be seen in MAS [28]. The calcium-binding proteins S100A8 (also known as myeloid-related protein (MRP)-8), S100A9 (MRP-14), and S100A12 are secreted by activated neutrophils and monocytes and may amplify IL-1 activity. S100A8/A9 forms a complex that can trigger the toll-like receptor 4 signaling pathway, which can lead to an increase in multiple proinflammatory cytokines, including IL-1, which can then further increase production of S100 proteins. The serum concentrations of S100A8/A9 have been shown to decrease with clinically inactive disease and may represent a novel predictive biomarker in sJIA [29]. TNF-α levels in the circulation and in synovial fluid are elevated in sJIA and correlate with fever and systemic disease activity rather than joint inflammation [30]. However, circulating levels do not rise and fall in association with fever spikes in sJIA and TNF inhibition has not convincingly been shown to improve systemic symptoms and is less effective for arthritis than in other JIA subtypes [31]. Macrophage migration inhibitory factor (MIF) is a pluripotent protein that has proinflammatory properties and significantly elevated levels have been found in the serum and synovial fluid of patients with sJIA [32]. An MIF polymorphism (MIF-173 C allele) is associated with sJIA [33] and is a predictor of poor outcome in sJIA [34]. Although proinflammatory cytokines have been well established as playing a central role in the pathogenesis of sJIA, there is growing evidence that anti-inflammatory pathways are also associated in active sJIA. Expression of IL-10, an immune-regulatory cytokine that limits proinflammatory responses, has been detected in active sJIA. However, studies have shown that the antiinflammatory response of IL-10 is deficient in sJIA [35]. A mixed M1/M2 phenotype of monocyte activation, which is associated with suppression or regulation of immune responses, has also been identified in sJIA [36]. Finally, T regulatory cells have been detected at reduced levels in active sJIA [37].

COMMON CLINICAL MANIFESTATIONS When all the common clinical manifestations of sJIA are present, the diagnosis is relatively straightforward. However, frequently, only some are present at onset, so that the differential diagnosis becomes very broad and challenges even the most experienced clinicians. The onset may at times be so abrupt that families can actually remember the date and time that the disease began. However, as the earliest manifestation is usually fever, the time of onset may not be recalled since the early symptoms would have been assumed to be part of a nonspecific or viral illness. The fever has a unique pattern: quotidian or double quotidian, a daily

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FIGURE 3.1 Typical once or twice daily fever patterns in a child with sJIA. Note the temperature sometimes drops to subnormal levels when the fever defervesces.

or double daily rapid spike to 39 C or above, usually occurring late in the day (Fig. 3.1). This fever is often associated with chills and rigors and such children can appear extremely ill and “toxic,” only to improve dramatically with defervescence. Initially, the fever pattern may be more hectic and less predictable, making diagnosis more difficult. In one population of sJIA patients, 12% had daily morning fevers, 37% had daily evening fevers, 15% had twice-daily fevers, 27% had intermittent fevers, and 5% had continuous fevers at presentation [2]. With time and initiation of treatment, the classic daily fever pattern often develops. Another feature of the fever is that the temperature often returns to below the baseline early in the morning. Examination of a well-documented fever chart is a very important part of making a diagnosis. Fever must be present to make the diagnosis, and therefore is present in 100% of patients. The other characteristic feature of sJIA is the rash. Present in about 90% of patients, the rash is diagnostic when it occurs together with the fever spike. Therefore, if the diagnosis is uncertain, it is critically important that the patient is examined at the time of a fever spike in order to look for the rash. Rash may precede the development of other features of sJIA by weeks or even months. The rash is typically a pink, salmon-colored macular rash (Fig. 3.2), characteristically concentrated in the warmer areas of the body (thigh, axilla, and trunk). Occasionally the rash occurs on the face, hands, and feet. Macules may have areas of central clearing and sometimes coalesce to form larger lesions. The rash may appear as linear streaks in areas of pressure and may be elicited by stroking the skin (Koebner phenomenon). Because of its light color, it may be extremely difficult to discern in patients with dark skin. Sometimes the rash appears as a very striking urticarial and pruritic eruption (Fig. 3.3). It may persist even in the absence of fever. Involvement of the reticuloendothelial system is seen in about 75% of patients with diffuse lymphadenopathy, hepatomegaly, and splenomegaly, usually all occurring together. Although these features may suggest

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FIGURE 3.2 Typical salmon-pink macular rash on the trunk and proximal upper limbs of a girl with sJIA.

FIGURE 3.3 Patient with sJIA with an extensive urticarial, pruritic rash.

lymphoreticular malignancy, the nodes and organs are typically soft and nontender and the nodes mobile. Liver function tests are frequently mildly abnormal with elevation in the levels of serum transaminases. These may worsen with the institution of nonsteroidal anti-inflammatory drug (NSAID) treatment.

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Serositis is another important clinical manifestation and typically presents with chest pain with or without shortness of breath, demonstrating involvement of the pleural and pericardial membranes. Some patients with pericarditis will refuse to lie supine because this exacerbates the chest pain. Careful examination for pleural and pericardial friction rubs should be undertaken and a chest X-ray done to look for pleural effusion and widening of the cardiothoracic silhouette. During active systemic disease, 2D-echocardiography reveals small pericardial effusions in .80% of patients, who are usually asymptomatic [38]. It is unusual for patients to have symptomatic serositis in the absence of other features of active systemic disease such as fever and rash. Rarely peritoneal involvement results in severe abdominal pain. Occasionally, the pleuropericardial inflammation may lead to cardiorespiratory compromise and even cardiac tamponade, requiring pericardial drainage. Some patients have recurrent episodes of fever and pericarditis as the major manifestations of their disease. The arthritis of sJIA may take several forms, either oligoarticular or polyarticular, transient with the systemic attacks or persistent. Arthritis was present in 88% of patients with sJIA at onset [2] and the vast majority of patients will have arthritis within the first 3 months of the disease. Rarely, arthritis only develops after more than 1 year of systemic symptoms and has been reported to develop as long as 9 years after disease onset [39]. If it is not present at onset, the diagnosis becomes even more difficult. The most common joints involved include the knee, wrist, and ankle [2]. Joints may be damaged rapidly, particularly hips and wrists with cartilage loss, erosions, and ankylosis (Fig. 3.4). In one cohort, approximately half of patients with

FIGURE 3.4 Rapid progression of joint space loss, erosions, and ankylosis of both wrists in a 15-year-old girl with systemic JIA, despite treatment with prednisone, intraarticular corticosteroids, methotrexate, and etanercept.

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sJIA developed clinical hip disease a median time of 24 months from diagnosis with 20% developing radiographic evidence of hip damage [40]. Cervical spine involvement can be seen at presentation in 13% of patients [2]. This may evolve to ankylosis of the C2-3 facet joints and possibly ankylosis of the entire cervical spine. Chronic persistent arthritis develops in approximately 50% of patients.

GROWTH Growth failure is a common and important morbidity in sJIA. It is a predictable and almost inevitable outcome of patients who follow a severe, persistent disease course, particularly when the disease begins in the prepubertal period. The major determinants of growth failure are the duration and severity of active disease and the duration and cumulative dose of systemic corticosteroid treatment, although other factors such as hypercatabolism and suboptimal nutrition may also play a role. A study of prepubertal sJIA patients with persistent chronic inflammation requiring treatment with prolonged daily oral prednisone showed a significant reduction in height velocity of more than two standard deviations during the first 4 years of follow-up [41]. Linear growth retardation was associated with the duration of prednisone therapy. Although most patients demonstrated at least partial catch-up growth after prednisone was discontinued, some had further loss of height velocity. Final adult height was below their predicted target height in 87% of the patients. Impaired linear growth in sJIA has been shown to be related to disease activity independent of corticosteroid treatment [42] and has been demonstrated even in the absence of systemic corticosteroid therapy [43]. The majority of patients with active sJIA have normal growth hormone (GH) production but levels of insulin-like growth factor 1 (IGF-1), a major mediator of GH activity, and its primary binding protein, IGF binding protein-3 (IGFBP-3), are low [42,44]. Studies of IL-6 transgenic mice support a pathogenetic role for chronic IL-6 overproduction in the growth impairment seen in sJIA. These mice have a 50% reduction in growth and have similarly normal GH secretions and low IGF-1 and IGFBP-3 levels as seen in sJIA [14]. It has been recently shown that inhibition of IL-6 with tocilizumab resulted in catch-up growth in patients with sJIA, with some patients often reaching above-normal height velocity [45]. A number of studies have suggested that GH therapy results in a significant improvement in linear growth in patients with sJIA but no long-term studies have demonstrated an improvement in final adult height. A controlled study of GH therapy in corticosteroid-dependent JIA, most of whom had sJIA, showed a sustained improvement in linear growth over a 4-year period [46]. Similarly, in a randomized study, JIA patients who received GH therapy for a period of 3 years demonstrated a significant increase in height

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standard deviation score as well as height velocity compared to untreated JIA patients [47]. The role of GH for growth failure in sJIA will ultimately depend on the results of long-term studies that evaluate its efficacy in improving final adult height.

LESS COMMON CLINICAL MANIFESTATIONS The less common manifestations of sJIA are listed in Table 3.1. Although neurological complications are not common, they are potentially fatal events [58] and therefore deserve special attention. Noninfectious meningitis has been reported in adult-onset Still’s disease [48], and we have observed this in a small number of children as well. We have seen the rapid development of severe hyponatremia resulting in cerebral edema in patients with sJIA who have fever and vomiting. This is most likely a consequence of inappropriate antidiuretic hormone (ADH) secretion. We urge particular vigilance for this complication in sJIA patients who present with fever and vomiting, with close attention to fluid balance, regular monitoring of electrolytes, and avoidance of hypotonic intravenous solutions. TABLE 3.1 Less Common and Rare Manifestations of Systemic Juvenile Idiopathic Arthritis Organ System Central nervous system

Manifestations

References

Encephalopathy with MAS

[48 50]

Noninfectious meningitis Cerebral edema with SIADH Epidural lipomatosis

Eye

Uveitis

[51]

Tenosynovitis of superior oblique muscle (Brown’s syndrome) ENT

Nasal septal perforation

[52,53]

Cricoarytenoid arthritis [52,54]

Skin/ subcutaneous tissue

Vasculitis

Lung

Lipoid pneumonia

[55,56]

Pulmonary hypertension

[56a]

Lymphedema

Interstitial lung disease Alveolar proteinosis (Continued )

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TABLE 3.1 (Continued) Organ System

Manifestations

References

Heart

Cardiac tamponade

[57]

Myocarditis Valvular abnormalities Muscle

Myositis

[57a]

Hematological

Isolated thrombocytopenia

[57b]

Renal

Calculi

[57c]

Hematuria and proteinuria Glomerulonephritis SIADH, Syndrome of Inappropriate antidiuretic hormone secretion; ENT, ear, nose, throat.

Uveitis occurs in ,2% of sJIA patients. We therefore recommend ophthalmological assessment at the time of diagnosis and annually thereafter. However, patients who require long-term systemic corticosteroids should be monitored more frequently (we suggest every 6 months) for the development of cataracts and glaucoma. Superior oblique muscle tenosynovitis resulting in Brown’s syndrome has been reported [51]. Nasal septal perforation has been reported in three sJIA patients. All had severe, refractory disease and one had associated leukocytoclastic vasculitis of the skin [52]. Pleuritis occurs less frequently than pericarditis. However, severe pulmonary manifestations are being reported with increased frequency. Lipoid pneumonia is a rare complication of severe, refractory disease with the development of progressive pulmonary cholesterol granulomas, which may result in respiratory failure [55]. In a recent review of sJIA patients with pulmonary disease at diagnosis, 64% had pulmonary arterial hypertension, 28% had interstitial lung disease, and 20% had alveolar proteinosis [59]. These patients had severe systemic disease and were exposed to several biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs). Sixty percent of these patients also had concomitant MAS at the time of their pulmonary disease [59]. Significant systemic inflammation likely plays a significant role in the pathogenesis of these pulmonary complications. Although myalgias are common, documented myositis is rare but may be associated with typical inflammatory findings on MRI scanning of muscles [60]. Myocarditis is similarly rare and usually accompanies symptomatic pericarditis [57].

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MACROPHAGE ACTIVATION SYNDROME MAS is an important complication of sJIA, occurring in at least 7% of patients [61], but patients may also manifest some of the clinical and laboratory features without developing the complete syndrome. Subclinical MAS has an estimated prevalence of 30 40% in patients with sJIA [62,63]. MAS can evolve rapidly with significant morbidity and mortality, making prompt diagnosis and treatment imperative. MAS is best considered a form of hemophagocytic lymphohistiocytosis (HLH), secondary to rheumatic diseases. Both HLH and MAS are characterized by excessive activation of monocytes and macrophages and high levels of proinflammatory cytokines, including TNF-α, IL-6, and IFN-γ. The proinflammatory features of MAS and HLH can be explained by defects in NK-cell and CD8 T-cell cytotoxicity. Although familial HLH has been characterized by homozygous defects in the cytolytic pathway genes, there is increasing evidence for single or multiple mutations in the same cytolytic pathway genes in patients with MAS secondary to sJIA. Polymorphisms in the UNCD13D gene were identified in a cohort of sJIA patients with MAS. This gene encodes for the Munc13-4 protein, which is responsible for allowing the perforin-containing vesicles to fuse with the NK cell immunologic synapse [64]. In a separate cohort of sJIA patients with MAS, defects in the PRF1 gene, encoding the perforin protein, were found in 20% of the patients [65]. Furthermore, heterozygous protein-altering variants in LYST and STXBP2 were found in sJIA patients with MAS [66]. The most common clinical features of MAS are sustained fever and hepatosplenomegaly, while lymphadenopathy, bruising, petechiae, and mucosal bleeding are also characteristic features. These features may be accompanied by an unexpected improvement in the patient’s arthritis. More severely affected patients can have multiorgan involvement with depressed level of consciousness, seizures, disorientation, and even coma; respiratory distress with pulmonary infiltrates; and cardiovascular instability with hypotension and shock. In a multinational study of over 300 sJIA patients with MAS, fever, hepatomegaly, and splenomegaly were the most common clinical manifestations occurring in 96%, 70%, and 58% of patients, respectively [67]. In those who underwent bone marrow aspiration, macrophage hemophagocytosis was detected in 60% of the patients [67]. Typical laboratory features include pancytopenia, elevated transaminases and sometimes bilirubin, elevated LDH, and elevated triglyceride levels. Serum ferritin levels are often extremely high. A dramatic and sharp drop in ESR, despite an ongoing febrile illness, is an important laboratory clue to the diagnosis. Coagulopathy with prolongation of the prothrombin time and partial thromboplastin time, marked elevation of d-dimers, and low levels of fibrinogen is seen. Renal involvement may range from mild hematuria and proteinuria to acute renal failure requiring dialysis. Cerebrospinal fluid

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analysis may reveal pleocytosis and elevated protein. Other features include hyponatremia, hypoalbuminemia, elevated VLDLs, and decreased HDLs. Active systemic disease, infections, and medication toxicities may mimic the clinical and laboratory manifestations of MAS and can also occur in association with MAS. MAS has been associated with viral, bacterial, and fungal infections, but has particularly been related to infections with the herpes viruses, especially with Epstein-Barr virus (EBV) infection. NSAIDs, gold injections, sulfasalazine, methotrexate, and etanercept have all been reported to be associated with the initiation of MAS [68]. There have also been reports of MAS in sJIA patients under treatment with other biologic agents such as tocilizumab [13,69], anakinra [22], and canakinumab [70]. Despite these reports, there does not seem to be an increased risk of developing MAS in those sJIA patients receiving biologic agents [71]. However, these agents may not be able to completely prevent the development of MAS either. Moreover, the clinical and laboratory manifestations of MAS may be less prominent in patients being treated with IL-1 and IL-6 inhibitors. There are no validated diagnostic criteria for MAS associated with sJIA. Stringent application of the proposed diagnostic criteria for HLH, revised by Henter et al. for the Histiocyte Society in 2004 [72], is not appropriate for several reasons. First, the clinical criteria of fever and splenomegaly are not specific and can also be seen with active sJIA. A persistent fever as opposed to the typical quotidian pattern of fever in sJIA is more suggestive of MAS or infection. Second, the hematological profile is problematic. Anemia with hemoglobin ,90 g/L can also be seen in active systemic disease. More importantly, the requirement of a drop in platelet count to ,100 3 109/L and neutrophil count ,1.0 3 109/L may result in an unnecessary delay in diagnosis. Since both platelet and neutrophil counts are characteristically high in active systemic disease, a significant and sudden drop in these counts may be more important than the absolute number. Similarly, a substantial drop in fibrinogen levels may be more important than a level ,1.5 g/L since fibrinogen is also elevated along with other acute phase proteins in sJIA. Third, it is well known that hemophagocytic changes may not be demonstrable pathologically. Tissue hemophagocytosis may be missed in the bone marrow early on and biopsies of liver, spleen, or lymph nodes are often not possible because of severe coagulopathy. On the other hand, mild hemophagocytic changes are not specific and may be seen in the absence of MAS. The inclusion of low NK-cell function, elevated ferritin, and elevated levels of soluble CD25 in the criteria may be helpful in establishing a diagnosis but have not been evaluated. Ferritin is also an acute phase protein and levels .500 microgram/L are frequently seen in active sJIA without other features of MAS. Extreme hyperferritinemia may be more helpful. In an attempt to address some of these issues, Ravelli et al. [73] proposed preliminary diagnostic guidelines for MAS in sJIA. The clinical criteria are central nervous system dysfunction, hemorrhages, and hepatomegaly.

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TABLE 3.2 Classification Criteria for Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis A febrile patient with known or suspected sJIA is classified as having MAS if the following criteria are met: Ferritin . 684 ng/mL and any two of the following: Platelet count # 181 3 109/L Aspartate aminotransferase . 48 U/L Triglycerides . 156 mg/dL Fibrinogen # 360 mg/dL Source: Adapted from Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, et al. Development and initial validation of classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis Rheumatol 2015. [Epub ahead of print].

The laboratory criteria include a reduction in platelet count to # 262 3 109/L (rather than true thrombocytopenia), elevated aspartate aminotransaminase (.59 U/L), white blood cell count # 4 3 109/L, and fibrinogen # 2.5 g/L. These guidelines have been studied in a large cohort of patients with sJIA associated MAS, active sJIA, and patients who did not have sJIA but were hospitalized with a systemic infection [74]. The preliminary diagnostic guidelines for MAS in sJIA as proposed by Ravelli performed better than the HLH-2004 guidelines in distinguishing MAS in sJIA from sJIA without MAS with a sensitivity and specificity of 86%, each [74]. The addition of hyperferritinemia (ferritin $ 500 ng/mL) allowed these preliminary guidelines to differentiate those patients with sJIA and MAS and the control patients with systemic infections with a sensitivity of 86% and a specificity of 95% [74]. Recently, new guidelines for the classification criteria for MAS in sJIA have been developed [75] (Table 3.2). Further prospective validation is needed. The initial treatment of MAS requires the prompt administration of high dose corticosteroids. In the multinational study of over 300 sJIA patients with MAS, nearly all patients received corticosteroid treatment (97.7%) [67]. Our preference is to use intravenous pulse methylprednisolone 30 mg/kg per dose up to a maximum of 1000 mg/dose for 3 5 days, followed by highdose oral or intravenous corticosteroids. If there is central nervous system involvement, dexamethasone may be preferable to prednisone. We frequently add intravenous immunoglobulin to this regimen, which has been reported to be effective in MAS [76]. Approximately half the patients with MAS may respond to corticosteroids alone. Treatment with anakinra has been reported

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to be effective in MAS [77 80] and given its proven efficacy in the treatment of sJIA, we should consider starting treatment of active sJIA complicated by MAS with both high-dose corticosteroids and anakinra. Higher doses of anakinra may be required for MAS [80]. If there is an inadequate response to corticosteroids, with or without anakinra, or if there is more severe multiorgan involvement, adding cyclosporine to the regimen may result in rapid and dramatic improvement [61,81,82]. Since MAS can follow a course of rapid progression and deterioration, some authors feel that cyclosporine should be added to corticosteroids as first-line therapy [83]. If there is rapidly evolving multiorgan failure, adding etoposide can be very helpful in reversing the manifestations of severe MAS. Although multiorgan involvement may be associated with a poor outcome, severe renal disease may fully recover if treatment is initiated promptly [84]. The reported recurrence risk of MAS is 17% and the reported mortality is 8 22% [61,82].

LABORATORY INVESTIGATIONS While there is a pattern of laboratory abnormalities that is characteristic of patients with sJIA, there are no specific tests that allow the diagnosis to be made with certainty. There is a marked elevation of the acute phase response consisting of anemia, typically hypochromic, microcytic with leukocytosis and left shift, and thrombocytosis. Iron deficiency may also contribute to the anemia as a result of poor nutrition. The ESR and CRP are both markedly elevated, and a persistently raised CRP may correlate with ongoing damage, a poor outcome, and the development of systemic amyloidosis. Other features of the acute-phase response include hypergammaglobulinemia, hypoalbuminemia, and raised levels of fibrinogen. The elevated immunoglobulin levels may result in confusion if specific antibodies are searched for. For instance, approximately one-fourth to one-third of patients will have an elevated antistreptolysin-o titer; however, this should not necessarily be assumed to be a result of a streptococcal infection. Raised serum ferritin may also be seen with elevation of other acute phase proteins, such as serum amyloid A. The raised ferritin in this case is a poor reflection of iron stores, and iron deficiency may best be determined by measurement of serum soluble transferrin receptor levels, which are not affected by chronic inflammation. Markedly high levels of MRP-8 and MRP-14 have been found in active sJIA and may distinguish sJIA from systemic infections, forms of leukemia, and Kawasaki disease [85,86]. Both the rheumatoid factor and antinuclear antibody (ANA) tests are typically negative, helping to differentiate sJIA from other autoimmune connective tissue diseases. Elevated levels of transaminases are commonly seen, particularly with active systemic disease, but may also be associated with MAS and treatment with

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NSAIDs, methotrexate, or biologic agents. There may be a mild underlying coagulopathy with elevation of d-dimers without other evidence of overt MAS. Synovial fluid analysis during active systemic disease may resemble the findings in infectious synovitis, with high white cell counts of a predominantly polymorphonuclear type.

RADIOLOGIC INVESTIGATIONS X-ray abnormalities in children with sJIA include soft tissue swelling, reduced bone density, loss of joint space, advanced maturation, erosions, and deformity. The early changes of soft tissue swelling and osteopenia are reversible. Radiographic damage occurs early, within 2 years of disease onset in about one-third of patients who develop joint space loss and erosions [87]. Destructive changes can occur rapidly over the course of 1 2 years, especially in the hips and wrists. The Poznanski score can be used as a valid measure of joint space loss, and radiographic progression during the first year of disease correlates with the Poznanski score at the final visit, Childhood Health Assessment Questionnaire (CHAQ), and yearly progression [88]. In a univariate analysis, systemic disease also correlated with yearly radiographic progression and the final Poznanski score. Radiographic damage at 2 years, measured by erosions with or without joint space narrowing, correlates with thrombocytosis and active systemic disease in children with sJIA. The most commonly involved joints are the wrist followed in frequency by the ankle, knee, tarsal, hip, and metacarpophalangeal joints [87]. Joint ankylosis is also common in unresponsive disease, and usually involves the carpus and apophyseal joints of the cervical spine, especially the second to third facet joints. Growth disturbances are also common, leading to micrognathia and retrognathia, shortened digits, and reduced height of vertebral bodies. Diagnostic imaging is also helpful for some of the complications of sJIA. Growth delay is common and X-rays of the hand may be useful in determining bone age and the potential for future growth (this may be difficult if there is arthritis involving the carpus). Osteoporosis resulting from active disease, treatment with corticosteroids, reduced exercise, and poor diet is common. Bone densitometry studies should be done to establish a baseline and to follow and determine the need for specific treatment. Patients with severe osteoporosis are at risk for spontaneous fractures, particularly those involving the vertebral bodies. Murray et al. [89] reported that almost onefourth of patients with sJIA had at least one fracture and the majority of these were vertebral. Those with severe erosive disease, growth failure, and high cumulative corticosteroid doses seem to be at highest risk of this complication. However, vertebral compression fractures can occur in the absence of significantly reduced bone mineral density measurements [90]. Synovial

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cysts are more common in sJIA than other types, and ultrasound and MRI studies may help detect and define these cysts.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of sJIA is one of the widest in pediatrics (Table 3.3), given the broad array of signs and symptoms that may develop. Furthermore, since there is no diagnostic test, it often remains a diagnosis of exclusion. Broad categories that must be considered include infection, malignancy, systemic autoimmune disease, vasculitis, and the autoinflammatory syndromes. However, careful attention to the signs and symptoms and appropriate diagnostic testing should allow us to arrive at a diagnosis. In approaching these patients, it is always imperative to rule out potentially treatable and life-threatening diseases. Thus malignancy and infection should be considered first. Lymphoreticular malignancies (leukemia, lymphoma) and neuroblastoma are suggested by the presence of lymphadenopathy and splenomegaly and are supported by the systemic and constitutional features. The marked elevation of the acute phase response with leukocytosis and thrombocytosis would go against leukemia, but may be seen in lymphoma and neuroblastoma. Bone marrow aspirates and appropriate use of diagnostic imaging (ultrasound and CT scan of chest and abdomen) are often performed looking for signs of lymphoreticular malignancy. A lymph node biopsy may also be performed. Signs more suggestive of sJIA would be the evanescent rash and typical periodicity of the fevers. Infections must be strongly considered in view of the fever, constitutional symptoms, leukocytosis, and elevated ESR. Bacterial infections to be considered include those associated with fever of unknown origin such as subacute bacterial endocarditis, abscess, osteomyelitis, and even tuberculosis. Bartonella infections have been reported to produce a similar constellation of symptoms and signs to sJIA. Mycoplasma pneumonia can also cause serositis, rash, and arthritis. Appropriate cultures, polymerase chain reaction tests, serological tests, and radiographic investigations should be able to exclude these. Systemic viral infections such as EBV and cytomegalovirus are suggested by the fever and reticuloendothelial involvement and occasionally the rash. Sore throat, a common manifestation of EBV infection, is frequent in adult-onset Still’s disease and also occurs in sJIA. However, leucopenia or lymphocytosis and thrombocytopenia would be more likely in these viral infections. HIV infection and Lyme disease should also be considered with the appropriate epidemiologic history. Reactive arthritis should be excluded especially when it occurs with fever and rash. Acute rheumatic fever occurs within 10 days to 3 weeks of an untreated streptococcal throat infection and has many features in common with sJIA. However, the characteristic features of the arthritis such as flitting arthritis, severe pain, and exquisite response to aspirin or naproxen,

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TABLE 3.3 Differential Diagnosis of Systemic Juvenile Idiopathic Arthritis Malignancy Leukemia, lymphoma, neuroblastoma Infection Viral: EBV, cytomegalovirus, hepatitis, HIV Bacterial: Infective endocarditis, osteomyelitis, tuberculosis, Bartonella, Mycoplasma, Lyme Inflammatory connective tissue diseases Systemic lupus erythematosus Mixed connective tissue disease/overlap syndrome Juvenile dermatomyositis Reactive arthritis Acute rheumatic fever Postsalmonella/shigella/yersinia arthritis Periodic fever/autoinflammatory syndromes Familial Mediterranean fever Hyperimmunoglobulin D syndrome TNF receptor-associated periodic fever syndrome Cryopyrin-associated periodic fever syndrome Familial cold autoinflammatory syndrome Muckle-Wells syndrome Neonatal-onset multisystem inflammatory disease Systemic inflammatory syndromes Crohn’s disease Sarcoidosis Noninfectious osteomyelitis Vasculitides Cutaneous polyarteritis nodosa Kawasaki disease

persistent fever pattern, erythema marginatum rash, and typical electrocardiographic abnormalities would not support the diagnosis of sJIA. Autoimmune connective tissue diseases to be ruled out include systemic lupus erythematosus (SLE), juvenile dermatomyositis (JDM), and mixed

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connective tissue disease (MCTD). SLE and MCTD in particular are associated with characteristic autoantibodies that are not present in sJIA (ANA, anti-dsDNA, anti-Ro, anti-La, anti-Sm, and anti-RNP). They frequently have reduced white blood cell and platelet counts and low levels of serum complement. Renal abnormalities, common in lupus, are infrequent in sJIA. Patients with sJIA often have severe myalgias associated with the fever spikes, muscle strength may be difficult to evaluate in the presence of painful polyarthritis, and transaminases may be elevated. However, they do not usually have elevated creatine kinase levels or the characteristic rashes seen in JDM. Serum sickness and adverse drug reactions can also mimic sJIA with fever, rash, arthritis, and elevated inflammatory markers. A history of exposure to a drug, erythema multiforme rash, and low serum complement (usually elevated in sJIA) should help to make this diagnosis. The autoinflammatory syndromes, particularly the cryopyrin-associated periodic fever syndromes, hyperimmunoglobulin D syndrome, and TNF receptor-associated periodic syndrome frequently have an earlier age of onset, positive family history, and episodes that are shorter in duration than flares of sJIA. Persistent arthritis is not characteristic except in neonatal onset multisystem inflammatory disease syndrome, which has its onset in the neonatal period. Other inflammatory disorders to be considered include Crohn’s disease, sarcoidosis, and systemic vasculitides such as polyarteritis nodosa (PAN), granulomatous polyangiitis (GPA), and Kawasaki disease, especially when these diseases are associated with arthritis. Cutaneous PAN has many clinical features in common with sJIA including fever, arthritis, splenomegaly, and a very similar laboratory profile. A careful examination for tender subcutaneous nodules should exclude this diagnosis. Atypical Kawasaki disease may initially be confused with sJIA and there are reports of sJIA that has followed classical Kawasaki disease.

TREATMENT The treatment of patients with sJIA has been one of pediatric rheumatology’s greatest challenges. Studies showing that joint damage occurs early and permanent long-term remissions are seen in fewer than one-half of patients reinforce the need for early aggressive treatment in those with a high risk of poor outcome. Unraveling the roles of IL-1 and IL-6 in the pathogenesis of the disease and the successful completion of well-designed clinical trials of IL-1 and IL-6 blockade have resulted in dramatic changes in the approach to treatment of sJIA and marked improvements in at least short-term outcomes. Updated recommendations for the treatment of sJIA [91] were published just 2 years after the American College of Rheumatology recommendations for treatment of JIA [92], to incorporate rapidly emerging data from these clinical trials.

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Initially, treatment is directed at improving the systemic manifestations of disease including the fever and constitutional symptoms. A trial of NSAIDs for 1 2 weeks is appropriate, particularly as observations and investigations are undertaken to confirm the diagnosis. It appears that indomethacin (1 3 mg/kg per day in 3 divided doses) and ibuprofen (30 40 mg/kg per day in 4 divided doses) may be more effective than other NSAIDs. Since these drugs are protein-bound within the circulation, care must be taken with dosing in patients who have hypoalbuminemia. The severity of arthritis and systemic manifestations determine whether more aggressive systemic treatment is required. Traditionally, systemic corticosteroids have been used: prednisone 1 2 mg/kg per day (maximum 60 mg) or intravenous pulse methylprednisolone 30 mg/kg per dose (maximum 1000 mg) for more severe systemic manifestations, such as symptomatic pericarditis or MAS. Reports of the successful use of IL-1 blockade, with or without systemic corticosteroids, and the well-founded concerns about the side effects of systemic corticosteroids has recently led to early use of IL-1 blockade without systemic corticosteroids [22]. In fact, the updated recommendations for the treatment of sJIA include the use of anakinra as a first-line treatment for severe disease with poor prognostic features. While some patients can be effectively treated with biologic agents alone, it is important to keep in mind that effective treatment of life-threatening complications is paramount and the role of systemic corticosteroids should not be overlooked in this era of new and effective biologic agents. Reducing prednisone to as low a dose as possible should be instituted early as the long-term course does not seem to be affected by corticosteroids. Concurrent use of IL-1 or IL-6 blockade with systemic corticosteroids may allow a rapid taper of the corticosteroids. Numerous case reports and small case series have documented significant benefit of anakinra, the IL-1 receptor antagonist [93,94]. In a small, controlled trial of anakinra in 24 patients with sJIA, randomized to receive anakinra 2 mg/kg per day or placebo [11], anakinra was shown to be effective after 1 month. Those on placebo were offered anakinra treatment after 1 month. Sustained responses to anakinra were less impressive as systemic corticosteroids were weaned. One possible reason for this is that younger children may require higher doses of anakinra, as suggested in a pharmacokinetic study of anakinra in sJIA [95]. Responses usually occur early and systemic symptoms may respond better than arthritis. The drug must be administered subcutaneously on a daily basis, making this difficult to tolerate, especially in young children. Subcutaneous injections are often painful and commonly cause local skin reactions. Canakinumab, a fully human, anti-IL1β monoclonal antibody, proved to be efficacious in active sJIA in two randomized, controlled trials [70]. In the first trial, involving 84 patients, canakinumab (4 mg/kg, maximum 300 mg by subcutaneous injection every 4 weeks) was significantly more effective

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than placebo 15 days after a single dose. Trial 2 utilized a randomized withdrawal design in which 100 patients, who had responded to canakinumab, were randomized to continue canakinumab every 4 weeks or to receive placebo. The risk of a disease flare was significantly lower in the canakinumab group. The average glucocorticoid dose was substantially reduced and one-third of patients were able to discontinue glucocorticoids. The response to canakinumab appears to be similarly robust in patients who have fever at the onset of treatment and those who do not [96]. Rilonacept, a fusion protein of human cytokine receptor extracellular domains of both receptor components required for IL-1 signaling and the Fc portion of human IgG1, was shown to be effective in active sJIA in a randomized trial involving 71 patients [97]. Time to response to rilonacept (loading dose of 4.4 mg/kg, followed by 2.2 mg/kg weekly by subcutaneous injection) was significantly shorter than in the placebo group. Responses were sustained in the 6-month extension phase of the trial. Responses were similar in those with and those without systemic symptoms at baseline. Onethird of patients were able to discontinue glucocorticoids. Two randomized controlled trials of tocilizumab, a humanized IL-6receptor monoclonal antibody, have convincingly demonstrated efficacy of this biologic agent in active sJIA. A Japanese randomized withdrawal design study of tociluzumab in 56 patients with active sJIA reported 68% achieved 70% improvement at the end of the 6-week open-label phase. In the randomized withdrawal phase 80% of patients in the tocilizumab group remained responders compared with 17% in the placebo group [98]. In an international trial, 112 patients were randomly assigned to receive tocilizumab (8 mg/kg for those $30 kg or 12 mg/kg for those ,30 kg) every 2 weeks by intravenous infusion [13]. After 12 weeks, response rates were significantly higher in the tocilizumab group than in the placebo group. After 1 year of treatment, almost 60% of patients on tocilizumab had 90% improvement and more than one-half of the patients had discontinued glucocorticoids. Sustained response to treatment with tocilizumab has been demonstrated in both the Japanese [99] and the international trial [13] cohorts. Reactions to tocilizumab infusions have been reported. In our experience, slowing down the infusion rate and premedicating patients with an antihistamine and hydrocortisone has allowed us to continue treatment with tocilizumab in most, but not all, patients. It is difficult to directly compare efficacy and safety of the various IL-1 and IL-6 inhibitors since there has not been uniformity in trial designs employed, characteristics of patients enrolled, the outcome measures used, and the glucocorticoid-weaning regimens followed. The choice of initial biologic agent may be determined by preference for intravenous or subcutaneous administration, affordability and access to tocilizumab in different countries, as well as clinical features, particularly whether there are features of MAS present.

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The response to other biologics does not appear to be as robust as in children with other forms of polyarthritis, even when doses used are higher than the usual ones recommended. The TNF antagonists etanercept [100,101] and infliximab [102] are not effective in treating the systemic symptoms but they may have a role in treating persistent arthritis, but the benefits may not be sustained. Some patients with polyarticular course sJIA may respond to abatacept [103] and a small number of patients with refractory disease have been reported to respond to the combination of abatacept and anakinra [104]. The safety of using this combination of biologics has not been adequately evaluated. The response of both systemic symptoms and arthritis to rituximab in patients with sJIA [105] has not been confirmed by a controlled study or widespread reports from other centers. Traditional DMARDs such as methotrexate [106] have no benefit for systemic features and are of limited efficacy for arthritis. Methotrexate is sometimes used in combination with biologic agents, but it is not clear if it further improves the efficacy of the biologics. Methotrexate may potentially worsen the neutropenia associated with IL-1 or IL-6 inhibitors. Cyclosporine can be very helpful in controlling MAS but has limited benefit for systemic symptoms or arthritis. Thalidomide at a dose of 3 5 mg/kg per day may be successful in combination with other immunosuppressive agents, even in children who have failed treatment with etanercept [107]. Patients treated with thalidomide should be carefully monitored for symptoms of peripheral neuropathy, a rare adverse event that could be irreversible. Some patients may respond to treatment with intravenous immunoglobulin, at a dose of 2 g/kg every 4 weeks, which may be effective as a steroidsparing agent but does not have much efficacy for the arthritis [108]. Intraarticular triamcinolone hexacetonide can be very effective as an adjunct to other treatments for particularly symptomatic joints, but there is a shorter duration of response in patients with active systemic disease. Despite the advent of new agents, some patients continue to manifest severe polyarthritis and/or steroid dependency. For a very small subgroup of patients, autologous stem cell transplantation may be considered. While initial results showed a mortality of almost 15%, changes in the preparation protocol seem to have reduced the mortality risk [109]. Some patients have been able to discontinue all other forms of treatment and achieved a greatly improved quality of life. The risks of serious infections and the development of MAS remain major concerns. Allogeneic stem cell transplantation may also be considered for those with refractory disease and refractory MAS. Occasionally, surgical intervention is required to correct deformities. This may include soft tissue release for severe joint contractures, especially around the hip, arthrodesis of the foot or ankle, and joint replacement surgery. Indications for joint arthroplasty include intractable pain and severe loss of mobility. Recent experience with hip arthroplasty suggests that the outcomes with a cementless arthroplasty are excellent [110].

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DISEASE COURSE, OUTCOME, AND PROGNOSIS Patients with sJIA can have widely disparate disease courses and outcomes. These range from a monocyclic course followed by complete remission with no disability to a persistently active disease course often well into adult life, characterized by destructive polyarticular arthritis, markedly impaired growth, prominent corticosteroid toxicity, osteoporotic fractures, and severe disability. Despite advances in the treatment of JIA, most of the larger studies suggest that more than 50% of sJIA patients have a persistently active disease course with only one-third of patients achieving remission without medication 10 years after disease onset [111 113]. The articular disease is more often persistent than the systemic symptoms, although these can also persist for longer than 10 years in 25 30% of patients [114,115]. Monocyclic disease occurs in approximately 40% of patients and a polycyclic course with recurrent episodes of active disease following remission occurs in less than 10% of patients [113,116]. Disease flares may occasionally occur after prolonged remissions. Older studies of functional outcome in sJIA consistently showed that a substantial proportion of patients have severe functional impairments. In studies from the 1970s and 1980s, 29 50% of patients were in Steinbrocker functional class III or IV [115,117]. Packham and Hall [118] reported that almost two-thirds of patients with sJIA who were followed for a mean of almost 30 years were classified as Steinbrocker class III or IV; 62% had Health Assessment Questionnaire (HAQ) scores reflecting severe disability and 75% had undergone arthroplasty. Although patients with milder disease are underrepresented in this study, it clearly demonstrates that patients with persistently active disease develop severe functional impairment. More recent studies prior to the biologic era, summarized by Adib [119], report a wide range in the proportion of patients in Steinbrocker class III and IV (0 30%). The Steinbrocker classification of functional ability may result in an underestimation of disease severity, since in several of these studies reporting less severe impairment, a high proportion of patients had arthroplasties [112,120]. Functional impairment in sJIA measured by the CHAQ or HAQ has been reported to be more severe than in the other JIA subtypes [120a]. In a study of 111 patients with systemic JRA, 22% had moderate-tosevere disability with a CHAQ score of .0.75, 7 years after disease onset [121]. Short-term outcomes of biologic studies demonstrate better functional outcomes and quality of life, but long-term studies have not yet been published. The identification of reliable predictors of disease course and outcome within the first few months of disease onset is invaluable in determining which patients might benefit from early aggressive therapy. In a retrospective study, persistent systemic symptoms together with thrombocytosis (platelet count .600 3 109/L) at 6 months after disease onset predicted poor

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outcome, defined as polyarticular arthritis with joint space narrowing and erosions at 2 years. Additional predictors included polyarticular arthritis, WBC .12 3 109/L and hemoglobin ,100 g/L [122]. In a subsequent study of 104 patients, persistent systemic symptoms (characterized by fever or the use or systemic corticosteroids) and thrombocytosis at 6 months were strongly predictive of poor functional outcome (CHAQ $ 0.75) [121]. Modesto et al. [123] identified young age (,8 years), lymphadenopathy and high articular index at onset and polyarticular disease with hip involvement at 6 months as predictors of poor outcome. Very early onset disease, before 18 months of age, has recently been reported to be associated with more severe disease and worse outcomes [124]. As might be expected, the disease course can be correlated with outcome. Persistently active disease is associated with worse clinical, radiological, and functional outcomes. Moreover, the cumulative duration of active disease correlates with outcome [111]. It has been suggested that males have a worse outcome than females [112] but this has not been consistent. De Benedetti et al. [34] evaluated the functional and prognostic significance of a polymorphism of the macrophage MIF gene. The MIF-173 C allele has been associated with higher serum and synovial fluid levels of MIF, poor response to glucocorticoid therapy, persistence of active disease, and poor functional outcome. It is likely that the future identification of combinations of clinical, laboratory, and genetic predictors will improve the sensitivity and specificity of predicting disease outcome in sJIA. Despite bearing the burden of a severe systemic disease, children with sJIA typically have normal cognitive development and performance, including normal performance on tests of IQ, memory, learning, attention, and fine motor activities. Although these patients report fewer social activities than their peers, they may not have a significant increase in social or emotional problems [125].

MORTALITY Although the mortality rate in JIA is considerably less than 0.5% [126], sJIA accounts for a disproportionate two-thirds of deaths in JIA. The most important causes of mortality are infections and MAS. Patients with sJIA should receive routine childhood immunizations with special attention to meningococcal, pneumococcal, and annual influenza vaccines. Live virus vaccines including the varicella vaccine may be administered prior to initiation of immunosuppressive therapy. Children requiring long-term immunosuppressive therapy should be considered candidates for antibiotic prophylaxis for pneumocystis carinii, depending on the particular immunosuppressive regimen followed. The mortality in earlier European series of patients with sJIA was reported to be as high as 14% with the majority of deaths resulting from

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TABLE 3.4 Causes of Death in Systemic Juvenile Idiopathic Arthritis Macrophage activation syndrome Infection Neurological complications Amyloidosis Cardiac complications Interstitial lung disease/lipoid pneumonia Treatment-related malignancy

amyloidosis [114,115,117]. However, with the declining incidence of amyloidosis in sJIA, lower mortality rates of ,5% have been reported [111,127]. The causes of mortality in sJIA are listed in Table 3.4. Severe cardiac involvement may result in myocarditis, cardiac tamponade, or arrhythmias [57]. Neurological complications include aseptic meningitis, and we have observed a syndrome of inappropriate ADH secretion in association with active systemic disease resulting in hyponatremia and cerebral edema [58]. There are a few reports of the development of fatal lipoid pneumonia in patients with active, refractory disease [55].

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[117] Ansell BM, Wood PHN. Prognosis in juvenile chronic polyarthritis. Clin Rheum Dis 1976;2:397 412. [118] Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. Rheumatology (Oxford) 2002;41(12):1428 35. [119] Adib N, Silman A, Thomson W. Outcome following onset of juvenile idiopathic inflammatory arthritis: I. frequency of different outcomes. Rheumatology (Oxford) 2005;44 (8):995 1001. [120] David J, Cooper C, Hickey L, Lloyd J, Dore C, McCullough C, et al. The functional and psychological outcomes of juvenile chronic arthritis in young adulthood. Br J Rheumatol 1994;33(9):876 81. [120a] Bowyer SL, Roettcher PA, Higgins GC, Adams B, Myers LK, Wallace C, et al. Health status of patients with juvenile rheumatoid arthritis at 1 and 5 years after diagnosis. J Rheumatol 2003;23:394 400. [121] Spiegel LR, Schneider R, Lang BA, Birdi N, Silverman ED, Laxer RM, et al. Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: a multicenter cohort study. Arthritis Rheum 2000;43(11):2402 9. [122] Schneider R, Lang BA, Reilly BJ, Laxer RM, Silverman ED, Ibanez D, et al. Prognostic indicators of joint destruction in systemic-onset juvenile rheumatoid arthritis. J Pediatr 1992;120(2 Pt 1):200 5. [123] Modesto C, Woo P, Garcia-Consuegra J, Merino R, Garcia-Granero M, Arnal C, et al. Systemic onset juvenile chronic arthritis, polyarticular pattern and hip involvement as markers for a bad prognosis. Clin Exp Rheumatol 2001;19(2):211 17. [124] Russo RA, Katsicas MM. Patients with very early-onset systemic juvenile idiopathic arthritis exhibit more inflammatory features and a worse outcome. J Rheumatol 2013;40 (3):329 34. [125] Feldmann R, Weglage J, Roth J, Foell D, Frosch M. Systemic juvenile rheumatoid arthritis: cognitive function and social adjustment. Ann Neurol 2005;58(4):605 9. [126] Wallace CA, Levinson JE. Juvenile rheumatoid arthritis: outcome and treatment for the 1990s. Rheum Dis Clin North Am 1991;17(4):891 905. [127] Kobayashi T, Tanaka S, Maeda M, Okubo H, Matsuyama T, Watanabe N. A study of prognosis in 52 cases with juvenile rheumatoid arthritis. Acta Paediatr Jpn 1993;35 (5):439 46.

Chapter 4

Macrophage Activation Syndrome A. Ravelli1,2, F. Minoia2, S. Davı`2 and A. Martini3 1

Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy, 2Department of Pediatric Sciences, Giannina Gaslini Institute, Genoa, Italy, 3Giannina Gaslini Institute, Genoa, Italy

INTRODUCTION Macrophage activation syndrome (MAS) is the term used to describe a potentially life-threatening complication of rheumatic diseases, which is seen most frequently in systemic juvenile idiopathic arthritis (sJIA) and in its adult equivalent, adult-onset Still’s disease [1 4], although it is encountered with increasing frequency in systemic lupus erythematosus of either childhood or adult onset [5,6] and Kawasaki disease [7]. In spite of recent reports in periodic fever syndromes [8,9], the occurrence of MAS in other autoinflammatory diseases is rare. MAS is characterized by an overwhelming inflammatory reaction due to an uncontrolled and dysfunctional immune response involving the continual activation and expansion of T lymphocytes and macrophages, which results in massive hypersecretion of proinflammatory cytokines [10,11]. It is still unclear whether MAS is a discrete clinical event or whether it simply represents the most severe end of the spectrum of disease activity in sJIA. This chapter summarizes the characteristics of MAS occurring in the context of sJIA and discusses the recent advances in classification systems and management.

CLINICAL, LABORATORY, AND HISTOPATHOLOGICAL FEATURES The clinical presentation of MAS is generally acute and occasionally dramatic. Typically, patients become acutely ill with the sudden onset of nonremitting high fever, profound depression of all three blood cell lines (leukopenia, anemia, and thrombocytopenia), hepatosplenomegaly, Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00004-9 © 2016 Elsevier B.V. All rights reserved.

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generalized lymphoadenopathy, and elevated serum liver enzymes. High concentrations of triglycerides and lactic dehydrogenase, and low sodium levels are observed consistently. There is often an abnormal coagulation profile, with prolongation of prothrombin and partial thromboplastin times, hypofibrinogenemia, and detectable fibrin degradation products. As a consequence, patients may have purpura, easy bruising, and mucosal bleeding. Central nervous system (CNS) dysfunction occurs frequently and may cause lethargy, irritability, disorientation, headache, seizures, or coma. Heart, lung, and kidney failure is usually seen in the sickest patients, who are more likely to require admission to the intensive care unit (ICU) or have a fatal outcome. Recently, multiorgan failure, together with CNS involvement, hemoglobin # 7.9 g/dL, and age at onset of MAS .11.5 years, were found to be independent predictors of severity of the clinical course of MAS [12]. A few patients may have pulmonary arterial hypertension, a serious and often fatal complication of sJIA that has frequently been observed in association with MAS [13]. Another fearsome complication is thrombotic thrombocytopenic purpura. In children with sJIA, the clinical and laboratory features of MAS may mimic a sepsis or an exacerbation of the underlying disease. However, the pattern of nonremitting fever is different from the remitting high-spiking fever seen in sJIA. Moreover, patients may show a paradoxical improvement in the underlying inflammatory disease at the onset of MAS, with disappearance of signs and symptoms of arthritis and a precipitous fall in the erythrocyte sedimentation rate (ESR). The latter phenomenon probably reflects the degree of hypofibrinogenemia secondary to fibrinogen consumption and liver dysfunction. Hyperferritinemia is an important laboratory hallmark of MAS. Phagocytic macrophages are considered an important source of serum ferritin [14]. In vitro studies have shown that intracellular ferritin accumulates markedly during the maturation of monocytes into macrophages, and that cultured monocytes in iron-containing medium or in the phagocytic process of erythrocytes produce ferritin quickly [15,16]. Very high ferritin levels are commonly seen in disorders characterized by histiocytic proliferation and active phagocytosis of erythrocytes, such as malignant histiocytosis and virus-associated hemophagocytic syndrome [17]. A sharp rise of ferritin, often above 10,000 ng/mL, has been reported in the acute phase of MAS [18 20]. Furthermore, a good correlation between ferritin level and response to therapy was observed, with the decrease of ferritin being associated with a favorable course of MAS [18]. These findings indicate that measurement of serum ferritin levels may assist in the diagnosis of MAS and represents a useful indicator of disease activity, therapy response, and prognosis. It has recently been proposed that the measurement of the soluble interleukin (IL)-2 receptor α chain (also known as soluble CD25) and soluble CD163, which may reflect the degree of activation and expansion of T cells and macrophages, respectively, are promising diagnostic markers for MAS

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FIGURE 4.1 Bone marrow aspirate showing macrophage hemophagocytosis in a patient with systemic juvenile idiopathic arthritis and macrophage activation syndrome.

and may help to identify subclinical forms [21]. However, these tests are not routinely performed or available in most pediatric rheumatology centers. A characteristic feature of MAS is seen on bone marrow examination, which reveals numerous well-differentiated macrophages actively phagocytosing hematopoietic cells (Fig. 4.1). Such cells may be found in various organs and may account for many of the systemic manifestations. However, in patients with MAS, the bone marrow aspirate does not always show hemophagocytosis (present in approximately 60% of patients) [12]. Therefore, failure to reveal hemophagocytosis does not exclude the diagnosis of MAS. Table 4.1 illustrates the main clinical, laboratory, and histopathological features of MAS occurring in the context of sJIA. The comparison of the features of active sJIA and MAS is presented in Table 4.2.

EPIDEMIOLOGY The true incidence of MAS in sJIA is unknown. It is estimated that around 10% of children with this disease develop overt MAS, but recent data suggests that the syndrome may occur subclinically or in mild form in another 30 40% of cases [21,22]. In a recent multinational study of 362 patients, MAS was found to occur more frequently in girls, with a female-to-male ratio of 6:4 [12]. This slight female predominance contrasts with the 1:1 sex ratio typical of sJIA. The median time interval between the onset of sJIA and the occurrence of MAS was 4 months, and MAS was diagnosed simultaneously with sJIA in 22% of the patients. The demographic, clinical,

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TABLE 4.1 Main Features of Macrophage Activation Syndrome Clinical Features Nonremitting high fever Hepatomegaly Splenomegaly Lymphoadenopathy Hemorrhages CNS dysfunction Laboratory Features Cytopenia Abnormal liver function tests Coagulopathy Decreased ESR Hypertriglyceridemia Elevated lactic dehydrogenase Hyponatremia Hypoalbuminemia Hyperferritinemia Increased soluble IL-2 receptor α (or soluble CD25) Increased soluble CD163 Histopathological Features Macrophage hemophagocytosis in the bone marrow Increased CD163 staining of bone marrow

laboratory, and histopathological features of MAS were overall comparable among patients seen in different geographic areas [23].

TRIGGERING FACTORS Although many instances of MAS lack an identifiable precipitating factor, the syndrome has been related to a number of triggers, including a flare of the underlying disease, toxicity of aspirin or other nonsteroidal anti-inflammatory drugs, viral infections, a second injection of gold salts, methotrexate, and sulfasalazine therapy [24].

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TABLE 4.2 Comparison of Clinical and Laboratory Features of Active Systemic Juvenile Idiopathic Arthritis (sJIA) and Macrophage Activation Syndrome (MAS) Feature

sJIA

MAS

Intermittent

Continuous

Maculopapular, evanescent

Petechial or purpuric

Hepatosplenomegaly

+

++

Lymphoadenopathy

+

++

Splenomegaly

+

++

Arthritis

++

2

Serositis

+

2

Hemorrhages

2

+

Encephalopathy

2

+

White blood cells and neutrophils

mm

k

Normal or k

k

Platelets

mm

k

Erythrocyte sedimentation rate

mm

Normal or k

Fever pattern Rash

Hemoglobin

Liver transaminases

Normal

mm

Bilirubin

Normal

Normal or m

Normal or m

mm

Triglycerides

Normal

m

Prothrombin time

Normal

m

Partial thromboplastin time

Normal

m

m

k

Lactic dehydrogenase

Fibrinogen D-dimer

m

mm

Ferritin

Normal or m

mm

Soluble IL-2 receptor α (or soluble CD25)

Normal or m

mm

Soluble CD163

Normal or m

mm

In around half the patients enrolled in a recent multinational study [12], MAS developed in the context of active underlying sJIA, in the absence of a specific inciting factor. An infectious trigger was identified in one-third of cases. Medications were believed to be an uncommon trigger of MAS

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(,4%). That drug toxicity was reported as a trigger in less than 4% of cases indicates that the responsibility of medications in inducing MAS may be much lower than previously thought. Biologic medications were implicated in most instances (still ,3% of all triggers) in which the syndrome was thought to be related to medication toxicity. Induction of MAS by medications that inhibit proinflammatory cytokines known to be involved in its pathogenesis is a paradoxical phenomenon. Possible explanations include the increased rate of infections (which, in turn, may trigger MAS) associated with biologic therapies or the induction of an unbalance between up- and downregulation of the various molecules that are part of the cytokine network [25]. Recently, severe, occasionally fatal episodes of MAS have been observed in clinical trials of IL-1 and IL-6 inhibitors [26,27]. However, increasing the dose of biologic medications will often abate MAS [28]. This suggests a lack of causality and possibly an associative relationship with biologic medications only in a few instances of MAS in the setting of sJIA. Serious episodes of MAS have been observed among patients who underwent autologous bone marrow transplantation for sJIA refractory to conventional therapy [29 32]. Although in most of these cases an infectious trigger for MAS was identified, it was hypothesized that the complication was favored by stringent T cell depletion, with resultant inadequate control of macrophage activation [31,33]. After an adaptation of the protocol, consisting in less profound T cell depletion, better control of systemic disease before transplantation and slow tapering of corticosteroids after the procedure, no further cases of MAS have occurred [31]. The development of hemophagocytosis in three patients with sJIA who received fludarabine as part of the conditioning regimen has been reported [30].

NOMENCLATURE AND CLASSIFICATION The clinical syndrome of acute hemorrhagic, hepatic, and neurological abnormalities in patients with sJIA was first described by Hadchouel et al. in 1985 [34]. The term MAS, which subsequently gained increasing popularity in the pediatric rheumatology community, was proposed in 1993 by the same investigators, who found evidence of activation of the monocyte-macrophage system in patients with the syndrome and noted that its clinical features were very similar to those observed in other hemophagocytic syndromes that are now collectively referred to as hemophagocytic lymphohistiocytosis (HLH) [35]. HLH is not a single disease but a hyperinflammatory syndrome that can occur in association with a variety of underlying conditions, both genetic and acquired (Table 4.3). Genetic HLH can be divided into two subgroups: familial HLH (FHLH) and the immune deficiencies Che`diak-Higashi syndrome, Griscelli syndrome, and X-linked lymphoproliferative syndrome. Acquired HLH can be observed following infections (herpes viruses in particular),

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TABLE 4.3 Hemophagocitic Lymphohistiocytosis Genetic HLH Familial HLH (Farquhar disease) Known genetic defects (perforin, munc 13-4, syntaxin 11) Unknown gene defects Immune deficiency syndromes Che`diak-Higashi syndrome Griscelli syndrome X-linked lymphoproliferative syndrome Acquired HLH Exogenous agents (infections, toxins) Infection-associated hemophagocytic syndrome Endogenous products (tissue damage, inborn error of metabolism such as lysinuric protein intolerance and multiple sulfates deficiency) Rheumatic diseases Macrophage activation syndrome Malignant diseases (especially lymphoma-associated hemophagocytic syndrome) Source: Modified from Janka G, zur Stadt U. Familial and acquired hemophagocytic lymphohistiocytosis. Hematol Am Soc Hematol Educ Program 2005;82 88.

during the course of rheumatic disorders, with malignant diseases (especially lymphomas), and with some metabolic diseases. Recently, the increasing recognition that MAS belongs to HLH has led to a proposal to rename MAS according to the contemporary classifications of HLH [37,38]. For uniformity, Athreya [37] suggested the suitable name, “rheumatic disease-associated hemophagocytic syndrome.” Uniform nomenclature would facilitate communication between pediatric rheumatologists and specialists in other fields, such as hematology, clinical immunology, and infectious diseases, who are very familiar with this syndrome but often unaware of the rheumatology literature on this subject. An international effort aimed at revising the nomenclature of both HLH and MAS is currently underway.

PATHOGENESIS An in-depth discussion of the pathogenesis of MAS is beyond the scope of this chapter, and has been covered elsewhere [10,11,39]. However, a few developments are worth noting. The starting point for most pathogenetic studies is based on the notion that MAS is characterized by a dysfunctional

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immune response that is similar to that seen in other forms of HLH. The prototype of these is FHLH, which is a constellation of rare autosomal recessive immune disorders resulting from homozygous deficiency in cytolytic pathway proteins [40 42]. In FHLH, the uncontrolled expansion of T cells and macrophages has been attributed to diminished natural killer (NK)-cell and cytotoxic T-cell function [40 43], due to mutations in particular genes whose products are involved in the perforin-mediated cytolytic pathway [44 47]. These mutations cause profound impairment of cytotoxic function that, through mechanisms that that have not yet been fully elucidated, leads to an exaggerated expansion and activation of cytotoxic cells with hypersecretion of proinflammatory cytokines, which ultimately results in hematologic alterations and organ damage [36]. Recent evidence suggests that defects in killing leads to prolonged interaction between the CD8 T cell or NK cell and the infected target cell resulting in a proinflammatory cytokine storm [48]. Although the pathophysiology of MAS is less clear, it probably involves related pathogenic pathways [11,49,50]. It has been recently shown that, as in FHLH, patients with MAS may have functional abnormalities of the exosome degranulation pathway involved in perforin-mediated cytolysis [51,52]. Furthermore, a number of studies suggest the presence of some genetic overlap between MAS and FHLH. The same biallelic mutations in the MUNC134 gene reported in FHLH have been identified in some sJIA patients with MAS [53 55]. Some of these mutations have been suggested to function as monoallelic-dominant negative mutations disrupting cytolysis [55,56]. Interferon regulatory factor 5 gene polymorphisms were also found to be risk factors for MAS in patients with sJIA [57]. Whole exome sequencing has led to the discovery of rare protein-altering variants in known HLH-associated genes as well as in new candidate genes [58]. In spite of the compelling evidence for a pathogenetic role of defects in cytotoxic cell function in FHLH, in many instances of MAS no such defects have been identified, or have been found to have only variable penetrance. This has prompted the search for alternative causative mechanisms. Recently, a murine model of MAS induced by repeated stimulation of Tolllike receptor (TLR)-9 in genetically intact mice suggested that situations of continual activation of TLR-9 may reproduce the environment that leads to the development of MAS in the absence of known cytolytic defects [59]. Interestingly, certain aspects of the disease in this model were IFN-γ dependent, establishing a connection to FHLH [59]. Several biomarkers reflect the degree of activation and expansion of T cells and macrophages and could help to identify subclinical MAS in patients with sJIA. The role of IL-1 in sJIA has been well described, but its involvement in the pathogenesis of MAS is not clearly defined. Patients with primary HLH have high levels of IL-1 [60], but the progression of the disease seems to be

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independent of IL-1 signaling pathway [61]. In addition, patients with MAS do not present the typical clinical features of IL-1-mediated diseases, such as cryopyrin-associated periodic syndromes. IL-6 is a pivotal cytokine of the acute-phase response and it is thought to play an important role in the development of MAS in presence of an infectious trigger [62]. A study of hepatic biopsies in patients with various types of HLH, including MAS, revealed extensive infiltration of the liver by hemophagocytic macrophages secreting IL-6 [63]. In IL-6 transgenic mice, prolonged exposure to high levels of IL-6 seemed to lower the threshold needed to trigger an episode of MAS [64]. Nevertheless, the role of IL-6 in the pathogenesis of MAS remains poorly understood. The key role of IFN-γ in HLH was previously highlighted by the observation that in perforin-deficient mice only the antibody directed to IFN-γ, and not to other cytokines tested, prolonged survival and prevented the development of histiocytic infiltrates and cytopenia [65]. Furthermore, a study of liver biopsies in patients with various forms of HLH, including MAS, revealed extensive parenchymal infiltration by IFN-γ-producing CD8 T lymphocytes and hemophagocytic macrophages secreting tumor necrosis factor (TNF)-α and IL-6 [63]. Evidence has been provided that the hyperproduction of IL-18 (which potently induces Th-1 responses and IFN-γ production and enhances NK cell cytotoxicity) and an imbalance between levels of biologically active free IL-18 and those of its natural inhibitor (the IL-18 binding protein) may be involved in secondary hemophagocytic syndromes, including MAS [66,67]. Another intriguing observation underscores the crucial regulatory role of IL-10 in the MAS process. Mice exposed to repeated TLR-9 stimulation coupled with blockade of the IL-10 receptor developed much more fulminant disease, including hemophagocytosis. This finding has led to the hypothesis that the combined immunologic abnormality of hyperactive TLR/IL-1β signaling and decreased IL-10 function may be responsible for a predisposition to MAS [11]. Altogether, the results of these studies highlight a critical importance of IFN-γ and IL-10 in the pathophysiology of HLH/MAS and provide the rationale for the modulation of the axes of these cytokines to treat disease. Findings suggest that MAS, or at least some of its forms, could be considered as part of the monogenic autoinflammatory disease spectrum. A 7-year-old European female with recurrent episodes characterized by leucopenia, chronic anemia, thrombocytopenia, elevation of acute phase reactants and transaminases, hypertriglyceridemia, and hyperferritinemia (all typically MAS biomarkers) has been reported [68]. The girl was found to have a mutation in the nucleotide-binding domain of the inflammasome component, NLRC4, associated with high levels of the inflammasome-dependent cytokines IL-1β and IL-18. The NK cell function was normal and the genetic testing for HLH and periodic fever syndromes were negative. The administration of the recombinant human IL-1 receptor antagonist, anakinra, led to

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clinical improvement, although serum levels of IL-18 did not normalize after treatment.

DIAGNOSTIC GUIDELINES Because MAS is a serious condition that can pursue a rapidly fatal course, prompt recognition of its clinical and laboratory features and immediate therapeutic intervention are critical. However, because it lacks a single distinguishing manifestation and is clinically heterogeneous, early diagnosis can be difficult. The diagnostic challenges posed by MAS in sJIA are compounded because it may mimic a flare of the underlying disease. Other important differential diagnoses would include infectious illnesses and side effects of medications. The difficulties in making the diagnosis emphasize the importance of reliable criteria that aid physicians in identifying MAS in its earliest stages and distinguishing it from confusable conditions. Two sets of guidelines are currently available for diagnosing MAS in patients with sJIA. The recognition that the syndrome is clinically similar to HLH has led some to recommend the use of the HLH-2004 guidelines, which were developed primarily for homozygous genetic disorders leading to hemophagocytosis [42]. An alternative approach is based on the application of the preliminary diagnostic guidelines for MAS complicating sJIA (Table 4.4), which were created through the analysis of a cohort of patients with MAS compared with a group of patients with a flare of sJIA [69]. Although both guidelines are considered potentially suitable for detecting MAS in sJIA, it has been argued that each of them suffers from several potential shortcomings [11,70,71]. The main limitation of using the HLH2004 guidelines is thought to be due to the fact that some individual criteria may not apply to patients with sJIA. Owing to the prominent inflammatory nature of sJIA, the occurrence of a relative drop in white blood cell count, platelets, or fibrinogen rather than the absolute decrease required by the HLH-2004 criteria may be more useful to make an early diagnosis. In addition, the minimum threshold level for hyperferritinemia required for the diagnosis of HLH (500 ng/mL) may not be suitable to detect MAS in children with sJIA. It is well known that many patients with active sJIA, in the absence of MAS, have ferritin levels above that threshold [72]. In the acute phase of MAS, ferritin levels may peak at values .5000 ng/mL. Thus, a 500 ng/mL threshold may not discriminate MAS from a flare of sJIA. Other HLH criteria that are not readily applicable to MAS are the identification of low or absent NK cell activity or sCD25 above normal limits for age, due to the limited availability and lack of timeliness of these assays. By comparison, the preliminary MAS guidelines have the disadvantage that that the study that led to their development lacked several laboratory measurements in a number of patients and had insufficient data available for some

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TABLE 4.4 Preliminary Diagnostic Guidelines for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis Laboratory Criteria 1. 2. 3. 4.

Decreased platelet count (#262 3 109/L) Elevated levels of aspartate aminotransferase (.59 U/L) Decreased white blood cell count (#4.0 3 109/L) Hypofibrinogenemia (#2.5 g/L)

Clinical Criteria 1. CNS dysfunction (irritability, disorientation, lethargy, headache, seizures, coma) 2. Hemorrhages (purpura, easy bruising, mucosal bleeding) 3. Hepatomegaly ($3 cm below the costal arch) Histopathologic Criterion Evidence of macrophage hemophagocytosis in the bone marrow aspirate Diagnostic Rule The diagnosis of MAS requires the presence of any two or more laboratory criteria or of any two, three, or more clinical and/or laboratory criteria. A bone marrow aspirate for the demonstration of hemophagocytosis may be required only in doubtful cases. Recommendations The previous criteria are of value only in patients with active sJIA. The thresholds of laboratory criteria are provided by way of example only.

important laboratory parameters of MAS, namely ferritin, triglycerides, and lactic dehydrogenase. Thus, both sets of criteria have their shortcomings. In a recent comparative analysis, the preliminary MAS guidelines were found to perform better than the HLH-2004 guidelines in identifying MAS in the setting of sJIA, whereas the adapted HLH-2004 guidelines (with the exclusion of assessment of bone marrow hemophagocytosis, NK cell activity, and sCD25 levels) and the preliminary MAS guidelines with the addition of a ferritin level .500 ng/mL discriminated best between MAS and systemic infection [73]. These findings led to the conclusion that the HLH-2004 guidelines are likely not appropriate for identification of MAS in children with sJIA.

NOVEL CLASSIFICATION CRITERIA FOR MAS COMPLICATING SJIA An international collaborative effort has been recently accomplished, with the intention of developing a set of classification criteria for MAS as part of sJIA, based on a combination of expert consensus, available evidence from the medical literature, and analysis of robust real patient data [70,74]. This project was conducted through the following steps: (1) Delphi survey

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among international pediatric rheumatologists aimed to identify MAS features potentially suitable for inclusion in classification criteria, (2) large-scale data collection of patients with sJIA-associated MAS and two potentially confusable conditions, (3) web-based consensus procedures among experts, (4) selection of candidate criteria through statistical analyses, and (5) selection of final classification criteria in a consensus conference. The first step of the project had a specific goal to identify candidate items using international consensus formation through the Delphi survey technique, involving 232 pediatric rheumatologists from 47 countries. It led to the selection of nine features that were felt to be important as potential diagnostic criteria for MAS by the majority of the respondents: falling platelet count, hyperferritinemia, evidence of macrophage hemophagocytosis in the bone marrow, elevated serum liver enzymes, falling leukocyte count, persistent continuous fever $ 38 C, falling ESR, hypofibrinogenemia, and hypertriglyceridemia [75]. In the second phase, international pediatric rheumatologists and pediatric hemato-oncologists were invited to participate in a retrospective cohort study of patients with sJIA-associated MAS and with two conditions potentially confusable with MAS, represented by those with active sJIA not complicated by MAS, and hospitalized children with systemic infection [12,23,73]. The data of 1111 patients (362 with sJIA-associated MAS, 404 with active sJIA without MAS, and 345 with systemic infection) were reported by 95 pediatric subspecialists practicing in 33 countries in 5 continents. This is the largest such reported collection of data on sJIA patients with or without MAS. The final part of the project was conducted through the involvement of a panel of experts, composed of 20 pediatric rheumatologists and 8 pediatric hematologists, with specific expertise in the care of children with MAS and related disorders. The experts were first asked, through a series of web-based consensus procedures, to classify a total of 428 patient profiles as having or not having MAS, based on the clinical and laboratory features recorded at disease onset. The profiles were selected randomly among the 1111 patients collected in the previous phase and comprised 161 patients with MAS, 140 patients with active sJIA without evidence of MAS, and 127 patients with systemic infection. The experts were purposely kept unaware of the original diagnosis as well as of the overall course of the patient. The minimum level of agreement required among experts was set at 80%. Subsequently, the best performing collections of classification criteria were selected by means of univariate and multivariate statistical analyses based on their ability to classify individual patients as having or not having MAS, using the experts’ diagnosis as the gold standard. Candidate classification criteria were partly derived from the literature and partly generated from the study data, by means of the combination of criteria approach or the MAS score method, as reported [74]. A total of 982 candidate-grouped classification criteria were tested. For each set of criteria, the sensitivity, specificity,

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area under the ROC curve (AUC-ROC), and kappa value for agreement between the classification yielded by the criteria and the diagnosis of the experts were calculated. It was established that in order to qualify for inclusion in the expert voting procedures phase at the consensus conference (see next), a set of classification criteria should demonstrate a kappa value $ 0.85, a sensitivity $ 0.80, a specificity $ 0.93, and an AUC-ROC $ 0.90. An exception was made for the historical literature criteria, which were retained for further consideration even if they did not meet all statistical requirements. The International Consensus Conference on MAS Classification Criteria was held in Genoa, Italy, on March 21 22, 2014, and was attended by all 28 experts who participated in the web-consensus evaluations. Attendees were randomized into two equally sized nominal groups and, using the Nominal Group Technique, were asked to decide, independently of each other, upon which of the classification criteria that met the preceding statistical requirements were easiest to use and most credible (ie, had the best face/content validity). A series of repeated independent voting sessions were held until the top three classification criteria were selected by each voting group. Then, an 80% consensus was attained on the best (final) set of classification criteria in a session with the two tables of participants combined (Table 4.5). A secondary aim of the project was to identify the laboratory tests whose change over time is most valuable for the timely diagnosis of MAS complicating sJIA. A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of experts was TABLE 4.5 The Classification Criteria for Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis A febrile patient with known or suspected systemic juvenile idiopathic arthritis is classified as having macrophage activation syndrome if the following criteria are met: Ferritin . 684 ng/mL and any two of the following: Platelet count # 181 3 109/L Aspartate aminotransferase . 48 U/L Triglycerides . 156 mg/dL Fibrinogen # 360 mg/dL Source: Adapted from Ravelli A, Minoia F, Davı` S, Horne A, Bovis F, Pistorio A et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/ Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2016 Mar;75(3):481 9.

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first asked to evaluate 115 profiles of patients with MAS, which included the values of laboratory tests at the pre-MAS visit and at MAS onset, and the change in values between the two time points. The experts were asked to choose the five laboratory tests whose change was most important for the diagnosis of MAS and to rank the five selected tests in order of importance. The relevance of change in laboratory parameters was further discussed and ranked by the same experts at the consensus conference. Platelet count was the most frequently selected test, followed by ferritin, aspartate aminotransferase (AST), white blood cell count, neutrophil count, fibrinogen, and ESR. Ferritin was assigned most frequently the highest score. At the end of the process, platelet count, ferritin, and AST were the laboratory tests whose change over time was felt by the experts as most important [76].

PERFORMANCE OF THE NEW CLASSIFICATION CRITERIA IN MAS OCCURRING DURING BIOLOGIC THERAPY Recently, several episodes of MAS have been observed in sJIA patients under treatment with the cytokine blockers canakinumab and tocilizumab in randomized controlled clinical trials and in postmarketing experience [26 28]. Because these agents inhibit the biologic effects of IL-1 and IL-6, respectively, which are among the proinflammatory cytokines involved in the physiopathology of MAS [11,62], it is conceivable that MAS episodes developing during treatment with these biologics may lack fever or some of the typical laboratory abnormalities of the syndrome. Clinical symptoms of patients with sJIA-associated MAS receiving tocilizumab were found to be milder than those of patients not receiving this medication [77]. Preliminary analyses in patients who had MAS while receiving tocilizumab or canakinumab have shown that a few cases did not meet the new criteria did so because of the absence of fever or a peak ferritin level ,684 ng/mL [78,79]. However, more data from the real world of clinical practice are needed to establish whether the criteria should be refined to increase their power to pick up the instances of MAS occurring during treatment with IL-1 and IL-6 inhibitors.

MANAGEMENT As no controlled studies on the treatment of MAS are available, the management of this condition is largely empiric and based on anecdotal experience. The mainstay of the therapy is traditionally constituted by the parenteral administration of high doses of corticosteroids. However, some fatalities have been reported among patients treated with massive doses of corticosteroids [24,80]. In the mid-1990s, the use of cyclosporine was advocated owing to its demonstrated benefit in the management of FHLH [35]. The observation of the marked efficacy of cyclosporine in some cases of MAS refractory

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to corticosteroids [81] has led to its proposed use as first-line treatment in MAS [82]. The experience with high-dose intravenous immunoglobulin, cyclophosphamide, plasma-exchange, and etoposide has provided conflicting results. Etoposide is part of the protocol developed for treating FHLH [42]. However, it has been argued that because this protocol carries a not insignificant risk of mortality both pre- and post-bone marrow transplantation, it may not be appropriate as first-line therapy for MAS as part of sJIA [11]. Whether or not a less aggressive use of etoposide for treating secondary forms of MAS, such as those complicating sJIA, will be beneficial, remains unclear. With the recent introduction of a variety of biologic agents, novel therapeutic approaches are being explored for MAS. The demonstration of increased production of TNF in the acute stage of MAS has provided the rationale for proposing inhibitors of this cytokine as potential therapeutic agents. However, although Prahalad et al. [19] reported the efficacy of etanercept in a boy with MAS, other investigators have observed the onset of MAS in patients with sJIA who were receiving etanercept [83]. The reports of MAS in the setting of TNF inhibition, together with the observations of a poorer efficacy of these biologic response modifiers in treating sJIA, has led to the assumption that this therapy may not be ideal for MAS occurring in children with sJIA [11]. Recently, several cases of sJIA-associated MAS who benefited dramatically from the administration of the IL-1 inhibitor, anakinra, after inadequate response to corticosteroids and cyclosporine, have been reported [84 87]. However, there has been the suspicion that anakinra triggered MAS in two children with sJIA [87,88], although the cause effect relationship is difficult to establish. In a large case series of 46 sJIA patients treated with anakinra at disease onset, this medication appeared to act as potential MAS trigger in five children [28]. However, increased dosing of anakinra resolved MAS in most cases [28]. Thus, although the published experience has been favorable, more information is needed to define the role of IL-1 blockade therapy for the treatment of refractory MAS as part of sJIA. Similar to IL-1 inhibition, IL-6 blockade through the anti-IL-6 receptor monoclonal antibody tocilizumab has proven highly efficacious in treating sJIA [27,89]. Whether tocilizumab will be similarly helpful in treating MAS is unclear at present, as there has been a case of MAS attributed to anti-IL-6 therapy [90]. Costimulatory blockade with CTLA-4-Ig has been anecdotally beneficial in children with severe sJIA with MAS [91], but its place in treating MAS remains unknown. A more aggressive intervention using antithymocyte globulin (ATG) has been used successfully in two patients with probable MAS [92]. However, ATG use carries a significant risk of serious infection and mortality [93]. The B-cell-depleting anti-CD20 antibody rituximab has been reported to lead to remission in a sizable percentage of children with refractory sJIA [94].

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Furthermore, this medication has anecdotally been used effectively to treat Epstein-Barr virus (EBV)-associated HLH/MAS in the setting of EBV infection [95,96]. However, to date no cases of rituximab therapy for MAS associated with sJIA have been reported. In summary, there is increasing evidence that biologic therapies, particularly IL-1 inhibitors, represent a valuable adjunct to corticosteroids and cyclosporine in treating MAS associated with sJIA. Ongoing clinical experience and future pathogenetic studies will help to define the place of biologic therapies in management of MAS in children with sJIA.

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[30] Wulffraat NM, Vastert B, Tyndall A. Treatment of refractory autoimmune diseases with autologous stem cell transplantation: focus on juvenile idiopathic arthritis. Bone Marrow Transplant 2005;35(Suppl. 1):S27 9. [31] De Kleer IM, Brinkman DM, Ferster A, Abinun M, Quartier P, Van Der Net J, et al. Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity. Ann Rheum Dis 2004;63:1318 26. [32] Sreedharan A, Bowyer S, Wallace CA, Robertson MJ, Schmidt K, Woolfrey AE, et al. Macrophage activation syndrome and other systemic inflammatory conditions after BMT. Bone Marrow Transplant 2006;37:629 34. [33] Wedderburn LR, Abinun M, Palmer P, Foster HE. Autologous haematopoietic stem cell transplantation in juvenile idiopathic arthritis. Arch Dis Child 2003;88:201 5. [34] Hadchouel M, Prieur AM, Griscelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drug or infection. J Pediatr 1985;106:561 6. [35] Ste´phan JL, Zeller J, Hubert PH, Herbelin C, Dayer JM, Prieur AM. Macrophage activation syndrome and rheumatic disease in childhood: a report of four new cases. Clin Exp Rheumatol 1993;11:451 6. [36] Janka G, zur Stadt U. Familial and acquired hemophagocytic lymphohistiocytosis. Hematol Am Soc Hematol Educ Program 2005;82 8. [37] Athreya BH. Is macrophage activation syndrome a new entity? Clin Exp Rheumatol 2002;20:121 3. [38] Ramanan AV, Schneider R. Macrophage activation syndrome—what’s in a name! J Rheumatol 2003;30:2513 16. [39] Weaver LK, Behrens EM. Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Curr Opin Rheumatol 2014;26:562 9. [40] Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematol Am Soc Hematol Educ Program 2009;127 31. [41] Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 1997;29:157 66. [42] Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124 31. [43] Sullivan KE, Delaat CA, Douglas SD, Filipovich AH. Defective natural killer cell function in patients with hemophagocytic lymphohistiocytosis and in first degree relatives. Pediatr Res 1998;44:465 8. [44] Stepp SE, Dufourcq-Lagelouse R, Deist FL, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999;286:1957 9. [45] Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003;115:461 73. [46] zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 2009;85:482 92.

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[47] zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 2005;14:827 34. [48] Jenkins MR, Rudd-Schmidt JA, Lopez JA, Ramsbottom KM, Mannering SI, Andrews DM, et al. Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J Exp Med 2015;212:307 17. [49] Grom AA, Mellins ED. Macrophage activation syndrome: advances towards understanding pathogenesis. Curr Opin Rheumatol 2010;22:561 6. [50] Grom AA. Natural killer cell dysfunction: a common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum 2004;50:689 98. [51] Grom AA, Villanueva J, Lee S, Goldmuntz EA, Passo MH, Filipovich A. Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. J Pediatr 2003;142:292 6. [52] Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A, et al. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther 2005;7:R30 7. [53] Vastert SJ, van Wijk R, D’Urbano LE, de Vooght KM, de Jager W, Ravelli A. Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology (Oxford) 2010;49:441 9. [54] Hazen MM, Woodward AL, Hofmann I, Degar BA, Grom A, Filipovich AH, et al. Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Arthritis Rheum 2008;58:567 70. [55] Zhang M, Behrens EM, Atkinson TP, Shakoory B, Grom AA, Cron RQ. Genetic defects in cytolysis in macrophage activation syndrome. Curr Rheumatol Rep 2014;16:439. [56] Spessott WA, Sanmillan ML, McCormick ME, Patel N, Villanueva J, Zhang K, et al. Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood 2015;125:1566 77. [57] Yanagimachi M, Goto H, Miyamae T, Kadota K, Imagawa T, Mori M, et al. Association of IRF5 polymorphisms with susceptibility to hemophagocytic lymphohistiocytosis in children. J Clin Immunol 2011;31:946 51. [58] Kaufman KM, Linghu B, Szustakowski JD, Husami A, Yang F, Zhang K, et al. Wholeexome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2014;66:3486 95. [59] Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M, et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest 2011;121:2264 77. [60] Henter JI, Andersson B, Elinder G, Jakobson A, Lu¨beck PO, So¨der O. Elevated circulating levels of interleukin-1 receptor antagonist but not IL-1 agonists in hemophagocytic lymphohistiocytosis. Med Pediatr Oncol 1996;27:21 5. [61] Krebs P, Crozat K, Popkin D, Oldstone MB, Beutler B. Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. Blood 2011;117:6582 8. [62] Strippoli R, Caiello I, De Benedetti F. Reaching the threshold: a multilayer pathogenesis of macrophage activation syndrome. J Rheumatol 2013;40:761 7. [63] Billiau AD, Roskams T, Van Damme-Lombaerts R, Matthys P, Wouters C. Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of

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[78] De Benedetti F, Scheider R, Weitzman S, Devlin C, Daimaru K, Yokota S et al. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with tocilizumab [Abstract]. Proceedings of the 30th annual meeting of the histiocyte society Toronto, ON: 28 30 October 2014. p. 56. [79] Grom AA, Ilowite NT, Pascual V, Brunner HI, Martini A, Lovell D, et al. Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab. Arthritis Rheumatol 2016;68 (1):218 28. [80] Grom AA. Macrophage activation syndrome. In: Cassidy J, Petty RE, editors. Textbook of pediatric rheumatology. 6th ed. Philadelphia, PA: Saunders Elsevier; 2010. p. 674 81. [81] Mouy R, Stephan JL, Pillet P, et al. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr 1996;129:750 4. [82] Ravelli A, De Benedetti F, Viola S, et al. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatr 1996;128:275 8. [83] Ramanan AV, Schneider R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol 2003;30:401 3. [84] Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology (Oxford) 2011;50:417 19. [85] Bruck N, Suttorp M, Kabus M, Heubner G, Gahr M, Pessler F. Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol 2011;17:23 7. [86] Kelly A, Ramanan AV. A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol 2008;4:615 20. [87] Lurati A, Teruzzi B, Salmaso A, Demarco G, Pontikati I, Gattinara M, et al. Macrophage activation syndrome (MAS) during anti-IL1 therapy (anakinra) in a patient affected by systemic juvenile arthritis (soJIA): a report and review of the literature. Pediatr Rheumatol Online J 2005;3:79 85. [88] Zeft A, Hollister R, LaFleur B, Sampath P, Soep J, McNally B, et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol 2009;15 (4):161 4. [89] Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo- controlled, withdrawal phase III trial. Lancet 2008;371:998 1006. [90] Kobayashi M, Takahashi Y, Yamashita H, Kaneko H, Mimori A. Benefit and a possible risk of tocilizumab therapy for adult-onset Still’s disease accompanied by macrophageactivation syndrome. Mod Rheumatol 2011;21:92 6. [91] Record JL, Beukelman T, Cron RQ. Combination therapy of abatacept and anakinra in children with refractory systemic juvenile idiopathic arthritis: a retrospective case series. J Rheumatol 2011;38:180 1. [92] Coca A, Bundy KW, Marston B, Huggins J, Looney RJ. Macrophage activation syndrome: serological markers and treatment with anti-thymocyte globulin. Clin Immunol 2009;132:10 18.

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[93] Mahlaoui N, Ouache´e-Chardin M, de Saint Basile G, Neven B, Picard C, Blanche S. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single center retrospective report of 38 patients. Pediatrics 2007;120:e622 8. [94] Alexeeva EI, Valieva SI, Bzarova TM, Semikina EL, Isaeva KB, Lisitsyn AO, et al. Efficacy and safety of repeat courses of rituximab treatment in patients with severe refractory juvenile idiopathic arthritis. Clin Rheumatol 2011;30:1163 72. [95] Balamuth NJ, Nichols KE, Paessler M, Teachey DT. Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus associated hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 2007;29:569 73. [96] Bosman G, Langemeijer SM, Hebeda KM, Raemaekers JM, Pickkers P, van der Velden WJ. The role of rituximab in a case of EBV-related lymphoproliferative disease presenting with haemophagocytosis. Neth J Med 2009;67:364 5.

Chapter 5

Assessment Tools in Juvenile Idiopathic Arthritis A. Consolaro and A. Ravelli Istituto Giannina Gaslini and Universita` degli Studi di Genova, Genova, Italy

INTRODUCTION The objectives of medical interventions in the care of juvenile idiopathic arthritis (JIA) patients are to alleviate patients’ subjective disease symptoms and to reduce the objective signs of inflammation with the ultimate aim of improving their health-related quality of life (HRQoL) and avoid any permanent damage due to the disease and side effects of medications [1]. The choice of therapeutic strategies for children with JIA is based on the assessment of the risk benefit balance, including the evaluation of costs. Consideration should be given to the side effects of medication and the expected outcomes, as they are determined by large multinational randomized clinical trials. Once treatment is initiated, the caring physician should assess the child’s response to the prescribed medications with regard to the risks, the benefits in terms of disease control, and improvement of health and the side effects. The reliable assessment of the results of treatment interventions requires the availability of standardized and well-validated outcome measures. In the past decades, there has been a considerable effort to develop and validate measures for the assessment of disease activity, disease damage, and parents’ and children’s perception of the disease state and course. The recent advances in this field of research are the objective of the present chapter.

THE CORE SET OF OUTCOME MEASURES AND DEFINITION OF IMPROVEMENT IN JIA Until the mid-1990s, the assessment of clinical response in JIA clinical trials was not standardized. Pediatric rheumatologists used multiple outcome measures, and the criteria adopted to assess the effects of antirheumatic Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00005-0 © 2016 Elsevier B.V. All rights reserved.

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drugs were often different. In addition, the amount of change that denoted clinically important improvement or worsening was not established. This lack of standardization hindered the efficiency of trials and made it impossible to compare different therapies using metaanalysis procedures. The evaluation and comparison of treatment response became much easier with the development of the core set of outcome measures and definition of improvement in JIA, which were published in 1997 [2]. The core set includes the following six variables: (1) physician global assessment of overall disease activity, (2) parent/patient global assessment of overall well-being, (3) physical functional ability, (4) count of joints with active arthritis, (5) count of joints with restricted motion, and (6) an acute-phase reactant (Table 5.1). According to the definition of improvement, patients are classified as responders in a clinical trial if they demonstrate an improvement of at least 30% from baseline in at least three of any six core set variables, with no more than one of the remaining variables worsening by more than 30%. Soon after their publication, these criteria became the gold standard for the assessment of response to therapy in JIA. They were then adopted by the American College of Rheumatology (ACR) and are currently known as the ACR Pediatric 30. The ACR Pediatric 30 criteria are accepted by both the US Food and Drug Administration and the European Medicines Agency for all phase III trials in JIA seeking drug registration [3]. Recently, the ACR Pediatric 30 was adapted for use in clinical trials in systemic JIA, by adding, besides the six core set variables, the demonstration of the absence of spiking fever (#38 C) during the week preceding the evaluation [4,5]. At the time when the ACR Pediatric 30 criteria were developed, the most effective antirheumatic medication for the treatment of JIA was low-dose methotrexate [6]. With the shift toward the use of higher doses of methotrexate [7] and, later on, the introduction of biologic agents, a 30% improvement in outcome variables was no longer considered sufficient to establish the effectiveness of a therapeutic intervention. Therefore, in most clinical trials

TABLE 5.1 The Core Set of Outcome Measures for Juvenile Idiopathic Arthritis Endorsed by the American College of Rheumatology The American College of Rheumatology Core Set of Outcome Measures 1. 2. 3. 4. 5. 6.

Physician global assessment of overall disease activity Parent/patient global assessment of overall well being Physical functional ability Count of joints with active arthritis Count of joints with restricted motion Acute-phase reactant

Source: Adapted from Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:1202 9.

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performed in the 2000s, patients were also evaluated for more stringent levels of improvement; that is, using the ACR Pediatric 50, 70, 90, and 100 response criteria (at least 50%, 70%, 90%, or 100% improvement, respectively, in at least three of any six JIA core set variables, with no more than one of the remaining variables worsening of more than 30%).

DISEASE ACTIVITY STATES The recent progress in the management of JIA have increased the potential to achieve complete disease quiescence or, at least, low levels of disease activity, and have consequently moved the therapeutic goals increasingly toward the achievement of an inactive disease status. A reliable documentation of the advances in therapeutic effectiveness has raised the need for well-established criteria that describe precisely the clinical states of remission or near-remission. In the early 2000s, a set of preliminary criteria for inactive disease and clinical remission on medication for select categories of JIA were developed through an international collaborative effort [8]. Based on these criteria, a patient is classified as having inactive disease at a specific point in time when he/she has no joints with active disease, no systemic manifestations attributable to JIA, no active uveitis, normal values of acute phase reactants, and a physician’s global assessment of disease activity indicating no disease activity. When the criteria for inactive disease are met for a minimum of 6 consecutive months while the patient is receiving antirheumatic medication, the patient is classified as being in the state of clinical remission on medication. When the criteria for inactive disease are met for a minimum of 12 consecutive months while the patient is off all antirheumatic medication, the patient is classified as being in the state of clinical remission off medication. In 2011, the criteria have been modified by providing a definition of uveitis and abnormal erythrocyte sedimentation rate (ESR) and by adding the duration of morning stiffness of #15 minutes [9] (Table 5.2). Clearly, the achievement of complete absence of any sign or symptom of active disease is the ideal objective of any therapeutic intervention in JIA. However, although this goal may be easier to achieve in children with oligoarthritis who are treated with intraarticular corticosteroid injections alone, it is still problematic in the subset of patients who have polyarticular or systemic disease. The definition of inactive disease requires the total absence of signs and symptoms of disease activity and is, therefore, very stringent. However, achievement of true inactive disease either in routine practice or in clinical trials remains problematic in many patients, particularly those with polyarticular or systemic JIA. Furthermore, the state of inactive disease is often not maintained over long periods [10]. It has been proposed that in standard clinical care a more attainable goal could be to induce and maintain

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TABLE 5.2 Criteria for Defining Clinical Inactive Disease in Persistent and Extended Oligoarticular, Rheumatoid Factor Positive and Negative Polyarticular, and Systemic Juvenile Idiopathic Arthritis. All Criteria Must Be Met Definition of Inactive Disease No joints with active arthritisa No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA No active uveitis as defined by the SUN Working Groupb ESR or CRP level within normal limits in the laboratory where tested or, if elevated, not attributable to JIA Physician’s global assessment of disease activity score of best possible on the scale used Duration of morning stiffness of #15 min ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; SUN, Standardization of Uveitis Nomenclature. a A joint is defined active when there is either swelling or both pain and limitation on motion. b Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data: results of the First International Workshop. Am J Ophthalmol 2005;140:509 16. Source: Adapted from Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011; 63:929 36.

at least a state of minimal disease activity, which is an intermediate state between high disease activity and remission, though very close to remission [11]. In adult patients with rheumatoid arthritis, this state is deemed to be a useful target of treatment by both the physician and the patient, given current treatment possibility and limitations [12]. The state of minimal disease activity in JIA has been described as the presence of a physician’s global rating of disease activity #3.4, a parent’s global rating of well-being #2.5, and a swollen joint count #1 in polyarthritis; and as the presence of a physician’s global assessment of disease activity #2.5 and a swollen joint count 5 0 in oligoarthritis [11] (Table 5.3).

THE JUVENILE ARTHRITIS DISEASE ACTIVITY SCORE Regular measurement of the level of disease activity in children with JIA is important for assessing the disease course over time, as well as the efficacy of therapeutic interventions [1,13]. Because no single measure can reliably capture overall disease activity in all phenotypes of JIA, the use of the so-called composite disease activity scores has been proposed. These scores

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TABLE 5.3 Definition of Minimal Disease Activity in Patients With Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis Definition of Minimal Disease Activity

Physician’s global assessment of disease activity, cma

Oligoarticular JIA

Polyarticular JIA

#2.5

#3.4 #2.1

Parent’s global assessment of well-being, cma Number of swollen joints

0

#1

To be classified as being in a minimal disease activity state, patients should meet all criteria for their disease subtype simultaneously. In addition to the above criteria, patients with systemic-onset disease should have no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to juvenile idiopathic arthritis. JIA, juvenile idiopathic arthritis. a Measured on a 10-cm visual analog scale, where 0=best and 10=worst. Source: Adapted from Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, et al. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Rheum 2008;59:1120 7.

are compiled by pooling several individual measures to generate a single indicator, which has the advantage of integrating multiple aspects of the disease into one summary number on a continuous scale. Composite scores can be used to assess disease activity in single patients, to compare disease status across patients or patient groups, and to assess therapeutic efficacy in clinical trials. Composite disease activity scores have long been used in adult rheumatology [14 16]. However, until recently, such measures were not available for children with chronic arthritis. In 2009, the first composite disease activity score for JIA, termed the Juvenile Arthritis Disease Activity Score (JADAS), was reported [17]. The JADAS consists of four variables: physician global rating of overall disease activity, parent/child ratings of well-being, count of active joints, and ESR. Three versions of the JADAS were developed, which differ in the active joints count incorporated: JADAS10, JADAS27, and JADAS71 (Table 5.4). The JADAS10 is based on the count of any involved joint, irrespective of its type, up to a maximum of 10 joints. Following a previous analysis that showed that the 27-joint reduced count is a good surrogate for the whole joint count in JIA [18], it was decided, due to its greater feasibility, to incorporate this reduced count in another version of the JADAS. The JADAS27 includes the following joints: cervical spine, elbows, wrists, metacarpophalangeal joints (from first to third), proximal interphalangeal joints, hips, knees, and ankles.

TABLE 5.4 Composition and Scoring of the Original and Clinical JADAS Versions JADAS10

JADAS27

JADAS71

cJADAS10

Physician global rating

VAS in cm (0 10)

VAS in cm (0 10)

Parent or child global rating

VAS in cm (0 10)

VAS in cm (0 10)

Active joint count

Simple count (0 10)a

Acute phase reactant

ESR/CRP normalizedb (0 10)

Score range

0 40

Select count (0 27)

0 57

cJADAS27

cJADAS71

Simple count (0 71)

Simple count (0 10)a

Select count (0 27)

Simple count (0 71)

0 101

0 30

0 47

0 91

a Simple count cut at 10 (ie, any joint count higher than 10 is given a score of 10).bThe ESR is normalized according to the following formula: (ESR (mm/hour) 20)/10. ESR values ,20 mm/hour are converted to 0 and ESR values .120 m/hour are converted to 10. CRP is normalized according to the following formula: (CRP (mg/L) 2 10)/10, CRP values ,10 mg/L are converted to 0 and CRP values .110 mg/L are converted to 10. Source: Adapted from Consolaro A, Calandra S, Robbiano C. Treating juvenile idiopathic arthritis according to JADAS-based targets. Ann Ped Rheum 2014;3:4 10.

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The active joints count included in the JADAS71 was meant to be unrestricted. However, this version of the score was developed and validated using a rheumatologic examination form that included 71 joints [18]. This form does not include the thoracic and lumbar spine, which are currently included in the standard rheumatologic examination adopted by the Paediatric Rheumatology International Trials Organization and by the Pediatric Rheumatology Collaborative Study Group. To solve this formal incongruence, in clinical trials it is advised to combine cervical, thoracic, and lumbar spine in a single joint. The sacroiliac joints are not considered because they are not included in the active joints count since they cannot be clinically swollen and they cannot present a limited range of motion. Notably, the JADAS has not been formally validated in juvenile spondyloarthropathies. The ESR value is normalized to a 0 10 scale according to the following formula: (ESR (mm/ hour) 2 20)/10. Before making the calculation, ESR values ,20 mm/hour are converted to 20 and ESR values .120 m/hour are converted to 120. The choice of ESR instead of C-reactive protein (CRP) level was dictated by its availability as a sole acute-phase reactant in most study data sets. The JADAS was calculated as the simple sum of the scores of its four components, which yields a global score of 0 40, 0 57, and 0 101 for the JADAS10, JADAS27, and JADAS71, respectively. The JADAS has been shown to be feasible and to have good capacity to predict disease outcomes [17]. Through regular application of the JADAS in day-to-day care, information related to patient disease activity may be collected as standardized quantitative data. Furthermore, JADAS scores can be plotted in a graph to provide an overview of the patient’s course over time (Fig. 5.1). Currently, computer-based utilities, such as office-based touchscreen computers and handheld computers, are emerging to address the workflow challenges in

FIGURE 5.1 JADAS10 values over the course of disease of a systemic JIA patient. Horizontal lines indicate the JADAS10 cut-off values for inactive disease (ID), minimal disease activity (MDA) and parent acceptable symptom state (PASS).

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obtaining, aggregating, calculating, and displaying data in real time, as well as to minimize errors in data analysis. By means of this technology, the JADAS can be automatically scored and results can be stored, together with other clinical information, in a database [19]. Information can be presented in real time with scores from previous visits. Thus, the availability of these instruments may foster regular assessments of the JADAS in routine practice and contribute to the improvement of the quality of care of children with JIA. Because the JADAS provides simple and intuitive reference values of the level of disease activity in individual patients, it is ideally suited for use in clinical decisionmaking, particularly in implementing a treat-to-target strategy aimed at achieving and maintaining tight disease control, with treatment escalation if a target JADAS score is not reached [20]. Recently, Nordal et al. developed and validated an alternative version of the JADAS by substituting the ESR with the CRP [21]. The CRP was truncated to a 0 10 scale according to the following formula: (CRP (mg/L) 2 10)/10, similar to the normalized ESR used in the original JADAS. Before calculation, CRP values ,10 mg/L are converted to 10 and CRP values .110 mg/L are converted to 110. JADAS-CRP is calculated similarly to the original JADAS as the simple sum of its four components, yielding a global score of 0 40, 0 57, and 0 101 depending on the joint count used for the JADAS10-CRP, JADAS27-CRP, and JADAS71-CRP, respectively. JADAS-CRP versions were validated by showing their high correlation (r=0.99) with the corresponding version of the original JADAS. By analogy with the Clinical Disease Activity Index versus the Disease Activity Score in adult rheumatoid arthritis [22], the feasibility of the JADAS for use in daily practice was enhanced by the establishment of a three-variable version that does not include the acute-phase reactant. Inflammatory markers frequently are not obtained or available at a visit, particularly in children who are not receiving medications and thus do not require laboratory monitoring or in children with persistent oligoarticular JIA, which is the most common and benign category. Therefore, pediatric rheumatologists often do not have laboratory results available during the clinical evaluation. The lack of this information would hinder the potential to make immediate therapeutic decisions based on the JADAS and therefore the potential benefit of intensifying therapy. Recently, the three-variable version of the JADAS that excluded the acute-phase reactant was found to correlate closely with the original tool [23]. The modified score was named JADAS3-10, -27, -71, according to the active joints count included. However, it was suggested that the acronym cJADAS (ie, clinical JADAS) is preferable to avoid any confusion due to the proximity of numbers [24].

DISEASE ACTIVITY STATES BASED ON THE JADAS To aid in interpretation of scores on the JADAS, criteria (ie, cutoff values) are needed for identifying high and low levels of JIA activity. These criteria

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may provide simple and intuitive reference values that can be used to monitor the disease course over time in an individual patient or to compare disease status across individual patients or patient groups. Furthermore, they may support decisions about enrollment into clinical trials as well as requirements for changes in therapies and for defining therapeutic goals. Recently, the cutoff values in the JADAS and in the cJADAS that correspond to the states of inactive disease, low disease activity, parent’s or child’s satisfaction with the outcome of the illness, and high disease activity were determined and validated [24 26]. High disease activity cutoffs were developed for nonsystemic JIA only (Table 5.5). All of the selected cutoff values revealed good metrologic properties in cross-validation analyses. The discriminant validity of the cutoffs for inactive disease and low disease activity was demonstrated by the observation that the cutoffs were met more frequently in patients judged by the physician or the parent as having disease remission, or deemed by the parent as being in an acceptable symptom state. Conversely, evidence of discriminant validity of the cutoffs for high disease activity was provided by the finding that the cutoffs were met more commonly in patients judged by the physician or the parent as having continued disease activity or disease flare, or deemed by the parent as not being in an acceptable symptom state. As expected, the trends observed for moderate disease activity cutoffs were in between those

TABLE 5.5 Cutoffs for Disease Activity States in Original and Clinical JADAS Versions JADAS10/71

JADAS27

cJADAS10

Inactive disease

#1

#1

#1

Low disease activity

1.1 2

1.1 2

1.1 1.5

Moderate disease activity

2.1 4.2

2.1 4.2

1.51 4

High disease activity

.4.2

.4.2

.4

Inactive disease

#1

#1

#1

Low disease activity

1.1 3.8

1.1 3.8

1.1 2.5

Moderate disease activity

3.9 10.5

3.9 8.5

2.51 8.5

High disease activity

.10.5

.8.5

.8.5

Oligoarthritis

Polyarthritis

Source: Adapted from Consolaro A, Calandra S, Robbiano C. Treating juvenile idiopathic arthritis according to JADAS-based targets. Ann Ped Rheum 2014;3:4 10.

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seen for low disease activity and high disease activity cutoffs. Evidence of discriminant validity of the cutoffs was also provided by the finding that the level of pain was lowest in patients with a JADAS below the cutoff value for inactive disease and became progressively greater in patients who met the cutoff values for low disease activity, moderate disease activity, and high disease activity. In the patient sample with longstanding disease, the cutoffs showed good construct validity, considering that patients with a JADAS below the threshold values for inactive disease or low disease activity were less likely to have physical functional disability or clinical or radiographic damage, whereas patients with a JADAS in the interval corresponding to moderate disease activity or above the high disease activity cutoff had a greater frequency of functional, clinical, or radiographic damage [24 26]. Importantly, the cutoff values revealed the ability to predict a worse disease prognosis because patients who had a level of disease activity above their thresholds were less likely to have inactive disease or a Childhood Health Assessment Questionnaire (CHAQ) [27] score of 0 at the last follow-up visit or showed a greater progression of radiographic joint damage [26].

MEASURES OF PHYSICAL FUNCTION The assessment of physical function is a fundamental component of the clinical evaluation of children with JIA. Currently, the most widely used functional status tool is the CHAQ [27]. However, CHAQ has been demonstrated to suffer from a ceiling effect, with a tendency for scores to cluster at the normal end of the scale, particularly in patients with fewer joints involved [28,29]. Another problem with the use of CHAQ is its length and complexity, including the requirement of a calculator to compute the scores. Lam and coworkers [30] devised three modified versions of CHAQ that measure functional strengths as well as weaknesses (ie, by using new response scales as well as by adding more challenging questions) to investigate whether they reduced the limitations of CHAQ, namely the ceiling effect and poor sensitivity for children with relatively good function. The new versions of CHAQ were found to suffer less from a ceiling effect and to be more normally distributed. Furthermore, they proved more sensitive at differentiating JIA patients from controls. To set up a functional measure more feasible than CHAQ for routine use in standard clinical care of children with JIA, Filocamo and coworkers [31] developed a shorter and simpler 15-item questionnaire, the Juvenile Arthritis Functionality Scale (JAFS). The JAFS was found to possess face and content validity, good reliability, strong discriminative validity, and fair responsiveness to clinical change over time in a large cohort of JIA patients. Other validated tools for the assessment of functional ability in JIA patients include the Juvenile Arthritis Functional Assessment Scale (JAFAS), Juvenile Arthritis Functional Assessment Report (JAFAR), and the Juvenile

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Arthritis Self-Report Index (JASI). The JAFAS, developed in 1989, is an observer-based scale, which requires a trained observer and standardized equipment, and is based on timing on 10 physical tasks [32]. The JAFAR assesses the ability of children older than 7 years to perform physical tasks in 23 items; two versions are available, one for children (JAFAR-C) and one for parents (JAFAR-P) [33]. Finally, the JASI is a 100-item instrument that explores physical function in five domains. It is a very comprehensive, valid, and reliable tool, although it takes a long time to complete [34]. To overcome the potential bias in answering that may be provided by subjective assessment of physical function, which can be influenced by level of understanding and emotional background of the questionnaire completer, Iglesias and coworkers [35] designed an observational functional ability scale, the CAPFUN. It consists of 20 items, which assess 10 activities in the upper limbs or cervical spine and 10 in the lower limbs. Each item is scored as 0 when it is impossible to perform, 1 when it is performed incompletely or with difficulties, and 2 when it is well performed. The mean value of upper and lower limb scores is added and their mean value, which ranges from 0 to 2, is defined as CAPFUN. This tool, which has the advantage of providing an objective assessment of physical function, revealed good internal reliability and construct validity.

MEASURES OF HEALTH-RELATED QUALITY OF LIFE The concept of quality of life has been defined by the World Health Organization as “an individual’s perception of their position in life in the context of the culture and value systems in which they live, and in relation to their goals, expectations, standards, and concerns” [36]. JIA is a chronic, in some cases multisystem, inflammatory condition that may influence many aspects of a child’s life, including not only the physical but also the social, emotional, intellectual, and economic aspects [37]. Therefore, a complete assessment of children with JIA requires an understanding of the impact of the disease, its complications, and its treatment on a child’s life. Assessment of HRQoL is increasingly recognized as a fundamental component of the clinical evaluation of children with JIA [38]. It has been suggested that measurement of HRQoL be incorporated into routine pediatric rheumatology care [39]. A number of HRQoL scales are available for use in children with JIA [40 43]. However, most of these measures have remained essentially research tools and are not routinely administered in most pediatric rheumatology centers (Table 5.6). The Child Health Questionnaire (CHQ) is a generic instrument, which is available in a number of different forms [41]. The form commonly adopted for JIA patients is the parent form 50 (PF50). This form contains 50 items distributed in the following dimensions: global health physical activities, everyday activities pain, behavior, well-being, self-esteem, general health,

TABLE 5.6 Measures of Health-Related Quality of Life Available for Juvenile Idiopathic Arthritis and Their Main Clinimetric Properties Measure of Quality of Life

Reliability

Validity

Responsiveness

Discriminative Ability

Easy to Use

Juvenile Arthritis Quality of Life Questionnaire (JAQQ)

NA

Strong

Very strong

Weak

Strong

Childhood Arthritis Health Profile (CAHP)

Moderate

Moderate

NA

Moderate

No

Quality of My Life Questionnaire (QoMLQ)

Moderate

Moderate

NA

NA

Strong

Childhood Health Questionnaire (CHQ)

Strong

Strong

Moderate

Moderate

Moderate

Pediatric Quality of Life Inventory Scale (PedsQL)

Strong

Strong

Moderate

Moderate

Moderate

Pediatric Rheumatology Quality of Life (PRQL)

Strong

Moderate

Moderate

Strong

Strong

Source: Modified from Cassidy JT, Petty RE, Laxer RM, Lindsay CB. Textbook of pediatric rheumatology. 5th ed. Philadelphia, PA: Elsevier; 2005.

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and family. It yields a physical and a psychosocial summary score. The CHQ has been validated for patients with JIA and has been found to be responsive to change in patients with JIA [44]. The Pediatric Quality of Life Inventory (PedsQL) is a generic HRQoL instrument for pediatric patients made of a generic core, which is completed by a module specific for the patient with pediatric rheumatology conditions [40]. The generic version evaluates physical, emotional, social, and school functioning domains, and the rheumatology module includes 22 items that are grouped into five domains: pain and hurt, daily activities, treatment, worry, and communication. Both measures have been validated in patients aging 2 18 years with various rheumatic diseases. The clinical use of both CHQ and PedsQL requires permission and could be not free of charge. The Juvenile Arthritis Quality of Life Questionnaire (JAQQ) was developed by Duffy and coworkers specifically for JIA patients [45]. It consists of 74 items covering gross motor function, fine motor function, psychosocial function, and general symptoms as well as a 100-mm visual analog scale (VAS) measure of pain. Each patient identifies the five most problematic items in each domain and only these are scored, thereby incorporating patient input. However, this may complicate direct comparison of results among patients for research purposes [46]. The JAQQ has been found to have moderate construct validity and responsiveness. The Quality of My Life Questionnaire (QoMLQ) measures both overall quality of life and HRQoL (each on a 100 mm VAS) [47]. It includes also a categorical item that asks about change in quality of life between visits. Child and parent responses on the QoMLQ have been found to have fair-to-good concordance and the instrument was demonstrated to be highly reliable and valid. The Pediatric Rheumatology Quality of Life (PRQL) scale is a 10-item questionnaire designed for pediatric patients with rheumatic conditions [48]. Items are grouped in two subdimensions, physical health and psychosocial health, each composed of five items. A four-point Likert scale is scored for each item or question. Questions refer the respondent to the previous month. The responses are Never (score 5 0), Sometimes (score 5 1), Most of the Time (score 5 2), and All the Time (score 5 3). A Not Assessable column was included in the parent version of the questionnaire to designate questions that cannot be answered because of developmental immaturity. The total score ranges from 0 to 30, with higher scores indicating worse HRQoL. The PRQL is short and simple, and is quick, taking less than 5 minutes to be completed and scored. It is proposed for use as both proxy report and patient self-report, with the suggested age range of 7 18 years for use as self-report. Some questionnaires have been translated into different languages [40,49]. The PRQL is currently undergoing translation and cross-cultural adaptation in multiple languages [50]. Pain is considered the main determinant of HRQoL in JIA [51]. Several studies have shown that pain is more prevalent in JIA than previously

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recognized and that a sizeable percentage of patients continue to report pain long after disease onset [52]. High levels of pain limit physical activities, disrupt school attendance, and contribute to psychosocial distress. The 10-cm horizontal line VAS is traditionally used to make these assessments. However, this VAS format has the disadvantage of requiring the use of a ruler to measure the distance of the mark from the left border. Another problem with the use of this VAS is that its length may be altered in printing and photocopying. It has been suggested that the 21-numbered circle VAS has at least three advantages over the traditional 10-cm horizontal line format: (1) it enables the assessor to score the VAS without a ruler, implying a simpler and quicker calculation, (2) it eliminates the need to reproduce an exact 10-cm line in printing or photocopying the questionnaires, averting the problem of minor distortion frequently seen with these procedures, and (3) it is better understood by patients [53,54].

PARENT/PATIENT ACCEPTABLE SYMPTOM STATE It has been argued that criteria for inactive disease are based only on physicianreported outcomes and an acute phase reactant, whereas parent proxy-reported and child self-reported outcomes are neglected [55]. A parent global assessment is included in minimal disease activity criteria for polyarthritis, but not for oligoarthritis. Hence, both clinical inactive disease and minimal disease activity definitions may not reflect adequately the parent and child perception of the disease status. A goal to analyze whether a therapeutic intervention leads to an acceptable state according to the parent or the child has led to proposal of the concept of parent/child acceptable symptom state in JIA [55]. This state has been defined as the symptom threshold beyond which the child health status is considered as satisfactory by the parent or the child. The cutoff values for parent-reported, child-reported, and physician-reported outcome measures, and acute phase reactants that defined the acceptable symptom state for parents and children have been estimated using both the 75th percentile method and receiver-operating-characteristic curve analysis [55]. The cutoff values for children were lower than those for parents, suggesting that children may request a more stringent disease control to feel satisfied. Cutoffs were higher in systemic arthritis than in the other JIA categories, reflecting the greater burden of disease in the systemic subset.

A MULTIDIMENSIONAL QUESTIONNAIRE FOR JIA As stated earlier, a number of measures for the assessment of parent/childreported outcomes in children with JIA have been developed over the years. However, outcomes not addressed by conventional instruments, such as evaluation of morning stiffness and overall level of disease activity, rating of disease status and course, proxy- or self-assessment of joint involvement and

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extra-articular symptoms, description of side effects of medications, and assessment of therapeutic compliance and satisfaction with the outcome of the illness, may provide valuable insights into the impact of the disease and its treatment. Filocamo and coworkers have recently developed a multidimensional questionnaire for the assessment of children with JIA in standard clinical care that incorporates all main parent/child-reported outcomes. This tool has been named the Juvenile Arthritis Multidimensional Assessment Report (JAMAR) [56]. This clinical instrument groups most of the parent/ child-reported outcomes used in the assessment of children with JIA and provides the physician with a thorough and systematic overview of the patient status to be scanned (eyeballed) at the start of the visit. This facilitates focusing on matters that require attention, leading to more efficient and effective clinical care. The JAMAR includes the following 15 measures/items: (1) assessment of physical function through the JAFS [31]; (2) rating of the intensity of child’s pain on a 21-numbered circle VAS [54]; (3) assessment of HRQoL, through the PRQL [43]; (4) rating of child’s overall well-being on a 21-numbered circle VAS [54]; (5) assessment of the presence of pain or swelling in the following joints or joint groups: cervical spine, lumbosacral spine, shoulders, elbows, wrists, small hand joints, hips, knees, ankles, and small foot joints; (6) assessment of morning stiffness; (7) assessment of extra-articular symptoms (fever and rash); (8) rating of the level of disease activity on a 21-numbered circle VAS [54]; (9) rating of disease status at the time of the visit as remission, continued activity, or relapse; (10) rating of disease course from previous visit as much improved, slightly improved, stable, slightly worsened, or much worsened; (11) checklist of the medications the child is taking; (12) checklist of side effects of medications; (13) report of difficulties with medication administration; (14) report of school problems caused by the disease; and (15) a question about satisfaction with the outcome of the illness [55]. The JAMAR is available as both proxy-report and patient self-report, with the suggested age range of 7 18 years for use as self-report. The JAMAR is undergoing translation and cross-cultural adaptation in more than 40 languages [50]. The questionnaire format has been found very user-friendly, easy to understand, and readily responded to by parents and children. It is quick, taking less than 15 minutes to complete and can be scanned by a health professional for a clinical overview in a few seconds. Scoring of its components can be accomplished in less than 5 minutes. Regular use of the JAMAR enables keeping a flow sheet of patient’s course over time. A flow sheet may facilitate the recognition of possible changes in functional capacity, pain, fatigue, and psychological status from previous visits. This method of handling clinical data is very useful in the management of a chronic disease such as JIA as it allows the clinician to record serial parent/patient data, together with joint examination findings,

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laboratory tests, medication regimen, and other information. A step forward would be the implementation of this or similar tools to be completed on electronic devices, including smartphones and tablets, at the time of the visits or at home. This would facilitate submission of parent- and childreported information prior to consultation and will soon lead to abandonment of the paper questionnaires.

PARENT AND PATIENT-CENTERED DISEASE ACTIVITY MEASURES Recently, composite disease activity scores for JIA entirely based on parentor child-reported outcome measures were developed. These tools were named the Juvenile Arthritis Parent Assessment Index (JAPAI) and the Juvenile Arthritis Child Assessment Index (JACAI), respectively [57]. The JAPAI and JACAI are composed of the following items: (1) parent/ child rating of overall well-being on a 0 10 cm VAS (0 5 best, 10 5 worst), (2) parent/child rating of pain intensity on a 0 10 cm VAS (0 5 no pain, 10 5 very severe pain), (3) assessment of physical function, and (4) assessment of HRQoL. To confer each item the same weight in the index, scores of physical function and HRQoL tools included in the composite scores are converted to a 0 10 score by specific formulae. Two different versions of the JAPAI and JACAI were devised: the JAPAI-4 and the JACAI-4 include all four items; the JAPAI-3 and the JACAI-3 include only the first three items (HRQoL assessment is excluded). After score adjustment, the JAPAI and JACAI scores are obtained as the simple linear sum of the scores of their components, which yields a global score of 0 40 for the four-item versions and of 0 30 for the three-item versions.

MEASURES OF DAMAGE JIA is characterized by prolonged synovial inflammation that may cause irreversible alterations in joint structures. Permanent changes may also occur in extra-articular organs/systems, such as the eye (as a complication of chronic anterior uveitis) or the kidney (due to systemic amyloidosis), or may result from side effects of medications [58]. In the past long-term outcome studies, the morbidity in JIA patients has been generally evaluated in terms of functional disability or by assessing structural joint damage through radiographs. However, these tools may not capture several forms of damage that children with JIA may develop over time, such as micrognathia, height retardation, localized growth disturbances, pubertal delay, or visceral organ failure [59]. The Juvenile Arthritis Damage Index (JADI) is the only available clinical tool devised to enable a thorough detection of articular and extra-articular damage in children with JIA [60]. This tool is simple, easy to use, and quick, taking only 5 15 minutes to score, which

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makes it practical for use in the clinical setting. It is completed by the physician using information obtained by physical examination and a review of the patient’s clinical history. The definitions for each item are concise and simple in order to make the instrument accessible to inexperienced assessors. The JADI is intended to capture damage, defined as persistent changes in anatomy, physiology, pathology, or function, which may be the consequence of previous active disease, side effects of therapy, or comorbid conditions, is not due to currently active arthritis, and is present for at least 6 months. Damage is often irreversible and cumulative and, thus, damage scores are frequently expected to increase or remain stable over time. However, because some forms of damage may improve or even resolve in growing children, in some cases scores may decrease. The index is composed of two parts, one devoted to the assessment of articular damage (JADI-A) and the other one devoted to the assessment of extra-articular damage (JADI-E). In the JADI-A, 36 joints or joint groups are evaluated for the presence of damage. The damage observed in each joint is scored on a two-point scale (0 5 no damage, 1 5 partial damage, 2 5 severe damage, ankylosis, or prosthesis). The damage is evaluated on clinical grounds. The only tool needed is a goniometer, although most joints can be assessed without one. The maximum total score is 72. The JADI-E includes 13 items in 5 organs/systems. Each item is scored as either 0 or 1 according to whether damage is absent or present, respectively. Due to the relevant impact of ocular damage on the child’s health, a score of 2 is given for each eye when the patient has had ocular surgery and a score of 3 when the patient has developed legal blindness. The maximum total score is 17.

CONCLUSIONS In the past decade, there has been a great deal of effort to develop and validate new quantitative measures for the clinical assessment of children with JIA. These instruments have expanded the spectrum of disease domains that can be addressed in a standardized manner. The availability of the new tools may help foster regular use of parent/child questionnaires in routine clinical practice and contribute to improve the quality of care of children with JIA. These goals can be further facilitated by the development of a European inventory of the use of these tests and by their incorporation in descriptions of standard of care. It is now widely agreed that the shift toward clinical care based on quantitative measurements leads to a more rational monitoring of the disease course over time and the effectiveness of therapeutic interventions. Notably, the use of a standardized and uniform set of clinical instruments across international pediatric rheumatology centers is fundamental to ensure that the data regarding disease characteristics, outcome, and treatment results are comparable.

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REFERENCES [1] Brunner HI, Ravelli A. Developing outcome measures for paediatric rheumatic diseases. Best Pract Res Clin Rheumatol 2009;23:609 24. [2] Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:1202 9. [3] Committee for Medicinal Product for Human Use (CHMP) European Medicines Agency. 2006. URL: ,http://www.ema.europa.eu/pdfs/human/ewp/042204.pdf.. [4] De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2385 95. [5] Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N, Horneff G, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2396 406. [6] Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. N Engl J Med 1992;326:1043 9. [7] Ruperto N, Murray KJ, Gerloni V, Wulffraat N, de Oliveira SKF, Falcini F, et al. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum 2004;50:2191 201. [8] Wallace CA, Ruperto N, Giannini EH. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004;31:2290 4. [9] Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011;63:929 36. [10] Wallace CA, Huang B, Bandeira M, Ravelli A, Giannini EH. Patterns of clinical remission in select categories of juvenile idiopathic arthritis. Arthritis Rheum 2005;52:3554 62. [11] Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, et al. Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis. Arthritis Rheum 2008;59:1120 7. [12] Wells G, Boers M, Shea B, Anderson J, Felson D, Johnson K, et al. MCID/Low Disease Activity State Workshop: low disease activity state in rheumatoid arthritis. J Rheumatol 2003;30:1110 11. [13] Filocamo G, Consolaro A, Solari N, Palmisani E, Dalpra` S, et al. Recent advances in quantitative assessment of juvenile idiopathic arthritis. Ann Paediatr Rheum 2012;1:84 96. [14] Prevoo MLL, van’T Hof MA, Kuper HH, van Leeuwen MA, Van de Putte LBA, van Riel PLCM. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44 8. [15] Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology 2003;42:244 57. [16] Aletaha D, Nell VP, Stamm T, Uffmann M, Pflugbeil S, Machold K, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther 2005;7:R796 806.

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[17] Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S, Filocamo G, et al. Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Rheum 2009;61:658 66. [18] Bazso A, Consolaro A, Ruperto N, Pistorio A, Viola S, Magni-Manzoni S, et al. Development and testing of reduced joint counts in juvenile idiopathic arthritis. J Rheumatol 2009;36:183 90. [19] Filocamo G, Consolaro A, Ferrari C, Ravelli A. Introducing new tools for assessment of parent- and child-reported outcomes in paediatric rheumatology practice: a work in progress. Clin Exp Rheumatol 2013;31:964 8. [20] Consolaro A, Negro G, Lanni S, Solari N, Martini A, Ravelli A. Toward a treat-to-target approach in the management of juvenile idiopathic arthritis. Clin Exp Rheumatol 2012;30: S157 62. [21] Nordal EB, Zak M, Aalto K, Berntson L, Fasth A, Herlin T, et al. Validity and predictive ability of the juvenile arthritis disease activity score based on CRP versus ESR in a Nordic population-based setting. Ann Rheum Dis 2012;71:1122 7. [22] Aletaha D, Smolen JS. The Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) to monitor patients in standard clinical care. Best Pract Res Clin Rheumatol 2007;21:663 75. [23] McErlane F, Beresford MW, Baildam EM, Chieng SE, Davidson JE, Foster HE, et al. Validity of a three-variable juvenile arthritis disease activity score in children with new-onset juvenile idiopathic arthritis. Ann Rheum Dis 2013;72:1983 8. [24] Consolaro A, Negro G, Gallo MC, Bracciolini G, Ferrari C, Schiappapietra B, et al. Defining criteria for disease activity states in non-systemic juvenile idiopathic arthritis based on a three-variable juvenile arthritis disease activity score. Arthritis Care Res (Hoboken). 2014. [25] Consolaro A, Bracciolini G, Ruperto N, Pistorio A, Magni-Manzoni S, Malattia C, et al. Remission, minimal disease activity, and acceptable symptom state in juvenile idiopathic arthritis: defining criteria based on the juvenile arthritis disease activity score. Arthritis Rheum 2012;64:2366 74. [26] Consolaro A, Ruperto N, Bracciolini G, Frisina A, Gallo MC, Pistorio A, et al. Defining criteria for high disease activity in juvenile idiopathic arthritis based on the juvenile arthritis disease activity score. Ann Rheum Dis 2014;73:1380 3. [27] Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in children with juvenile rheumatoid arthritis. Arthritis Rheum 1994;37:1761 9. [28] Ruperto N, Ravelli A, Migliavacca D, Viola S, Pistorio A, Duarte C, et al. Responsiveness of clinical measures in children with oligoarticular juvenile chronic arthritis. J Rheumatol 1999;26:1827 30. [29] Brunner HI, Klein-Gitelman MS, Miller MJ, Barron A, Baldwin N, Trombley M, et al. Minimal clinically important differences of the Childhood Health Assessment Questionnaire. J Rheumatol 2005;32:150 61. [30] Lam C, Young N, Marwaha J, McLimont M, Feldman BM. Revised versions of the Childhood Health Assessment Questionnaire (CHAQ) are more sensitive and suffer less from a ceiling effect. Arthritis Rheum Arthritis Care Res 2004;51:881 9. [31] Filocamo G, Sztajnbok F, Cespedes-Cruz A, Magni-Manzoni S, Pistorio A, Viola S, et al. Development and validation of a new short and simple measure of physical function for juvenile idiopathic arthritis. Arthritis Rheum 2007;57:913 20. [32] Lovell DJ, Howe S, Shear E, Hartner S, McGirr G, Schulte M, et al. Development of a disability measurement tool for juvenile rheumatoid arthritis. The juvenile arthritis functional assessment scale. Arthritis Rheum 1989;32:1390 5.

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[33] Howe S, Levinson J, Shear E, Hartner S, McGirr G, Schulte M, et al. Development of a disability measurement tool for juvenile rheumatoid arthritis. The juvenile arthritis functional assessment report for children and their parents. Arthritis Rheum 1991;34:873 80. [34] Wright FV, Kimber JL, Law M, Goldsmith CH, Crombie V, Dent P. The juvenile arthritis functional status index (JASI): a validation study. J Rheumatol 1996;23:1066 79. [35] Iglesias MJ, Cuttica RJ, Herrera CM, Micelotta M, Pringe A, Brusco MI. Design and validation of a new scale to assess the functional ability in children with juvenile idiopathic arthritis (JIA). Clin Exp Rheumatol 2006;24:713 18. [36] [No authors listed] The World Health Organization Quality of Life assessment (WHOQOL): position paper from the World Health Organization. Soc Sci Med 1995;41:1403 9. [37] Duffy CM. Measurement of health status, functional status, and quality of life in children with juvenile idiopathic arthritis: clinical science for the pediatrician. Pediatr Clin North Am 2005;52:359 72. [38] Nunnally JC, Bernstein IH. Psychometric theory. 3rd ed. New York, NY: McGraw-Hill; 1994. [39] Tucker LB. Whose life is it anyway? Understanding quality of life in children with rheumatic diseases. J Rheumatol 2000;27:8 11. [40] Varni JW, Seid M, Knight TS, Burwinkle T, Brown J, Szer IS. The PedsQL(TM) in pediatric rheumatology - Reliability, validity, and responsiveness of the Pediatric Quality of Life Inventory(TM) generic core scales and rheumatology module. Arthritis Rheum 2002;46:714 25. [41] Landgraf JM, Abetz L, Ware JE. The CHQ user’s manual. 1st ed. Boston, MA: The Health Institute, New England Medical Center; 1996. [42] Duffy CM, Arsenault L, Duffy KNW, Paquin JD, Strawczynski H. Validity and sensitivity to change of the juvenile arthritis quality of life questionnaire (JAQQ). Arthritis Rheum 1993;36 S144. [43] Bertamino M, Rossi F, Pistorio A, Lucigrai G, Valle M, Viola S, et al. Development and initial validation of a radiographic scoring system for the hip in juvenile idiopathic arthritis. J Rheumatol 2010;37:432 9. [44] Selvaag AM, Flato B, Lien G, Sorskaar D, Vinje O, Forre O. Measuring health status in early juvenile idiopathic arthritis: determinants and responsiveness of the Child Health Questionnaire. J Rheumatol 2003;30:1602 10. [45] Duffy CM, Arsenault L. The juvenile arthritis quality of life questionnaire: a responsive index for chronic childhood arthritis. Arthritis Rheum 1992;35(Suppl.9):S222. [46] Luca NJ, Feldman BM. Health outcomes of pediatric rheumatic diseases. Best Pract Res Clin Rheumatol 2014;28:331 50. [47] Gong GWK, Young NL, Dempster H, Porepa M, Feldman BM. The Quality of My Life (QoML) questionnaire: the minimal clinically important (MCID) for pediatric rheumatology patients. J Rheumatol 2007;34:581 7. [48] Filocamo G, Schiappapietra B, Bertamino M, Pistorio A, Ruperto N, Magni-Manzoni S, et al. A new short and simple health-related quality of life measure for paediatric rheumatic diseases: initial validation in juvenile idiopathic arthritis. Rheumatology 2010;49:1272 80. [49] Ruperto N, Ravelli A, Pistorio A, Malattia C, Cavuto S, Gado-West L, et al. Cross-cultural adaptation and psychometric evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ) in 32 countries. Review of the general methodology. Clin Exp Rheumatol 2001;19:S1 9.

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[50] Consolaro A, Ruperto N, Filocamo G, Lanni S, Bracciolini G, Garrone M, et al. Seeking insights into the EPidemiology, treatment and Outcome of Childhood Arthritis through a multinational collaborative effort: introduction of the EPOCA study. Pediatr Rheumatol Online J 2012;10:39. [51] Kimura Y, Walco GA. Pain in children with rheumatic diseases. Curr Rheumatol Rep 2006;8:480 8. [52] Anthony KK, Schanberg LE. Assessment and management of pain syndromes and arthritis pain in children and adolescents. Rheum Dis Clin North Am 2007;33:625 60. [53] Pincus T, Bergman M, Sokka T, Roth J, Swearingen C, Yazici Y. Visual analog scales in formats other than a 10 centimeter horizontal line to assess pain and other clinical data. J Rheumatol 2008;35:1550 8. [54] Filocamo G, Davi S, Pistorio A, Bertamino M, Ruperto N, Lattanzi B, et al. Evaluation of 21-numbered circle and 10-centimeter horizontal line visual analog scales for physician and parent subjective ratings in juvenile idiopathic arthritis. J Rheumatol 2010;37:1534 41. [55] Filocamo G, Consolaro A, Schiappapietra B, Ruperto N, Pistorio A, Solari N, et al. Parent and child acceptable symptom state in juvenile idiopathic arthritis. J Rheumatol 2012;39:856 63. [56] Filocamo G, Consolaro A, Schiappapietra B, Dalpra` S, Lattanzi B, Magni-Manzoni S, et al. Introducing a new approach into clinical care of children with juvenile idiopathic arthritis: the Juvenile Arthritis Multidimensional Assessment Report. J Rheumatol 2011;38:953. [57] Consolaro A, Ruperto N, Pistorio A, Lattanzi B, Solari N, Galasso R, et al. Development and initial validation of composite parent and child centered disease assessment indices for juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2011. [58] Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007;369:767 78. [59] Ravelli A. Toward an understanding of the long-term outcome of juvenile idiopathic arthritis. Clin Exp Rheumatol 2004;22:271 5. [60] Viola S, Felici E, Magni-Manzoni S, Pistorio A, Buoncompagni A, Ruperto N, et al. Development and validation of a clinical index for assessment of long-term damage in juvenile idiopathic arthritis. Arthritis Rheum 2005;52:2092 102.

Chapter 6

Childhood Uveitis A. Brambilla and G. Simonini Rheumatology Unit, NEUROFARBA Department, Anna Meyer Children Hospital, University of Florence, Firenze, Italy

INTRODUCTION Uveitis embraces a group of severe and disabling inflammatory diseases affecting the vascular layer of the eye (uvea). Different population-based studies reported an annual incidence of roughly 22.6 52.4/100,000 personyears, with higher rates documented in developed western countries. Differences by sex have been reported, women being affected more than men at almost any age [1 4]. Approximately 5 10% of total cases develop during childhood, with an estimated incidence of 4 7/100,000 children per year and a prevalence of 28/100,000 children per year [5]. Despite being considered a rare disease, it represents a sight-threatening condition accounting for up to 10% of pathologies leading to blindness. The International Uveitis Study Group (IUSG) developed a classification system based on the anatomical extension of ocular inflammation [6]. Anterior uveitis (ie, iritis and iridocyclitis) affects the anterior chamber and is responsible for nearly 30 40% of total cases of pediatric uveitis. Intermediate uveitis (ie, para planitis, hyalitis) is the less frequent during childhood (about 20% of total cases) and involves pars plana and vitreous. Posterior uveitis accounts for up to 40 50% of childhood uveitis and is characterized by the involvement of retina and/or chorid (ie, choroiditis, chorioretinitis, retinitis, neuroretinitis). The term panuveitis refers to the broad extension of inflammation to all ocular segments and encompasses 1.5 11.3% of pediatric cases. The Standardized Uveitis Nomenclature Working Group endorsed the anatomical classification scheme provided by IUSG and proposed a standardized approach to report clinical data embracing classification system, inflammation grading schema, and outcome measures. The clinical course of the disease may be acute, chronic, or recurrent. Acute uveitis is generally symptomatic and tends to come to a complete Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00006-2 © 2016 Elsevier B.V. All rights reserved.

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resolution within 3 months from its onset. Children commonly show conjunctiva hyperemia, photophobia, ocular pain, lacrimation, and visual loss. Acute-recurrent uveitis is characterized by the relapse of disease after 3 months of remission, whereas the persistence of disease with prompt (within 3 months) relapses after discontinuation of therapy defines the condition of chronic uveitis. Children affected by chronic uveitis may be asymptomatic and frequently present bilateral involvement [7]. The most common causes of childhood uveitis are reported in Table 6.1. Among the broad spectrum of possible etiologies, juvenile idiopathic arthritis (JIA) is the most common cause of anterior chronic uveitis in childhood. It is responsible for 1.8 47% of total uveitis, with the higher incidence recorded in western countries [8]. Infectious diseases are found to be more frequent among underdeveloped countries. The main role is played by toxoplasmosis and herpes virus infection, although HIV and Cytomegalovirus (CMV) infections are becoming more frequent. Systemic vasculitis and autoimmune conditions (ie, Kawasaki disease, systemic lupus erythematous, Behc¸et’s disease, and inflammatory bowel

TABLE 6.1 Common Causes of Uveitis in Children Etiologic Group

Disease

Infectious disease

Bacterial: Syphilis, tuberculosis, Lyme disease, brucellosis, cat scratch disease, leprosy Viral: Herpes simplex virus 1 2, cytomegalovirus, Epstein Barr virus, varicella-zoster virus, mumbles, rubella Fungal: Aspergillosis, coccidioidomycosis, histoplasmosis, blastomycosis, candidiasis, cryptococcosis Parasitic: Toxocariasis, toxoplasmosis, pneumocystosis

Chronic inflammatory disease

Juvenile idiopathic arthritis, psoriasis, inflammatory bowel disease

Autoimmune condition

Systemic lupus erythematosus, Sjogren disease

Tumor

Leukemia, lymphoma, neuroblastoma

Vasculitis

Bechet’s disease, systemic lupus erythematosus, Kawasaki disease, sarcoidosis, polyarteritis nodosa, Wegener’s granulomatosis

Other

Vogt Koyanagi Harada syndrome, Blau disease, tubulointerstitial nephritis, and uveitis

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diseases) may be complicated with ocular inflammation and periodic ophthalmological evaluation may therefore be needed to assess potential ocular involvement. Masquerade syndrome refers to those conditions presenting with intraocular infiltrating cells not related to immune-mediated mechanisms. Hematologic malignancies (ie, leukemia, intraocular lymphoma), retinoblastoma, retinal detachment, or degeneration and intraocular trauma are the most common causes of masquerade syndrome [9]. The cases without an identifiable origin are addressed as idiopathic and represent nearly half of total patients. A close collaboration between pediatric rheumatologist and pediatric ophthalmologist is pivotal in order to define the proper diagnostic work-up and therapeutic pathway.

JUVENILE IDIOPATHIC ARTHRITIS-ASSOCIATED UVEITIS The association between Juvenile Idiopathic Arthritis and ocular inflammation was first described by Ohm in 1910 [10] and subsequently confirmed by several authors. Data regarding the incidence of uveitis in JIA (4 24%) differ considerably due to the features of different medical centers and geographical variations. A recent metaanalysis estimated worldwide incidence at about 8.3% [5]. To date, JIA-related uveitis embodies the most common cause of pediatric uveitis in developed countries. Children affected by JIA develop ocular involvement in up to 50% within 3 months and in up to 90% within 4 years from the diagnosis. Only 2 7% of patients are diagnosed with uveitis before the onset of arthritis [11]. Ocular inflammation may also appear for the first time during adult age. Bilateral involvement is detected in up to 75% of cases. Patients with unilateral uveitis usually show contralateral extension within 1 year from the diagnosis. Children affected by uveitis may present a severe articular involvement, however the presence of ocular inflammation does not seem to affect the long-term prognosis of joint involvement in JIA. The clinical course of the two conditions may be completely independent as well. The probability of developing JIA-related uveitis is driven by several risk factors; among these, we should take into account the following.

Type of Arthritis According to International League of Associations for Rheumatology (ILAR) criteria, JIA is classified in seven different subtypes: systemic, oligoarthritis, polyarthritis (rheumatoid factor (RF)-negative), polyarthritis (RF-positive), psoriatic, enthesitis-related arthritis, and undifferentiated arthritis. Among these, oligoarthritis, polyarthritis RF-negative, and psoriatic arthritis have the

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highest risk of developing secondary uveitis, especially in female patients [12,13]. Children affected by oligoarthritis and psoriatic arthritis develop uveitis in up to 30% of the cases, and nearly half of them show positive antinuclear antibody (ANA) titer. Moreover, ocular inflammation may be detected in approximately 10% of patients affected by polyarthritis RFnegative, frequently affecting second childhood. Enthesitis-related arthritis is complicated with uveitis in up to 20% of cases, generally presenting with acute uveitis affecting male teenagers.

Age and Gender Regardless the subtype of arthritis, a younger age at diagnosis is associated with an increased risk of secondary uveitis [13]. Data reported in the literature highlighted a difference by gender, females being affected more than males, especially considering children under 7 years of age [14]. However, recent clinical trials suggested that these results might be biased by the higher prevalence of JIA with positive ANA titer among young female patients compared to the male counterpart [15].

Laboratory Markers Positive ANA titer is considered a risk factor as well, since 65 90% of patient with JIA-associated arthritis present incremented ANA levels. Conversely, no correlation with RF has been acknowledged.

Genetic Factors Hereditary factors are possibly involved into uveitis pathogenesis. Familial cases of uveitis have been reported in the literature and a high concordance of disease has been evidenced among identical twins [16,17]. Genetic predisposition conceivably implicates human leukocyte antigen (HLA) along with genes involved in inflammatory pathways. Presence of HLA DR5 or HLA DR 15 has been detected in patients affected by oligoarthritis complicated with uveitis, whereas allele HLA DR1 seems to be protective against ocular inflammation [18 20]. Moreover, enthesitis-related arthritis HLA B27-positive carries a significant risk of developing acute uveitis. Polymorphisms in gene regions coding for inflammatory cytokines or their receptors may contribute to uveitis pathogenesis as well; tumor necrosis factor (TNF), interleukin 1 (IL-1), or interleukin 6 (IL-6) have been advocated as possible mediators [19,21]. This evidence is also supported by the favorable response documented after biologic therapies targeted at specific blockage of cytokines pathway [22].

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DIAGNOSIS The diagnosis of uveitis requires complete ocular evaluation with slit-lamp examination [23]. JIA-associated uveitis typically presents a nongranulomatous bilateral involvement with chronic course. The anterior chamber is primarily affected, isolated or in the context of panuveitis, whereas posterior involvement alone is less common. Patients affected by Behc¸et’s disease may develop iridocyclitis or severe vasculitis leading to persisting vitritis and periphlebitis. Retinitis, retinal hemorrhages, optic nerve edema, and cystoid macular edema may be seen as well. In the case of granulomatous chronic uveitis, sarcoidosis and infectious diseases (Mycobacterium tuberculosis, Toxoplasma gondii, Toxacara canis) should be considered. Slit-lamp examination evidences mutton-fat keratic precipitates, snowball, and snow banking of the pars plana region with inflammatory exudates. Posterior segment involvement is common (choroidal and retinal granuloma, retinochoroiditis, neuroretinitis, papillitis). Etiological diagnosis is investigated through the collection of clinical history, complete physical examination, and proper laboratory workup. Systemic infections, autoimmune diseases, and tumoral conditions should be considered. Considering patients affected by JIA, according to ILAR, an ophthalmologic evaluation should be performed at the time of diagnosis and periodically repeated regardless of the absence of symptoms. The frequency of ocular examination is defined on the basis of the subtype of arthritis, the age at onset, and the presence of ANA (Table 6.2).

COMPLICATIONS Compared to adults, childhood uveitis is characterized by poor prognosis and higher risk of secondary complications, with considerable socioeconomic burden. Nowadays, uveitis represents the third leading cause of blindness in developed countries. Among children suffering from JIA, visual complications are reported in up to 80% of patients after 3 years and in almost 100% of patients after 20 years of disease. They develop as a consequence of persistent or recurrent ocular inflammation, but also as result of chronic steroid treatment [24 27]. The most common complications include cataract (19 81% of patients), glaucoma (8 38%), band-shaped keratopathy (7 10%), synechiae (8 75%), cystoid macular edema (8 42%), ocular hypotony (19%), retinal detachment, retinal ischemia, and optic atrophy [28]. Up to 30% of patients show reduced visual acuity and up to 10% develop blindness. From 28% to 70% of affected children may require surgical therapy [26]. The final visual outcome is influenced by negative prognostic factors as the severity of illness, posterior ocular involvement, presence of

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TABLE 6.2 Suggested Screening Intervals for Uveitis in Patients with Juvenile Idiopathic Arthritis as Classified by International League of Associations for Rheumatology Criteria Juvenile Idiopathic Arthritis Subtype

Antinuclear Antibody

Age at Juvenile Idiopathic Arthritis Onset (Years)

Juvenile Idiopathic Arthritis Duration (Years)

Recommended Screening Intervals (Months)

OA, RF PA, PsA, AA

Positive

#6

#4

3

OA, RF PA, PsA, AA

Positive

#6

.4

6

OA, RF PA, PsA, AA

Positive

#6

$7

12

OA, RF PA, PsA, AA

Positive

.6

#2

6

OA, RF PA, PsA, AA

Positive

.6

.2

12

OA, RF PA, PsA, AA

Negative

#6

#4

6

OA, RF PA, PsA, AA

Negative

#6

.4

12

OA, RF PA, PsA, AA

Negative

.6

NA

12

ERA

NA

NA

NA

12

RF+PA, SyA

NA

NA

NA

12

OA, oligoarthritis; RF PA, polyarthritis (RF-negative); RF+PA, polyarthritis (RF-positive); PsA, psoriatic arthritis; ERA, enthesitis-related arthritis; SyA, systemic arthritis; AA, other arthritis. NA, not applicable.

complications at the diagnosis, long duration of the disease, younger age at the onset, and delayed reference to a specialized center.

TREATMENT Targeted antimicrobial treatment is necessary for infectious uveitis. Treatment for noninfectious uveitis is based on a step-by-step approach, in order to control local inflammation, achieve a corticosteroid-sparing effect,

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and reduce the risk of visual complications [29,30]. Local steroid therapy associated with mydriatics is proposed for mild-to-moderate conditions, especially in the case of anterior involvement. Severe ocular inflammation may instead require oral or intravenous systemic steroid treatment. In corticosteroid-resistant and corticosteroid-dependent cases systemic immunomodulatory agents should be considered. They comprise both immunosuppressive agents (methotrexate (MTX), azathioprine (AZA), mycophenolate mofetil (MMF), cyclosporine (Cy A)) and biologic response modifier. MTX is considered the first-choice therapy since it is effective in inducing and maintaining ocular remission in up to 73% of patients, even if the clinical response requires 4 8 weeks to be elicited. For patients intolerant of or nonresponders to MTX, biologic therapies represent a valid alternative option. Biologics are genetically engineered proteins aimed at inhibition of specific components of the immune system (cytokines) responsible for inducing and maintaining inflammation. The main adverse events include potential allergic reaction and increased risk of reactivation of latent infections. Successful anti-TNF-α therapies have been reported for uveitis associated with JIA, Behc¸et’s disease, inflammatory bowel diseases, sarcoidosis, as well as for idiopathic uveitis. Infliximab and adalimumab demonstrated similar efficacy and tolerance during induction phase, whereas adalimumab seems to be superior to infliximab for long-term maintenance therapy. A subset of patients fail to respond to TNF-α blockers or is unable to tolerate these therapies and may therefore benefit from switching to another drug. Overall, about 25% of children with autoimmune chronic uveitis who received adalimumab and infliximab do not respond to these treatments. Preliminary evidence suggests the promising role of non anti-TNF-α, such as abatacept, rituximab, tocilizumab, golimumab, canakinumab, gevokizumab, and alemtuzumab, for severe sight-threatening refractory cases. Given the high cost and the lack of long-term safety data, the experience with these agents is still limited to few cases managed in highly specialized centers. Suggested therapeutic pathway for noninfectious chronic uveitis is reported in Fig. 6.1.

CORTICOSTEROIDS Steroid therapy represents the first choice treatment for the acute inflammatory phase [30]. Mild anterior uveitis may benefit by exclusive topic application, whereas systemic therapy is required in posterior/panuveal involvement or in complicated cases. Prolonged corticosteroid administration may induce several side effects, such as moon face (facies cushingoide), hypertension, hyperglycemia, osteoporosis, dyspeptic disorders, and failure to thrive. Collateral effects have been demonstrated also after topic therapy, especially cataracts and glaucoma [29,30]. These conditions are considered dose-dependent since an

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Systemic steroid treatment

Topic costicosteroid (CS)

±

(Prednisolone acetate 1%)

Prednisone (po): 2 mg/kg per day Methylprednisolone (iv): bolus 30 mg/kg for 3 continuous or alternate days

Alternately

Methotrexate 10–15 mg/m2, up to 20–25 mg/m2 once a week

Azathioprine Mycophenolate mofetil Cyclosporine

Alternatively In case of relapse add in acute phase

Adalimumab 24 mg/m2 sc every 2 weeks Infliximab 3–6 mg/kg iv every 4–6 weeks

Abatacept Rituximab Tocilizumab Golimumab, canakinumab, gevokizumab, Alemtuzumab

FIGURE 6.1 Proposed therapeutic algorithm for noninfectious uveitis.

increased risk of secondary cataract has been associated to prolonged topic corticosteroid independently from the activity of the underlying disease [31]. All things considered, corticosteroid administration should be time-limited and aimed at achieving ocular remission. Local therapy is based primarily on prednisolone or dexamethasone at a maximum dosage of 3 drops/day [29,32]. Oral prednisone (0.5 2 mg/kg per day) is considered in mild-to-severe conditions or in case of relapse. Patients presenting with severe panuveitis, ocular complication, or optic nerve involvement necessitate intravenous methylprednisolone at 30 mg/kg per dose (max. 1 g) in 3 5 hours, repeatable during the following days until a maximum of 3 infusions per week. Once ocular remission is achieved, the patient receives oral maintenance therapy with subsequent tapering (prednisone 0.5 1 mg/kg per day).

IMMUNOSUPPRESSANT AGENTS Methotrexate MTX is a competitive inhibitor of dihydrofolate reductase, the enzyme implied in the conversion of dihydrofolate to the active tetrahydrofolate. The blockage of this pathway leads to the inhibition of RNA transcription and

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DNA synthesis, especially in B and T lymphocytes. MTX represents the first choice among systemic long-term therapies for uveitis [32]. The recommended dosage is 10 15 mg/m2 once a week (orally or subcutaneously) and the therapeutic effect is generally achieved 6 10 weeks later [29]. Prospective trials concerning MTX efficacy have not been reported in the literature, whereas retrospective studies highlight a percentage of remission between 84% and 91% of the treated cases [29,32]. In a recent metaanalysis MTX induced a reduction of ocular inflammation in up to 73% of children affected by autoimmune chronic uveitis refractory to steroid therapy [33]. Preliminary evidence suggested its role in the prevention of uveitis development among children affected by JIA. In particular, a cohort of children affected by JIA receiving MTX developed uveitis less frequently than the group receiving different therapies. Further investigations are required in order to analyze the possible application in patients affected by oligoarticular arthritis. If the preventive purpose is confirmed, MTX could be considered in long-term treatment for both ocular and articular involvement [34]. The main collateral events due to MTX administration involve gastrointestinal problems (nausea, vomiting, stomachache, diarrhea,) and increased transaminase levels. The association of folic acid 24 hours after MTX administration and the preference for subcutaneous injections are recommended in order to reduce the incidence of nausea. Moreover, periodical clinical and laboratory follow-up are requested (every 4 weeks initially, then every 3 months) [29].

Other Immunosuppressant Therapies Other than MTX, AZA, MMF, and Cy A can be contemplated as secondchoice systemic immunosuppressant therapies. AZA is recommended at a dosage of 1 2 mg/kg per day orally, eventually associated with steroid therapy. MMF is administered at 600 mg/m2 twice a day orally, but its efficacy in JIA-related arthritis is still limited. Cy A is potentially useful as complementary therapy associated with other immunosuppressants. It is administered orally at 2.5 5 mg/kg per day. With regard to tacrolimus, a calcineurin inhibitor, and sirolimus, inhibitor of T-cell activation, no data concerning childhood have been reported in the literature [29].

BIOLOGIC RESPONSE MODIFIERS Tumor Necrosis Factor Alpha Inhibitors Inflammatory process is mediated by several cytokines released by activated T lymphocytes, monocytes, and macrophages. Proinflammatory cytokines play a pivotal role in the pathogenesis of autoimmune conditions, including uveitis. Increased TNF-α levels have been reported in humor aqueous of

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affected patients and TNF-α inhibitors demonstrated a good efficacy in both inducing and maintaining ocular remission [35]. To date, the therapies approved for pediatric population comprise infliximab, etanercept, and adalimumab. Besides presenting a similar mechanism of action, these molecules showed different efficacy in uveitis treatment. A recent metaanalysis highlighted a superior efficacy of adalimumab and infliximab if compared to etanercept, which is not routinely recommended [30].

Infliximab Infliximab (IFX) is a chimeric monoclonal antibody targeting TNF-α. It is administered intravenously at a dosage of 5 10 mg/kg at weeks 0, 2, and 6 (induction phase), then every 4 8 weeks (maintenance phase). Pediatric patients may require higher dose by weight or more frequent infusion compared with adults. IFX represents an efficient alternative for short-term treatment of uveitis [36]. A retrospective clinical trial documented a significant resolution of ocular inflammation in 16 patients undergoing MTX and IFX therapies, evaluated at 3, 6, 9, and 12 months [37]. However, efficacy in long-term treatment seems to be limited, with subsequent possibility of ocular relapse [38,39]. Moreover, most of the patients enrolled in clinical trials were treated with IFX associated with MTX, preventing us from establishing the individual role of the two drugs. Etanercept Etanercept is a fusion protein of IgG1 Fc domain and TNF-α receptor, targeting free TNF-α and TNF-β. Recommended dosage is 0.4 mg/kg twice a week (subcutaneous route), max 50 mg per week. Favorable outcomes have been reported for articular involvement, whereas the effectiveness in ocular inflammation seems to be limited. Infliximab superiority on etanercept was reported in adults affected by JIA-related uveitis [40]. A randomized controlled trial involving pediatric patients did not show significant difference between the administration of etanercept and placebo. All things considered, etanercept is not currently recommended as first-choice systemic biologic therapy for uveitis [41]. Adalimumab Adalimumab is a fully humanized monoclonal antibody against TNF-α. The route of administration is subcutaneous injection at 24 mg/m2 once a week. Several clinical trials suggested its efficacy in the treatment of uveitis [42,43]. We reported the superiority of adalimumab compared to infliximab in maintaining long-term ocular remission among 33 children affected by chronic uveitis [44]. This evidence has been confirmed by a multicenter study involving 108 children affected by JIA-related arthritis. Both infliximab and adalimumab provided good safety and efficacy data, however

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adalimumab is more likely to achieve long-term remission, especially if administered as first TNF-α inhibitor [45,46]. However, a subset of patients who fail to respond or are unable to tolerate a specific TNF-α blocker may benefit from switching to another anti-TNF drug. A recent metaanalysis provides evidence that, when a previous course of anti-TNF-α failed to induce/ maintain remission in chronic uveitis of children, switching to a new antiTNF-α treatment (adalimumab and infliximab) has a favorable effect in the improvement of intraocular inflammation: 0.75 (95% CI 0.51 100) [47].

Non anti-TNF-Alpha Biologic Activity Modifiers Overall, about 25% of children with autoimmune chronic uveitis who received adalimumab and infliximab do not respond to these treatments [30], and among these an additional 25% do not respond properly to a second course of a different anti-TNF-α treatment [47]. In this clinical setting, the availability of several different molecules, mostly off-label, poses the clinical question if it can be useful and safe to administer another class of biologic drugs, such as abatacept or rituximab, for patients with refractory autoimmune uveitis.

Abatacept Abatacept is a soluble recombinant protein obtained by the fusion of extracellular domain of cytotoxic T lymphocyte antigen 4 with IgG1 Fc domain. It selectively binds to an antigen-presenting cell, inhibiting the costimulation signal necessary for T-cell activation. Recommended administration route is intravenous injection at 10 mg/kg at weeks 0, 2, and then every 4 weeks. Data concerning the use of abatacept for the treatment of uveitis are still limited. Few case series reported a reduction in ocular inflammation, frequency of ocular relapse, and need of steroid treatment among patients affected by JIA-related uveitis undergoing abatacept therapy. No further ocular complications nor worsening of previous complications was reported [48 51]. However, a recent clinical trial enrolling children affected by severe, longstanding, refractory uveitis did not demonstrate sustained response after abatacept therapy, and 3 out of 21 patients developed new ocular complication under treatment [52]. We reported the long-term efficacy of abatacept in a case series of three children with chronic idiopathic uveitis, multirefractory and resistant to other immunosuppressive and/or biologic response modifier therapies [53]. Rituximab Rituximab is a monoclonal antibody targeting B lymphocyte antigen CD20, currently approved for the treatment of lymphoma, autoimmune conditions, and ocular inflammatory diseases. Preliminary results suggest its potential

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role for the treatment of JIA-related uveitis refractory to other therapies [54]. In a retrospective multicenter trial enrolling 10 patients affected by severe refractory uveitis, rituximab induced ocular remission in 7 out of 10 patients, with better results obtained in ANA-positive and HLA B27 negative oligoarthritis. Further investigation is required in order to confirm efficacy and safety data [55].

Tocilizumab Tocilizumab is a humanized antibody against IL-6, a proinflammatory cytokine involved in proliferative and differentiation process of T and B lymphocytes. Tocilizumab administration at 8 mg/kg monthly (intravenous route) happened to be effective in inducing ocular remission among a cohort of patients affected by severe, refractory, JIA-related uveitis [56]. Few case series proposed Tocilizumab as a safe and promising therapy for adults affected by severe and refractory noninfectious uveitis [57], whereas data concerning efficacy and safety in pediatric patients needs still to be confirmed. Anti-interleukin-1 treatments Very few cases are currently available in the literature regarding the use of this drug approach in treating chronic autoimmune uveitis in childhood. One child with Blau syndrome received anakinra at 3 mg/kg daily in combination with MMF [58]; additionally two—one with Blau syndrome [59] and one with juvenile Behc¸et’s disease [60]—received canakinumab in combination with MTX. We recently provided data in judging the efficacy and safety of non anti-TNF-α biologic activity modifiers in autoimmune chronic uveitis in different categories with refractory and long-standing disease: in this clinical setting of rescue therapy a successful treatment outcome can be achieved in about two-thirds of cases, thus suggesting a possible efficacy of these antiinflammatory strategies. At the same time, beside specific intolerances or contraindications, the scarce available data do not currently support a different escalating strategy, bypassing disease-modifying antirheumatic drugs and/or anti-TNF drugs [61].

REFERENCES [1] Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology 2004;111:491 500. [2] Acharya NR, Tham VM, Esterberg E, et al. Incidence and prevalence of uveitis: results from the Pacific Ocular Inflammation Study. JAMA Ophthalmol 2013;131:1405 12. [3] Chams H, Rostami M, Mohammadi SF, Ohno S. Epidemiology and prevalence of uveitis: review of literature. Iran J Ophthalmol 2009;21:4 16.

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[4] Llorenc¸ V, Mesquida M, Sainz de la Maza M, et al. Epidemiology of uveitis in a Western urban multiethnic population. The challenge of globalization. Acta Ophthalmol 2015;1 7. [5] Miserocchi E, Fogliato G, Modorati G, Bandello F. Review on the worldwide epidemiology of uveitis. Eur J Ophtalmol 2013;23:705 17. [6] Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data: results of the First International Workshop. Am J Ophthalmol 2005;140:509 16. [7] Petty RE, Rosenbaum JT. Uveitis in juvenile idiopatic arthritis. In: Cassidy J, editor. Textbook of pediatric rheumatology, 6th ed; 2011. p. 305 14. [8] Tugal-Tutkun I. Pediatric uveitis. J Ophtal Vis Res 2011;6:259 69. [9] Grange LK, Kouchouk A, Dalal MD, Vitale S, et al. Neoplastic masquerade syndromes among uveitis patients. Am J Ophthalmol 2014;157:526 31. [10] Ohm J. Bandfoermige Hornhauttrueburg bei einem neunjaehring Maedchen und ihre Behandlung mit subcinjunctivalen Jodkaliumeinspritzungen. Klin Monatsbl Augenheil 1910;48:243 6. [11] Cassidy JT, Sullivan DB, Petty RE. Clinical patterns of chronic iridocyclitis in children with juvenile rheumatoid arthritis. Arthritis Rheum 1977;20:224 7. [12] Petty ER, Smith JR, Rosenbaum JT. Arthritis and uveitis in children: a pediatric rheumatologicy perspective. Am J Ophthalmol 2003;135:879 84. [13] Cassidy J, Kivlin J, Lindsley C, Nocton J. Ophthalmologic examinations in children with juvenile rheumatoid arthritis. Pediatrics 2006;117:1843 5. [14] Qian Y, Acharya NR. Juvenile idiopathic arthritis associated uveitis. Curr Opin Ophthalmol 2010;21:468 72. [15] Saurenmann RK, Levin AV, Feldman BM, et al. Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term followup study. Arthritis Rheum 2007;56:647 57. [16] Thomson W, Silman AJ. Juvenile idiopathic arthritis. In: Silman AJ, Hochberg MC, editors. Epidemiology of rheumatic disease. 2nd ed. Oxford: Oxford University Press; 2001. p. 72 84. [17] Glass DN, Giannini HE. Juvenile rheumatoid arthritis as a complex genetic trait. Arthritis Rheum 1999;42:2261 8. [18] Malagon C, Van Kerckhove C, Giannini EH, et al. The iridocyclitis of early onset pauciarticular juvenile rheumatoid arthritis: outcome in immunogenetically characterized patients. J Rheumathol 1993;19:160 3. [19] Du L, Kijlstra A, Yang P. Immune response genes in uveitis. Ocul Immunol Inflamm 2009;17:249 56. [20] Kotaniemi K, Savolainen A, Karma A. Recent advances in uveitis of juvenile idiopathic arthritis. Surv Ophthalmol 2003;48:489 502. [21] Xiang Q, Chen L, Fang J, et al. TNF receptor-associated factor 5 gene confers genetic predisposition to acute anterior uveitis and pediatric uveitis. Arthritis Res Ther 2013;15: R113. [22] Horai R, Crispi RR. Cytokines in autoimmune uveitis. J Interferon Cytokine Res 2011;31:733 44. [23] Majumder PD, Biswas J. Pediatric uveitis: an update. Oman J Ophthalmol 2013;6:140 50. [24] Anesi SA, Foster CS. Importance of recognizing and preventing blindness from juvenile idiopathic arthritis-associated uveitis. Arthritis Care Res 2012;64:653 7.

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[25] Rothova A, Suttorp-van Schulten MS, Frits Tretters W, Kijilstra A. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Opthalmol 1996;80:332 6. [26] Rosenberg K, Feuer WJ, Davis JL. Ocular complications of pediatric uveitis. Opthalmology 2004;111:2299 306. [27] Ozdal PC, Vianna RN, Deschenes J. Visual outcome of juvenile rheumatoid arthritisassociated uveitis in adults. Ocul Immunol Inflamm 2005;13:33 8. [28] Heiligenhaus A, Niewerth M, Ganser G, Heinz C, Minden K, German Uveitis in Childhood Study Group. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology 2007;46:1015 19. [29] Simonini G, Cantarini L, Bresci C, Lorusso M, Galeazzi M, Cimaz R. Current therapeutic approaches to autoimmune chronic uveitis in children. Autoimmun Rev 2010;9:674 83. [30] Simonini G, Druce K, Cimaz R, Macfarlane GJ, Jones GT. Current evidence of anti-tumor necrosis factor α treatment efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach of individual drugs. Arthritis Care Res 2014;66:1073 84. [31] Thorne JE, Woreta FA, Dunn JP, Jabs DA. Risk of cataract development among children with juvenile idiophatic arthritis-related uveitis treated with topical corticosteroids. Ophtalmology 2010;117:1436 41. [32] Rabinovich CE. Treatment of juvenile idiopathic arthritis-associated uveitis: challenges and update. Curr Opin Rheumatol 2011;23:432 6. [33] Simonini G, Paudyal P, Jones GT, Cimaz R, Macfarlane GJ. Current evidence of methotrexate efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach. Rheumatology (Oxford) 2012;52:825 31. [34] Papadopoulou C, Kostik M, Bohm M, et al. Methotrexate therapy may prevent the onset of uveitis in juvenile idiopatic arthritis. J Pediatr 2013;163:879 84. [35] Santos Lacomba M, Marcos Martin C, Gallardo Galera JM, et al. Aqueous humor and seru tumor necrosis factor-alpha in clinical uveitis. Ophthal Res 2001;33:251 5. [36] Holzinger D, Frosch M. New treatment approaches in juvenile idiopathic arthritis. Int J Adv Rheumatol 2009;7:1 7. [37] Ardoin SP, Kredich D, Rabinovich E, Schanberg LE, Jaffe GJ. Infliximab to treat chronic chronicnoninfectious uveitis in children: retrospective case series with long-term follow up. Am J Ophtalmol 2007;144:844 9. [38] Simonini G, Zannin ME, Caputo R, et al. Loss of efficacy during long-term infliximab therapy for sight-threatening childhood uveitis. Rheumatology (Oxford) 2008;47:1510 14. [39] Tugal-Tutkun I, Ayranci O, Kasapcopur O, Kir N. Retrospective analysis of children with uveitis treated with infliximab. J AAPOS 2008;12:611 13. [40] Tynjala P, Lindahl, Honkanen V, Lahdenne P, Kotaniemi K. Infliximab and etanercept in the treatment of chronic uveitis associated with refractory juvenile idiopathic arthritis. Ann Rheum Dis 2007;66:548 50. [41] Smith JA, Thompson DJ, Whitcup SM, et al. A randomized, placebo-controlled, doublemasked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum 2005;53:18 23. [42] Biester S, Deuter C, Michels H, et al. Adalimumab in the therapy of uveitis in children. Br J Ophtalmol 2007;91:319 24. [43] Tynjala P, Kotaniemi K, Lindahl P, et al. Adalimumab in juvenile idiopathic arthritisassociated chronic anterior uveitis. Reumatology (Oxford) 2008;47:339 44.

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[44] Simonini G, Taddio A, Cattalini M, et al. Prevention of flare recurrences in childhoodrefractory chronic uveitis: an open-label comparative study of adalimumab versus infliximab. Arthritis Care Res (Hoboken) 2011;63:612 18. [45] Zannin ME, Birolo C, Gerloni VM, et al. Safety and effecacy of infliximab and adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1 year follow up data from the Italian Registry. J Rheumatol 2013;40:74 9. [46] Simonini G, Taddio A, Cattalini M, et al. Superior efficacy of adalimumab in treating childhood refractory chronic uveitis when used as first biologic modifier drug: adalimumab as starting anti-TNF-α therapy in childhood chronic uveitis. Pediatr Rheumatol Online J 2013;15:11 16. [47] Simonini G, Druce K, Cimaz R, Macfarlane GJ, Jones GT. Does switching anti-TNFα biologic agents represent an effective option in childhood chronic uveitis: the evidence from a systematic review and meta-analysis approach. Semin Arthritis Rheum 2014;44:39 46. [48] Zulian F, Balzarin M, Falcini F, et al. Abatacept for severe anti-tumor necrosis factor alpha refractory juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2010;62:821 5. [49] Elhai M, Deslandre CJ, Kahan A. Abatacept for refractory juvenile idiopathic arthritisassociated uveitis: two new cases. Comment on the article by Zulian et al. Arthritis Care Res 2011;63(2):307 10. [50] Angeles-Han S, Flynn T, Lehman T. Abatacept for refractory juvenile idiopathic arthritisassociated uveitis—a case report. J Rheumatol 2008;35:1897 8. [51] Kenawy N, Cleary G, Mewar D, Beare N, Chandna A, Pearce I. Abatacept: a potential therapy in refractory cases of juvenile idiopathic arthritis-associated uveitis. Graefes Arch Clin Exp Ophthalmol 2011;249:297 300. [52] Tappeiner C, Miserocchi E, Bodaghi B, et al. Abatacept in the treatment of severe, longstanding, and refractory uveitis associated with juvenile idiopathic arthritis. J Rheumatol 2015;42:706 11. [53] Marrani E, Paganelli V, de Libero C, Cimaz R, Simonini G. Long-term efficacy of abatacept in pediatric patients with idiopathic uveitis: a case series. Graefe Arch Clin Exp Ophthalmol 2015;253:1813 16. [54] Miserocchi E, Pontikaki I, Modorati G, Gattinara M, Meroni PL, Gerloni V. Anti-CD 20 monoclonal antibody (rituximab) treatment for inflammatory ocular diseases. Autoimmun Rev 2011;11:35 9. [55] Heiligenhaus A, Miserocchi E, Einz C, Gerloni V, Kotaniemi K. Treatment of severe uveitis associated with juvenile idiopathic arthritis with anti-CD20 monoclonal antibody (rituximab). Rheumatology (Oxford) 2011;50:1390 4. [56] Tappeiner C, Heinz C, Ganser G, Heiligenhaus A. Is Tocilizumab an effective option for treatment of refractory uveitis associated with juvenile idiopathic arthritis? J Rheumatol 2012;39:1294 5. [57] Calvo-Rı´o V, de la Hera D, Beltra´n-Catala´n E, et al. Tocilizumab in uveitis refractory to other biologic drugs: a study of 3 cases and a literature review. Clin Exp Rheumatol 2014;32:S54 7. [58] Aro´stegui JI, Arnal C, Merino R, et al. NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheum 2007;56:3805 13.

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[59] Simonini G, Xu Z, Caputo R, et al. Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis. Arthritis Rheum 2013;65:513 18. [60] Ugurlu S, Ucar D, Seyahi E, Hatemi G, Yurdakul S. Canakinumab in a patient with juvenile Behc¸et’s syndrome with refractory eye disease. Ann Rheum Dis 2012;71:1589 91. [61] Simonini G, Cimaz R, Jones GT, MacFarlane GJ. Non anti TNF biologic modifier drugs in non-infectious refractory chronic uveitis: the current evidence from a systematic review. Semin Arthritis Rheum 2015;45:238 50.

Chapter 7

Amplified Musculoskeletal Pain Syndromes D.D. Sherry The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

INTRODUCTION One of the most common diagnoses in new patients in a pediatric rheumatology clinic is that of amplified pain. These children have severe pain yet an overt primary cause for the pain cannot be found. The pain is disproportionate in both severity and disability. Amplified pain can be diffuse, localized, intermittent, or a combination of these [1 3]. All pain is subjective and does not require tissue damage. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage” [4]. Therefore, it is prudent to take self-reported pain, from a competent individual, at face value [5]. Short-term malingering is probably common but long-term malingering about pain is very rare. Nevertheless, it is paramount in the doctor patient relationship to believe the child and validate the pain experience.

NOMENCLATURE The most commonly identified forms of amplified pain are complex regional pain syndrome (CRPS) and fibromyalgia. These terms may be useful to classify a relatively uniform population for study; in the clinic these terms are inadequate because children may have features of several, seemingly distinct forms of amplified pain [6]. For example, CRPS, which is characterized as localized with overt autonomic signs such as cyanosis, coolness, or increased perspiration, may lose these features and the pain becomes widespread fulfilling the criteria for fibromyalgia. Likewise there are children with CRPS

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00007-4 © 2016 Elsevier B.V. All rights reserved.

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in one limb and pain elsewhere, either peripheral or central, without autonomic changes. The term amplified musculoskeletal pain is descriptive, does not presume an etiology, and conjures up an image of an amplifier taking in a soft sound and making it quite loud, thus giving validity to the degree of pain these children experience [7]. Regarding the classification schemes used to study children with amplified pain there are several, some of which have subsets within it. Diffuse idiopathic musculoskeletal pain includes those with fibromyalgia and localized idiopathic musculoskeletal pain includes those with CRPS [1]. It is important to know the criteria used when assessing any study and reporting outcomes, therefore, since CRPS and fibromyalgia are the most reported forms, these terms will be used as appropriate. Likewise, the vast majority of pediatric CRPS literature is on CRPS type I, so all references about CRPS is type I. Type II usually implies nerve damage and rarely is a diagnostic dilemma; it is usually not treated by rheumatologists.

HISTORY The study of musculoskeletal pain is a recent phenomenon. It was in 1951 that Nash and Apley’s study on pediatric growing pains not due to arthritis appeared and CRPS was first reported in a child in 1971 [8,9]. Interestingly, both of these reports commented on the psychological aspects of these children. The first report on fibromyalgia in children was in 1985 and many still use the criteria proposed then [10]. Although not called amplified pain, the report by Sherry et al. in 1991 describes many of the children who fall between fibromyalgia and CRPS [11].

CRITERIA The criteria for the amplified pain syndromes are summarized in Table 7.1. CRPS is more overt and easily recognized due to the autonomic signs [4,12]. In 1990 the American College of Rheumatology (ACR) published fibromyalgia criteria in 1990 and revised it in 2010, eliminating the need to test for painful trigger points [4,12 14]. In 1985 Yunus and Masi published criteria for childhood fibromyalgia although they have not had rigorous validation [10]. Malleson has proposed the term idiopathic musculoskeletal pain but this term is rarely used [1].

INCIDENCE AND PREVALENCE Musculoskeletal pain in school children is common, with 20% reporting back pain, 16% reporting limb pain, and 40% reporting chronic and recurrent musculoskeletal pain [15 18]. Widespread pain and fibromyalgia are

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TABLE 7.1 Criteria for Different Forms of Amplified Musculoskeletal Pain Complex Regional Pain Syndrome, Type I [4] Criteria 2 4 must be satisfied. 1. The presence of an initiating noxious event, or a cause of immobilization. 2. Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event. 3. Evidence or history of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain. 4. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction. Complex Regional Pain Syndrome, Type II [4] All three criteria must be satisfied 1. The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve. 2. Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of the pain. 3. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction. Budapest Clinical Diagnostic Criteria for Complex Regional Pain [12] All four statements must be met: 1. The patient has continuing pain that is disproportionate to any inciting event. 2. The patient has at least one sign in two or more of these categories: a. Sensory: hyperalgesia or allodynia b. Vasomotor: asymmetric temperature or skin color c. Sudomotor/edema: edema or asymmetric sweating d. Motor/trophic: decreased range of motion, motor dysfunction, or trophic changes (hair, skin, nail). 3. The patient reports at least one symptom in three or more of these categories: a. Sensory: reports hyperesthesia or allodynia b. Vasomotor: reports asymmetric temperature or skin color c. Motor/trophic: reports decreased range of motion, motor dysfunction, or trophic changes. 4. No other diagnosis can better explain the signs and symptoms. 1990 American College of Rheumatology Criteria for Fibromyalgia [14] Both criteria must be satisfied: 1. Widespread pain (bilateral, and above and below the waist and axial pain) present for at least 3 months. 2. Pain (not tenderness) upon digital palpation with 4 kg of pressure on 11 of the following 18 sites: a. Occiput: at insertion of suboccipital muscle b. Low cervical: at anterior aspect of the intertransverse spaces of C5 C7 c. Trapezius: at the midpoint of the upper border d. Second rib: just lateral to the second costochondral junction at the upper rib border e. Scapula: the medial border just above the spine of the scapula (Continued )

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TABLE 7.1 (Continued) f. g. h. i.

Lateral epicondyle: 2 cm distal to the epicondyle Gluteal: in the upper outer quadrant of the buttocks Greater trochanter: 1 cm posterior to the trochanteric prominence Knees: at the medial fat pad 1 cm proximal to the joint mortise.

2010 American College of Rheumatology Criteria for fibromyalgia [13] All three conditions must be satisfied: 1. Absence of a disorder to explain the pain. 2. Symptoms present for 3 months. 3. One of the following: a. widespread pain index $ 7 and symptom severity score $ 5 b. widespread pain index 3 6 and symptom severity score $ 9. Widespread pain equals the number of areas of pain in the last week (0 19) Areas include: shoulder girdle, upper arm, lower arm, buttocks/trochanter, upper leg, lower leg, jaw (2 points if bilateral), and 1 point each for upper back, lower back, chest, abdomen, neck. Symptom severity score (0 12) Fatigue, waking unrefreshed, cognitive symptoms scored 0 3 each (0 5 no problem, 1 5 mild or intermittent, 2 5 moderate or considerable, 3 5 severe, continuous) Plus considering a host of somatic symptoms rated as 0 5 no symptoms, 1 5 few symptoms, 2 5 moderate number of symptoms, 3 5 great deal of symptoms (somatic symptoms include muscle pain, irritable bowel syndrome, tiredness, thinking problems, muscle weakness, headache, abdominal pain, numbness and tingling, dizziness, insomnia, depression, constipation, upper abdominal pain, nausea, nervousness, chest pain, blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud phenomenon, hives, tenderness, vomiting, heartburn, oral ulcers, dysgeusia, seizures, xerophthalmia, shortness of breath, loss of appetite, rash, sensitivity, hearing difficulties, easy bruising, hair loss, urinary frequency, dysuria, bladder spasms). Yunus and Masi Criteria for Childhood Fibromyalgia [10] All four major and three minor, OR the first three major, four painful sites, and five minor need to satisfied Major: 1. Generalized musculoskeletal aching at three or more sites for 3 or more months 2. Absence of underlying condition or cause 3. Normal laboratory tests 4. Five or more typical tender points (see sites under 1990 ACR criteria, earlier). Minor: 1. Chronic anxiety or tension 2. Fatigue 3. Poor sleep 4. Chronic headaches 5. Irritable bowel syndrome 6. Subjective soft tissue swelling 7. Numbness (Continued )

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TABLE 7.1 (Continued) 8. Pain modulation by physical activities 9. Pain modulation by weather factors 10. Pain modulation by anxiety or stress. Diffuse Idiopathic Pain [1] Both criteria must be satisfied: 1. Generalized musculoskeletal aching at three or more sites for 3 or more months. 2. Exclusion of disease that could reasonably explain the symptoms. Localized Idiopathic Pain [1] All three criteria must be satisfied: 1. Pain localized to one limb persisting a. 1 week with medically directed treatment, or b. 1 month without medically directed treatment. 2. Absence of prior trauma that could reasonably explain the symptoms. 3. Exclusion of diseases that could reasonably explain the symptoms.

estimated to be present in 2 6% of children [19 22]. The incidence of adult onset CRPS is estimated to be between 5 and 26 per 100,000 but no data has been reported for children [23,24]. There are no data estimating the incidence and prevalence of amplified pain in children but most pediatric rheumatology clinics see many more new patients with amplified pain than juvenile idiopathic arthritis, which has an incidence of about 8 per 100,000 [25 27].

AGE, SEX, AND RACE The vast majority of children with amplified pain are preadolescent to adolescent with the mean age between 12 and 14 years, and 80% are female [1,10,11,28,29]. Children as young as 2 years old have had CRPS and older teens may be underrepresented due to referral bias [30]. Being female was one of the predictors of widespread pain in one study; females more frequently have chronic pain regardless of location and the sex discrepancy increases with age [16,22]. There are no population-based studies of race in amplified pain but in areas with a high proportion of minorities, there is an overwhelming predominance of white patients [28,31,32]. There are no data comparing populations between developed nations to developing nations.

ETIOLOGY AND PATHOGENESIS There is no known cause of the amplified musculoskeletal pain syndromes. The onset has been related to injury, illness, psychological stress, hormones, and even genetics. The presentation in children differs from adults even in

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classic CRPS. In children CRPS is usually in the foot while in adults it is usually in the hand; technetium bone scintigraphy shows decreased rather than increased uptake in children, and children are much more successfully treated without medications but with physical and occupational therapy, which is also the case in childhood fibromyalgia [28,29,33,34]. Injury, usually a fracture or surgery, frequently precedes CRPS in adults whereas minor injury is more commonly reported in children, including immunization [35]. It may be that minor trauma localizes the site of amplified musculoskeletal pain and, for a host of other reasons, the pain becomes amplified. There is debate if hypermobility, which may cause microtrauma, is associated with amplified pain [36,37]. Illness, especially myocardial infarction, has been associated in adults with CRPS [38]. Children with a host of different illnesses including muscular dystrophy, new-onset diabetes, cerebral palsy, sickle cell anemia, juvenile idiopathic arthritis, systemic lupus erythematosus, and leukemia have developed amplified pain. Cause and effect is hard to establish and these illnesses also can lead to pain and stress. Sleep disorders were thought to be causative of fibromyalgia and both adults and children have abnormal polysomnography but treating the sleep disorder does not lessen symptoms [39 41]. Children who resolved their fibromyalgia as well as their sleep complaints had no change in their abnormal amount of α δ sleep [42]. From the other perspective, only 3 of 108 adults with a primary sleep disorder had fibromyalgia [43]. Psychological stress is a constant feature of the vast majority of reports of children with amplified musculoskeletal pain, although none are controlled studies [9,11,33,44 48]. School and individualizing from their family are unique stressors experienced by young people that are important in those with amplified pain [44,48,49]. Cause and effect of psychological stress is hard to establish and chronic pain is emotionally challenging. However, two studies from Finland indicate depression may predict children who later develop fibromyalgia or chronic pain [22,50]. It is important to realize that not all children with amplified pain are inappropriately stressed. The female preponderance is not understood. Hormonal treatments and sex hormone levels are not associated with fibromyalgia [51,52]. Pain thresholds differ between the sexes and girls have lower pain thresholds, which could play a role, as well as differences in coping and cultural expectations [53]. The role of ischemia in the production of pain has been postulated in CRPS and fibromyalgia. CRPS is related to increased sympathetic nervous system activity and alpha-adrenoceptor responsiveness [54 56]. In fibromyalgia, ischemic injury is seen on biopsy and contrast-enhanced ultrasound studies showed decreased blood flow [57]. However, this is dynamic, deconditioning increases sympathetic tone leading to ischemia, and it can be ameliorated by exercise [58].

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Children with CRPS had abnormal functional magnetic resonance imaging with activation in the basal ganglia and parietal lobe; however, these findings persisted after treatment when symptom-free [59]. This could lead to an increased risk of recurrence. Small fiber dysfunction in fibromyalgia and CRPS, manifest by decreased intraepidural nerve fiber density, has been recently shown, but it is also found in a variety of somatic and neurologic conditions [60]. This may be an epiphenomenon. Genetics may play an additional role in the onset of amplified pain. There are many families with multiple members with fibromyalgia and CRPS [61 63]. A gene has yet to be located but one small study found women with HLA-DR2 [15] were more resistant to treatment [64].

CLINICAL PRESENTATION Amplified pain is not a wastebasket diagnosis but, like all clinical diagnoses, is based on the presence and absence of salient features (Table 7.2). The history and physical examination are remarkably consistent between children with localized and diffuse amplified musculoskeletal pain syndromes. There are many children who develop amplified pain spontaneously but it is not uncommon for them to relate it to a recent or distant trauma. Regardless of medicine and other treatments, most are still getting worse when they present. Immobilization usually is associated with an exacerbation of pain. In adults, the presence of 5 out of 10 pain 1 week after being casted was predictive of developing CRPS [65]. The autonomic signs (cyanosis, coolness, edema, perspiration changes) may or may not be present and may be transient. Wilder et al. reported 70 children with CRPS: 86% had allodynia, 77% edema, 77% coolness, 73% cyanosis, and 31% hyperhidrosis [32]. Allodynia frequently TABLE 7.2 Common Patterns Seen in Amplified Pain 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Insufficient inciting event (minor trauma or illness) Increasing pain Increasing dysfunction Disproportionate pain Disproportionate dysfunction Lack of response to medicinal, physical, and other treatments Incongruent affect given the pain level La Belle indifference about the disability Typical personality (overly mature, perfectionistic, pleaser, accomplished) Multiple life changes Multiple psychological stressors Allodynia with a variable border Able to do things when asked even if previously were not able to.

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has a variable border and it, too, can be transient. Amplified pain can involve any part of the body and many children have several painful areas. Sometimes only a small area is painful (finger or nose). Most children have constant pain but it can be migratory or intermittent. The onset is usually gradual but some have a sudden and specific onset. Diffuse pain may be vague in location and character and occasionally is described as a discomfort rather than pain per se but is nonetheless affecting function. Most children will have an incongruent affect when reporting pain, smiling and seemingly not distressed when the pain is 6 out of 10 or even 10 out of 10. They often are unconcerned about the degree of disability and pain, la belle indifference. It is less common for them to have marked pain behaviors such as screaming and crying, which are upsetting to the family and health care providers. There also seem to be personality traits that are common, specifically, overly mature, accomplished in school or other activities, perfectionistic, and pleasers who meet other’s needs rather than their own [11,33,48]. Children with amplified pain commonly have a host of other somatic symptoms and pain symptoms so they frequently have several diagnoses including chronic daily headache and irritable bowel syndrome. Children with a head injury, sometimes a minor bump, exhibit symptoms that suggest concussion but they have prolonged symptoms that outlast any typical concussion and are resistant to treatment. Children with lightheadedness with standing, increased heart rates, and the feeling of cognitive dysfunction suggest the diagnosis of postural orthostatic tachycardia syndrome but rarely are their orthostatic heart rates over 45 and likewise are resistant to medical therapies [66]. Children who complain of inability to think and concentrate or learn almost always maintain their usual grades in school. These somatic symptoms seem to be remembered or amplified symptoms similar to the amplification of pain. Children with amplified pain are also prone to both motor and sensory conversion symptoms including blindness and other visual symptoms such as being unable to read, stiffness that is not true dystonia, shaking and pseudoseizures, memory loss, fainting, and swallowing difficulties [11,67]. There are a significant number of children with amplified pain who have suicidal ideation and suicidal attempts. Although not a manifestation of suicidal ideation, self-cutting is also not uncommon. Suicidal ideation and cutting behaviors as well as conversion and somatization all bespeak the high degree of psychological stress these children are under. The physical examination should include careful assessment of the musculoskeletal and neurologic system. Allodynia is common but is not in a dermatome or in the distribution of a peripheral nerve and the border is usually variable on repeat testing. Glove and stocking and total body allodynia can occur. Autonomic signs such as decreased skin temperature and cyanosis

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may only be present after exercising or moving the limb or when the limb in is a dependent position. Both the 1990 ACR and Yunus & Masi criteria for fibromyalgia include counting painful points (Table 7.1). A tender point needs to be identified by the patient as painful, not just tender, when 4 kg of pressure is applied. The 2010 ACR criteria eliminate the need for tender point assessment and are currently being validated for use in children. It is important to also check control points such as the forehead since many children report pain to virtually their entire body [68]. There are children with diffuse amplified pain who do not report painful fibromyalgia points although they are otherwise identical to children fulfilling the 1990 criteria. Prolonged severe back pain used to almost always be due to an identifiable cause in childhood and warrants a careful investigation. It may be due to a serious illness [69]. However, children with amplified pain may just have back pain so attention should be paid to the nonorganic back pain signs including the axial loading test, distracted straight leg raising, passive rotation test, overreaction, and allodynia [70].

SLEEP An early study reported that normal controls deprived of stage 4 sleep developed altered α δ sleep and developed symptoms and mood changes similar to patients with fibrositis (fibromyalgia) [71]. This has led to the idea that restoring normal sleep may help symptoms. Nonrestorative sleep is a major feature of the new 2010 fibromyalgia criteria [13]. Children with fibromyalgia have altered α δ sleep, however, it does not change with medication or even after effective treatment when they have no pain and sleep well [39,40,42]. Good sleep hygiene and extended bed times may help [72]. These children, regardless of how little they say they sleep, do not fall asleep in class and are not hypersomnolent. Medication to induce sleep is not helpful in most children with fibromyalgia or other amplified musculoskeletal pain syndromes and the search for a medication can be frustrating for patient and physician; we have not found it necessary [42].

MEASUREMENT OF PAIN, DYSFUNCTION, AND STRESS The amount of pain and dysfunction are not necessarily concordant. The best way to assess pain is by self-report but verbal scale may vary from a visual scale and so both are preferable. There are various tools to assess the quality of pain (eg, McGill Pain Questionnaire and Pediatric Pain Questionnaire) but are not typically used in the general rheumatology clinic [73,74]. There are several short and useful tools to assess the amount of dysfunction; the most common in rheumatology clinics is the Childhood Health Assessment Questionnaire [75]. However, the Functional Disability

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Inventory (FDI) is shorter and validated for childhood pain [76]. The amount of dysfunction may not be entirely due to pain and some of the most incapacitated children are those with concurrent conversion. The amount of stress and psychological dysfunction is difficult, at best, to quantify but needs to be assessed [11,33,47,48,77 81]. Chronic pain exacts a psychological toll on the child and family regardless of preexisting psychological issues.

DIFFERENTIAL DIAGNOSIS Pain is one of the most common reasons to see a doctor and there are multiple conditions that need to be considered when evaluating a child for amplified pain (Table 7.3). The most common conditions erroneously thought to be amplified pain are enthesitis or a spondyloarthropathy [82]. Children with amplified pain are often incorrectly thought to have trauma, especially Salter-Harris I fractures, growing pains, or arthritis.

LABORATORY EXAMINATION Rarely are laboratory tests required by the time the child is seen by the rheumatologist. Blood and urine tests are normal and they save sometimes a benign positive antinuclear antibody test that usually can be discounted without further testing [83]. Children with CRPS may have normal or slightly slowed nerve conduction velocities that are inconsequential [84]. Once the diagnosis is established any further testing is fraught with false positive results that raise questions about the diagnosis, cause anxiety, and delay treatment. Many families want “one more test” in the mistaken belief that there really is some serious underlying disease causing damage and not amplified pain.

IMAGING EXAMINATIONS X-ray studies are normal or show osteoporosis depending on the duration of disuse. Rarely do children have the spotty osteoporosis seen in adults with CRPS [33]. Of all imaging tests, technetium radionuclide bone scans are probably the most useful if the diagnosis is in doubt [85]. The technetium scan usually shows decreased radionuclide uptake in the affected limb; a normal study helps rule out osteomyelitis, osteoid osteoma, or a stress fracture, but abnormal scans are subject to interobserver variation especially in mild abnormal scans [86]. Magnetic resonance images commonly show regional bone marrow edema but, early on, are unable to differentiate between the edema of amplified pain and the edema of trauma including fractures [86].

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TABLE 7.3 Differential Diagnosis of Amplified Musculoskeletal Pain Diagnosis

Age

Distinctive Characteristics

Malignancy

Any

Bone or joint pain that can be migratory or episodic, usually abnormal labs

Spinal cord tumor

Any

Abnormal neurologic examination, Babinski present, altered gait or scoliosis

Pernio (chilblains)

Any

Follows cold exposure of fingers and toes, burning pain with red to purple swollen papules

Spondyloarthropathy

Older child or adolescent

Enthesitis, response to nonsteroidal agent or prednisone

Fabry

Adolescent

Burning episodic pain of two hands and feet, macular papular hyperkeratotic lesions in perineum and lower trunk, erythrocyte sedimentation rate usually elevated

Raynaud

Adolescent

Tricolor (white, blue, red) changes to fingers and toes with cold exposure, comfortable but not severely painful

Erythromelalgia

Any

Intense pain with redness, warmth, swelling of hands and feet by cold

Growing pains

Children

Nocturnal pain that may interfere with sleep, can follow certain activities and may be associated with hypermobility; usually diminished with nonsteroidal agents

Restless leg syndrome

Adolescent

An uncomfortable feeling, not usually painful, diminished with moving the legs. It usually does not cause awakening

Myofascial pain

Adolescent

Specific sustained contraction of a muscle generally in the head, jaw, or upper back that is well localized

Chronic recurrent multifocal osteomyelitis

Any

Specific point tenderness, usually elevated inflammatory markers

Compartment syndrome

Adolescent

Severe calf muscle pain during exercise

Progressive diaphyseal dysplasia

Adolescent

Severe leg pain, fatigue, constitutional symptoms, waddling gait with abnormal radiographs (Continued )

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TABLE 7.3 (Continued) Diagnosis

Age

Distinctive Characteristics

Mononeuropathy

Adolescent

Posttraumatic nerve injury

Transient migratory osteoporosis

Adolescent

Rapidly developing painful osteoporosis

Vitamin C deficiency

Any

Bone pain, bruising, usually in the setting of autism or eating disorder

Vitamin D deficiency

Adults

Widespread pain and debilitated patients with multiple risk factors for vitamin D deficiency

Thyroid disease

Any

Widespread pain with hypothyroidism or hyperthyroidism

Munchausen by proxy

Children

Usually intermittent pain, overmedicalized and overtreated for multiple conditions by multiple health care providers

PATHOLOGY There is scant information regarding the histopathology of tissue from children with amplified pain. Skin, muscle, and nerve biopsies in three children with CRPS showed endothelial swelling, basement membrane thickening and reduplication, and patchy muscle fiber atrophy consistent with ischemic injury [87]. Ischemic changes present in the knee synovium have been observed by the author. Decreased blood flow following dynamic and during static exercise, measured by contrast-enhanced ultrasound, is very suggestive of muscle ischemia in adults with fibromyalgia [57]. Other various abnormalities in muscle and skin have been reported including decreased intraepidural nerve fiber density but it is unclear if these changes are causal or due to other processes such as ischemia [60,88].

TREATMENT In evaluating the effectiveness of any treatment for amplified pain, it is paramount to recognize the importance of the mind body connection; an individual child can have a remarkable result whatever the treatment. The first child reported with CRPS had a spontaneous remission 1 day before she was scheduled for a psychiatric evaluation and 2 days before a sympathetic block, evidently from a flight into health [8]. She remained well for 2 years under continued psychiatric care. Single case reports or small series are not evidence for effectiveness and long-term remission rates in large cohorts are

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probably the best measure of any treatment given the lack of double-blinded, placebo-controlled, long-term studies. The number of widely disparate treatments demonstrates that there are no proven therapies established by well-controlled therapeutic trials [2,89]. There is a plethora of single case reports or reports on very small groups of children raising the question of publication bias. Additionally, many children are administered multiple treatments and modalities making interpretation impossible. Therefore, treatment is largely based on clinical experience and a very few larger patient series. There is a temptation to extrapolate data from adult studies to children, however, there is data indicating children with CRPS or fibromyalgia significantly differ from their adult counterparts [28,32,59,79,90 92]. Even if adults had similar findings and outcomes, a recent Cochrane study concluded there is no high-quality evidence for the majority of CRPS therapies [92]. Prudence is called for when considering therapy for children with amplified pain considering the risk benefit ratio of medications and procedures compared to more standard, conservative therapy [93]. No agents have been approved by the Food and Drug Administration for children with CRPS or fibromyalgia. There are two goals of treatment, to restore function and relieve pain. Many treatments are aimed at pain relief but since pain is subjective and the amplification of pain is not directly responsive to specific treatment, the focus first should be on restoration to full function. Functional improvement usually precedes the decrease in pain so teaching the child skills to cope with pain is often effective in relieving distress even if the pain persists. However, since children with CRPS and fibromyalgia have marked reduction or resolution of pain, the absence of pain should remain a goal for any treatment program. Setting too low a goal is a disservice since many children meet the expectations of the treatment team, including resolving all pain [94].

PSYCHOTHERAPY It is imperative that the health care team believe these children have real pain and that it is not in their heads. Many children with amplified pain have been traumatized by peers, teachers, and even health care professionals saying the pain is all psychological or malingering. Patients and parents can be very defensive and offended when discussing the role of stress as it relates to amplified pain. Many children with amplified pain do not feel stressed since their stress and associated emotions are resolved in the pain symptom. However, both the child and family are controlled by the pain and it significantly affects the individual and family dynamics [44,46,48 50,77 79,95 97]. All children with amplified pain and their families should have a psychological assessment to look at both the individual and family psychodynamics. Therapy, especially cognitive behavioral therapy (CBT), can help the child strategize and cope with the more immediate pain

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especially as physical and occupational therapy begins [98 100]. Social and academic school issues are frequent sources of stress and need to be evaluated [44,48,49,101]. Family or marital therapy is sometimes indicated in order to decrease the child’s stress [11,48,77]. A randomized controlled trial of CBT in 114 children (half in an education group) showed depressive symptoms resolved in both groups and there was no difference between the groups in sleep quality, physical activity, pain severity, or a meaningful reduction in pain [99]. However, the children treated with CBT had a greater reduction in their FDI score, from 21 to 13 versus 19 to 17 in the education group. Parents tended to overly protect the child in pain, especially parents who focused more on their child’s physical health rather than the child’s emotional health [77]. It seems reasonable to recommend psychotherapy based on an initial psychological evaluation [102 105]. There is frequently a need to address family issues [106 108]. Creative arts therapy such as music, dance, and art therapy can benefit children who have difficulty with verbal expression. Psychological treatments in children are effective for long-term headache pain control and may benefit children with musculoskeletal and recurrent abdominal pain, but data regarding the effectiveness on disability or mood is lacking [107]. Children with fibromyalgia have less depression than adults but a higher incidence of anxiety that may warrant medicinal treatment [79]. Psychotherapy is not used in isolation of physical and occupational therapy and the best outcomes include all three [28,29,109,110].

PHYSICAL AND OCCUPATIONAL THERAPY Virtually all authors advocate physical and occupational therapy to restore function [28,29,33,42,84,100,109 116]. The quality and quantity of physical and occupational therapy varies between studies and some children can work through the pain without formal therapy while others need up to 5 6 hours of daily therapy [29]. In 1978 Bernstein et al. reported on 23 children with CRPS treated without medications but with intense physical and occupational therapy with all having an excellent outcome [33]. The next study, by Wilder et al. in 1992, treated 70 children with CRPS using drugs and procedures such as nerve blocks along with mild physical therapy and only 46% resolved all symptoms [32]. In 1999 Sherry et al. expanded Bernstein’s treatment protocol of intense physical and occupational therapy without medications, treating 103 children with CRPS [29]. They reported that 92% resolved all symptoms and at 5 years 88% were symptom free. This was replicated by Brooke and Janselewitz in 2012 and 89% of 32 children with CRPS resolved all symptoms [109]. The relapse rate in both of the latter two studies was 20 30% but the majority of children with relapses were able to treat themselves without having to repeat the intense therapy program. Logan et al., in 2012, used

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slightly less intense physical and occupational therapy and continued pain medications in many [110]. They reported 95% of 56 children with CRPS spectrum conditions had significant improvement in function although the pain dropped much less (from 65 to 47 out of 100) than in the studies in which no pain medications were used. In adults with CRPS, a systematic review found strong evidence for the use of rehabilitation physical therapy to both reduce pain and improve function [117]. However, controlled trials of physical and occupational therapy are rare. Children with fibromyalgia were randomized to have weekly aerobic training versus Qigong training [118]. Pain levels did not change in the Qigong training group (63 61 out of 100) but dropped from 65 to 47 out of 100 in the aerobic training group. Aerobic training was not associated with an increase in fibromyalgia symptoms. In a small study, 10 children with fibromyalgia treated with an intense physical and occupational therapy program without medications remarkably improved with restoration of full function and a drop in pain from 65 to 17 out of 100 [42]. A large study of 64 children with fibromyalgia treated with intense physical and occupational therapy and psychotherapy, also without medications, were followed for a year posttreatment [28]. In this study both subjective and objective measures of pain and function significantly improved. Pain dropped from 71 at first visit to 20 at 1 year; 33% reported no pain and another 15% had pain levels # 10 out of 100. The FDI dropped from 26 to 5 and all objective measures of function significantly improved to normal values and were maintained at 1 year. Endurance was initially at the 25th percentile for age and sex and at 1 year was 90th percentile. Emotional, social, and school function were also all significantly improved. In adults with fibromyalgia Vierck and Thompson argue that physical therapy should be first-line therapy based on its beneficial effects on muscle vasoconstriction, stress, depression, fatigue, concentration, and sleep [119,120]. A metaanalysis of adults with fibromyalgia who exercise confirms improved well-being [121]. Evidence-based guidelines from the American Pain Society and the Association of the Scientific Medical Societies in Germany for fibromyalgia in adults emphasize self-management strategies including exercise and cognitive behavioral techniques [122]. The intense physical and occupational therapy and psychotherapy program used in children has not been tested in an adult population.

TRANSCUTANEOUS NERVE STIMULATION There are no controlled studies of the use of transcutaneous nerve stimulation (TENS) in children with amplified pain. There are anecdotal reports of successfully using TENS in a small number of children with CRPS [112]. However, there was no difference between actual and sham TENS observed

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in volunteers with induced ischemic pain, so the usefulness of TENS in amplified pain is questionable [123].

ACUPUNCTURE There are no efficacy trials of acupuncture in children with amplified pain. Sham acupuncture frequently is equally effective and needle placement was not critical in one study of 114 adults with fibromyalgia [124]. Some children report an exacerbation of pain following acupuncture so it is not benign.

MEDICAL TREATMENT There are no approved drugs for children with amplified pain. Most of the reports in children are anecdotal or are very small series without long-term outcomes. There is a publication bias for reports of treatments that are associated with benefit; however, if no benefit is realized these reports are unlikely to be written or published. Medications are fraught with side effects and placebo effects. Studies in adults are larger and many are double-blinded but most have no benefit in clinically significant ways. Some will decrease pain but without an increase in function. Unfortunately a statistically significant result may not be clinically meaningful. To drop the pain from a 6 to a 5 out of 10 may generate an impressive P value if the population is large enough but the patient still has level 5 pain.

TRICYCLIC ANTIDEPRESSANTS Studies of amitriptyline and nortriptyline in adults with fibromyalgia report mixed results and a Cochrane Systematic Review concluded that there is no supportive unbiased evidence to substantiate its use; only a minority of patients will obtain satisfactory pain relief [125]. A placebo-controlled trial showed amitriptyline had no effect on the NREM sleep abnormalities [39]. A sizeable number of children will have significant electrocardiographic findings that contraindicate the use of amitriptyline, however computer programs miss these so the electrocardiogram requires a careful reading by a pediatric cardiologist before initiating therapy [126]. These agents are fraught with side effects that can mimic fibromyalgia and can increase the risk of suicide so a monitoring plan needs to be established if begun.

OTHER ANTIDEPRESSANTS A systematic review concluded that there was little evidence to support one class of antidepressant over another and there were no long-term (greater than 12-week) studies [127]. Pain, on average, improved 26% and quality of life, 30%. These agents are also associated with increased risk of suicide in young people.

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ANTIEPILEPTICS Gabapentin and pregabalin are the most commonly used agents (pregabalin is not approved in children presently). A metaanalysis of these agents in adults with fibromyalgia concluded pregabalin is most likely effective, defined as a 30% or more reduction in pain, but its use was limited by side effects [128]. A systematic review of eight treatments for fibromyalgia in adults (duloxetine, fluoxetine, gabapentin, milnacipran, pramipexole, pregabalin, amitriptyline, cyclobenzaprine, and tramadol plus acetaminophen) concluded all eight suggested improvement over placebo without strong differences between agents although milnacipran and pregabalin are more likely to be discontinued due to side effects [129].

BISPHOSPHONATES There are several short-term outcome studies of unique populations of CRPS in adults that have reported benefit [130,131]. An 11-year-old was treated with 11 courses of pamidronate over 2 years along with physical therapy and resolved her pain [132]. A systematic review of bisphosphonates for CRPS concluded there was strong evidence of benefit but long-term outcome studies need to be done [117]. There are concerns of serious side effects in children.

STEROIDS Ruggeri et al. treated six children with dexamethasone without benefit [133]. Additionally steroids have too many potential side effects to recommend them.

OPIOIDS Opioids have no place in the treatment of children with amplified pain [134]. The author knows of two overdose deaths.

KETAMINE One child with CRPS did not respond to oral ketamine [135]. In a 12-week trial in 60 adults with CRPS, by the end there was no difference between ketamine and placebo and there were significant psychomimetic side effects [136]. Ketamine coma is unproven to have any lasting benefit, is not approved in the United States and has very significant side effects [137].

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INVASIVE PROCEDURES Zernikow et al. have argued against the use of invasive procedures in children for CRPS and the same can be said for fibromyalgia [93]. A recent review of these procedures for childhood CRPS emphasized that there is only weak evidence for their use [138]. The risks do not outweigh the benefit.

SYMPATHETIC BLOCKS AND SYMPATHECTOMY Sympathetic blockade, at best, is beneficial only in the short term. In a large study in adults with CRPS, results were good or lasting in only 7% of 273 patients [38]. A Cochrane systematic review was unable to determine if it is effective and found little evidence to support blocks as standard of care in CRPS [139]. Sympathetic blocks have been tried in fibromyalgia and include the failure of a surgical ganglionic blockade and sympathectomy in a 14-year-old girl [140].

PERIPHERAL NERVE BLOCKS A peripheral block followed by a Bier block (intravenous regional anesthesia) in 13 children with CRPS was beneficial at 2 months [141]. Continuous peripheral blockade to allow for physical therapy was reported in two children with good short-term results at 2 and 5 months [142].

EPIDURAL INFUSIONS Epidural infusions, mostly for CRPS, have not been systematically studied. Multiple agents have been used including baclofen, clonidine, morphine, ketamine, and bupivacaine. Side effects include sepsis in one child and epidural abscess in two children [143,144].

SPINAL CORD STIMULATORS Spinal cord stimulators were used in six children and they had either mild improvement or worsening of pain [116]. In one study of seven children, two failed to have any benefit and one became infected; the rest had prolonged relief and the stimulator was eventually removed [145]. A plethora of side effects have been reported including lead migration, paraplegia, paralysis, epidural abscess, squamous cell carcinoma, conversion syndrome, urinary retention, spinal fluid leakage, panic attacks, schizophreniform disorder, and headache.

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AMPUTATION Adults with intractable CRPS or CRPS with recurrent infections have resorted to amputation and even then, only 2 of 28 patients had pain relief [146].

MISCELLANEOUS THERAPIES There are, and will be more, allopathic and nonallopathic therapies for amplified pain. Most of these are not done in isolation of other therapies and have been reported as single case studies or small cohorts. Children have tried such things as herbal therapy, healing touch, medical marijuana, a host of creams, lidocaine, fentanyl, and clonidine patches, calcitonin, massage, magnet therapy, homeopathy, reflexology, aromatherapy, elimination diets, special diets and vitamins, hyperbaric oxygen, and scrambler therapy to name a few. None can be recommended.

A PHILOSOPHY OF THERAPY There are now several treatment teams in the United States that focus on restoration of function with physical and occupational therapy and a psychological evaluation that determines if counseling is indicated. Some children need little to no physical therapy; many can do well with outpatient therapy and if it fails, intense one-on-one physical and occupational therapy 5 6 hours a day (weekdays) for an average of 3 4 weeks is indicated. Functional activities, desensitization, and aerobics are emphasized [2,28,29,109]. Children who are very dysfunctional, especially those unable to do activities of daily living, have severe postexercise screaming or other pain behaviors, or require a behavior modification program (usually for concomitant conversion) require inpatient treatment. Medications for pain, sleep, nausea, or other somatic complaints are not used. There is no consistent evidence of benefit for these, most are not approved for use in children, and many have significant side effects. Besides, the majority of children respond well to physical and occupational therapy with counseling. Invasive therapies such as infusions, blocks, spinal cord stimulators, or pain pumps have essentially no role in childhood CRPS, fibromyalgia, or other amplified pain syndromes. The message behind administered therapies is that the health care provider is in control and will stop the pain rather than have the child work through the pain and resolve it on his or her own.

COURSE AND OUTCOMES There are no very long-term studies of the amplified pain syndromes in children but a recent 6-year study of childhood fibromyalgia reports 80% of

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young adults still had symptoms of and half-fulfilled criteria for fibromyalgia [147]. Other authors report 92% of children with fibromyalgia, relatively untreated, had pain a mean of 33 months later (range 15 60 months) [148]. Population studies of childhood widespread pain reported continuing symptoms in 30% when studied either 1 or 4 years later; 10% had pain at 3 baseline, 1, and 4 years [22]. However, when treated in a vigorous exercise program with counseling 88% of children with CRPS were symptom-free at 5 years, and at 1 year 64 children with fibromyalgia had minimal to no pain and full function [28,29]. In general, children with CRPS do better than those with fibromyalgia. Reoccurrence after an intense exercise program is between 20% and 30% although at least half can reinstitute therapy and resolve their pain without formal retreatment [29,109]. Relapses were more common in those with significant underlying psychopathology, especially a suicide attempt. No difference in outcome between girls and boys or between younger children and older adolescents was observed. Duration of pain prior to therapy did not predict outcome. Other untoward outcomes need to be looked for in this population. Other chronic pain conditions may arise including abdominal pain, gastroparesis, chest pain, and headache. Other psychological problems such as conversion, suicidal ideation, disordered eating, self-injury (cutting), school avoidance, anxiety, incapacitating dizziness or fatigue, palpations, fainting, cognitive difficulties, or prolonged concussive symptoms may develop in addition to or following amplified pain. When these arise it is prudent to readdress the role of psychological stress, minimize medical management, and have the child maintain function.

CONCLUSION Musculoskeletal pain is common and frequently presents to the pediatric rheumatologist. An accurate diagnosis and consistent management is important. Once the diagnosis of amplified pain is established, reassurance that no biologic damage is occurring and treatment with appropriate physiotherapy should begin. The psychological effect of the pain and dysfunction on the child and family should be assessed and appropriately treated. Many children with amplified pain require the services of a multidisciplinary team. Although challenging, these are the most debilitated patients we see who can be restored to full heath and function, which is quite rewarding. The immediate problem of restoring function and resolving pain is the initial goal while the long-term goal is to help the child and family better function in all ways to lessen the risk of recurrence or the development of other stress-induced symptoms.

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[134] McNicol ED, Midbari A, Eisenberg E. Opioids for neuropathic pain. Cochrane Database Syst Rev 2013;8:Cd006146. [135] Bredlau AL, McDermott MP, Adams HR, Dworkin RH, Venuto C, Fisher SG, et al. Oral ketamine for children with chronic pain: a pilot phase 1 study. J Ped 2013;163 (1):194 200.e1. [136] Sigtermans MJ, van Hilten JJ, Bauer MC, Arbous MS, Marinus J, Sarton EY, et al. Ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome type 1. Pain 2009;145(3):304 11. [137] Henson P, Bruehl S. Complex regional pain syndrome: state of the art update. Curr Treat Opt Cardiovasc Med 2010;12(2):156 67. [138] Zernikow B, Wager J, Brehmer H, Hirschfeld G, Maier C. Invasive treatments for complex regional pain syndrome in children and adolescents: a scoping review. Anesthesiology 2015;122(3):699 707. [139] Cepeda MS, Carr DB, Lau J. Local anesthetic sympathetic blockade for complex regional pain syndrome. Cochrane Database Syst Rev 2005;(4):CD004598. [140] Buchta RM. Reflex sympathetic dystrophy in a 14-year-old female. J Adolescent Health Care 1983;4(2):121 2. [141] Dadure C, Motais F, Ricard C, Raux O, Troncin R, Capdevila X. Continuous peripheral nerve blocks at home for treatment of recurrent complex regional pain syndrome I in children. Anesthesiology 2005;102(2):387 91. [142] Bredahl C, Kristensen AK, Christensen KS, Bredahl C, Kristensen AK, Christensen KS. Treatment of reflex dystrophy with continuous peripheral nerve block. Ugeskrift Laeger 2007;169(1):59 60. [143] Ingelmo PM, Marino G, Fumagalli R. Sepsis after epidural catheterization in a child with chronic regional pain syndrome type I. Ped Anaesthesia 2005;15(7):623 4. [144] Lin YC, Greco C. Epidural abscess following epidural analgesia in pediatric patients. Ped Anaesthesia 2005;15(9):767 70. [145] Olsson GL, Meyerson BA, Linderoth B. Spinal cord stimulation in adolescents with complex regional pain syndrome type I (CRPS-I). Eur J Pain 2008;12(1):53 9. [146] Dielissen PW, Claassen AT, Veldman PH, Goris RJ. Amputation for reflex sympathetic dystrophy. J Bone Joint Surg Br 1995;77(2):270 3. [147] Kashikar-Zuck S, Cunningham N, Sil S, Bromberg MH, Lynch-Jordan AM, Strotman D, et al. Long-term outcomes of adolescents with juvenile-onset fibromyalgia in early adulthood. Pediatrics 2014;133(3):e592 600. [148] Rabinovich C, Schanberg L, Stein L, Kredich DW. A follow up study of pediatric fibromyalgia patients. Arthritis Rheum 1990;33(Suppl.):S146.

Chapter 8

Systemic Lupus Erythematosus: Etiology, Pathogenesis, Clinical Manifestations, and Management T. Lehman, F. Nuruzzaman and S. Taber Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, NY, United States

INTRODUCTION Systemic lupus erythematosus (SLE) is a chronic inflammatory disease affecting virtually all organ systems. The illness course is “predictably unpredictable,” with episodic flares of varied severity with diverse clinical manifestations. Uncontrolled disease may lead to permanent end-organ damage. Childhood onset occurs in approximately 15% of cases [1]. Although SLE is typically considered a disease of young adult women, children with SLE may be of any age and either sex [2]. Children with SLE often present to primary care physicians with nonspecific symptoms. This may result in delayed diagnosis. The etiology of the underlying immune dysregulation seen in SLE remains unknown. Clinical disease expression is undoubtedly the end result of various environmental and immunologic stimuli acting on a genetically predisposed individual. Abnormalities of T cells, B cells, dendritic cells, Fcγ receptors, proinflammatory cytokines, the complement pathway, and apoptosis have all been found and are suspected to play a role in the pathogenesis of SLE. Mucocutaneous, musculoskeletal, and renal manifestations are common in childhood SLE (cSLE). Renal involvement is a major cause of morbidity and mortality [3]. While corticosteroids remain the first-line drugs for treatment of SLE, their well-known adverse effects mandate the use of steroid sparing agents whenever possible. The recent advances in the treatment of lupus nephritis (LN) have resulted in much improved long-term survival. As a result neuropsychiatric (NP), musculoskeletal, cardiopulmonary, hematologic, and Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00008-6 © 2016 Elsevier B.V. All rights reserved.

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dermatologic manifestations are becoming increasingly important in limiting quality of life. An additional consequence of the improved survival is an increasing number of children with chronic corticosteroid toxicity, placing them at risk for premature arteriosclerosis, osteoporosis, and sequelae of hypertension.

DEFINITION/CLASSIFICATION The diagnosis of SLE is based on the appropriate clinical and laboratory manifestations. Classification as having “definite SLE” for research studies requires 4 of the 11 criteria as determined by the American College of Rheumatology. These criteria include malar rash, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis, pleuritis or pericarditis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, and positive antinuclear antibody [4]. However, cSLE patients may initially present with fewer criteria. The clinical picture must be considered and alternative causes of the child’s symptoms excluded before diagnosis is confirmed. Multisystem disease in the presence of antinuclear and other antibodies strongly suggests the diagnosis. While no single specific test exists for the diagnosis of SLE, the constellation of clinical symptoms and relevant laboratory findings is typically sufficient for the diagnosis.

EPIDEMIOLOGY cSLE is a rare disease with an incidence of 0.3 0.9 per children-years and a prevalence of 3.3 8.8 per 100,000 children [5,6]. Ethnicity plays a role in incidence and prevalence, with higher rates of disease in Hispanic, Black, North American First Nation, South East, and South Asian populations [2,7]. Onset of cSLE occurs at a median age of 11 12 years with infrequent presentation before the age of 5. As in adult onset SLE, approximately 80% of patients with cSLE are female [8,9].

GENETICS Genome-wide association (GWA) studies have demonstrated that genetics significantly predispose to SLE [10]. The SLE-associated gene variants that contribute to disease pathogenesis can be grouped into those involving DNA degradation, apoptosis, and clearance of cellular debris; those with defective clearance of immune complexes containing nuclear antigens; those with tolllike receptor and type I interferon (IFN) pathway activation; NF-κB signaling; B-cell function and signaling; T-cell signaling and function; and monocyte and neutrophil signaling and function [11]. The frequency of these variant pathways differs by ethnicity. GWA studies in Caucasian and Chinese populations confirmed an association of interferon-regulatory factor 5 (IRF5)

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with SLE [12]. IRF5 is important for transactivation of type 1 IFN and IFN-responsive genes and for the production of proinflammatory cytokines [13]. Additionally, strong associations occur within the human leukocyte antigen (HLA) region. For example, it has been shown that there are highly conserved haplotypes bearing class II alleles HLA-DRB1 03:01 and HLADRB1 15:015 associated with SLE in European populations [11]. Despite the apparent contribution of genetic factors, incomplete disease concordance rates between monozygotic twins suggests other factors in SLE pathogenesis are yet to be elucidated [14].

ETIOLOGY/PATHOGENESIS The production of autoantibodies is the sentinel event in the pathogenesis of SLE. Appearance of these autoantibodies may precede clinical manifestations of SLE by years [15]. Ultimately, immune complex formation with subsequent tissue deposition and complement activation result in further dysregulation of the immune system. Lupus patients usually show high IFN-α activity [16]. IFN-α promotes B-cell responses and immunoglobulin class switching, which may in turn increase IgG and IgA antibody production [17]. Apoptosis, or programmed cell death, appears to further accelerate the development of SLE. SLE is associated with a reduction in the clearance of apoptotic bodies from the phagocytic/macrophage system, leading to a larger apoptotic burden of circulating self-DNA or self-RNA complexes. These become antigenic targets for both humoral and cell-mediated autoimmune responses. Additionally disorders of epigenetic processes, involving DNA methylation, histone modification of noncoding RNA, and nucleosome remodeling, may alter gene expression, resulting in SLE [18]. The variety of factors discussed here illustrates the complexity of the pathogenesis of SLE.

CLINICAL MANIFESTATIONS AND TREATMENT General Principles The treatment of SLE in childhood is a particular challenge. In addition to considering the impact of the medications on growth and physical development, physicians must also consider the impact of the desire for a seemingly “normal” life as children enter adolescence and early adulthood. With their increasing sense of independence from parents and medical authority figures, their compliance often wanes. This is particularly true for teenage patients for whom body image issues come to the forefront when faced with the effects of corticosteroid therapy. Multidisciplinary care with active participation of social workers, psychologists, nutritionists, and physical and occupational therapists benefits these patients. Children should be educated as to the nature and severity of SLE as early as possible and should be encouraged

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to participate actively in their own medical care. cSLE patients and their families must be made aware of the potentially life-threatening consequences of treatment noncompliance or abrupt treatment withdrawal. Preventative measures such as sunscreen usage, physical activity, maintenance of a healthy body mass index (BMI) through diet and exercise, infection avoidance, and compliance with medications and medical follow up should be reinforced. In our experience, Compliance is the single best predictor of disease outcome in children with SLE. Treatment of SLE must be individually tailored to each patient’s clinical manifestations. Depending upon the extent and severity of internal organ involvement, appropriate medication regimens range from low-dose corticosteroids and antimalarials, to inpatient treatment with pulse methylprednisolone and cytotoxic medications such as cyclophosphamide (CYC) and rituximab (RTX). There is no consensus regarding the best management of the clinical manifestations of lupus in children.

Lupus Nephritis LN is found in the majority of patients. Renal involvement occurs at higher rates in children with lupus than in adult lupus patients [19]. A high index of suspicion should be maintained, and symptoms such as headache, vision changes, weight gain, and swelling of the extremities should raise a red flag for possible renal involvement. Treating physicians should routinely screen for hematuria and proteinuria, as well as for clinical and laboratory signs of evolving nephrotic syndrome and hypertension. Typically, microscopic hematuria and proteinuria precede more overt clinical signs of nephritis. Persistent decrease in renal function, reproducible proteinuria, and active urinary sediment are common. Indications for renal biopsy, to determine the extent of disease, vary from institution to institution. The World Health Organization (WHO) classification system uses histologic appearance (on light and electron microscopy, as well as immunofluorescence) to determine the type of renal involvement, while chronicity and activity scores measure cumulative damage and continuing inflammation and disease activity, respectively. The treatment of new or worsening LN typically requires corticosteroid therapy. Corticosteroids effects are rapid, nonspecific, and may provide immediate disease control. However, the beneficial effects must be weighed against the adverse effects of corticosteroid use [20 22].The use of corticosteroids for SLE is associated with significant adverse long-term effects, which are playing an increasingly important role in the morbidity and mortality of cSLE. High doses of corticosteroids may be required for remission induction. However, their use in high dosage cannot be viewed as a long-term treatment option. Steroid sparing agents and aggressive use of alternate

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immunosuppressive therapies must be instituted early in the disease course. However, large trials comparing different treatment strategies in pediatric lupus are lacking. Renin angiotensin aldosterone system inhibitors are considered firstline therapy for proteinuria. Mild, class II or III LN with low activity scores on renal biopsy, normal renal function, blood pressure, and proteinuria below the nephrotic range may respond to low-dose corticosteroids (up to 0.5 mg/kg per day) and antimalarials (hydroxychloroquine 7 mg/kg per day up to 200 mg/day). The exact mechanism of antimalarial drugs such as hydroxychloroquine in LN remains unknown, although withdrawal of these drugs has been associated with disease flares [23]. The guidelines for the use of additional immunosuppression in class II disease vary. More severely affected patients with highly active WHO class III or IV LN require higher steroid doses as well as the addition of an immunosuppressive or cytotoxic agent. Oral prednisone doses of 1 2 mg/kg per day are used. In patients with severe nephrotic syndrome, hypertension, or deteriorating renal function, we advocate the use of pulse methylprednisolone (in addition to daily oral prednisone therapy) in conjunction with cytotoxic medications such as CYC. Albumin infusions and diuretics are often needed for severe nephrotic syndrome. In 2012, CARRA (the Childhood Arthritis and Rheumatology Research Alliance) developed a consensus treatment plan (CTP) for induction therapy of newly diagnosed proliferative LN in juvenile SLE patients. This CTP recommends the use of either CYC IV q4 weeks, or mycophenolate mofetil (MMF) 600 mg/m2 per dose po bid (max. 3000 mg/day), for a total 6 months. Additionally, it recommends three steroid regimens (primarily oral, primarily intravenous, or mixed oral/intravenous) with a slow taper over 24 weeks [24]. CYC is a cytotoxic agent that has been shown to improve the course of LN in children by cross-linking DNA strands, thus interfering with cell division [2,25]. The use of CYC is not without risk, although serious adverse effects can generally be avoided by intravenous administration in a monitored, inpatient setting. Laboratory parameters, fluid status, and evidence of infections are determined prior to and following the administration of CYC. CYC is withheld in any patient with a suspected infection, and appropriate antimicrobial treatment promptly initiated. Nausea, vomiting, alopecia, and leukopenia may be seen. Hemorrhagic cystitis is a known risk with the use of CYC; however, this is more commonly seen with daily oral dosing. The use of pre- and post-CYC intravenous hydration and close monitoring of fluid status decreases the risk of both hemorrhagic cystitis and the syndrome of antidiuretic hormone secretion (SIADH). Gonadal toxicity and premature ovarian failure remain a concern. In our experience, those patients who have received a cumulative dose of greater than 17 g/m2 are at higher risk of infertility. Leuprolide is an option for females, and sperm-banking for male patients concerned about future fertility. All postpubertal females are

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screened for pregnancy prior to CYC administration to avoid potential teratogenic effects. MMF inhibits purine synthesis and blocks the proliferation of activated T and B lymphocytes. Adult SLE patients have shown good response to 3 g/day of MMF when compared with monthly CYC therapy [26]. In children, however, the experience with MMF is limited. A subgroup analysis including adolescents aged 12 18 years from the ALMS trial noted similar efficacy in adolescents and adults. However, the numbers were small (24 patients in the induction phase and 16 in the maintenance phase) and therefore not sufficient to yield statistically significant results [27]. In our experience, many children are intolerant to large doses of MMF due to gastrointestinal upset, diarrhea, and leukopenia. The result is often noncompliance, which may complicate interpretation of medication response. The use of RTX in addition to CYC for severe or relapsed LN is an alternative regimen, which may allow for a lower cumulative CYC dose. RTX is a chimeric mouse/human monoclonal antibody against the B-cell surface antigen CD20. CD20 is expressed on the surface of premature and mature B cells, but not on the surface of plasma cells. RTX targets the CD20 antigen, causing cell death. Because there is relative sparing of T cells, RTX is less immunosuppressive than other cytolytic therapies [28]. At this time, we advocate the use of RTX in conjunction with CYC for the induction of remission in pediatric SLE patients with proliferative LN. Our current clinical practice for newly diagnosed, severe, or CYC-refractory LN consists of a protocol occurring over 18 months, where patients received 6 infusions of RTX 750 mg/m2 (up to a maximum dose of 1 gram per infusion), followed 24 hours later by CYC at 750 mg/m2. The infusions are given in three sets (0, 6, and 18 months), with doses of both RTX and CYC given initially and then repeated 2 weeks later. Patients with active diffuse proliferative glomerulonephritis receive additional infusions of CYC 750 mg/m2 at 6, 10, and 14 weeks after the start of therapy. First-year follow-up of patients treated with this regimen has shown both substantial reduction in the total dosage of CYC and elimination of the need for steroids in doses above 0.25 mg/kg per day, while providing sustained clinical improvement [29]. Other recent retrospective studies also indicate that RTX may improve disease activity in pediatric SLE patients [30]. Controlled studies are warranted. Infusion reactions are the most commonly seen adverse event associated with the use of RTX in children. Mild pruritis, rash, and hypotension are not uncommon, and more severe reactions including serum sickness have also been reported [31]. In our experience, infusion reactions resolve with slowing of the infusion rate, and are often avoided altogether with the use of premedications. We have seen no cases of serum sickness. Development of human antichimeric antibodies (HACAs) is a concern as this may place patients at risk for allergic reactions and loss of efficacy over time. It is possible that the coadministration of RTX with CYC may prevent the formation

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of HACAs, but this remains to be determined. With the use of combination immunosuppressive therapy, infection is again of particular concern. Class V LN with heavy proteinuria often responds to high-dose oral corticosteroids, which should be tapered as quickly as possible. There does not appear to be a role for cytotoxic therapy in class V LN patients at this time. Class V LN is one of the few instances in which azathioprine (AZA) may be useful in the treatment of LN in children [32]. Cyclosporine (CsA) and AZA are among the immunosuppressive steroid sparing agents used to treat LN. CsA bears a risk of renal toxicity and hypertension in patients already at risk for both. While in adults, there is evidence to suggest a role for CsA, it is not widely used in children with SLE. AZA is a purine analog, which interferes with DNA synthesis. No formal studies have been conducted comparing AZA with CYC in children with SLE, and a retrospective study observed a beneficial effect largely among Caucasian patients [33]. Thus, CsA and AZA are used infrequently in children with SLE in favor of newer more promising therapies with improved toxicity profiles.

Neuropsychiatric Lupus Central nervous system (CNS) involvement is another major cause of morbidity and mortality in SLE, with prevalence ranging from 15% to 91% depending on the diagnostic criteria and patient selection [34]. While overt NP involvement may be seen, subtle manifestations with cumulative cognitive dysfunction may only be appreciated with specialized NP testing [35]. NP manifestations may include cognitive dysfunction, seizures, headaches, neuropathy, psychosis and other psychiatric disturbances, and stroke syndromes. These may be caused directly by the underlying disease (primary NPSLE), or by secondary factors related to SLE, such as infection, drug side effects, or metabolic derangements [34]. Few trials exist for the treatment of NPSLE in either adults or children and current data exists largely in case report form. In children with SLE and new onset CNS symptoms, infectious etiologies (bacterial, fungal, and obscure opportunistic infections seen in immunocompromised patients) as well as vascular phenomena including thrombi or hemorrhage (secondary to antiphospholipid syndrome) must always be excluded with CNS imaging, and where appropriate, cerebrospinal fluid analysis and culture. Only after this has been accomplished should corticosteroid therapy be instituted. In severe cases, pulse intravenous methylprednisolone is given for three consecutive days (dosing as before) followed by oral corticosteroids (1 2 mg/kg per day). Milder cases not requiring hospitalization deserve an initial trial of oral corticosteroids. Often, a rapid and significant improvement in mental status and neurologic symptoms is seen with the use of high-dose steroids alone, though it should be noted that steroids may be both a treatment and a cause of psychosis [36].

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The successful use of CYC in severe cases has been described in adults and children with NPSLE [37,38]. A controlled trial of 32 patients with severe NPSLE found that intravenous pulse CYC was more effective than intravenous methylprednisolone, although the difference was small [39]. Additionally, plasmapheresis has been used in adults and children both independently of and in addition to CYC [40]. The use of intravenous immunoglobulin (IVIG) has also been reported [41]. Case reports describe the successful use of MMF and AZA to treat NPSLE in adults, although controlled studies have not been performed [42 44]. A large multicenter retrospective study of 144 pediatric patients with inflammatory CNS disease, 18 of whom had NPSLE, suggested that RTX improves neurologic outcomes [45]. A Chinese study of 109 adult patients who received intrathecal methotrexate and dexamethasone injections found that IT injection is a safe and effective treatment of NPSLE [46]. In all cases, NP symptoms should be optimally treated with such agents as anticonvulsants, antidepressants, and antipsychotics. Anticoagulation should be initiated in most patients with nonhemorrhagic stroke due to aPL or thrombosis. In the absence of other NPSLE features, headache can be treated as in patients without lupus, though ibuprofen should be avoided due to reports of aseptic meningitis [47]. Case reports describe the successful use of electroconvulsive therapy for NPSLE catatonia that is refractory to immunosuppression [48,49]. A multidisciplinary approach with consultation of neurology and psychiatry may help facilitate both diagnosis and treatment.

Pulmonary Manifestations Pulmonary manifestations are commonly seen in children with SLE, and may include pleuritis, pleural effusions, interstitial pneumonia, pulmonary infarction, pulmonary hypertension, pneumonitis, and hemorrhage [35,50 52]. As a large number of patients have subclinical lung disease with abnormal pulmonary function tests, regular testing should be performed [53]. In the immunocompromised patient with pulmonary symptoms, pneumonia and other infection must also be considered and ruled out promptly. Mild cases of pleuritis and pneumonitis typically respond to low-dose oral corticosteroids, though patients with tachypnea and severe pain may require intravenous methylprednisolone and supportive therapy including oxygen and analgesia. Acute pulmonary hemorrhage represents a potentially life-threatening emergency, and must be treated quickly and aggressively with the support of a pediatric critical care unit. Pediatric patients with alveolar hemorrhage may have a worse outcome than adult SLE patients with the same presentation [54]. We advocate for the immediate use of intravenous methylprednisolone pulses in addition to intravenous CYC, though plasmapheresis, IVIG, and MMF have also been used [54,55], and case reports suggest that RTX therapy may be successful [56]. Pulmonary arterial

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hypertension in SLE is rare and associated with poor prognosis; bosentan may improve outcomes [57].

Cardiac Manifestations Cardiac abnormalities in children with lupus include pericardial disease, myocardial disease, valvular disease, coronary artery disease, and heart failure. Often, cardiac disease is initially silent, and may not be symptomatic until significant morbidity is present. Studies have documented abnormal echocardiograms in as many as 68% of pediatric lupus patients [53]. Pericarditis is the most common cardiac manifestation in children with lupus, and may be associated with the presence of anti-Ro and anti-La antibodies [58]. Patients may be asymptomatic, or may present with chest pain, dyspnea, tachycardia, and low-grade fever. Nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose glucocorticoids are typically effective management, but patients who develop large pericardial effusions with resulting cardiac tamponade require pericardiocentesis, and pulse methylprednisolone with or without surgery may be needed for severe constrictive pericarditis. Clinical myocarditis is more rare [58], and may treated with glucocorticoids. Valvular heart disease may also occur, and may or may not be associated with antiphospholipid antibodies [59]. Patients with classic Libman Sacks endocarditis are at high risk of infection, and should receive antibiotic prophylaxis as recommended by the American Heart Association. Children with SLE are also at risk for early atherosclerosis and coronary artery disease, the initial presentation of which may be myocardial ischemia and infarction [60]. A 3-year study indicated that routine statin use in pediatric SLE patients has no significant effect on subclinical atherosclerosis, though certain subgroups may benefit from targeted therapy [61]. Hydroxychloroquine may also improve lipid profiles [62]. Heart failure in children with SLE is typically secondary to other underlying comorbidities, and should be managed accordingly.

Hematologic Manifestations The hematologic manifestations of SLE are varied, and each of the cell lines can be affected. Leukopenia, thrombocytopenia, and anemia are commonly seen in children with SLE. Leukopenia and anemia are particularly common in poorly controlled disease and may be markers of disease activity. Anemia tends to be microcytic or normocytic, as related to chronic disease. Thrombocytopenia may be the presenting symptom of SLE in children, and in our experience, may predate the development of other signs and symptoms of SLE by many years. All children with suspected immune thrombocytopenia should have periodic lupus serologies performed, as well as monitoring of renal function and urinary sediment. Symptoms of fatigue, infection

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related to leukopenia, petechiae, easy bruisability, pallor, or epistaxis should be worked up thoroughly in any lupus patient. Autoimmune hemolytic anemia is not uncommon and may be severe with profound hemolysis requiring transfusion. Coagulation abnormalities related to the lupus anticoagulant may be seen as well, often presenting with menorrhagia in adolescent females. Antiphospholipid antibody syndrome (APS) and the presence of anticardiolipin antibodies (ACLA) put patients at risk for thrombotic events. It is our practice to treat ACLA-positive patients with a daily dose of baby aspirin 81 mg daily as prophylaxis for thrombosis. Treatment of lupus-related cytopenias consists, initially, of the use of corticosteroids. Mild to moderate anemia, leukopenia, and thrombocytopenia may respond quickly to oral corticosteroid therapy. In more severe cases, pulse methylprednisolone may be used. Once treatment with CYC is initiated, typically for other accompanying disease manifestations, an improvement in hematologic manifestations is generally seen. Thrombocytopenia deserves particular mention. The use of RTX for severe and refractory immune thrombocytopenic purpura and autoimmune hemolytic anemia has shown rapid and durable response [63,64]. These reviews report regimens of either four weekly doses of 375 or 500 mg/m2 every 2 weeks following the rheumatoid arthritis guidelines rather than the lymphoma guidelines. We advocate for the use of larger doses in combination with CYC as described for the treatment of LN. In the setting of secondary APS, thrombosis must be treated aggressively. IVIG, plasmapheresis, and CYC have all been used for ongoing thrombus formation and hemorrhage. In general, chronic management of APS is much the same in children as in adults. Long-term anticoagulation must be instituted with coumadin or low-dose molecular weight heparin, and should be stopped only in the face of active bleeding. Several small studies and case reports have reported about the outcome of APS patients with RTX or autologous stem cell transplantation (ASCT). RTX has been used mainly to treat nonthrombotic manifestations of APS: a recent phase II trial showed a complete or partial response in terms of thrombocytopenia, skin ulcers, nephropathy, and cognitive dysfunctions in 11 out of 19 patients [65]. ASCT has also been used safely in APS patients and may eradicate aPL antibodies, at least in a proportion of patients [66].

Systemic Lupus Erythematosus-Related Musculoskeletal Disease Arthritis, myositis, and avascular necrosis are frequently seen in children with SLE. Arthritis tends to be nondeforming, and commonly involves the small joints of the hands and feet. Myositis can be seen, and is difficult to distinguish from steroid or other drug-related myopathies. The presence of proximal muscle weakness with elevations of the muscle enzymes and acute phase reactants suggests myositis related to SLE activity. In cases of steroid myopathy, muscle enzymes tend to be normal with little laboratory evidence

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to suggest worsening disease activity. Avascular necrosis is a known complication of corticosteroid therapy and is unpredictable in relation to dosing or duration of corticosteroid treatment. Treatment of SLE-related arthritis, arthralgias, and tenosynovitis can be accomplished with low-dose corticosteroids. Physical and occupational therapy is very effective in maximizing function, particularly when the small joints of the hands are affected. The judicious use of NSAIDs can be undertaken, however caution must be exercised with the use of these medications, as side effects including transaminitis and interstitial nephritis are difficult to differentiate from SLE-related organ involvement. Ibuprofen is generally avoided because of reports of ibuprofen-related aseptic meningitis in SLE patients [47]. Myositis can be treated with the use of corticosteroids, antimalarials, and NSAIDs. Medication-related myopathies may be severe and longterm intensive rehabilitation may be required in order to restore strength.

Cutaneous Involvement Rashes are very common in SLE, and can vary tremendously from patient to patient. The classically described malar or “butterfly” rash, with sparing of the nasolabial fold, is often seen at presentation. This rash is typically photosensitive, but nonscarring. Vasculitic lesions of the palms, soles, and hard palate are common, as are urticarial rashes. Vasculitic lesions may evolve to gangrene in the case of superinfection or interrupted blood supply. Discoid lupus (DL) is a separate entity that is described later in this chapter. In our experience, the cutaneous manifestations of SLE are more responsive to systemic than topical corticosteroids. For severe, gangrenous vasculitis with a threatened digit or limb, antimicrobial coverage in conjunction with pulse solumedrol and consideration of CYC may be reasonable. For all SLE patients, and particularly those with cutaneous involvement and a history of photosensitivity, the use of sunscreen should be advised. The use of long sleeves, long pants, and sunhats should be encouraged, as should the avoidance of midday sun. This is particularly important for patients living in warm climates. Flares of disease activity can be seen in photosensitive SLE patients following sun exposure. Such flares may be severe and may involve any organ system.

NEW DEVELOPMENTS Recently, a new drug called belimumab has been FDA approved for the treatment of autoantibody-positive SLE in adults. It is an IgG1 monoclonal antibody that inhibits the activity of the soluble cytokine BLyS (B lymphocyte stimulator, also known as BAFF) [67]. Recent trials have shown that belimumab treatment improved SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains [68]. Its success in the

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treatment of other organ system involvement, in conjunction with standard therapy, has been seen in large phase III trials [69]. At this time, belimumab is not yet approved for use in pediatric patients.

GENERAL ASPECTS OF MANAGEMENT While early disease control is crucial for the treatment of children with SLE, a comprehensive approach to care may also reduce long-term morbidity and mortality. In all patients, blood pressure should be as tightly controlled as possible, with the use of antihypertensive agents if necessary. Good blood pressure control is essential for maximal long-term renal, cardiac, and cognitive outcome. Additionally, as lupus patients appear to have an increased risk of early atherosclerotic disease, cardiac risk factors should be minimized with diet, exercise, and maintenance of a healthy BMI. All patients should be counseled as to the dangers of tobacco, alcohol, and illicit drug use. Sexually active adolescents should also be educated about the potential teratogenic effects of common medications. Should a patient wish to become pregnant, she should be transitioned to safer medications for the fetus. Pregnant females who have positive anti-Ro antibodies should also be educated about the possibility of congenital heart block and other manifestations of neonatal lupus in the baby. Osteopenia and osteoporosis are known complications of long-term corticosteroid use. Peak bone mass is achieved in childhood, and the effects of corticosteroids on bone health in children are a particular concern. We advocate the use of calcium and vitamin D supplementation where appropriate. At this time, the use of bisphosphonates in children remains controversial with inadequate data as to long-term safety and future teratogenicity.

COURSE AND PROGNOSIS SLE is a chronic condition, and is manifested by intermittent flares and disease activity. No cure currently exists for SLE, a concept that is initially difficult for many families to accept. The long-term prognosis for children with SLE continues to improve with advances in our understanding of the immune system, better therapies, and improved pediatric intensive care. With early, aggressive treatment, it is our hope that the incidence of renal failure, perhaps the greatest cause of morbidity and mortality, will continue to decrease. Vigilant prevention of infection and general health maintenance, as described earlier, will likely play an increasing role as pediatric SLE patients live longer into adulthood. Patients of non-Caucasian and African-American descent with early disease onset appear to have the poorest long-term prognosis [33].

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ALTERNATE FORMS OF LUPUS: NEONATAL, DISCOID, DRUG-INDUCED SLE is distinct from, and should not be confused with other subtypes of lupus: neonatal, discoid, and drug-induced. Neonatal lupus is seen predominantly in the infants of SSA/Ro and SSB/La positive mothers (who themselves may or may not fulfill criteria for the diagnosis of SLE or other rheumatologic disorders, and who may not know that they have positive serologies). These babies are at risk for congenital heart block requiring pacing. Affected infants present in the first days of life with heart block, rash, transaminitis, and thrombocytopenia. Any or all of these manifestations may be present. The exact etiology of this condition is unknown, but evidence suggests that apoptosis of fetal cardiocytes is followed by exposure of Ro and La antigens, which are in turn bound by maternal autoantibodies, with ensuant inflammation and fibrosis [70]. Discoid lupus (DL) lesions are localized to the skin, and may cause significant pain and scarring. DL patients do not fulfill criteria for SLE, although they are at increased risk of developing systemic involvement, particularly in the face of early-onset disease [71]. Drug-induced lupus (DIL) is diagnosed when clinical and serologic manifestations of SLE appear in patients taking certain medications. Antihistone antibodies may be seen. In true DIL, clinical and serologic manifestations disappear following removal of the offending drug. Drugs implicated in DIL include antiepileptics, tetracyclines, and most recently, anti-TNF-α drugs.

KEY POINTS G

G

G

The etiology of SLE remains unknown. Although great strides are being made toward clarifying the immune dysregulation seen in SLE, clinical disease expression is undoubtedly the end result of varied environmental and immunologic stimuli acting on a genetically predisposed individual. Abnormalities of the T cells, B cells, dendritic cells, Fcγ receptors, proinflammatory cytokines, the complement pathway, and apoptosis have all been found to play a role in the pathogenesis of SLE. As with any chronic medical condition, the treatment of SLE in children is a particular challenge. As children enter adolescence and early adulthood, the desire for a seemingly “normal” life with a sense of independence from parents and medical authority figures may dominate, and compliance may wane. This is particularly true for teenage patients for whom body image issues come to the forefront when faced with the effects of corticosteroid therapy. Treatment of SLE must be individually tailored to each patient’s clinical manifestations. Corticosteroids remain the first line of treatment for SLE.

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However, depending upon the extent and severity of internal organ involvement, medication regimens can range from low-dose corticosteroids and antimalarials to inpatient treatment with pulse methylprednisolone and cytotoxic medications such as CYC and RTX.

REFERENCES [1] Cassidy JT, Petty RE, Laxer R, Lindsley C. Textbook of pediatric rheumatology. London: Elsevier Health Sciences; 2010. p. 315 43. [2] Lehman TJ, McCurdy DK, Bernstein BH, et al. Systemic lupus erythematosus in the first decade of life. Pediatrics 1989;83(2):235. [3] Barsalou J, Levy DM, Silverman ED. An update on childhood-onset systemic lupus erythematosus. Curr Opin Rheumatol 2013;25(5):616 22. [4] Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25(11):1271 7. [5] Kamphuis S, Silverman ED. Prevalence and burden of pediatric-onset systemic lupus erythematosus. Nat Rev Rheumatol 2010;6(9):538 46. [6] Pineles D, Valente A, Warren B, et al. Worldwide incidence and prevalence of pediatric onset systemic lupus erythematosus. Lupus 2011;20(11):1187 92. [7] Hiraki LT, Benseler SM, Tyrrell PN, et al. Ethnic differences in pediatric systemic lupus erythematosus. J Rheum 2009;36:2539 46. [8] Hiraki LT, Benseler SM, Tyrrell PN, et al. Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus: a longitudinal study. J Pediatr 2008;152:550 6. [9] Pluchinotta FR, Schiavo B, Vittadello F, et al. Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes. Lupus 2007;16:550 5. [10] Kirino Y, Remmers EF. Genetic architectures of seropositive and seronegative rheumatic diseases. Nat Rev Rheumatol 2015;11(7):401 14. [11] Rullo O, Tsao B. Recent insights into the genetic basis of systemic lupus erythematosus. Ann Rheum Dis 2013;72(Suppl. 2):ii56 61. [12] Harley JB, Alarcon-Riquelme ME, Criswell LA, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008;40:204 10. [13] Lee HS, Bae SC. What can we learn from genetic studies of systemic lupus erythematosus? Implications of genetic heterogeneity among populations in SLE. Lupus 2010;19(12):1452 9. [14] Sestak AL, Fu¨rnrohr BG, Harley JB, et al. The genetics of systemic lupus erythematosus and implications for targeted therapy. Ann Rheum Dis 2011;70(Suppl. 1):i37 43. [15] Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003;349:1526 33. [16] Kirou KA, Lee C, George S, et al. Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus. Arthritis Rheum 2004;50(12):3958 67. [17] Crow MK. Interferon-alpha: a new target for therapy in systemic lupus erythematosus? Arthritis Rheuma 2003;48(9):2396 401. [18] Zhang Z, Zhang R. Epigenetics in autoimmune diseases: pathogenesis and prospects for therapy. Autoimmun Rev 2015; pii:S1568 9972. [19] Livingston B, Bonner A, Pope J. Differences in clinical manifestations between childhood-onset lupus and adult-onset lupus: a meta-analysis. Lupus 2011;20:1345 55.

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[20] Fardet L, Flahault A, Kettaneh A, et al. Corticosteroid-induced clinical adverse events: frequency, risk factors and patient’s opinion. Br J Dermatol 2007;157:142. [21] Hoes JN, Jacobs JW, Verstappen SM, et al. Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis. Ann Rheum Dis 2009;68:1833. [22] Huscher D, Thiele K, Gromnica-Ihle E, et al. Dose-related patterns of glucocorticoidinduced side effects. Ann Rheum Dis 2009;68:1119. [23] The Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematoss. N Engl J Med 1991;324(3):150 4. [24] Mina R, von Scheven E, Ardoin SP, et al. Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2012;64(3):375 83. [25] Lehman TJ, Onel K. Intermittent intravenous cyclophosphamide arrests progression of the renal chronicity index in childhood systemic lupus erythematosus. J Pediatr 2000;136 (2):243 7. [26] Ginzler EM, Dooley MA, Aranow C. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005;353(21):2219 28. [27] Sundel R, Solomons N, Lisk L. Efficacy of mycophenolate mofetil in adolescent patients with lupus nephritis: evidence from a two-phase, prospective randomized trial. Lupus 2012;21:1433 43. [28] Yildirim-Toruner C, Diamond B. Current and novel therapeutics in the treatment of systemic lupus erythematosus. J Allergy Clin Immunol 2011;127(2):303 12. [29] Lehman TJ, Singh C, Ramanathan A, et al. Prolonged improvement of childhood onset systemic lupus erythematosus following systematic administration of rituximab and cyclophosphamide. Pediatr Rheumatol 2014;12:3. [30] Watson L, Beresford MW, Maynes C, et al. The indications, efficacy and adverse events of rituximab in a large cohort of patients with juvenile-onset SLE. Lupus 2015;24 (1):10. [31] Bennett CM, Rogers ZM, Kinnamon DD, et al. Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura. Blood 2006;107 (7):2639 42. [32] Fu LW, Yang LY, Chen WP, et al. Clinical efficacy of cyclosporin a neoral in the treatment of paediatric lupus nephritis with heavy proteinuria. Br J Rheumatol 1998;37 (2):217 21. [33] Hagelberg S, Lee Y, Bargman J, et al. Longterm followup of childhood lupus nephritis. J Rheumatol 2002;29(12):2635 42. [34] Steup-Beekman GM, Zirkzee EJM, Cohen C, et al. Neuropsychiatric manifestations in patients with systemic lupus erythematosus: epidemiology and radiology pointing to an immune-mediated cause. Ann Rheum Dis 2013;72:ii76 9. [35] Caeiro F, Michielson FM, Bernstein R, et al. Systemic lupus erythematosus in Iranian children. Iran J Med Sci 2006;31(1):44 6. [36] Alpert O, Marwaha R, Huang H. Psychosis in children with systemic lupus erythematosus: the role of steroids as both treatment and cause. Gen Hosp Psychiatr 2014;36 (5):549e1 2. [37] Neuwelt CM, Lacks S, Kaye BR, et al. Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus. Am J Med 1995;98 (1):32 41.

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[38] Bacca V, Lavalle C, Garcia R, et al. Favorable response to intravenous methylprednisolone and cyclophosphamide in children with severe neuropsychiatric lupus. J Rheumatol 1999;26(2):432 9. [39] Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, et al. Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis 2005;64(4):620. [40] Neuwelt CM. The role of plasmapheresis in the treatment of severe central nervous system neuropsychiatric systemic lupus erythematosus. Ther Apherl Dial 2003;7(2):173 82. [41] Milstone AM, Meyers K, Elia J. Treatment of acute neuropsychiatric lupus with intravenous immunoglobulin (IVIG): a case report and review of the literature. Clin Rheumatol 2005;24(4):394 7. [42] Jose J, Paulose BK, Vasuki Z. Mycophenolate mofetil in neuropsychiatric systemic lupus erythematosus. Indian J Med Sci 2005;59(8):353 6. [43] Olfat MO, Al-Mayouf SM, Muzaffer MA. Pattern of neuropsychiatric manifestations and outcome in juvenile systemic lupus erythematosus. Clin Rheumatol 2004;23(5):395. [44] Tomietto P, D’Agostini S, Annese V, et al. Mycophenolate mofetil and intravenous dexamethasone in the treatment of persistent lupus. J Rheumatol 2007;34(3):588. [45] Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 2014;83(2):142 50. [46] Zhou HQ, Leng XM, Zhang FC. Neuropsychiatric manifestations in systemic lupus erythematosus and the treatment of intrathecal methotrexate plus dexamethasone. Zhonghua Yi Xue Za Zhi 2006;86(11):771 4. [47] Samuelson CO, Williams HJ. Ibuprofen-associated aseptic meningitis in systemic lupus erythematosus. West J Med 1979;131(1):57 9. [48] Leon T, Aguirre A, Pesce C, et al. Electroconvulsive therapy for catatonia in juvenile neuropsychiatric lupus. Lupus 2014;23(10):1066 8. [49] Mon T, L’ecuyer S, Farber NB, et al. The use of electroconvulsive therapy in a patient with juvenile systemic lupus erythematosus and catatonia. Lupus 2012;21(14):1575 81. [50] Glidden RS, Mantzouranis EC, Borel Y. Systemic lupus erythematosus in childhood: clinical manifestations and improved survival in fifty-five patients. Clin Immunol Immunopathol 1983;29(2):196 210. [51] Mochizuki T, Aotsuka S, Satoh T. Clinical and laboratory features of lupus patients with complicating pulmonary disease. Respir Med 1999;93(2):95. [52] Schaller J. Lupus in childhood. Clin Rheum Dis 1982;8(1):219 28. [53] Al-Abbad AJ, Cabral DA, Sanatani S, et al. Echocardiography and pulmonary function testing in childhood onset systemic lupus erythematosus. Lupus 2001;10(1):32. [54] Araujo DB, Borba EF, Silva CA. Alveolar hemorrhage: distinct features of juvenile and adult onset systemic lupus erythematosus. Lupus 2012;21(8):872 7. [55] Samad AS, Lindsley CB. Treatment of pulmonary hemorrhage in childhood systemic lupus erythematosus with mycophenolate mofetil. South Med J 2003;96(7):705. [56] Pottier V, Pierrot M, Subra JF. Successful rituximab therapy in a lupus patient with diffuse alveolar haemorrhage. Lupus 2011;20(6):656 9. [57] Mok M, Tsang PL, Lam YM, et al. Bosentan use in systemic lupus erythematosus patients with pulmonary arterial hypertension. Lupus 2007;16(4):279. [58] Oshiro AC, Derbes SJ, Stopa AR, et al. Anti-Ro/SS-a and anti-La/SS-B antibodies associated with cardiac involvement in childhood systemic lupus erythematosus. Ann Rheum Dis 1997;56(4):272.

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[59] Roldan CA, Shively BK, Lau CC, et al. Systemic lupus erythematosus valve disease by transesophageal echocardiography and the role of antiphospholipid antibodies. J Am Coll Cardiol 1992;20(5):1127. [60] Ishikawa S, Segar WE, Gilbert EF, et al. Myocardial infarct in a child with systemic lupus erythematosus. Am J Dis Child 1978;132(7):696. [61] Schanberg LE, Sandborg C, Barnhart HX, et al. Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum 2012;64(1):285 96. [62] Ardoin SP, Sandborg C, Schanberg LE. Management of dyslipidemia in children and adolescents with systemic lupus erythematosus. Lupus 2007;16(8):618. [63] Jovancevic B, Lindholm C, Pullerits R. Anti B-cell therapy against refractory thrombocytopenia in SLE and MCTD patients: long-term follow-up and review of the literature. Lupus. 2013;22(7):664 74. [64] Olfat M, Silverman ED, Levy DM. Rituximab therapy has a rapid and durable response for refractory cytopenia in childhood-onset systemic lupus erythematosus. Lupus. 2015. [65] Erkan D, Vega JA, Ramon G, et al. A pilot open-label phase II trial of Rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum 2013;65: 464 75. [66] Statkute L, Traynor A, Oyama Y, et al. Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation. Blood 2005;106:2700 9. [67] Kandala NB, Connock M, Grove A, et al. Belimumab: a technological advance for systemic lupus erythematosus patients? Report of a systematic review and meta-analysis. BMJ Open 2013;3(7):e002852. [68] Manzi S, Sa´nchez-Guerrero J, Merrill JT, et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis 2012;71:1833 8. [69] Dooley MA, Houssiau F, Aranow C, et al. BLISS-52 and -76 Study Groups. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus 2013;22:63 72. [70] Buyon JP, Rupel A, Clancy RM. Neonatal lupus syndromes. Lupus 2004;13(9):205 12. [71] Moises-Alfarro C, Berron-Perez R, Carrasco-Dazza D, et al. Discoid lupus erythematosus in children: clinical, histopathologic, and follow-up features in 27 cases. Pediatr Dermatol 2003;20(2):103 7.

Chapter 9

Neonatal Lupus Syndromes A. Brucato1, R. Cimaz2 and V. Ramoni1,3 1

Department of Internal Medicine, Ospedale Papa Giovanni XXIII (previously named Ospedali Riuniti), Bergamo, Italy, 2A. Meyer Children’s Hospital and University of Florence, Florence, Italy, 3I.R.C.C.S Policlinico San Matteo Foundation, Division of Rheumatology, Pavia, Italy

INTRODUCTION Neonatal lupus (NL) is an in vivo model of acquired autoimmune disease in which anti-Ro/SSA antibodies are transmitted through the placental barrier from a mother to her fetus [1]. The term neonatal lupus is misleading, since most of the mothers are not affected by systemic lupus erythematosus (SLE), and their infants too are not affected by SLE, but the term has been used since some of these infants may develop a skin rash resembling that observed in adults with subacute cutaneous lupus erythematosus.

ANATOMICAL AND PATHOLOGICAL FINDINGS The majority of the initially reported cases demonstrated fibrosis and or calcification of the atrioventricular (AV) node, and in several cases sinoatrial (SA) nodal scarring was described [2,3]. Endocardial fibroelastosis (EFE) has been demonstrated in anti-SSA/ Ro SSB/La-exposed fetuses with and without the presence of heart block, and it is currently acknowledged as a manifestation of NL [4 6]; the clinical significance of the detection of EFE is not clear [6]. Llanos analyzed the largest series of 18 autopsies of cardiac NL cases. Fibrosis of the AV node/distal conduction system was the most characteristic finding. Pathological findings included fibrosis/calcification of the AV node, SA node and bundle of His, EFE, papillary muscle fibrosis, valvular disease, calcification of the atrial septum, and mononuclear pancarditis. Clinical rhythm did not always correlate, with two cases of advanced block observed on the echocardiogram but with no reported pathology of the AV node. This could be explained by a functional disorder. Moreover echocardiograms did not consistently detect pathologies such as EFE or valvular diseases, that Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00009-8 © 2016 Elsevier B.V. All rights reserved.

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may be now considered part of the spectrum of NL, supporting evaluation of anti-SSA/Ro SSB/La antibodies in the mothers of children with unexplained valvular defects (see “Immunomediated Valvular Damage” section) [7].

PATHOGENESIS The manifestations are not only associated but causally related with the presence of anti-Ro/SSA antibodies [1,8]; their pathogenicity is supported also by the fact that, with the only exception of congenital heart block (CHB), clinical manifestations disappear in temporal relationship with clearance of antibodies from the baby’s circulation. These antibodies, in fact, cross the placenta beginning at approximately 16 weeks of gestation and reach the fetal tissues. Years ago antibodies to native 60-kD and denatured 52-kD Ro/ SSA were found to be enriched only in the heart eluate, and not in the eluates from brain, kidney, and skin of a child who died with congenital complete heart block (CCHB) [1]. The pathogenic antibodies may display at least three effects, not mutually exclusive, on cardiac tissues: myocarditis, arrhythmogenesis, and interference with apoptosis.

Myocarditis An inflammatory component is supported by the mononuclear cell infiltration in the myocardium as well as by the deposition of IgG, complement, and fibrin [3,5]. The first cardiac lesion may be a pancarditis resulting in fibrosis of the conducting system. The picture might vary from a clear inflammatory state to the presence of calcifications only, depending on the time when the pathological evaluation is performed. A generalized myocarditis/cardiomyopathy, possibly also with EFE, may rarely occur after birth. Echocardiographic evidence of myocarditis remains extremely rare [9,10]. Llanos et al. reported mononuclear pancarditis (macrophages and giant cells) [7].

Arrhythmogenesis and Electrophysiological Effects Boutdjir showed incredible effects on conduction and heart rate of whole human fetal hearts obtained after elective termination of normal pregnancy. Perfusion of the heart with purified anti-52-kD SSA/Ro antibody resulted in bradycardia associated with widening of the QRS complex and, at 33 minutes of perfusion, complete AV block. Reperfusion of the heart with antibody-free solution resulted in recovery. Superfusion of hearts with IgG fractions also induced bradycardia and AV dissociation [11].

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Other publications have shown arrhythmogenic effects of anti-Ro/SSA antibodies in animal or human myocardial tissues [12 14] interfering with both L-type and T-type calcium channels. An autoantibody binding site has been identified on the extracellular loop (domain I, S5 S6) of alpha(1D) L-type Ca channel (the pore-forming subunit of the channel) [15]. Anti-Ro/SSA may also target an extracellular epitope of a1G T-type calcium channels in human fetal cardiomyocytes [16], but the Buyon’s group did not confirm this finding [17]. A Swedish study showed that pups born to rats immunized with the p200 peptide developed AV block [18] and that p200-specific autoantibodies bound cultured cardiomyocytes, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and apoptosis. These important findings might be the link between reaction with calcium receptors, arrhythmogenesis, apoptosis, and fibrosis [18]. Furthermore, QT interval may be prolonged in children from anti-Ro/ SSA-positive mothers [19], raising the possibility that other ionic channels might be affected as well. Two different groups then observed prolongation of the corrected QT interval (QTc) in anti-Ro/SSA-positive adults [20 22]. Recently anti-Ro-positive sera, purified IgG, and affinity purified anti-52kD Ro from patients with autoimmune diseases and QTc prolongation were tested on IKr using HEK293 cells expressing HERG channel and native cardiac myocytes. Anti-Ro inhibit IKr to prolong action potential duration by directly binding to the HERG channel protein. 52-kD Ro antigen-immunized guinea pigs showed QTc prolongation on ECG. The authors concluded that anti-Ro/SSA inhibit IKr by cross-reacting with the HERG channel likely at the pore region where homology between 52Ro antigen and HERG channel is present. Together, they proposed that adult patients with anti-Ro/SSA with QTc prolongation should receive counseling about drugs that may increase the risk for arrhythmias [23]. Other interferences of anti-Ro/SSA antibodies have been demonstrated with M1 muscarinic acetylcholine [24], serotoninergic 5-hydroxytryptamine (5-HT4) receptors [25], and with inner ear antigens, such as Cogan peptide [26].

Apoptosis, Transforming Growth Factor-β, Toll-Like Receptor, and the Road to Scar Ro and La antigen are expressed on the surface blebs of apoptotic cells including human fetal myocytes [27]. Tran demonstrated the subcellular translocation also of La autoantigen in vivo during apoptosis in the fetal conduction system in mice, and showed that transplacental anti-La autoantibodies bind specifically to apoptotic cells [28]. Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies [29].

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Accordingly, it has been reported that anti-SSA/Ro autoantibodies, once bound to apoptotic fetal cardiocytes, might promote phagocytosis by macrophages and the secretion of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β. TNF-α may induce an inflammatory process, but TGF-β induces a profibrotic activation of myofibroblast. This might be one of the fetal factors facilitating fibrosis at the level of the conduction tissue [30]. Accordingly, the profibrotic TGF-β genotype has been detected in a twin with CCHB but not in his healthy twin [31]. To be expressed on the surface of apoptotic fetal cardiomyocites Ro60 requires binding with its Y3 RNA [32]. β(2)-glycoprotein I (β(2)GPI) interacts with Ro60 on the surface of apoptotic Jurkat cells and prevents binding of anti-Ro60 IgG, preventing opsonization of apoptotic cardiomyocytes by maternal anti-Ro60 IgG [33]. Surface binding of anti-Ro60 to apoptotic cardiocytes activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/ uPAR) system. Subsequent plasmin generation facilitates increased binding of anti-Ro60 by disrupting and cleaving circulating β2GPI, thereby eliminating its protective effect [34]. Activation of toll-like receptors (TLRs) by ssRNA after FcγR-mediated phagocytosis of immune complexes may be relevant. Both macrophage transfection with noncoding ssRNA that bind Ro60 and an immune complex generated by incubation of Ro60-ssRNA with IgG from a CHB mother or affinity purified anti-Ro60 significantly increased TNF-α secretion. Dependence on TLR was supported by the significant inhibition of TNF-α release by IRS661 and chloroquine. Fibrosis markers were increased in fetal cardiac fibroblasts after incubation with supernatants from macrophages transfected with ssRNA or incubated with the immune complex. Supernatants generated from macrophages with ssRNA in the presence of chloroquine did not cause fibrosis. In a CHB heart, but not a healthy heart, TLR7 immunostaining was localized to a region near the AV groove. These data support an injury model in CHB, whereby endogenous ligand, Ro60associated ssRNA, forges a nexus between TLR ligation and fibrosis instigated by binding of anti-Ro Abs to the target protein likely accessible via apoptosis, and explains a possible protective role of chloroquine [35].

Genetics Susceptibility genes may involve a broad spectrum of candidates ranging from affector pathways involving antigen presentation (eg, human leukocyte antigen, HLA) to effector pathways controlling inflammation and fibrosis. Maternal genes HLA DRB1 02 and  03 are strongly associated with the presence of SSA/Ro SSB/La [36]. A polymorphism at 308 promoter (TNF-2) of the TNF-α gene and leucine polymorphism at codon 10 of the TGF-β gene (potentially conferring increased inflammation and scarring

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potential, respectively) occur more frequently in children with CHB than their unaffected siblings [37]. Siren reported an increased frequency of Class I HLA-Cw3 in CHB children [38]. HLA alleles enriched in the mothers were DRB1 03DQB1 02, DQA1 05, and HLACw7 [39]. A family in which CHB developed in a fetus conceived by in vitro fertilization of a donor egg implanted in an unrelated woman with anti-SSA/Ro antibodies provided insight into these issues. There was an HLA mismatch between the affected fetus and the surrogate mother. However both the biologic and surrogate mother shared DQ2 and the profibrosing leucine polymorphism at codon 10 of TGF-β. This observation showed that it is possible that there is no direct association of maternal genes beyond a contributory role in generating the autoantibody [40]. Clancy genotyped 116 NL children and merged with 3351 controls. The most significant associations with CHB were found in the HLA region. The region near the MICB gene showed the strongest variant, between NOTCH4 and BTNL2, and several single nucleotide polymorphisms near the TNF-α gene. Outside the HLA region, an association was detected at 21q22, upstream of the transcription regulator ets-related isoform 1. HLA notwithstanding, no individual locus previously implicated in autoimmune diseases achieved genome-wide significance [41]. The same group found a highly significant enrichment for genes related to fibrosis, apoptosis, and innate immune cell, T cell, and interferon functions; the most significant non-HLA associations included the sialyltransferase gene ST8SIA2, the integrin gene ITGA1, and the complement regulator gene CSMD1, identifying novel candidate genes associated with cardiac NL [42]. The Swedish group performed genotyping in 86 families. HLA-DRB1 04 and HLA-Cw 05 variants were significantly more frequently transmitted to CHB cases, whereas HLA-DRB1 13 and HLA-Cw 06 were significantly less often transmitted. Furthermore a marked association of increased paternal (but not maternal) HLA-DRB1 04 transmission to affected offspring was observed. The authors concluded that HLA-DRB1 04 and HLA-Cw 05 were identified as novel fetal HLA allele variants that confer susceptibility to CHB, whereas DRB1 13 and Cw 06 emerged as protective alleles. Additionally, a paternal contribution to fetal susceptibility to CHB was demonstrated [43].

Other Pathogenetic Mechanisms Only a minority (1 2%) of mothers with anti-Ro and anti-La antibodies deliver an affected child. Also intriguing is the discordance of the disease in monozygotic twins [44,45]. The persistent presence of maternal cells in the fetal heart (microchimerism) is a hypothesis to explain a local immune-mediated response [46].

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CHB was associated with higher maternal age and displayed a season-ofbirth pattern in a Swedish study [47]. Gestational weeks 18 24 occurring during January through March correlated with a higher proportion of CHB children, eventually due to lower levels of vitamin D in those winter months (but the American group did not confirm this finding). Counseling might be not to conceive from September to December for anti-SSA-positive woman.

EVALUATION OF THE FINE SPECIFICITIES OF THE MATERNAL AUTOANTIBODY PROFILE SSA/Ro is a complex system, associated with RNA, the function of which is not completely known, that comprises at least two polypeptides of molecular weight, respectively, of 52 and 60 kD. Novel interest was raised by a small central portion of 52 kD Ro, from 200 to 239 amino acids named p200 that could represent the fine specificity of anti-Ro Ab associated to CHB. Salomonsson et al. [48] described the presence of anti-p200 in nine out of nine mothers who delivered babies with CHB, and demonstrated that anti-p200 inoculation in rat pups was associated with cardiocytes Ca2+-homeostasis dysregulation, leading to an increase in heart cell death, atrium-ventricular conduction prolongation, and to CHB [18]. Clancy et al. [49] did not confirm these findings. Strandberg et al. showed an association between high titers of maternal anti-p200 Ab and CHB in a wide multicenter study [50]. An animal model demonstrated that the inoculation of anti-p200, but not of anti-52-kD Ro Ab without p200 peptide specificity, was able to cause heart block in rat pups [51]. In a study of 115 anti-Ro-positive mothers, both maternal anti-Ro52 and p200 autoantibodies were less than 50% specific for cardiac NL, but antip200 was the least likely of the Ro autoantibodies to be false-positive in mothers who have never had an affected child [52]. We retrospectively evaluated 207 Italian women carrying anti-Ro/SSA Ab. CHB occurred in 42 children, whereas 165 were not affected. Anti-p200 were more frequently positive (81.0% vs 59.1%, P 5 0.013) and at a higher titer in CHB mothers (OR for CHB: 2.98). CHB risk significantly decreased in the absence of this specificity (OR: 0.34). However, while the negative predictive value related to anti-Ro/SSA 60 kD Ab ELISA was 100%, almost 20% of mothers negative for anti-p200 Ab delivered babies with CHB. An ELISA screening for anti-Ro/SSA 60 kD Ab is mandatory given the probability of developing CHB also in the absence of anti-p200 Ab [53].

EPIDEMIOLOGY AND DEFINITION OF CONGENITAL COMPLETE ATRIOVENTRICULAR BLOCK NL affects equally males and females. CCHB has an incidence of 1:20,000 live births [54]; however these numbers include CCHB associated with

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anatomical malformations, and exclude in utero deaths. Overall studies of CCHB due to all etiologies observe that 14 42% of cases are due to anatomical abnormalities; assuming that the remaining are autoimmune the global incidence of immune-mediated CCHB is probably 1 in 20,000 30,000 [55]. Confusion exists regarding congenital versus acquired AV block; for these reasons we proposed a new definition: “an AV block is defined as congenital if it is diagnosed in utero, at birth or within the neonatal period (0 27 days after birth)” [56]. This definition is now generally accepted [55].

CLINICAL FEATURES Risk of Delivering a Child With Congenital Complete Heart Block: 1 2% In a prospective study we found that the prevalence of CHB in newborns of 100 women already known to be anti-Ro/SSA-positive and with known connective tissue disease was 2% (95% confidence interval 0.2 7%) [57]. We studied only mothers who had been found to be anti-Ro/SSA-positive by counterimmunoelectrophoresis, a method with high specificity and low sensitivity, to exclude women with low or dubious titers of anti-Ro/SSA. This finding has been confirmed by other groups: Gladman et al. reported no cases of CHB in 100 live births in 96 women [58]; Cimaz et al. observed 2 cases of CCHB out of 128 infants (1.6%) [59], and Costedoat-Chalumeau et al. 1 case/99 infants (1%) [60]. Motta et al. observed a prevalence of 1/50 (2%) [61], Gerosa et al. 1/60 (1.7) [62], Friedman et al. 2/74 (2.7%) [63], Rein et al. 0/70 (0%) [64], and Jaeggi et al. 1/165 (0.6%) [65]. Overall a metaanalysis including all the studies available would give a prevalence of 10/746 cases (1.3%) in women with anti-SSA/Ro and no history of a previous child with NL.

Is It Possible to Refine the Risk? If the mother is anti-La/SSB-positive the risk might increase to 3%, while if negative might decrease to 0.9% [66]. If the mother has antithyroid Ab or is hypothyroid the risk should increase, with an estimated odd ratio of 8.6 [67,68]. We observed that the risk for CHB was ,1% in women anti-p200negative [53]. Does the Antibody Titer Matter? The Canadian group tested in ELISA 186 anti-Ro/SSA-positive women and found that all cardiac complications of NL were associated with at least moderate titer of anti-SSA (.50 U/mL); no case of cardiac NL was observed in mothers low-positive for anti-Ro (,50 U/mL) [69].

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In practice, positivity for anti-Ro/SSA must be reliable, and ELISA low titers probably are not relevant. These findings might be important in deciding which woman to monitor during pregnancy.

Cardiac Manifestations Atrioventricular Block CCHB is the most severe manifestation of NL, since it is irreversible and carries a high morbidity and mortality rate, mainly related to the ventricular rate, which usually ranges between 30 and 80 beats/minute; the lower the rate, the higher the possibility of fetal hydrops, neonatal cardiac failure, and death [70 74]. The more relevant clinical data are reported in Table 9.1. In our series 8/28 fetuses had hydrops [73]. The fetuses with hydrops had the same age of presentation, a lower mean heart rate and their mortality was 37.5%. Pacemakers were implanted in 22/26 infants born alive, at a median of 45 days (range 1 day to 5 years). Steroids ameliorated rapidly the hydrops in three of five cases. In 2011 two large series of cardiac NL were published, one from Europe and one from the United States. The Fetal Working Group of the European Association of Pediatric Cardiology published a large retrospective series [72]. Survival in the neonatal period was 93%, similar in steroid-treated and untreated fetuses. Variables associated with death are reported in Table 9.1. The presence of .1 of these variables was associated with a 10-fold increase in mortality before birth and a 6-fold increase in the neonatal period independently of treatment. No significant effect of treatment with fluorinated corticosteroids (CSs) was seen. The American group also published a large study in 2011: the main findings are summarized in Table 9.1 [71]. CCHB is most frequently detected in utero by prenatal ultrasound, between 16 18 and 24 weeks of gestational age [74]. This window is related to the timing of transplacental passage of autoantibodies (that does not start before the third month of gestation) and of the ontogenic development of the cardiac conduction system, that is not fully developed until about 22 weeks. The rapidity of clinically detectable injury is supported by the report of normal sinus rhythm progressing to irreversible third-degree block within 1 week, observed in the United States, Sweden, and Italy [63,75]. Most of these infants are delivered preterm (35 weeks gestation) [71,76,77]. In utero death is usually related to intractable heart failure, but may occur suddenly [70,73]. Other Electrocardiographic Abnormalities Incomplete AV blocks (first and second degree) and sinus bradycardia have been reported [76,78]. This last finding is of importance, since it suggests

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TABLE 9.1 Outcome of Infants With Cardiac Neonatal Lupus in Three Large International Series and in One Italian Series Lopes 2008 [74]

Eliasson 2011 [72]

Izmirly 2011 [71]

Fesslova 2009 [73]

Number of fetuses

57 with normal cardiac anatomy

175

325

28

Total mortality

13 (23%)

27 (15%)

57 (17.5%)

4 (20%)

Mortality in utero

6 (10%)

16 (9%)

19 (6%)

Perinatal mortality

7 (12%)

11 (7%)

38 (12%)

Pacemaker implantation

51%

66%

70%

84%

Late-onset cardiomyopathy

3%

4.6%

4 cases of heart transplantation

Not reported

Treated with fluorinated corticosteroids

10%

38%

90%

71%

Effects of corticosteroids

None

None on mortality; possibly reversal on incomplete AV block

Possibly reversal on incomplete AV block

Possible favorable effect on fetal hydrops

Reversal of II degree AV after fluorinated corticosteroids

None

In 3/7 fetuses treated vs 0/8 untreated

In 4/13 fetuses treated vs 1/8 untreated

No cases of II degree AV block

Variables associated with death

Atrial rate ,120 bpm, ventricular rate ,55 bpm, hydrops

Gestational age ,20 weeks, ventricular rate ,50 bpm, hydrops, impaired left ventricular function

Earlier gestational age, lower ventricular rate, hydrops, EFE

Lower ventricular rate, hydrops

(Continued )

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TABLE 9.1 (Continued) Lopes 2008 [74]

Eliasson 2011 [72]

Fesslova 2009 [73]

86%

Survival at 10 years for a child born alive Maternal antiRo/SSA antibodies

Izmirly 2011 [71]

72%

80% of 162 pregnancies with documented antibody status

100%

100%

that the sinus node can also be affected. We have shown QT prolongation in infants from mothers with anti-SSA/Ro antibodies [19]. The French group has not confirmed this finding in 152 pregnancies in 96 anti-SSA-positive women [60]. On the other hand a QT interval prolongation has been reported also in adults positive for anti-SSA/Ro [20 22], and recently it has been shown that anti-Ro-positive sera inhibit IKr to prolong action potential duration by directly binding to the HERG channel protein inducing QTc prolongation [23]. Therefore this topic is still a matter of debate. Two relevant papers concerning ECG abnormalities in infants born from anti-Ro/SSA-positive mothers are two prospective controlled observational Italian studies. Gerosa prospectively followed 60 anti-Ro-positive and 36 anti-Ro-negative women before and during pregnancy and underwent weekly fetal echocardiography from the 18th to 26th weeks of gestational age. Infants’ ECG and/or ECG-Holter were performed at 1, 3, 6, and 12 months. ECGs of 200 consecutive neonates were used as a healthy control group. One of 61 fetuses of anti-Ro-positive mothers developed CHB; another anti-Ro-positive baby developed second-degree AV block (30th week). The prevalence of transient first-degree AV block detected postnatally was significantly higher in the anti-Ro-positive group (p 5 0.002). No differences in QTc interval prolongation prevalence ($440 ms) was observed between the anti-Ro-positive and -negative groups, but both were significantly higher than that of the control population (p , 0.001). ECG-Holter showed QTc prolongation in 59% of infants of anti-Ro-positive and in 60% of infants of anti-Ro-negative mothers. Holter QTc was $ 470 ms in four infants of the anti-Ro-positive group and two of the anti-Ro-negative group. This prospective study confirmed that ECG abnormalities (first-degree AV block and QTc interval

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prolongation) are frequent in infants of mothers with autoimmune diseases, independently of maternal disease, autoantibody profile, and treatment during pregnancy [62]. Motta evaluated neonates born from mothers with connective tissue disease and positive (51 infants) or negative (50 control infants) for anti-SSA/ Ro antibodies. No infant showed sinus bradycardia. A first-degree AV block at birth was observed in five study groups and no control group infants (p 5 0.023). AV blocks spontaneously reverted or remained stable during the first year of life. Mean QTc of infants born from anti-SSA/Ro-positive mothers was slightly prolonged as compared with the control group (0.404 6 0.03 s vs 0.395 6 0.02 s; P 5 0.060) [61]. These two studies overall concluded that several minor ECG abnormalities may be present in infants born to anti-SSA-positive mothers but also born to women with autoimmune diseases but that are anti-SSA-negative, and that their clinical relevance is modest.

Immunomediated Valvular Damage Valvular disease caused by the dysfunction of the AV valve tensor apparatus may be a severe complication of NL [7], reported in 14/255 (5.5%) babies [71]. A study has detailed the clinical approach of six affected babies [79]. Autoimmune Endocardial Fibroelastosis and Cardiomyopathy Fetal EFE has been associated with maternal anti-SSA antibodies, both with and without conduction disorders [4,6,7]; prenatal echocardiographic signs of EFE are manifest as areas of patchy echogenicity (fibrosis) on the endocardial surfaces. The long-term implication of this finding is not clear, but EFE may be linked to the following development of severe cardiomyopathy. A subset of patients with CCHB may in fact develop late-onset dilated cardiomyopathy (approximately 4 8%) [71,72,77,80 82]. Biopsy revealed hypertrophy, interstitial fibrosis, and rarely myocyte degeneration. The majority of affected children die from congestive heart failure or require cardiac transplantation, while a recovery was reported in a few cases [80].

Skin Rash A skin rash can be present in the neonatal period, but more frequently it appears between the second and third month of life [83]. Unlike CHB, it disappears with the clearance of maternal autoantibodies from the baby’s circulation, usually without any residual. The rash is erythematous and scaly, similar to subacute cutaneous lupus erythematosus (this is the origin of the name Neonatal Lupus). It is frequently annular in shape, and mostly located in sun-exposed areas with a characteristic predilection for the periorbital area. Ultraviolet exposure may be an exacerbating factor. Data regarding

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skin pathology are scanty. Penate described five cases and reviewed the literature, observing vacuolar alteration at the dermoepidermal interface and adnexal structures. Some cases exhibit a superficial and deep perivascular and periadnexal lymphocytic infiltrate without epidermal alteration [84]. Since these lesions are self-limiting, usually no treatment is required.

Neurological Problems and the Possible Role of Fluorinated Corticosteroids Hydrocephalus and macrocephaly have been occasionally suggested [85]. The presence of maternal anti-Ro/SSA antibodies per se may be associated with learning disabilities in the offspring [86]. Animal [87,88] and human [89,90] observations suggest that repeated antenatal steroid doses can interfere with the development of the immature brain, suggesting that dexamethasone may negatively affect the child’s neuropsychological development. In light of these findings CHB babies who are both treated in utero with high-dose dexamethasone and exposed to maternal anti-Ro/SSA antibodies could be at risk for neurodevelopmental defects. We have therefore tested 16 CCHB patients for neuropsychological development, IQ, and learning disabilities. The children had been exposed in utero to a mean dose of 186.6 mg of dexamethasone. IQ levels were always normal; only one child had a learning disability, of borderline clinical significance, but this child had never been exposed to dexamethasone [91]. The issue has been further studied by other groups. Questionnaires related to neuropsychiatric development were sent to all mothers enrolled in the Research Registry for NL. Controls consisted of healthy friends; 121 antiRo-exposed children and 22 friend controls were studied. Forty percent of the anti-Ro-exposed children were reported to have a neuropsychiatric disorder, compared with 27% of the friend controls (p 5 0.34). The prevalence of depression, anxiety, developmental delays, learning, hearing, and speech problems were not significantly different between groups. Parental reporting of neuropsychiatric abnormalities was high in anti-Ro-exposed children regardless of the NL manifestation. However, it did not reach significance [92]. Medical records of a Swedish cohort of siblings with (n 5 60) and without (n 5 54) CHB born to anti-Ro/SSA-positive mothers were retrieved from primary healthcare centers. Impaired neurodevelopment was reported in 16% (18/114) during the follow-up of 13 years. Reported problems included speech (9%), motor (8%) and learning (8%) impairment, attention deficit (5%), and behavioral impairment (4%). Learning impairment was significantly influenced by maternal SLE (p , 0.005), while attention deficits was influenced by both maternal SLE (p , 0.05) and CHB in the child (p , 0.05). The authors concluded that in addition to well-established factors such as male sex and being born preterm, both maternal SLE and CHB may influence neurodevelopment [93].

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The Canadian group confirmed our reassuring findings [94] performing a prospective, blinded assessment of the cognitive functioning of children aged 6 16 years with in utero exposure to maternal anti-Ro antibodies in the following three groups: no CHB and no prenatal dexamethasone treatment (n 514), CHB without prenatal treatment (n 510), and CHB with prenatal dexamethasone treatment (n 516). Domains assessed included intelligence, visual perceptual and visual motor skills, auditory and visual attention, verbal learning and memory, visual memory, executive function, and behavior. All cohorts scored within the normal range and were not significantly different in any domains. There were no significant associations between the neurocognitive function scores, the minimal fetal heart rate, and either the duration or dosage of dexamethasone therapy. Overall although it is possible that repeated course of dexamethasone may be detrimental to the newborn’s neurodevelopment, a child’s final intellectual maturation remains a complex process, involving the interplay of biological, social, and cultural factors. We and the Canadian group observed no negative effects on the neurodevelopment of our patients, many of them exposed to very high dosages of dexamethasone (much higher than those used to enhance fetal lung maturity). CHB is a rare disease, but these reassuring findings might be clinically relevant also for the large number of newborns treated with repeated courses of antenatal fluorinated steroids to induce fetal lung maturity.

Laboratory Abnormalities Anemia, thrombocytopenia and neutropenia have been described [95,96]. Hepatic involvement has also been described [97,98]; it can vary from asymptomatic increase in transaminases to severe cholestasis. This has been noted to be present at birth in some cases but has not been clinically evident until several weeks in others. We observed hematologic abnormalities in 27% of the babies and elevation of liver enzymes in 26% [59]. As for skin rash these manifestations are transient and usually do not need medical treatment. At variance with previous studies, Motta observed a low frequency of hematologic abnormalities and no cases of hepatobiliary disease in 50 infants [61].

PROGNOSIS Infants CCHB is a severe disease (Table 9.1). Mortality, usually in utero or in the first 3 months of life, can reach 30%. In the perinatal life, pacemaker implantation is considered only if clinically indicated, while in the following years prophylactic pacemaker treatment might be considered even in asymptomatic patients because of unpredictable Stokes Adams attacks; overall 60 70% of these children are paced [55,72].

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Median age at pacemaker implantation was 3.2 years in 127 Swedish children [82]. The probability to develop left ventricular dysfunction or cardiomyopathy over time is 4 8% [71,72,77,80 82]. After pacemaker implantation, most of these children can live an almost normal life. The possibility for these children to develop SLE or another connective tissue disease in later life seems to be rare [99,100], not higher than in asymptomatic children of mothers with autoimmune diseases [100,101].

Maternal Most mothers are asymptomatic at the time of NL detection. In a review of 856 mothers more than half were classified as asymptomatic, and in the remaining cases SLE or primary Sjogren’s syndrome were diagnosed in the majority of cases [55]. The long-term prognosis of these mothers is good, since only half of them eventually develop a connective tissue disease, mild and non-lifethreatening in most cases [99,102 104]. Rivera showed that the probability of an asymptomatic mother developing SLE by 10 years was 18.6%, and developing probable/definite Sjogren’s was 27.9% [105].

RISK OF RECURRENCE The risk of recurrence of CHB is 15 20% [106,107]. This probability seems lower in Sweden: 12% [47]. The risk of CHB seems similar even after a case of skin rash only [55].

Obstetric Management of Pregnancy at Risk of Developing Congenital Complete Heart Block A woman is at risk if she is definitely anti-Ro/SSA-positive. If the positivity is uncertain or the titer is very low, we advise to confirm it with standard methods or in reference laboratories. The management of anti-Ro/SSA-positive women is based on expert opinion. Routine management might differ from management in research centers. Protocols vary from weekly serial sonograms to no particular screening [108]. Most centers perform serial echocardiograms and obstetric sonograms at least every 2 weeks starting from the 16 weeks’ gestation. The goal is to detect early fetal abnormalities, such as mechanical PR prolongation (firstdegree AV block), frequent ectopic beats, echodensities, pericardial or pleural effusions, decreased contractility, and valve regurgitations, which might

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precede complete AV block and which might be a target of preventive therapy [109]. Prophylactic therapy with dexamethasone or betamethasone is not recommended, because of the low risk of CCHB and the potential side effects [110]. Other steroids are not useful since they do not cross the placenta in active form.

Assessment of First-Degree Atrioventricular Block In Utero Fetal ECG is not available. The relative timing of atrial and ventricular contractions determined by echocardiography can infer AV conduction time. Mechanical PR interval assessed by echocardiography measures the AV conduction time. Friedman studied this parameter in 98 fetuses weekly from 16 weeks [63]: prolongation of PR interval was uncommon and did not precede advanced block; complete block occurred in one case within 1 week of a normal echocardiogram. An Israeli group assessed the fetal AV conduction time with tissue velocity-based fetal kinetocardiogram in 70 fetuses. Six fetuses developed a first-degree block; treatment with dexamethasone resulted in normalization in all [64]. The Canadian groups prospectively evaluated 165 fetuses. CCHB developed in just one. Of 15 untreated fetuses either with AV prolongation or with second-degree block, progressive block developed in none; three of these infants had a neonatal first-degree block that spontaneously resolved in two cases or has not progressed in the third case [65]. Overall the natural history of fetal first-degree block remains unknown [75], with few data on spontaneous reversibility and progression. Investigators are encouraged to share echo tapes to validate the reliability of these candidate biomarkers [108].

Fluorinated Steroids and Regression of Second-Degree Atrioventricular Block Permanent reversal of fetal second-degree AV block is rare, and only one case of spontaneous resolution of second-degree AV block in fetuses of antiRo/SSA-positive mothers have been reported [71], whereas cases of reversal after steroid treatment have been described [111 113]. In two large studies reversal to normal sinus rhythm was observed in some cases (Table 9.1) [71,72]. However, to differentiate incomplete from complete AV block is very difficult in utero, requiring a particular expertise.

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TREATMENT In Utero Therapy There is no known effective therapy for CCHB. Prenatal interventions try to diminish the autoimmune response and/or the cardiac inflammatory injury, and to increase fetal heart rate [114].

Fluorinated Corticosteroids Fluorinated CSs (dexamethasone and bethametasone) are used, since they are not metabolized by the placenta and are available to the fetus in an active form. Steroid therapy has been reported as effective in the resolution of inflammatory signs (pleural effusions, ascites, and hydrops) in a few case reports [111,113]. However treatment is not able to revert third-degree heart block (presumably fibrosis of conducting system), even if the prognosis of these fetuses is related not only to the block itself, but also to other conditions (cardiac contractility, hydrops, etc.). Therapy is based on expert opinions [114]. Three main studies retrospectively evaluated the effects of fluorinated CSs in CCHB: one Canadian [115], one European [72], and one American [71] the Canadian study found CSs effective, the European ineffective, and the American gave dubious results. The Canadians studied 37 cases of fetal CHB. Twenty-one fetuses were treated with dexamethasone and had a 1-year survival rate of 90%, compared with 46% without glucocorticoid (p , 0.02). Immune-mediated conditions (myocarditis, hepatitis, cardiomyopathy) resulting in postnatal death or heart transplantation were significantly more common in untreated compared with patients treated with steroids (0/18 vs 4/9 live births; P , 0.007) [115]. The European study observed 175 fetuses; 67 cases (38%) were treated with fluorinated CSs. In steroid-treated fetuses, intrauterine survival was 91%, the same as in those not treated. On the other hand CSs were associated to a possible regression of incomplete AV block (Table 9.1). In the American study CSs were given to the majority of the fetuses (90%) and a possible beneficial role in the regression of II degree AV block was observed [71] (Table 9.1). These authors correctly observed that in a retrospective study fluorinated CSs are generally prescribed in more severe cases, which is the likely reason for their association with mortality rather than direct causality. Fetal cardiologists lack consensus on treatment, with some centers always using fluorinated steroids [115] and other centers never using them [74], even in the most severe cases [72]; many fetal cardiologists use steroids only in fetuses with hydrops. Repeated course of steroids may induce potential harm for the mother and the fetus (see “Neurological Problems and the Possible Role of Fluorinated Corticosteroids” section). The possible negative effects seem

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more linked to dexamethasone, and it has been suggested that betamethasone should be preferred when available [116,117]. A previous Cochrane review show that only betamethasone and not dexamethasone significantly reduces neonatal mortality [118]. On the other hand a recent Cochrane review observed that dexamethasone may have some benefits compared with betamethasone such as less intraventricular hemorrhage, and a shorter length of stay in the neonatal intensive care unit [119], concluding that trials comparing the commonly used CSs are urgently needed. We now use bethametasone instead of dexamethasone in CCHB, in agreement with the French group [120]. Possible beneficial effects need to be balanced against adverse effects, including specific fetal risks (oligohydramnios and adrenal suppression). We suggest the following schema. If the block is incomplete (eg, second degree), bethametasone 4 mg once or twice daily to the mother is started, with a note of caution: to differentiate incomplete from complete AV block may be difficult in utero. If the block is recent (the more common clinical situation) bethamethasone is recommended as well; the dose is tapered and betamethasone is discontinued if no change occurs after several weeks. If the block is associated with signs of myocarditis, heart failure, or hydropic changes, betamethasone is recommended. If the block is complete and present for more than 2 4 weeks, with no effusions and no signs of hydrops, only serial echograms should be performed, with no therapy [114].

Intravenous Immunoglobulins Ruffatti treated two consecutive cases of anti-Ro/La-related second-degree block with betamethasone (4 mg/day), weekly plasmapheresis, and intravenous immunoglobulin (IVIG) (1 g/kg) administered every 15 days begun shortly after CHB was detected and continued until delivery. The newborns were also treated with IVIG (1 g/kg) fortnightly until the anti-Ro/La antibody levels became undetectable. In both cases second-degree AV block reverted to a stable sinus rhythm with a first-degree AV block [121]. The puzzle is that other groups reported quite good outcomes even without any therapy [74]. Also David et al. used IVIG to prevent progression of incomplete early AV block at the dose of 400 mg/kg/day for 5 days; after two maternal infusions the fetal heart rate reverted to sinus rhythm [122]. We treated two fetuses with incomplete AV block with IVIG but blocks remained unchanged [10]. Probably IVIG might be useful also in treating fetal myocarditis. We have treated with IVIG (400 mg/kg/day for 5 days) a mother whose fetus had CCHB and clear echocardiographic evidence of myocarditis: the myocarditis quickly resolved, but the complete AV block persisted [10]. A possible therapeutic window for IVIG in the early treatment of complete or incomplete AV block is accordingly under discussion [114,121,123,124].

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On the other hand IVIG was ineffective in preventing the recurrence of CHB in women who previously had a fetus with NL; in these studies IVIG was administered at a substitutive dose: 400 mg/kg at weeks 12, 15, 18, 21, and 24 of pregnancy [125,126]. IVIGs were also effective in treating fetuses with EFE [127].

Betaagonists Terbutaline or salbutamol, selective beta-2 adrenergic agonists, may increase the fetal heart rate, improving ventricular function, particularly as a bridge to reach a more advanced gestational age [73,128], gaining some days. Salbutamol can be given orally to the mother, at a dosage of 2 mg 6 10 times daily, according to maternal compliance. Possible Protective Effect of Hydroxychloroquine Hydroxychloroquine (HCQ) is an inhibitor of TLR ligation. A potential involvement of TLR signaling has been suggested in the pathogenesis of cardiac NL, thus revealing a potential target for prevention of the disease [35,129]. Two retrospective case-control studies suggested a benefit of HCQ in lowering the risk of CHB [130,131]. The first study was limited to children born to Ro/SSA-positive SLE mothers, and comprised 50 cardiac NL cases and 151 noncardiac NL controls [130]. Seven (14%) cardiac NL children were exposed to HCQ compared with 56 (37%) controls (p 5 0.002; OR50.28). A subsequent study was performed to evaluate HCQ independent of maternal disease [131]: 257 pregnancies in mothers with a previous child with cardiac NL were evaluated (40 exposed and 217 unexposed to HCQ). The recurrence rate of CHB in fetuses exposed to HCQ was 7.5% (3/40) compared with 21.2% (46/217) in the unexposed group (p50.05). There were no deaths in the HCQ exposed group compared with a case fatality rate of 22% in the unexposed group. These data suggest that HCQ may protect these fetuses. HCQ has been used safely and regularly during pregnancy, and has been associated with prevention of SLE flares [132,133]. The Preventive Approach to Congenital Heart Block with Hydroxychloroquine is an open-label prospective trial that is currently recruiting in order to assess the utility of HCQ to prevent the recurrence of CHB in high-risk women with a previously affected child [114].

Postnatal Treatment Postnatal treatment of CCHB is based on pacemaker implantation, frequently in the neonatal period; the pacemaker is implanted by thoracotomic route, with an electrode on the epicardial surface connected to an impulse generator placed in an abdominal subfascial pouch. In the presence of extreme

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bradycardia, isoproterenol (0.1 0.3 mcg/kg/min) may be administered as well. Pacemaker implantation in these preterm infants should not be considered a routine, but a surgical procedure to be used in presence of clinical conditions requiring pacing (heart failure, failure to thrive) [70,73] (see “Prognosis” section). Noncardiac manifestations such as skin rash or hematology abnormalities do not require any treatment, since they spontaneously disappear, usually during the second semester of life.

OTHER PREGNANCY OUTCOMES IN WOMEN WITH ANTI-Ro/SSA ANTIBODIES It is not clear if anti-Ro/SSA antibodies are linked to other adverse pregnancy outcomes, both in SLE and non-SLE women. Most of the available data come from retrospective studies. In a large multicenter study we have prospectively followed 100 anti-Ro/SSA-positive women (53 SLE) and 107 anti-Ro/SSA-negative women (58 SLE) [134]. Mean gestational age at delivery (38 weeks vs 37.9 weeks), pregnancy loss (9.9% vs 18.6%), preterm birth (21.3% vs 13.9%), cesarean sections (49.2% vs 53.4%), preeclampsia (6.6% vs 8%), and intrauterine growth retardation (0% vs 2.3%) were similar in anti-Ro/SSA-positive and -negative mothers: anti-Ro/SSA antibodies cause CHB but do not affect other pregnancy outcomes, both in SLE and in nonSLE women.

ANTI-Ro/SSA-NEGATIVE CONGENITAL HEART BLOCK Anti-Ro/SSA-negative cases of fetal AV block have been reported. Of course the possible explanation is incomplete testing, mainly in cardiological series [55]. Still we studied 45 consecutive unselected cases with a wide battery of tests in a multilab work, and 9 (20%) were definitely anti-Ro/SSA-negative. These blocks are more often incomplete, and infant deaths more often occurred for noncardiac causes [135].

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[20] Lazzerini PE, Acampa M, Guideri F, Capecchi PL, Campanella V, Morozzi G, et al. Prolongation of the corrected QT interval in adult patients with anti-Ro/SSA-positive connective tissue diseases. Arthritis Rheum 2004;50:1248 52. [21] Lazzerini PE, Capecchi PL, Guideri F, Bellisai F, Selvi E, Acampa M, et al. Comparison of frequency of complex ventricular arrhythmias in patients with positive versus negative anti-Ro/SSA and connective tissue disease. Am J Cardiol 2007;100:1029 34. [22] Bourre´-Tessier J, Clarke AE, Huynh T, Bernatsky S, Joseph L, Belisle P, et al. Prolonged corrected QT interval in anti-Ro/SSA-positive adults with systemic lupus erythematosus. Arthritis Care Res 2011;63:1031 7. [23] Yue Y, Castrichini M, Srivastava U, Fabris F, Shah K, Li Z, et al. Pathogenesis of the novel autoimmune-associated long QT Syndrome. Circulation 2015;132:230 40. [24] Waterman S, Gordon T, Rischmueller M. Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjogren syndrome. Arthritis Rheum 2000;43:1647 54. [25] Kamel R, Eftekhari P, Garcia S, Berthouze M, Berque-Bestel I, Peter JC, et al. A highaffinity monoclonal antibody with functional activity against the 5-hydroxytryptaminergic (5-HT4) receptor. Biochem Pharmacol 2005;70:1009 18. [26] Lunardi C, Bason C, Leandri M, Navone R, Lestani M, Millo E, et al. Autoantibodies to inner ear and endothelial antigens in Cogan’s syndrome. Lancet 2002;360:915 21. [27] Miranda ME, Tseng CE, Rashbaum W, Ochs RL, Casiano C a, Di Donato F, et al. Accessibility of SSA/Ro and SSB/La antigens to maternal autoantibodies in apoptotic human fetal cardiac myocytes. J Immunol 1998;161:5061 9. [28] Tran H, Macardle P, Hiscock J, Cavill D, Bradley J, Buyon J, et al. Anti-La/SSB antibodies transported across the placenta bind apoptotic cells in fetal organs targeted in neonatal lupus. Arthritis Rheum 2002;46:1572 9. [29] Clancy RM, Neufing PJ, Zheng P, O’Mahony M, Nimmerjahn F, Gordon TP, et al. Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block. J Clin Invest 2006; 116:2413 22. [30] Clancy RM, Askanase AD, Kapur RP, Chiopelas E, Azar N, Miranda-Carus ME, et al. Transdifferentiation of cardiac fibroblasts, a fetal factor in anti-SSA/Ro SSB/La antibody-mediated congenital heart block. J Immunol 2002;169:2156 63. [31] Cimaz R, Borghi MO, Gerosa M, Biggioggero M, Raschi E, Meroni PL. Transforming growth factor beta1 in the pathogenesis of autoimmune congenital complete heart block: lesson from twins and triplets discordant for the disease. Arthritis Rheum 2006;54:356 9. [32] Reed JH, Sim S, Wolin SL, Clancy RM, Buyon JP. Ro60 requires y3 RNA for cell surface exposure and inflammation associated with cardiac manifestations of neonatal lupus. J Immunol 2013;191:110 16. [33] Reed JH, Clancy RM, Purcell AW, Kim MY, Gordon TP, Buyon JP. β2-glycoprotein I and protection from anti-SSA/Ro60-associated cardiac manifestations of neonatal lupus. J Immunol 2011;187:520 6. [34] Briassouli P, Halushka MK, Reed JH, Molad Y, Fox-Talbot K, Buyon L, et al. A central role of plasmin in cardiac injury initiated by fetal exposure to maternal anti-Ro autoantibodies. Rheumatol 2013;52:1448 53. [35] Clancy RM, Alvarez D, Komissarova E, Barrat FJ, Swartz J, Buyon JP. Ro60-associated single-stranded RNA links inflammation with fetal cardiac fibrosis via ligation of TLRs: a novel pathway to autoimmune-associated heart block. J Immunol 2010;184:2148 55.

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[36] Gottenberg JE, Busson M, Loiseau P, Cohen-Solal J, Lepage V, Charron D, et al. In primary Sjogren’s syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheum 2003;48:2240 5. [37] Clancy RM, Backer CB, Yin X, Kapur RP, Molad Y, Buyon JP. Cytokine polymorphisms and histologic expression in autopsy studies: contribution of TNF-alpha and TGF-beta 1 to the pathogenesis of autoimmune-associated congenital heart block. J Immunol 2003;171:3253 61. [38] Sire´n MK, Julkunen H, Kaaja R, Ekblad H, Koskimies S. Role of HLA in congenital heart block: susceptibility alleles in children. Lupus 1999;8:60 7. [39] Colombo G, Brucato A, Coluccio E, Compasso S, Luzzana C, Franceschini F, et al. DNA typing of maternal HLA in congenital complete heart block: comparison with systemic lupus erythematosus and primary Sjogren’s syndrome. Arthritis Rheum 1999;42:1757 64. [40] Brucato A, Ramoni V, Penco S, Sala E, Buyon J, Clancy R. Passively acquired anti-SSA/ Ro antibodies are required for congenital heart block following ovodonation but maternal genes are not. Arthritis Rheum 2010;62:3119 21. [41] Clancy RM, Marion MC, Kaufman KM, Ramos PS, Adler A, Harley JB, et al. Identification of candidate loci at 6p21 and 21q22 in a genome-wide association study of cardiac manifestations of neonatal lupus. Arthritis Rheum 2010;62:3415 24. [42] Ramos PS, Marion MC, Langefeld CD, Buyon JP, Clancy RM. Enrichment of associations in genes with fibrosis, apoptosis, and innate immunity functions with cardiac manifestations of neonatal lupus. Arthritis Rheum 2012;64:4060 5. ¨ stberg T, Salomonsson S, Ding B, Eliasson H, Ma¨larstig A, et al. The HLA [43] Meisgen S, O locus contains novel foetal susceptibility alleles for congenital heart block with significant paternal influence. J Intern Med 2014;275:640 51. [44] Cooley HM, Keech CL, Melny BJ, Menahem S, Morahan G, Kay TW. Monozygotic twins discordant for congenital complete heart block. Arthritis Rheum 1997;40(2):381 4. [45] Watson RM, Scheel JN, Petri M, Kan JS, Provost TT, Ratrie H, et al. Neonatal lupus erythematosus. Report of serological and immunogenetic studies in twins discordant for congenital heart block. Br J Dermatol 1994;130:342 8. [46] Stevens AM, Hermes HM, Lambert NC, Nelson JL, Meroni PL, Cimaz R. Maternal and sibling microchimerism in twins and triplets discordant for neonatal lupus syndromecongenital heart block. Rheumatology 2005;44:187 91. [47] Ambrosi A, Salomonsson S, Eliasson H, Zeffer E, Skog A, Dzikaite V, et al. Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern. Ann Rheum Dis 2012;71:334 40. [48] Salomonsson S, Do¨rner T, Theander E, Bremme K, Larsson P, Wahren-Herlenius M. A serologic marker for fetal risk of congenital heart block. Arthritis Rheum 2002;46:1233 41. [49] Clancy RM, Buyon JP, Ikeda K, Nozawa K, Argyle DA, Friedman DM, et al. Maternal antibody responses to the 52-kD SSA/Ro p200 peptide and the development of fetal conduction defects. Arthritis Rheum 2005;52:3079 86. [50] Strandberg L, Winqvist O, Sonesson SE, Mohseni S, Salomonsson S, Bremme K, et al. Antibodies to amino acid 200 239 (p200) of Ro52 as serological markers for the risk of developing congenital heart block. Clin Exp Immunol 2008;154:30 7. [51] Ambrosi A, Dzikaite V, Park J, Strandberg L, Kuchroo VK, Herlenius E, et al. Anti-Ro52 monoclonal antibodies specific for amino acid 200 239, but not other Ro52 epitopes, induce congenital heart block in a rat model. Ann Rheum Dis 2012;71:448 54.

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[52] Reed JH, Clancy RM, Lee KH, Saxena A, Izmirly PM, Buyon JP. Umbilical cord blood levels of maternal antibodies reactive with p200 and full-length Ro52 in the assessment of risk for cardiac manifestations of neonatal lupus. Arthritis Care Res 2012;64:1373 81. [53] Scarsi M, Radice A, Pregnolato F, Ramoni V, Grava C, Bianchi L, et al. Anti-Ro/SSAp200 antibodies in the prediction of congenital heart block. An Italian multicentre crosssectional study on behalf of the FIRMA Group. Clin Exp Rheumatol 2014;32:48 54. [54] Michae¨lsson M, Engle M. Congenital complete heart block: an international study of the natural history. Cardiovasc Clin 1972;4:85 101. [55] Brito-Zero´n P, Izmirly P, Ramos-Casals M, Buyon J, Khamashta M. The clinical spectrum of autoimmune congenital heart block. Nat Rev Rheumatol 2015;11:301 12. [56] Brucato A, Jonzon A, Friedman D, Allan LD, Vignati G, Gasparini M, et al. Proposal for a new definition of congenital complete atrioventricular block. Lupus 2003;12:427 35. [57] Brucato A, Frassi M, Franceschini F, Cimaz R, Faden D, Pisoni MP, et al. Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum 2001;44:1832 5. [58] Gladman G, Silverman ED, Yuk-Law, Luy L, Boutin C, Laskin C, et al. Fetal echocardiographic screening of pregnancies of mothers with anti-Ro and/or anti-La antibodies. Am J Perinatol 2002;19:73 80. [59] Cimaz R, Spence DL, Hornberger L, Silverman ED. Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies. J Pediatr 2003;142:678 83. [60] Costedoat-Chalumeau N, Amoura Z, Lupoglazoff JM, Huong DLT, Denjoy I, Vauthier D, et al. Outcome of pregnancies in patients with anti-SSA/Ro antibodies: a study of 165 pregnancies, with special focus on electrocardiographic variations in the children and comparison with a control group. Arthritis Rheum 2004;50:3187 94. [61] Motta M, Rodriguez-Perez C, Tincani A, Lojacono A, Chirico G. Outcome of infants from mothers with anti-SSA/Ro antibodies. J Perinatol 2007;27:278 83. [62] Gerosa M, Cimaz R, Stramba-Badiale M, Goulene K, Meregalli E, Trespidi L, et al. Electrocardiographic abnormalities in infants born from mothers with autoimmune diseases—a multicentre prospective study. Rheumatology 2007;46:1285 9. [63] Friedman DM, Kim MY, Copel JA, Davis C, Phoon CKL, Glickstein JS, et al. Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR interval and dexamethasone evaluation (PRIDE) prospective study. Circulation 2008;117:485 93. [64] Rein AJJT, Mevorach D, Perles Z, Gavri S, Nadjari M, Nir A, et al. Early diagnosis and treatment of atrioventricular block in the fetus exposed to maternal anti-SSA/Ro SSB/La antibodies a prospective, observational, fetal kinetocardiogram-based study. Circulation 2009;119:1867 72. [65] Jaeggi ET, Silverman ED, Laskin C, Kingdom J, Golding F, Weber R. Prolongation of the atrioventricular conduction in fetuses exposed to maternal anti-Ro/SSA and anti-La/SSB antibodies did not predict progressive heart block: a prospective observational study on the effects of maternal antibodies on 165 fetuses. J Am Coll Cardiol 2011;57:1487 92. [66] Gordon P, Khamashta MA, Rosenthal E, Simpson JM, Sharland G, Brucato A, et al. Anti52 kDa Ro, anti-60 kDa Ro, and anti-La antibody profiles in neonatal lupus. J Rheumatol 2004;31:2480 7. [67] Spence D, Hornberger L, Hamilton R, Silverman E. Increased risk of complete congenital heart block in infants born to women with hypothyroidism and anti-Ro and/or anti-La antibodies. J Rheumatol 2006;33:167 70.

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[68] Askanase A, Iloh I, Buyon J. Hypothyroidism and antithyroglobulin and antithyroperoxidase antibodies in the pathogenesis of autoimmune associated congenital heart block. J Rheumatol 2006;33:2099. [69] Jaeggi E, Laskin C, Hamilton R, Kingdom J, Silverman E. The importance of the level of maternal anti-Ro/SSA antibodies as a prognostic marker of the development of cardiac neonatal lupus erythematosus a prospective study of 186 antibody-exposed fetuses and infants. J Am Coll Cardiol 2010;55:2778 84. [70] Vignati G, Brucato A, Pisoni MP, Pome` G, La Placa S, Mauri L, et al. Clinical course of pre- and post-natal isolated congenital atrioventricular block diagnosed in utero. G Ital Cardiol 1999;29:1478 87. [71] Izmirly PM, Saxena A, Kim MY, Wang D, Sahl SK, Llanos C, et al. Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of antiSSA/Ro-associated cardiac neonatal lupus. Circulation 2011;124:1927 35. [72] Eliasson H, Sonesson SE, Sharland G, Granath F, Simpson JM, Carvalho JS, et al. Isolated atrioventricular block in the fetus: a retrospective, multinational, multicenter study of 175 patients. Circulation 2011;124:1919 26. [73] Fesslova V, Vignati G, Brucato A, De Sanctis M, Butera G, Pisoni MP, et al. The impact of treatment of the fetus by maternal therapy on the fetal and postnatal outcomes for fetuses diagnosed with isolated complete atrioventricular block. Cardiol Young 2009;19:282 90. [74] Lopes LM, Tavares GMP, Damiano AP, Lopes MAB, Aiello VD, Schultz R, et al. Perinatal outcome of fetal atrioventricular block one-hundred-sixteen cases from a single institution. Circulation 2008;118:1268 75. [75] Sonesson SE, Salomonsson S, Jacobsson LA, Bremme K, Wahren-Herlenius M. Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/ Ro52-kD antibodies. Arthritis Rheum 2004;50:1253 61. [76] Brucato A, Cimaz R, Catelli L, Meroni P. Anti-Ro-associated sinus bradycardia in newborns. Circulation 2000;102:E88 9. [77] Eronen M, Sire`n MK, Ekblad H, Tikanoja T, Julkunen H, Paavilainen T. Short- and longterm outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 2000;106:86 91. [78] Cimaz R, Airoldi M, Careddu P, Centinaio G, Catelli L, Franceschini F, et al. Transient neonatal bradycardia without heart block associated with anti-Ro antibodies. Lupus 1997;6:487 8. [79] Cuneo BF, Fruitman D, Benson DW, Ngan BY, Liske MR, Wahren-Herlineus M, et al. Spontaneous rupture of atrioventricular valve tensor apparatus as late manifestation of anti-Ro/SSA antibody-mediated cardiac disease. Am J Cardiol 2011;107:761 6. [80] Moak JP, Barron KS, Hougen TJ, Wiles HB, Balaji S, Sreeram N, et al. Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coll Cardiol 2001;37:238 42. [81] Udink ten Cate FE, Breur JM, Cohen MI, Boramanand N, Kapusta L, Crosson JE, et al. Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children. J Am Coll Cardiol 2001;37:1129 34. [82] Eliasson H, Sonesson S, Salomonsson S, Skog A, Wahren-Herlenius M, Gadler F. Outcome in young patients with isolated complete atrioventricular block and permanent pacemaker treatment: a nationwide study of 127 patients. Heart Rhythm 2015; June 18. pii:S1547 5271(15)00802 4.

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[117] Urban R, Lemancewicz A, Przepie´sc´ J, Urban J, Krtowska M. Antenatal corticosteroid therapy: a comparative study of dexamethasone and betamethasone effects on fetal Doppler flow velocity waveforms. Eur J Obstet Gynecol Reprod Biol 2005;120:170 4. [118] Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Database Syst Rev Proph 2000;CD000065. [119] Brownfoot F, Gagliardi D, Bain E, Middleton P, Crowther C. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2013;8:CD006764 doi:10.1002/14651858.CD006764.pub3. [120] Costedoat-Chalumeau N, Amoura Z, Villain E, Cohen L, Fermont L, Le Thi Huong D, et al. Obstetrical management of patients at risk of neonatal lupus syndrome: review of the literature. J Gynecol Obs Biol Reprod 2006;35:146 56. [121] Ruffatti A, Milanesi O, Chiandetti L, Cerutti A, Gervasi M, De Silvestro G, et al. A combination therapy to treat second-degree anti-Ro/La-related congenital heart block. A strategy to avoid stable third-degree heart block? Lupus 2012;21:666 71. [122] David AL, Ataullah I, Yates R, Sullivan I, Charles P, Williams D. Congenital fetal heart block: a potential therapeutic role for intravenous immunoglobulin. Obs Gynecol 2010;116(Suppl.):543 7. [123] Kaaja R, Julkunen H. Prevention of recurrence of congenital heart block with intravenous immunoglobulin and corticosteroid therapy: comment on the editorial by Buyon et al [letter]. Arthritis Rheum 2003;48:280 1. [124] Tran H, Cavill D, Buyon J, Gordon T. Intravenous immunoglobulin and placental transport of anti-Ro/La antibodies: comment on the letter by Kaaja and Julkunen. Arthritis Rheum 2004;50:337 8; author reply 338. [125] Pisoni CN, Brucato A, Ruffatti A, Espinosa G, Cervera R, Belmonte-Serrano M, et al. Failure of intravenous immunoglobulin to prevent congenital heart block: findings of a multicenter, prospective, observational study. Arthritis Rheum 2010;62:1147 52. [126] Friedman DM, Llanos C, Izmirly PM, Brock B, Byron J, Copel J, et al. Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: results of a multicenter, prospective, open-label clinical trial. Arthritis Rheum 2010;62:1138 46. [127] Trucco SM, Jaeggi E, Cuneo B, Moon-Grady AJ, Silverman E, Silverman N, et al. Use of intravenous gamma globulin and corticosteroids in the treatment of maternal autoantibody-mediated cardiomyopathy. J Am Coll Cardiol 2011;57:715 23. [128] Groves AM, Allan LD, Rosenthal E. Therapeutic trial of sympathomimetics in three cases of complete heart block in the fetus. Circulation 1995;92:3394 6. [129] Alvarez D, Briassouli P, Clancy RM, Zavadil J, Reed JH, Abellar RG, et al. A novel role of endothelin-1 in linking toll-like receptor 7-mediated inflammation to fibrosis in congenital heart block. J Biol Chem 2011;286:30444 54. [130] Izmirly PM, Kim MY, Llanos C, Le PU, Guerra MM, Askanase AD, et al. Evaluation of the risk of anti-SSA/Ro SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis 2010;69:1827 30. [131] Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 2012;126:76 82.

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[132] Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JL, Tura BR, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus 2001;10:401 4. [133] Clowse MEB, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006;54:3640 7. [134] Brucato A, Doria A, Frassi M, Castellino G, Franceschini F, Faden D, et al. Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study. Lupus 2002;11:716 21. [135] Brucato A, Grava C, Bortolati M, Ikeda K, Milanesi O, Cimaz R, et al. Congenital heart block not associated with anti-Ro/La antibodies: comparison with anti-Ro/La-positive cases. J Rheumatol 2009;36:1744 8.

Chapter 10

Juvenile Dermatomyositis C. Pilkington1,2 1 2

Great Ormond Street and University College Hospitals, London, United Kingdom, JDRC, Department of Rheumatology, Institute of Child Health, London, United Kingdom

INTRODUCTION Dermatomyositis (DM) in children is a rare inflammatory disease that predominantly affects muscle and skin, but it can be a multiorgan systemic disease. It has a variable disease course with a spectrum of severity. The disease needs to be diagnosed early and treated aggressively to improve outcome, especially if there are features present that are associated with a poor prognosis. Adequate disease control depends on careful monitoring to prevent long-term morbidity. Over the last few years, international collaborations have fostered research and improved knowledge about the disease, as well as developing tools for disease assessment.

INCIDENCE OF JUVENILE DERMATOMYOSITIS There are between two and five cases of juvenile dermatomyositis (JDM) per million children per year: this is a rare disease. The incidence of JDM is based on publications from different groups worldwide, which give different incidence rates for different age groups and have a variable sex ratio. A paper from the United States reported an incidence of 3.7 cases per million per year in 5 9 year-olds and an incidence of 4.3 cases per million per year in 10 14 year-olds [1]. The sex ratio was 1 girl:1.3 boys in 5 9 yearolds, and 4.7 girls to 1 boy in 10 14 year-olds. In 1992, the UK British Pediatric Surveillance Unit undertook a prospective survey of all new cases of JDM seen by pediatricians (rheumatologists, neurologists, and dermatologists) in the United Kingdom for a year. They found 1.9 new cases per million children in 1992 1993 with a sex ratio of 5 girls:1 boy [2]. The low incidence of JDM has prompted various groups to collect data from several centers to be able to study larger cohorts of patients, and to Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00010-4 © 2016 Elsevier B.V. All rights reserved.

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allow physicians to build up expertise in this area. One such center is in the United Kingdom, which has set up a JDM registry for the United Kingdom and Ireland, allowing data from 10 centers within the United Kingdom to be collated centrally. So far, over 500 patients have been recruited; it is the largest European cohort to date. The data from 151 of these patients has been analyzed and published [3]. In this series the sex ratio of female:male was 2.2:1, with the ethnicity of the patients reflecting the UK population groups; the majority of the patients were Caucasian (90%), with possibly a higher incidence than might be expected of 2.4% in the Black ethnic group.

JUVENILE DERMATOMYOSITIS EPIDEMIOLOGY Unlike adult DM, pediatric cases of DM are not associated with malignancy. However, many physicians will screen older teenagers for malignancies such as lymphoma. There has been speculation that JDM has a seasonal variation, perhaps reflecting viral triggers, but this is not borne out by the literature. The series from the United States found that 55% of their cases had an onset between February and April [1]. The UK survey found several clusters, which varied with the year. The largest cluster was seen in April to May 1992 [2].

PATHOGENESIS The cause of JDM is unknown and its pathogenesis is poorly understood. It is an inflammatory condition that responds to immunosuppressive treatment and is felt to be an autoimmune disease. The underlying pathology appears to be vasculopathic rather than a true vasculitis. Inflammatory cells are rarely found within the vessel wall, though some researchers believe that the endothelium may be the primary target. In children, more than in adults, there are cases that are clinically termed vasculitic, where there appears to be more widespread inflammation affecting blood vessels throughout the skin, muscles, and other organs. Early in the disease, the muscle biopsy can have normal histopathology, with only upregulation of major histocompatibility complex (MHC) class I molecules on immunological staining. Later on, the typical muscle biopsy findings will show variation in muscle fiber size with perifascicular atrophy and a perivascular inflammatory cell infiltrate. There may be increased fibrotic connective tissue between muscle bundles.

CLINICAL MANIFESTATIONS Symptoms at Diagnosis There are now several studies of JDM that have been published from centers caring for large numbers of these patients: Chicago in the United States [4],

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Toronto in Canada [5], and London in the United Kingdom [3]. Most patients have a characteristic skin rash at presentation, though it can be mild and short-lived, or can occur later in the disease course. The earlier series from Chicago reported all the patients presenting with a skin rash and muscle weakness, whereas 84% of the patients in the series from Toronto and 88% from the UK series had a skin rash. The muscle weakness is proximal and symmetrical (100% in the US, 82% in the UK). The proximal muscle weakness may present as tiredness initially with younger patients asking to be carried by their parents rather than walking, especially as they may have difficulty walking up and down the stairs. Not many parents notice that the children have weakness of the neck flexors, though it is usually present early on, until the children have difficulty lifting their heads off the pillow. In school-age children, they may start to complain that they cannot get up from the floor after sitting crosslegged on the floor, or are having difficulties in their sporting activities. In severe cases, the muscle weakness progresses to involve the distal muscles too, though children may still be able to move their fingers and toes even when they are unable to move the rest of the body spontaneously. Proximal muscles include the muscles of the larynx and pharynx, resulting in a nasal voice (17%) and swallowing difficulties (29%). This has to be carefully checked, as many parents do not notice these symptoms until after repeated questioning. The dysphagia is associated with a significant risk of aspiration, and patients may need to have nasogastric tube feeding until the dysphagia has recovered. Pain is a common symptom; often it is myalgia (68% in the UK series) or arthralgia (66%), and a third of the cases have arthritis (36%). Children with JDM are irritable (51% in the UK series) and this is more pronounced than in many other inflammatory conditions, especially in the younger children. It is a useful symptom to document as it may precede a flare in disease. Other symptoms include more generalized problems such as fatigue (78%), weight loss (43%), fevers (30%), headaches (18%), and abdominal pain (18%).

Clinical Signs: Rash A careful assessment needs to be made of the skin. The rash can be the classical heliotrope (purple pink in color) rash over the eyelids (Fig. 10.1), with or without periorbital edema. Common are Gottron’s papules over the extensor surfaces (any of the small joints of the hands, as well as the elbows and the knees) or periungual erythema. The periungual erythema may be accompanied by periungual swelling, and capillary loop dilation in the nail beds. There can also be dilation of the vessels in the eyelids, often along the margins of the eyelids. Less commonly there can be a facial rash that is around the eyes and nose, which classically does not spare the nasolabial folds (as opposed to systemic lupus erythematosus, SLE), and often affects the

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FIGURE 10.1 Heliotrope rash.

ears. A less common rash is found over the shoulders and chest (Shawl sign) or on the trunk. A poor prognostic sign is the development of skin ulcers, and these were present at diagnosis in 23% of the UK series. The ulcers can start off as small areas on the sides of the chest walls under the arms, and may be easily missed. Patients may have small ulcers near the inner canthus of the eye, which often heal, leaving a small pitted scar. Periorbital edema can be slight swelling of the upper eyelid, or more extensive edema around the eyes. More generalized edema is associated with severe disease and was present in 32% of the UK series. The edema may be secondary to leaky blood vessels as the serum albumin is often normal. There may be livido reticularis or a widespread vasculitic rash.

Clinical Signs: Calcinosis Calcinosis is due to the deposition of calcium as subcutaneous plaques or nodules, deeper flecks that can become plaques within the muscles (Fig. 10.2), or sheets within the fascia around the muscles. It can be present at diagnosis (32% in the UK series, but only 3% in the Toronto series). Careful palpation of the skin for calcinotic nodules allows the superficial calcinosis to be charted. Later on in the disease, even after resolution of the myositis, the calcinosis can progress to sheet-type calcification [6,7]. The calcium can extrude through the skin, or can discharge as a milky-looking fluid. These deposits are a prominent source of discomfort and disability.

Clinical Signs: Muscle Weakness Muscle strength needs to be tested thoroughly. The manual muscle testing (MMT) of eight muscles (MMT8) has been validated in different centers [8,9]. It tests the muscle power of individual muscles that are commonly affected in JDM. The muscle power is graded for each muscle out of 10,

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FIGURE 10.2 Calcinosis.

giving an overall score out of 80. The muscles that are tested are neck flexors, shoulder abductor, elbow flexor, wrist extensor, hip abductor, hip extensor, knee extensor and ankle dorsiflexors. Muscle function and endurance is measured using the Childhood Myositis Assessment Score (CMAS) [10]. This involves asking the child to do some set maneuvers, such as sit-ups for abdominal muscles; Gower’s sign, where children are observed getting up off the floor; and including timed ones such as lifting the head up for 2 minutes. This assesses a different aspect of muscle function, not simply muscle power. It is correlated less directly with the MMT8, and more closely with the Childhood Health Assessment Questionnaire (CHAQ) that asks parents about functional difficulties with performing tasks associated with activities of daily living [11,12]. Both the CMAS and the CHAQ are affected by muscle weakness, but they are also affected by synovitis and contractures.

General Assessment at Onset Patients need to have their joints assessed for active synovitis (found in 36% of the UK series) and for contractures (27%). Lipoatrophy (10%) can be localized over the face or limbs, or more generalized with marked loss of subcutaneous fat (Fig. 10.3) and association with hypertriglyceridemia and insulin resistance. Though it is rare for the heart to be involved, patients need a full cardiovascular examination. The respiratory system needs to be

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FIGURE 10.3 Lipoatrophy.

assessed for effects secondary to aspiration, for respiratory muscle weakness, and for signs of interstitial lung disease (ILD). The gastrointestinal and neurological systems need to be examined to exclude vasculitis.

Disease Course The natural history of JDM falls into three groups: a monocyclic group with one episode of JDM, a polycyclic group with cycles of disease relapse, and a chronic persistent group who often have severe disease that is difficult to control and can be fatal. A retrospective study of 65 JDM patients in Canada reported that 37% of the patients had a monocyclic course and 63% a chronic or polycyclic course (median follow-up time of 7.2 years). Steroids had been used in 95% of this cohort, but 40% still had a rash and 23% were still weak at time of follow-up [13]. Poor prognosis is associated with skin ulceration, severe muscle weakness that has also involved more distal muscles, dysphagia or dysphonia, severe nailfold capillary abnormalities, severe gut involvement (which may lead to perforation), lung involvement with interstitial lung disease, central nervous system (CNS) involvement, generalized edema, and persistent severe disease activity. Another poor prognostic indicator is the presence of calcinosis (Table 10.1).

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TABLE 10.1 Poor Prognostic Factors Skin ulceration Severe muscle weakness that has also involved more distal muscles Dysphagia or dysphonia Severe nailfold capillary abnormalities Severe gut involvement Interstitial lung disease Central nervous system involvement Generalized edema Persistent severe disease activity Calcinosis

The disease can remit within 2 3 years, or may persist for 10 15 years. Management is aimed at controlling disease activity, preventing fatalities, and preventing the functional disability that results from disease damage.

DIAGNOSTIC INVESTIGATIONS Laboratory Tests Markers of inflammation (such as anemia and elevated erythrocyte sedimentation rate) need to be assessed using blood tests. Muscle enzymes (creatinine kinase, aspartate alanine transferase, alkaline phosphatase, lactate dehydrogenase, aldolase) are often (but not invariably) raised at onset. Antinuclear antibody and rheumatoid factor can be positive in JDM but are not recognized features of JDM. Investigations for infections (viral, streptococcal, mycoplasma) need to be sent to exclude postinfectious myositis. In adult DM, there are specific myositisassociated antibodies (MSAs) found that correlate with different disease courses (such as anti-Jo1 and lung disease). The adult correlations do not hold true in JDM, but different MSAs may be important in children [14].

Radiological In some centers, MRI scans have replaced muscle biopsies to document myositis. However, there is no consensus on a protocol for MRI imaging, or on the reporting of scan images. Changes can be mild and may need the appropriate images to be taken, as well as radiologists used to looking for the more subtle signs of myositis or edema of the muscle fascia [15,16].

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In some centers MRI is used as a way of ensuring that the muscle biopsy is taken from an affected muscle. Ultrasound scans can be used to look for muscle inflammation, but it is dependent on operator expertise. Electromyogram (EMG) can be used, but many children find the procedure painful. Speech therapy assessment of swallowing can be valuable, but as symptoms can be silent, video fluoroscopy is a more definitive investigation of swallowing problems. A chest X-ray can ensure there are no signs of infection secondary to aspiration. If the video fluoroscopy shows swallowing problems, a high-resolution CT scan of the chest should be done. Calcinosis is difficult to chart objectively and X-rays can help document its extent. CNS vasculitis, if suspected, requires a brain MRI to delineate its extent.

Muscle Biopsy A typical muscle biopsy will show variation in the muscle fiber sizes with perifascicular atrophy and a perivascular inflammatory cell infiltrate. There is often an increased connective between muscle bundles with fibrotic tissue. Early in disease, there can be normal histopathology, with only upregulation of MHC class I molecules on immunological staining [17]. This is missed in laboratories that do not routinely do this staining on their muscle biopsies. An open muscle biopsy has to be done under general anesthesia and leaves a scar that can be painful. Some centers do not use open muscle biopsies but needle biopsies under local anesthesia. This can only be done in centers that routinely do these procedures, as an inadequate biopsy sample does not allow the diagnosis to be confirmed. Recently there has been an attempt to bring together some of the international experts in order to develop an assessment tool for scoring the features found on muscle biopsies that will allow biopsies done at different centers to be compared. Most expert histopathologists can agree on the severity of an abnormal muscle biopsy, but so far individual pathological signs have not been compared to clinical outcomes to see which ones are predictive (in the early stages of the disease) of a poor outcome, such as the development of calcinosis.

Functional Tests Lung function tests are needed if there is respiratory muscle weakness or if there are any signs of dysphagia. A restrictive pattern on lung function tests can be due to muscle weakness or interstitial lung disease (ILD), and a diffusion factor (DLCO) can help differentiate the two. If there are any clinical signs of cardiac involvement, further investigations should include an ECHO and an ECG.

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DIAGNOSIS Diagnostic Criteria The diagnostic criteria remain those published by Bohan and Peter in 1975 [18,19] (Table 10.2) and are the same for pediatric as well as adult cases of DM. Cases need to have a typical rash such as the heliotrope rash with periorbital edema or Gottron’s papules. This needs to be associated with three out of the following four: 1. Progressive muscle weakness that is symmetrical and affects the proximal limb girdle muscles and neck flexors 2. Raised muscle enzymes such as creatinine kinase, lactate dehydrogenase, or AST transaminase 3. A muscle biopsy consistent with the diagnosis of DM 4. An EMG consistent with DM. If these criteria are not fulfilled, then the patient can be classed as probable JDM, polymyositis (absent skin rash) that is very rare in children, or amyopathic JDM (typical skin rash without myositis).

Diagnostic Problems Many pediatricians feel that a typical case of DM does not need a muscle biopsy or an EMG to confirm the diagnosis. This is compounded by published reports of patients with a diagnosis of JDM having normal muscle biopsies or EMGs; the myositis can be patchy within individual muscles as well as within muscle groups. A survey of international pediatric rheumatologists reported that only 61.3% used muscle biopsy and 55.5% used EMG routinely. Many pediatricians use an MRI scan instead; 59% used MRI scans routinely [20]. This leaves many pediatric cases in the probable category with a typical rash, muscle weakness, and elevated muscle enzymes.

TABLE 10.2 Diagnostic Criteria G G

Typical rash (heliotrope, Gottron’s) Plus three of G Progressive muscle weakness: symmetrical Proximal limb girdle + neck flexor G m Muscle enzymes in serum G +ve muscle biopsy G +ve electromyogram

Source: Adapted from Refs. [18,19]

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There are several international efforts underway to suggest up-to-date diagnostic criteria. One of these efforts is including classification criteria for myositis in children and in adults. This working group has included pediatric and adult rheumatologists, neurologists, and dermatologists.

Differential Diagnosis The diagnosis of a typical case of JDM is straightforward. However, some cases present without a typical rash. These patients may have had a short-lived mild heliotrope rash that parents ascribed to sunburn or they may have polymyositis. Polymyositis is extremely rare in children. Patients have normal capillary nailfolds and muscle biopsy is mandatory to make the diagnosis. Myositis can occur as a postinfectious complication following a number of infections including viral, streptococcal, or mycoplasma infections. The myositis can be severe enough to need steroids, but patients usually do not need a prolonged course of steroids, and only relapse if the infection recurs. Myositis may occur as part of a connective tissue disease such as systemic lupus erythematosus (SLE), scleroderma, mixed connective tissue disease (MCTD), or a systemic vasculitis such as polyarteritis nodosa (PAN). In some cases, patients may have characteristics of both diagnoses and may be termed as having an overlap syndrome. This is a confusing area, and further work needs to be done to clarify the definition of the overlap syndromes. Neuromuscular diseases are a differential diagnosis for cases lacking a skin rash. However, patients with a muscular dystrophy such as Duchenne’s or Becker’s can be distinguished on history (insidious onset, no systemic features, no myalgia) and confirmed with a biopsy. Myasthenia gravis is rare and can usually be distinguished from JDM by the element of fatigability and confirmed by finding antiacetylcholine receptor antibodies.

TREATMENT Evidence Base for Drug Treatment In the days before steroids, one-third of the patients died, one-third recovered, and one-third recovered with severe disabilities [21]. Oral steroids are effective in treating cases of JDM, but they do not prevent calcinosis, they do not keep severe disease controlled, and there is little evidence about doses and the most effective route of administration. Most physicians used to treating JDM agree that all patients need steroids, they should not be tapered too early, and they need to be tapered slowly. There is evidence that IV steroids help patients improve more rapidly [22] because of poor gut absorption with

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oral administration, but they do not affect long-term outcome. Some physicians prefer to give steroids orally at 2 mg/kg per day for at least a month before starting to taper. There is evidence that adding a disease-modifying drug (DMARD) early in the disease course, such as methotrexate, appears to help prevent calcinosis [23] and may shorten the length of time on steroids. The evidence for the effectiveness of the individual DMARDs is based on case series and clinician’s experience; there are no good trials. In the United Kingdom, pediatric rheumatologists favor methotrexate, whereas pediatric neurologists favor cyclosporin A as the first-line DMARD of choice. The difficulty arises with patients whose disease is not fully controlled on these medications. Some groups have felt that continuing skin disease is unimportant if the myositis is quiescent. However, whereas calcinosis in adult DM is felt to be due to damage and is reversible, calcinosis in children is felt to be due to ongoing disease, even if the myositis has resolved. Increasing calcinosis warrants stepping up the immunosuppressive treatment. This can halt the progress of the calcinosis and can allow it to regress. Patients can respond to changing the DMARD (ie, cyclosporin to methotrexate), changing the route of administration of the DMARD (ie, oral to subcutaneous or IM methotrexate), or adding a second DMARD such as azathioprine to methotrexate (personal practice, Figs. 10.4 and 10.5). However, some calcinosis is extremely resistant to treatment, and many medications have been tried with case reports of success, but sometimes more powerful immunosuppressive treatment may be needed (drug treatment review in Ref. [24]). There is evidence that IVIG is effective [25], as well as cyclophosphamide [26]. This tends to be reserved for severe cases with poor prognostic signs. There are reports of biologics such as anti-TNF [27,28] and rituximab [29] being effective.

FIGURE 10.4 New calcinosis on treatment: steroids from onset for 16 months, developed calcinosis, methotrexate added for 6 months, increasing calcinosis so azathioprine added.

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FIGURE 10.5 Calcinosis: 1 year later, on methotrexate and azathioprine, off steroids for 2 months.

Nonmedical Treatment Treatment of JDM needs to be multidisciplinary and involve therapists. Historically, active physiotherapy early on was felt to cause calcinosis through increasing muscle inflammation. There is little evidence to support this. A small study of JDM patients has demonstrated that there is no increase in muscle enzymes or MRI signal immediately after a supervised exercise session [15]. Long-term disability has been found to correlate with the presence of contractures [30]. It is important for physiotherapists to be involved in early treatment to prevent contractures, and if they are present, to treat them (see chapter: Physiotherapy Management of Pediatric Rheumatology Conditions). Physiotherapists also need to be involved in helping patients to rebuild their muscle strength. Aerobic exercise testing on a treadmill in patients with JDM has revealed an impairment in their maximal aerobic exercise capacity, stressing the importance of a supervised exercise program to rebuild strength [31]. The interventions of an occupational therapist will help with the activities of daily living, and there needs to be liaison with the patient’s school to help the child appropriately during their illness.

Recent Developments International collaborative efforts have led to the development of new disease activity and damage assessment tools [32,33]. This work was done by the International Myositis and Clinical Studies Group (IMACS), which brought together experts in the field of myositis in adults and children from around the world. The assessment tools are needed to allow standardized

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assessments to be done for patients in many centers and so allow multicenter drug trials and long-term outcome studies to be done in big enough groups to produce valid data (reviewed in Ref. [34]). A slightly different approach was undertaken by a different group: the Pediatric Rheumatology International Trials Organization (PRINTO) in collaboration with the Pediatric Rheumatology Collaborative Study Group (PRCSG; an American/Canadian group). Their work involved a questionnaire survey followed by a consensus conference to produce the domains and variables to be included in the preliminary disease activity and damage core sets for JDM [35], as well as definitions of disease remission and flare. These were remarkably similar to the ones produced by the IMACS group. At present, various groups are working on producing up-to-date diagnostic and classification criteria for patients with myositis. This will allow clarification of the definitions of subgroups so that further research can be based on homogenous groups. This will improve understanding of the disease and allow clinicians to tailor their treatments more effectively.

KEY POINTS G G G G G G G G

JDM is a rare disease Typical JDM is easy to diagnose, atypical cases are not Diagnostic criteria are outdated Disease treated late has a poorer prognosis Disease severity is variable Increasing calcinosis is a sign of disease activity Assessments need to be detailed and standardized International collaboration is needed for treatment trials.

ACKNOWLEDGMENTS The author thanks Sue Maillard and Simon Arscott for their careful reading of the manuscript, Virginia Brown for her help in preparing this manuscript, and the Cathal Hayes Research Foundation for funding the UK Registry and Repository for JDM.

REFERENCES [1] Medsger Jr TA, WN Jr Dawson, Masi AT. The epidemiology of polymyositis. Am J Med 1970;48(6):715 23. [2] Symmons DP, Sills JA, Davis SM. The incidence of juvenile dermatomyositis: results from a nation-wide study. Br J Rheumatol 1995;34(8):732 6. [3] McCann LJ, Juggins AD, Maillard SM, Wedderburn LR, Davidson JE, Murray KJ, et al. The Juvenile Dermatomyositis National Registry and Repository (UK and Ireland)—clinical characteristics of children recruited within the first 5 yr. Rheumatology (Oxford) 2006;45 (10):1255 60.

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[4] Pachman LM. Polymyositis and dermatomyositis in children. In: Maddison PJ, et al., editors. Oxford textbook of rheumatology. 2nd ed. Oxford: Oxford University Press; 1998. p. 821 8. [5] Ramanan AV, Feldman BM. Clinical features and outcomes of juvenile dermatomyositis and other childhood onset myositis syndromes. Rheum Dis Clin North Am 2002;28(4): 833 57. [6] Miyamae T, Mori M, Inamo Y, Kohno Y, Takei S, Maeda M, et al. Multi-center analysis of calcinosis in children with juvenile dermatomyositis. Ryumachi 2003;43(3):538 43. [7] Ostrov BE, Goldsmith DP, Eichenfield AH, Athreya BH. Hypercalcemia during the resolution of calcinosis universalis in juvenile dermatomyositis. J Rheumatol 1991;18 (11):1730 4. [8] Bode RK, Klein-Gitelman MS, Miller ML, Lechman TS, Pachman LM. Disease activity score for children with juvenile dermatomyositis: reliability and validity evidence. Arthritis Rheum 2003;49(1):7 15. [9] Rider LG. Assessment of disease activity and its sequelae in children and adults with myositis. Curr Opin Rheumatol 1996;8(6):495 506. [10] Lovell DJ, Lindsley CB, Rennebohm RM, Ballinger SH, Bowyer SL, Giannini EH, et al. in cooperation with the Juvenile Dermatomyositis Disease Activity Collaborative Study Group. Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies. II. The Childhood Myositis Assessment Scale (CMAS): a quantitative tool for the evaluation of muscle function. Arthritis Rheum 1999;42(10):2213 19. [11] Huber AM, Feldman BM, Rennebohm RM, Hicks JE, Lindsley CB, Perez MD, et al. Validation and clinical significance of the childhood myositis assessment scale for assessment of muscle function in the juvenile idiopathic inflammatory myopathies. Arthritis Rheum 2004;50(5):1595 603. [12] Huber AM, Hicks JE, Lachenbruch PA, Perez MD, Zemel LS, Rennebohm RM, et al. Validation of the Childhood Health Assessment Questionnaire in the juvenile idiopathic myopathies. Juvenile Dermatomyositis Disease Activity Collaborative Study Group. J Rheumatol 2001;28(5):1106 11. [13] Huber AM, Lang B, LeBlanc CM, Birdi N, Bolaria RK, Malleson P, et al. Medium- and long-term functional outcomes in a multicenter cohort of children with juvenile dermatomyositis. Arthritis Rheum 2003;43(3):541 9. [14] Wedderburn LR, Li CK. Paediatric idiopathic inflammatory muscle disease. Best Pract Res Clin Rheumatol 2004;18(3):345 58. [15] Maillard SM, Jones R, Owens C, Pilkington C, Woo P, Wedderburn LR, et al. Quantitative assessment of MRI T2 relaxation time of thigh muscles in juvenile dermatomyositis. Rheumatology (Oxford) 2004;43(5):603 8. [16] Chapman S, Southwood TR, Fowler J, Ryder CA. Rapid changes in magnetic resonance imaging of muscle during the treatment of juvenile dermatomyositis. Br J Rheumatol 1994;33(2):184 6. [17] Li CK, Varsani H, Holton JL, Gao B, Woo P, Wedderburn LR. MHC class I overexpression on muscles in early juvenile dermatomyositis. J Rheumatol 2004;31(3):605 9. [18] Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292(7):344 7. [19] Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975;292(8):403 7.

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[20] Brown VE, Pilkington CA, Feldman BM, Davidson JE. An international consensus survey of the diagnostic criteria for juvenile dermatomyositis (JDM). Rheumatology (Oxford) 2006;45(8):990 3. [21] Bitnum S, Daeschner Jr CW, Travis LB, Dodge WF, Hopps HC. Dermatomyositis. J Pediatr 1964;64:101 31. [22] Pachman LM, Cooke N. Juvenile dermatomyositis:a clinical and immunologic study. J Pediatr 1980;96(2):226 34. [23] Fisler RE, Liang MG, Fuhlbrigge RC, Yalcindag A, Sundel RP. Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol 2002;47(4):505 11. [24] Pilkington CA, Wedderburn LR. Paediatric idiopathic inflammatory muscle disease: recognition and management. Drugs 2005;65(10):1355 65. [25] Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003;362(9388): 971 82. [26] Riley P, Maillard SM, Wedderburn LR, Woo P, Murray KJ, Pilkington CA. Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety. Rheumatology (Oxford) 2004;43(4):491 6. [27] Maillard S, Wilkinson N, Riley P, et al. The treatment of severe idiopathic myositis with anti-TNF therapy. Arthritis Rheum 2002;44(9):S307. [28] Miller ML, Smith R, Abbott KA, et al. Use of etanercept in chronic juvenile dermatomyositis. Arthritis Rheum 2002;44(9):S306. [29] Levine. A pilot study of rituximab therapy for refractory dermatomyositis. Arthritis Rheum 2002;46(S1):S488. [30] Espadaa G, Weissbord P, Barana M, et al. Dermato-polymyositis: survival analysis and long-term functional outcome in juvenile patients. Arthritis Rheum 2002;46(9):S308. [31] Takken T, Spermon N, Helders PJ, Prakken AB, Van Der NJ. Aerobic exercise capacity in patients with juvenile dermatomyositis. J Rheumatol 2003;30(5):1075 80. [32] Isenberg DA, Allen E, Farewell V, Ehrenstein MR, Hanna MG, Lundberg IE, et al. International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology (Oxford) 2004;43(1):49 54. [33] Pilkington C, Murray KJ, Isenberg D, et al. Development of disease activity and damage indices for myositis—intial testing of four tools in juvenile dermatomyositis. Arthritis Rheum 2001;44(9):S294. [34] Pilkington C. Clinical assessment in juvenile idiopathic inflammatory myopathies and the development of disease activity and damage tools. Curr Opin Rheumatol 2004;16(6): 673 7. [35] Ruperto N, Ravelli A, Murray KJ, Lovell DJ, Andersson-Gare B, Feldman BM, et al. Preliminary core sets of measures for disease activity and damage assessment in juvenile systemic lupus erythematosus and juvenile dermatomyositis. Rheumatology (Oxford) 2003;42(12):1452 9.

Chapter 11

Localized Scleroderma in Children F. Zulian and F. Sperotto Pediatric Rheumatology Unit, Department of Pediatrics, University of Padova, Padova, Italy

JUVENILE LOCALIZED SCLERODERMA Localized scleroderma (LS), also known as morphea, includes a group of disorders whose manifestations are confined to the skin and subdermal tissues and, with some exceptions, do not affect internal organs. They range from very small plaques involving only the skin, to diseases that may cause significant functional and cosmetic deformity, with a variety of extracutaneous features. Contributions to the literature over the past few years have expanded our understanding of some of the epidemiologic features of this group of disorders, provided descriptions of the range of extracutaneous manifestations, and underlined the efficacy of some therapeutic options.

CLINICAL CLASSIFICATION The classification used most widely currently includes five subtypes: circumscribed morphea (CM), linear scleroderma, generalized morphea, pansclerotic morphea, and the new mixed subtype where a combination of two or more of the previous subtypes is present (Table 11.1) [1]. CM is characterized by oval or round circumscribed areas of induration with a central waxy, ivory color surrounded by a violaceous halo (Fig. 11.1). The superficial variety is usually confined to the dermis. Very rarely lesions are small, less than 1 cm in diameter (guttate). In the deep variety the entire skin feels thickened, taut, and bound down, and the primary site of involvement is the panniculus or subcutaneous tissue. CM lesions occur most frequently on the trunk and less often on the extremities or face. The term generalized morphea is used when four or more individual plaques larger than 3 cm become confluent, involving at least two out of seven

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TABLE 11.1 Preliminary Classification of Juvenile Localized Scleroderma [1] Type

Subtype

Features

Circumscribed morphea

Superficial

Oval or round circumscribed areas of induration limited to epidermis and dermis, often with altered pigmentation and violaceous, erythematous halo (lilac ring). They can be single or multiple

Deep

Oval or round circumscribed deep induration of the skin involving subcutaneous tissue extending to fascia and underlying muscle. The lesions can be single or multiple.Sometimes the primary site of involvement is in the subcutaneous tissue without involvement of the skin

Trunk/ limbs

Linear induration involving dermis, subcutaneous tissue, and, sometimes, muscle and underlying bone and affecting the limbs and/or the trunk

Head

En coup de sabre. Linear induration of the skin that affects the face and/or the scalp and sometimes involves muscle and underlying boneParry Romberg or progressive hemifacial atrophy: Loss of tissue on one side of the face that may involve dermis, subcutaneous tissue, muscle, and bone. The skin is unaffected and mobile

Linear scleroderma

Generalized morphea

Induration of the skin starting as individual plaques (4 or more and larger than 3 cm) that become confluent and involve at least two anatomic sites

Panclerotic morphea

Circumferential involvement of limb(s) affecting the skin, subcutaneous tissue, muscle, and bone. The lesion may also involve other areas of the body without internal organ involvement

Mixed morphea

Combination of two or more of the previous subtypes. The order of the concomitant subtypes, specified in brackets, will follow their predominant representation in the individual patient (ie, mixed (linear-circumscribed))

anatomical sites (head neck, right-upper extremity, left-upper extremity, rightlower extremity, left-lower extremity, anterior trunk, posterior trunk) (Fig. 11.2). Linear scleroderma is the most common subtype in children and adolescents [2]. It is characterized by one or more linear streaks that typically involve an upper or lower extremity (Fig. 11.3). With time, the streaks become progressively more indurate and can extend through the dermis, subcutaneous tissue, and muscle to the underlying bone. The lesions frequently

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FIGURE 11.1 Circumscribed morphea of the abdomen.

FIGURE 11.2 Generalized morphea involving the trunk.

follow a dermatomal distribution or Blaschko’s lines (Fig. 11.4) [4] and are unilateral in 85 95% of cases [2]. The face or scalp may also be involved, as in the en coup de sabre (ECDS) variety. This term was applied historically because the lesion was reminiscent of the depression caused by a sword wound (Fig. 11.5).

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FIGURE 11.3 Linear scleroderma of the right thigh (early lesion) extending down to the leg.

FIGURE 11.4 Linear scleroderma of the trunk.

The Parry Romberg syndrome (PRS), characterized by a progressive hemifacial atrophy of the skin and tissue below the forehead with mild or absent involvement of the superficial skin, is considered the severe end of the spectrum of ECDS and for this reason included in the linear head subtype [5]. Evidence for this close relationship is the presence of associated

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FIGURE 11.5 Scleroderma en coup de sabre associated with facial hemiatrophy in a teenager.

disorders, including seizures and dental and ocular abnormalities, reported with similar prevalence in both conditions [5]. In both circumscribed and linear morphea subtypes, deep variants where the entire skin feels thickened, taut, and bound down can be present [1]. Pansclerotic morphea is an extremely rare but severe disorder characterized by generalized full-thickness involvement of the skin of the trunk, extremities, face, and scalp with the sparing of the fingertips and toes [6]. The involvement of the entire body without internal organ involvement helps differentiate this from systemic sclerosis (SSc). A few reports have raised awareness of the possible evolution of chronic ulcers, frequently complicating pansclerotic morphea, to squamous cell carcinoma, a threatening complication already reported in SSc [7,8]. The mixed subtype results from a combination of two or more of the previous subtypes. The order of the concomitant subtypes, specified in brackets, follows their predominant representation in the individual patient, eg, mixed (linear-circumscribed) [1].

ASSOCIATED CONDITIONS Other disorders not included in the more recent classification of LS can precede, follow, or be concomitant with LS. Lichen sclerosus et atrophicus is characterized by shiny white plaques often preceded by violaceous discoloration with some predilection for the

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anogenital area, wrists, and ankles. The superficial layers of the skin are usually involved. Atrophoderma of Pasini and Pierini consists of hyperpigmented atrophic patches usually on the trunk with well-demarcated borders. These lesions usually represent the end stage of juvenile localized scleroderma (JLS). Bullous morphea is a very rare subtype characterized by bullous lesions possibly resulting from a localized trauma or related to lymphatic obstruction from the sclerodermatous process [9]. In eosinophilic fasciitis, the fascia is the predominant site of involvement [10]. The lesions typically involve the extremities, spare the hands and feet, and have an appearance that is described as peau d’orange. Hypergammaglobulinemia and eosinophilia are often present.

EPIDEMIOLOGY LS is more frequent than SSc but still is a rare condition. In the general population, the incidence of LS is 2.7 cases per 100,000 [11], and in children under the age of 16 years there are 3.4 cases per million per year [12]. In a population-based study of LS [11], CM accounted for 56%, generalized morphea for 13%, linear morphea for 20%, and deep morphea for 11%. The female-to-male ratio of LS is 2.4:1, the mean age at onset is approximately 7.3 years [13], and there are no differences in the various LS subtypes [2]. The disease can start as early as at birth [3]. It can be misdiagnosed as skin infection, nevus, or salmon patch, and this may lead to a consistent delay in diagnosis.

ETIOLOGY AND PATHOGENESIS The cause and pathogenesis of LS are unknown. Abnormalities of the immune system, regulation of fibroblasts, and production of collagen represent the most important points investigated by experimental studies. Multiple studies have demonstrated increased levels of cytokines and other molecules that influence fibroblasts and collagen synthesis. Autoimmunity, environmental factors, infection, and trauma have all been associated with localized disease. It seems certain that autoimmunity plays an important role because of the multiplicity of abnormal serum antibodies that occurs in patients with LS and because of the association of similar cutaneous abnormalities in patients with chronic graft versus host disease (GVHD) [14]. The clinical and histopathological similarities of LS to chronic GVHD have suggested that nonself cells or chimerism may be involved in the pathogenesis of the disease [15]. A large number of chimeric infiltrating cells, mainly epithelial or dendritic cells, have been found in biopsies of LS patients.

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Some drugs and environmental toxins have resulted in scleroderma-like reactions, including bleomycin, ergot, bromocriptine, pentazocine, carbidopa, and vitamin K1 [16]. A few studies have examined a putative association of LS and Borrelia burgdorferi, the spirochete that causes Lyme disease. Many studies have documented evidence of infection with B. burgdorferi in patients with morphea who live in areas endemic for Lyme disease, or have a history of tick bites [17]. This was not confirmed in patients with morphea who do not live in endemic areas [18]. Trauma has been implicated in the initiation of lesions and particularly with the onset of eosinophilic fasciitis [2,19].

EXTRACUTANEOUS MANIFESTATIONS One-fifth of patients with LS present extracutaneous manifestations and 4% of them may have multiple features [20]. Extracutaneous findings are more frequent in patients with linear scleroderma and consist essentially of arthritis (19%), neurological findings (4%), or other autoimmune conditions (3%). In these patients, organ impairment is milder and not life-threatening compared to SSc [21]. Articular involvement is the most frequent extracutaneous feature, and is more common in patients with linear scleroderma. The joint involved may be completely unrelated to the site of the skin lesion. Children with LS who develop arthritis often have a positive RF [2,20], and sometimes an elevated erythrocyte sedimentation rate (ESR). The most frequent neurological conditions are seizures and headaches, although behavioral changes and learning disabilities also have been described [20,22]. Abnormalities seen on magnetic resonance imaging (MRI), such as calcifications, white matter changes, vascular malformations, and changes consistent with central nervous system (CNS) vasculitis, also have been reported [23]. Gastroesophageal reflux is the only gastrointestinal complication reported so far [24]. In a cohort of 14 consecutive patients, esophageal involvement was found in eight (57%), seven had pathological pH test findings, and in four of them, concomitant esophageal dysmotility was also present [24]. Odontostomatologic involvement has been recently described especially in patients with localized scleroderma of the face [25]. Ocular involvement has been reported in 3.2% of patients affected by LS [26]. As expected, two-thirds of patients with ocular manifestations have the ECDS subtype but, interestingly, the other third have no facial skin lesion. The most frequent lesions (42%) are on eyelids and eyelashes; one-third consists of anterior segment inflammation, such as anterior uveitis or episcleritis, the remaining are mainly CNS-related abnormalities. Although extracutaneous manifestations should be considered on every patient with

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LS, routine screening for internal organ manifestations (other than uveitis in linear scleroderma of the face) is generally not recommended.

LABORATORY FINDINGS The diagnosis of LS is established on clinical grounds; no laboratory abnormality is diagnostic. The acute-phase reactants, ESR and C-reactive protein (CRP), are usually within the normal ranges with the exception of the deep subtypes in which eosinophilia and hypergammaglobulinemia may be found [2,27]. RF is present in 25 40% of patients [2,20] and is often related to the presence of articular involvement [20]. Autoantibodies are found in many patients with LS. Antinuclear antibodies can be present in any subtype, with a frequency ranging from 23% to 73% [2,27]. Antihistone antibodies have been detected in 47% of patients with LS with a different prevalence in the various subtypes—higher in generalized morphea, lower in CM [28]. Antitopoisomerase I antibodies (anti-Scl 70), a marker of SSc in adults, were found to be positive in 2 3% of children with LS but not in adults with LS [2,28]. Conversely, anticentromere antibodies were found in 12% of adults with LS but only in 1.7% of children [2,29]. Anti-DNA topoisomerase IIα antibodies (anti-topo IIα) were detected in 76% of patients with LS and in 85% of those with generalized morphea [30]. Immunoblotting showed no cross-reactivity of anti-topo IIα with antitopo I autoantibodies, which are almost exclusively detected in SSc. Anti-topo IIα, however, is not completely specific for LS, being present also in patients with SSc (14%), in those with systemic lupus erythematosus (8%), and even in dermatomyositis (10%). Anticardiolipin antibodies (aCL) have been found in 46% of the patients with LS and lupus anticoagulant (LAC) in 24% while β2-glycoprotein-I (β2GPI) antibodies were absent [31]. In children aCL were found in 12.6% of patients [2]. Serum concentrations of soluble interleukin (IL)-2 receptor have been increased in cases of LS and may differentiate active from inactive disease [32], although this finding is not supported by all studies [19].

DISEASE MONITORING Various methods for the clinical monitoring of LS have been developed but none has been validated in large cohort of patients. A semiquantitative scoring method, the Localized Scleroderma Severity Index (LoSSI), is based on the evaluation of three parameters: lesion extension, intensity of inflammation, and new lesion development or existing lesion extension [33]. The extension score is based on the evaluation of 14 cutaneous anatomic sites, each divided into 3 segments; the intensity score is

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related to the degree of erythema of the lesion’s edge and/or skin thickness by palpation. The last parameter is calculated on the basis of the appearance of new lesions or enlargement of the existing ones. The overall composite score ranges between 0 and 168. The limitation of this method is that it is quite subjective and does not evaluate the real size of the lesions. A computerized skin score (CSS) method for the measurement of circumscribed lesions allows a more precise evaluation of the extension of each lesion [34]. It involves demarcating the indurate borders of the scleroderma lesions on an adhesive transparent film, transferring them to a card, scanning, and recording the data in a computer. Calculation of the affected area, performed by computer software, takes into account the child’s growth and in this way allows the longitudinal monitoring of the lesions. Infrared thermography (IT) has been shown to be of value in the detection of active LS lesions in children with high sensitivity (92%) but low specificity (68%) [35]. The false-positive results are related to the fact that old lesions lead to a marked atrophy of skin, subcutaneous fat, and muscle, with increased heat conduction from deeper tissues. Laser Doppler flowmetry (LDF) is another noninvasive method for the measurement of cutaneous microcirculation for the evaluation of scleroderma lesions [36]. LDF can detect the increase of blood flow in clinically active lesions. It represents a complementary tool in evaluating LS in the sense that while IT can quantitate thermographic changes of visible lesions and may reveal hidden active lesions, LDF can confirm the presence of active lesion and exclude activity in atrophic lesions. High-frequency ultrasound can detect several abnormalities of LS lesions such as increased blood flow, increased echogenicity due to fibrosis, and loss of subcutaneous fat [37,38]. The main limits of this tool are its operator dependency and the lack of standardization. The use of MRI is indicated when CNS or orbital involvement are suspected [39], and to demonstrate the depth of soft-tissue lesions in the deep subtypes of LS [40,41].

TREATMENT Over the years, many treatments for LS have been tried [42]. Management decisions must be based on the particular subtype of disease and the fact that these disorders may spontaneously enter remission after 3 5 years. CM is generally of cosmetic concern only, and treatments with potentially significant toxicity are not justified. Treatment should therefore be directed toward topical therapies such as moisturizing agents, topical glucocorticoids, or calcipotriene [42]. Phototherapy with ultraviolet (UV) represents another possible therapeutic choice for LS [43,44]. The use of UV light therapy, with or without chemical agents such as psoralen, has been reported to be beneficial for localized or superficial lesions in a number of studies. Limitations for the

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use of UV phototherapy in children are the need for prolonged maintenance therapy, leading to a high cumulative dosage of irradiation, and the increased risk for potential long-term effects such as skin aging and carcinogenesis [45]. When there is a significant risk for disability, such as in progressive linear scleroderma crossing joint lines and generalized or pansclerotic morphea, systemic treatment, particularly with methotrexate, should be considered. A weekly regimen of methotrexate of 10 15 mg/m2 as a single oral or subcutaneous dose per week is recommended. During the first 3 months of therapy, a course of glucocorticoids should be used as adjunctive bridge therapy. Recently, a randomized trial comparing a 12-month course of oral methotrexate (15 mg/m2) for 12 months with a 3-month course of oral prednisone (1 mg/kg per day, maximum dose 50 mg) showed that methotrexate was effective and well tolerated in more than two-thirds of patients with JLS [46]. New lesions appeared in only 6.5% of methotrexate-treated patients compared with 16.7% of the prednisone group. Patients who do not respond to this treatment may be treated with mycophenolate mofetil at a dose of 500 1000 mg/m2 [47]. There are, to date, no published trials of biologics or combination treatments. Surgical reconstruction may be required if the disease has not been adequately controlled. Surgery should be performed only after the active phase of the disease has abated and when the child’s growth is complete. Facial recontouring is a surgical treatment option that may improve quality of life in adolescents with facial asymmetry due to scleroderma ECDS [48].

COURSE OF THE DISEASE AND PROGNOSIS Unlike SSc, the prognosis with regard to survival for LS is usually benign. The course is characterized by an early inflammatory phase, with progression to multiple or extensive lesions, then stabilization, and finally improvement with softening of the skin and increased pigmentation around the lesions. In a population-based study of LS [11], 50% of patients had documented skin softening of 50% or more or had disease resolution by 3.8 years after the diagnosis. A small number of patients had active disease for more than 20 years. One-fourth of patients with linear scleroderma and 44% of those with deep morphea developed significant disability. Progression to SSc occurs very rarely in children [49].

REFERENCES [1] Laxer RM, Zulian F. Localized scleroderma. Curr Opin Rheumatol 2006;18(6):606 13. [2] Zulian F, Athreya BH, Laxer RM, et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatology (Oxford) 2006;45:614 20.

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[3] Zulian F, Vallongo C, de Oliveira SKF, et al. Congenital localized Scleroderma. J Pediatr 2006;149(2):248 51. [4] Weibel L, Harper JI. Linear morphea follows Blaschko’s lines. Br J Dermatol 2008;159:175 81. [5] Jablonska S, Blaszczyk M. Long-lasting follow-up favours a close relationship between progressive facial hemiatrophy and scleroderma en coup de sabre. J Eur Acad Dermatol Venereol 2005;19:403 4. [6] Diaz-Perez JL, Connolly SM, Winkelmann RK, et al. Disabling pansclerotic morphea in children. Arch Dermatol 1980;116:169 73. [7] Parodi PC, Riberti C, Draganic Stinco D, et al. Squamous cell carcinoma arising in a patient with long standing pansclerotic morphea. Br J Dermatol 2001;144:417 19. [8] Wollina U, Buslau M, Weyers W, et al. Squamous cell carcinoma in pansclerotic morphea of childhood. Pediatr Dermatol 2002;19:151 4. [9] Daoud MS, Su WP, Leiferman KM, et al. Bullous morphea: clinical, pathologic, and immunopathologic evaluation of thirteen cases. J Am Acad Dermatol 1994;30:937 43. [10] Shulman LE. Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome? J Rheumatol 1974;1(Suppl. 1):46. [11] Peterson LS, Nelson AM, Su WPD, et al. The epidemiology of morphea (localized scleroderma) in Olmsted County 1960 1993. J Rheumatol 1997;24:73 80. [12] Herrick AL, Ennis H, Bhushan M, Silman AJ, Baildam EM. Incidence of childhood scleroderma in the UK and Ireland. Arthritis Care Res (Hoboken) 2010;62:213 18. [13] Mayes MD, Lacey Jr JV, Beebe-Dimmer J, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003;48:2246 55. [14] Aractingi S, Socie G, Devergie A, et al. Localized scleroderma-like lesions on the legs in bone marrow transplant recipients: association with polyneuropathy in the same distribution. Br J Dermatol 1993;129:201 3. [15] McNallan KT, Aponte C, el-Azhary R, et al. Immunophenotyping of chimeric cells in localized scleroderma. Rheumatology (Oxford) 2007;46:398 402. [16] Haustein UF, Haupt B. Drug-induced scleroderma and sclerodermiform conditions. Clin Dermatol 1998;16:353 66. [17] Aberer E, Stanek G, Ertl M, et al. Evidence for spirochetal origin of circumscribed scleroderma (morphea). Acta Derm Venereol 1987;67:225 31. [18] Weide B, Schittek B, Klyscz T, et al. Morphea is neither associated with features of Borrelia burgdorferi infection, nor is this agent detectable in lesional skin by polymerase chain reaction. Br J Dermatol 2000;143:780 5. [19] Vancheeswaran R, Black CM, David J, et al. Childhood-onset scleroderma: is it different from adult-onset disease? Arthritis Rheum 1996;39:1041 9. [20] Zulian F, Vallongo C, Woo P, et al. Localized scleroderma in childhood is not just a skin disease. Arthritis Rheum 2005;52:2873 81. [21] Leitenberger JJ, Cayce RL, Haley RW, et al. Distinct autoimmune syndromes in morphea: a review of 245 adult and pediatric cases. Arch Dermatol 2009;145:545. [22] Blaszczyk M, Krolicki L, Krasu M, et al. Progressive facial hemiatrophy: central nervous system involvement and relationship with scleroderma en coup de sabre. J Rheumatol 2003;30:1997 2004. [23] Flores-Alvarado DE, Esquivel-Valerio JA, Garza-Elizondo M, et al. Linear scleroderma en coup de sabre and brain calcification: is there a pathogenic relationship? J Rheumatol 2003;30:193 5.

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[24] Guariso G, Conte S, Galeazzi F, et al. Esophageal involvement in juvenile localized scleroderma: a pilot study. Clin Exp Rheumatol 2007;25:786 9. [25] Trainito S, Favero L, Martini G, Pedersen TK, Favero V, Herlin T, et al. Odontostomatologic involvement in juvenile localised scleroderma of the face. J Paediatr Child Health 2012;48:572 6. [26] Zannin ME, Martini G, Athreya BH, et al. Ocular involvement in children with localized scleroderma: a multicenter study. Br J Ophthalmol 2007;91(10):1311 14. [27] Falanga V, Medsger Jr TA, Reichlin M, et al. Linear scleroderma: clinical spectrum, prognosis, and laboratory abnormalities. Ann Intern Med 1986;104:849 57. [28] Sato S, Fujimoto M, Ihn H, et al. Clinical characteristics associated with antihistone antibodies in patients with localized scleroderma. J Am Acad Dermatol 1994;31:567 71. [29] Ruffatti A, Peserico A, Glorioso S, et al. Anticentromere antibody in localized scleroderma. J Am Acad Dermatol 1986;15:637 42. [30] Hayakawa I, Hasegawa M, Takehara K, et al. Anti-DNA topoisomerase IIα autoantibodies in localised scleroderma. Arthritis Rheum 2004;50:227 32. [31] Sato S, Fujimoto M, Hasegawa M, et al. Antiphospholipid antibody in localised scleroderma. Ann Rheum Dis 2003;62:771 4. [32] Ihn H, Sato S, Fujimoto M, et al. Clinical significance of serum levels of soluble interleukin-2 receptor in patients with localized scleroderma. Br J Dermatol 1996;134:843 7. [33] Arkachaisri T, Pino S. Localized scleroderma severity index and global assessments: a pilot study of outcome instruments. J Rheumatol 2008;35:650 7. [34] Zulian F, Meneghesso D, Grisan E, et al. A new computerized method for the assessment of skin lesions in localized scleroderma. Rheumatology (Oxford) 2007;46:856 60. [35] Martini G, Murray KJ, Howell KJ, et al. Juvenile-onset localized scleroderma activity detection by infrared thermography. Rheumatology (Oxford) 2002;41:1178 82. [36] Weibel L, Howell KJ, Visentin MT, et al. Laser Doppler flowmetry for assessing localized scleroderma in children. Arthritis Rheum 2007;56:3489 95. [37] Li SC, Liebling MS, Haines KA, et al. Ultrasonography is a sensitive tool for monitoring localized scleroderma. Rheumatology (Oxford) 2007;46(8):1316 19. [38] Li SC, Liebling MS, Haines KA, et al. Initial evaluation of an ultrasound measure for assessing the activity of skin lesions in juvenile localized scleroderma. Arthritis Care Res 2011;63:735. [39] Ramboer K, Dermaerel P, Baert AL, et al. Linear scleroderma with orbital involvement: follow up and magnetic resonance imaging [letter]. Br J Ophthalmol 1997;81:90 3. [40] Horger M, Fierlbeck G, Kuemmerle-Deschner J, et al. MRI findings in deep and generalized morphea. Am J Roentgenol 2008;190:32 9. [41] Schanz S, Fierlbeck G, Ulmer A, et al. Localized scleroderma: MR findings and clinical features. Radiology 2011;260:817. [42] Zulian F. New developments in Localized scleroderma. Curr Opin Rheumatol 2008;20 (5):601 7. [43] Kreuter A, Hyun J, Stu¨cker M, et al. A randomized controlled study of low-dose UVA1, medium-dose UVA1, and narrowband UVB phototherapy in the treatment of localized scleroderma. J Am Acad Dermatol 2006;54:440. [44] De Rie MA, Bos JD. Photochemotherapy for systemic and localized scleroderma. J Am Acad Dermatol 2000;43:725 6. [45] Staberg B, Wulf HC, Klemp P, et al. The carcinogenic effect of UVA irradiation. J Invest Dermatol 1983;81:517 19.

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[46] Zulian F, Martini G, Vallongo C, et al. Methotrexate in juvenile localized scleroderma: a randomised, double-blind, placebo-controlled trial. Arthritis Rheum 2011;63:1998 2006. [47] Martini G, Ramanan AV, Falcini F, et al. Successful treatment of severe or methotrexateresistant juvenile localized scleroderma with mycophenolate mofetil. Rheumatology (Oxford) 2009;48:1410 13. [48] Palmero ML, Uziel Y, Laxer RM, et al. En coup de sabre scleroderma and parry-romberg syndrome in adolescents: surgical options and patient-related outcomes. J Rheumatol 2010;37:2174 9. [49] Birdi N, Laxer RM, Thorner P, Fritzler MJ, Silverman ED. Localized scleroderma progressing to systemic disease. Case report and review of the literature. Arthritis Rheum 1993;36:410 15.

Chapter 12

Juvenile Systemic Sclerosis I. Foeldvari Hamburger Centre of Pediatric and Adolescent Rheumatology, Scho¨n-Klinik-Eilbek, Hamburg, Germany

INTRODUCTION Juvenile systemic sclerosis (jSSc) is a rare potentially life-threatening autoimmune disease of childhood, currently incurable, and is of unknown cause. JSSc is characterized by cutaneous and visceral fibrosis. The disease shows a progressive course with a long-term fatal outcome. It is classified according the proposed pediatric classification criteria [1]. The recently published adult classification criteria [2] seems to be more sensitive for cases without skin involvement, and it is planned to be validated in pediatric cases too. The organ involvement pattern differs from the adult form. Survival seems to be better in pediatric patients with a 5-year survival of 90 95%. The validation of the outcome measures for children with jSSc is currently under evaluation. Regarding effective treatment, there is no pediatric data and the pediatric rheumatologist needs to rely on the experiences in adult disease.

INCIDENCE AND PREVALENCE There are no good data regarding prevalence and incidence. According to an older study in Finland around 0.05 per 100,000 is the incidence of the disease [3]. A cross-sectional study from the United Kingdom from 2010 showed an incidence rate of 0.27 (95% CI 0.1 0.5) per million of children per year [4]. It is assumed that 5 10% of the patients with SSc first develop the disease in childhood.

CLASSIFICATION It is currently classified according the preliminary pediatric classification criteria [1]. This criteria was created in an effort of the Paediatric Rheumatology European Society (PRES) juvenile scleroderma working group (Table 12.1). This classification was reached over a Delphi process Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00012-8 © 2016 Elsevier B.V. All rights reserved.

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TABLE 12.1 The Provisional Classification Criteria for Juvenile Systemic Sclerosis Major Criteria G

a

Minor Criteria a

Induration /sclerosis

G G G G G G G G

Vascular changesa Pulmonary involvementa Gastrointestinal involvementa Renal involvementa Cardiovascular involvementa Musculoskeletal involvementa Neurologic involvementa Serologya

a Typical for limited systemic sclerosis [5]. Source: Defined in Ref. [1].

involving pediatric and adult rheumatologists as pediatric and adult dermatologists specialized in SSc. This classification was accepted by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) too [1]. The acceptance by the ACR and EULAR was a very important step to create a common language to classify these patients in most parts of the world. The major expected advantage of this classification criteria is that patients with jSSc can be classified earlier; they need to have as major organ involvement the typical skin involvement of the SSc in the limited form [5], and two other scleroderma-specific organ manifestations (see Table 12.1 and the publication for detailed description of the required organ involvement [1]). It is different from the previous preliminary adult classification [6] criteria from the early 1980s, because here, only skin and pulmonary features are listed as possible minor criteria. The prospective validation of the childhood criteria is still in process. The criteria is in the process of getting validated as part of the prospective juvenile systemic scleroderma inception cohort project: www.juvenile-scleroderma.com. A validation is planned in a common effort of the EULAR and ACR. In the frame of the ongoing initiatives to update and improve classification criteria for adult SSc, a new adult classification criteria was developed [2]. This newly published criteria is very sensitive to classify adult patients with SSc early in the disease course [7] and in the preliminary validation of children as well [7a]. This new adult classification uses a scoring system; when nine points from the listed weighted items are reached, then the patient can be classified with SSc.

ETIOLOGY/PATHOGENESIS SSc is a disease of unknown cause, and the pathogenesis remains incompletely unknown. It has been considered a disease of disordered connective

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tissue metabolism, presenting with varying degrees of skin or major organ fibrosis. It has been recognized that the tissue fibrosis seen in SSc is the end result of a complex biologic process involving immune activation and widespread vascular injury [8]. In fact, compelling clinical and biologic evidence suggests that the primary target for both initiating and propagating the disease are blood vessels [9,10]. We still do not know how the disease is initiated. Understanding the biologic events that occur primary to the onset of Raynaud’s phenomenon or other clinical signs of active vascular disease is critical in developing novel and effective treatment strategies. In a pathogenesis of SSc, the main focus is the abnormalities in the regulatory T lymphocytes (Tregs). Reiff et al. [11] showed in their paper differences in the Treg population comparing adult and juvenile SSc patients. They could show a decreased number of resting Tregs and in increased frequency of CD45RA expressing effector memory (EMRA) CD4 T lymphocytes, which were characterized by an increased frequency of CCR/protein expressing cells. Other theories point to the persistence of maternal microchimeric cells [12,13], which persist into the adulthood; however another recent study argues again this theory [14]. The theory of the maternal microchimerism would explain the similarities to graft-versus-host disease. Environmental and genetic factors play [15,16] an important role too, which is reflected in the high rate of other autoimmune diseases in household contacts and relatives [17,18]. Interestingly, the frequency of SSc in twins is no different in monozygotic compared to dizygotic twins [19]. Mitochondrial inheritance, birth order, and parental age do not seem to have an influence [20].

CLINICAL MANIFESTATIONS Regarding distribution of the organ involvement in children with jSSc the best sources are the two existing multinational multicenter surveys of patients with jSSc [21,22]. The pattern of organ involvement is presented in Table 12.2. In both studies, the participating centers were asked to describe the organ involvement, without requesting a standardized assessment algorithm to define the extent of the organ involvement, which makes the data softer. A third source of data is a yet-unpublished summary of case reports by the author of this chapter, which is presented in Table 12.2, in which 17 published case reports of jSSc patients in English literature were collected with the prerequisite that sufficient data regarding organ involvement, outcome, and demographic data of the patients was present. The pattern of organ involvement and distribution of ethnicity was found to be similar when compared to the two abovementioned surveys: 39 of the 51 patients were female, the mean age at diagnosis was 9.4 years, and the mean followup period was 3.25 years. In both surveys the mean age of onset was 8.8 years, with the youngest patient at onset with 0.3 years.

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TABLE 12.2 Pattern of Organ Involvement of Juvenile Systemic Sclerosis Patients Organ Involvement

Foeldvari et al., n 5 135 (%)

Martini et al., N 5 153 (%)

Published Case Reports (1961 1997) n 5 51 (%)

Skin

135 (100)

116 (75.8)

51 (100)

Joints

106 (79)

97 (63.5)

23 (45)

GI tract

88 (65)

106 (69)

30 (58)

Esophagus only

63 (47)

47 (31)

17 (33)

Pulmonary

68 (50)

64 (41.8)

27 (53)

Cardiovascular

60 (44)

44 (28.8)

15 (29)

Central nervous system

21 (16)

4 (3)

Renal

17 (13)

15 (9.8)

7 (14)

Muscular

13 (10)

37 (24.2)

7 (14)

Raynaud’s syndrome

97 (72)

128 (83.7)

31 (56)

Calcinosis

36 (27)

28 (18.3)

2 (4)

Sjo¨gren’s syndrome

7 (5)

?

3 (6)

CREST

1

?

1 (2)



75.8% skin induration; 66% sclerodactyly; 44.1% edema.

In 90% of the patients with jSSc, Raynaud’s phenomenon occurs, and in around 70% of jSSc patients it is the first sign of the disease. Raynaud’s phenomenon is one of the minor defining criteria of jSSc according the newly proposed criteria. The classical Raynaud’s [23] attack has three phases: the first presents the vasoconstriction, where the fingers turn white, followed by a bluish discoloration, and then with the reperfusion a reddish discoloration occurs. It mostly occurs distally from the proximal interphalangeal joint on the fingers; usually the thumbs are spared. In the severe course of the attacks a “rat bite” necrosis/loss of tissue on the fingertips with or without ulceration can occur (Fig. 12.1). Microvasculature changes of the nailfolds are pathognomic for the secondary Raynaud’s associated to connective tissue disease [24], and some patterns are suggestive of SSc— the “scleroderma pattern” [25]. It has to be mentioned that some changes are age-dependent, and that has to be considered in the interpretation of the changes [26 28]. A recent study compared the pattern of adult and juvenile patients with SSc [29].

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FIGURE 12.1 “Rat bite” necrosis.

FIGURE 12.2 Early odematous phase of the skin.

After the occurrence of the Raynaud’s phenomenon in the further course of jSSc a diffuse edematous swelling of the fingers occurs (Fig. 12.2). This is painless but it often causes a decreased range of movements in the fingers. The skin involvement spreads from distal to proximal. The dynamic of the progress is individual. In the following months the fibrosis takes over the place of the edematous changes, which causes the typical skin changes of jSSc. These changes lead to loss of the possibility to make skin

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folds, which can be quantitatively measured with the modified Rodnan skin score [30]. The fibrosis can lead to loss of the mimic in the face. In the diffuse subtype the spread of the skin involvement is faster and it reaches a plateau usually after 1 3 years. In some patients extensive subcutaneous calcification can occur. The subtype of skin involvement was not assessed in the first study [21], but in the study of Zulian [22], 138 of the 153 patients had a diffuse pattern of skin involvement. In the first survey only one patient with CREST syndrome was reported, but in the second survey no CREST syndrome was reported. In the current summary of the juvenile scleroderma inception cohort (www.juvenile-scleroderma.com) around 70% of patients have diffuse subset, and no patient with CREST syndrome is in the cohort [7a]. This pattern of distribution of the subsets between diffuse and limited involvement differs from the pattern of distribution in adult SSc patients. Musculoskeletal involvement is often secondary to the skin involvement. Joint swelling is a rare presentation of the disease, but joint contractures occur frequently, caused by the fibrosis of the skin; it is described in 79% of the cases. Interestingly in MRI evaluation, real arthritis with synovitis was found in adult patients [31]. Subcutaneous calcifications can lead to joint contractures too. The so-called tendon friction rub is a hallmark of SSc, and can be felt during the physical examination and eventually even heard. Synovitis and tendon friction rub are predictive of worsening modified skin score in adults [32]. Myopathy can occur in 10% of the patients, caused by fibrosis on the muscular tissue or through secondary muscle atrophy or microvascular changes. According to the current concept, cardiac and pulmonary involvement is not viewed as separate organ involvements; it is considered as one complex of organ involvement, where changes in one interfere with changes in the other. Cardiopulmonary involvement occurs in around 50% of the patients, and since the renal crisis is a treatable condition, this is the organ involvement complex with the highest mortality. It can occur before the occurrence of the skin involvement. The two typical manifestations are pulmonary interstitial fibrosis and pulmonary hypertension. The interstitial fibrosis [33] (Figs. 12.3. and 12.4.) occurs early in the diffuse subtype. The first clinical symptoms occur late in the disease course and are dyspnea, fatigue, and dry cough. The dyspnea is classified according to the New York classification criteria. To prevent the long-term delirious effect of the progressive interstitial fibrosis, it is important to make the diagnosis early in the disease course. The interstitial fibrosis also leads to increased pulmonary pressure, which leads to secondary right-heart changes. The other typical complication is pulmonary hypertension, a hallmark of the limited subtype that occurs mostly later in the disease course. It is defined as a mean pulmonary artery pressure greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise, with normal pulmonary artery

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FIGURE 12.3 High-resolution computer tomography of the lung.

edge wedge pressure (ie, #15 mm Hg) and an increased pulmonary vascular resistance index $ 3 Wood units 3 m2 [34]. It is caused by the imbalance between vasoconstrictive, thrombogenic, mitogenic, and proinflammatory factors as opposed to anticoagulant, antimitotic, and vasodilating mechanisms, which lead to endothelial dysfunction. Regarding the prevalence of this complication in the pediatric population, currently there is no existing data, but the limited subtype represents just around 10% of the patients [22]. In the 50 patients in the inception cohort 10% of the patients also had pulmonary hypertension [7a]. The pulmonary hypertension leads to an elevated right-ventricular systolic pressure including a loud single P2, murmur of tricuspid insufficiency, and a murmur of pulmonary insufficiency. There may also be an S3 or S4 right-ventricular gallop. A myocardial dysfunction [35] can occur too, which is often not recognized, and it decreases myocardial contractility [36,37]. Cardiac troponin is a sensitive marker of myocardial involvement [38]. In 10% of cases it comes to asymptomatic pericardial effusion. Cardiac arrhythmia can also occur. The gastrointestinal system is the third most involved organ system. In 48% of the pediatric patients, an involvement of the esophagus with disturbance of the esophageal motility occurs [39] (Fig. 12.4), often associated with gastroesophageal reflux. In 17% of the patients an involvement of the further part of the gastrointestinal system occurs, with associated decreased

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FIGURE 12.4 Gastrointestinal involvement with dilated esophagus and colon. The dilated colon causes the pictures of bloated abdomen.

motility, malabsorption, intestinal pseudoobstruction, and in extreme cases with pneumatosis intestinalis. Only 10% of the pediatric cases have renal involvement. Renal crisis in children is rarely described; there are none in the inception cohort or in the two large case series. The renal crisis [40], the main life-threatening presentation of renal involvement in adults, is characterized with sudden-onset high

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blood pressure; 90% of patients have blood pressure levels greater than 150/ 90 mm Hg, and 30% have diastolic recordings greater than 120 mm Hg, and/ or rapidly progressive oliguric renal failure during the course of SSc. It is a better treatable condition since the introduction of the angiotensin-converting enzyme inhibitors. It mostly occurs in the first 5 years of the disease. Sjo¨gren’s syndrome occurs only in 4% of the pediatric cases, and is often underrecognized [41,42]. The patients have the feeling of sand in their eyes, need to drink a lot of fluid to be able to swallow, and have the feeling of dryness in the mouth. It can cause recurrent swelling of the parotis. In Sjo¨gren’s syndrome a secondary phenomenon to SSc is characterized by fibrosis of the parotis and lacrimal glands, and the dominating picture is not the lymphocitic infiltration as in the classical Sjo¨gren’s syndrome. Surprisingly in one of the cohorts [21] 14% of the patients had an involvement of the central nervous system judged by the physician who filled out the survey. In some of these cases vasculitis of the central nervous system was described. From the laboratory values blood sedimentation rate is mostly in the normal range. An increased level of gammaglobulin is observed. In the case of increased vasculitic activity the Factor VIII-related antigen can be elevated. Antinuclear antibodies (ANAs) positivity occurred in 120 of 150 patients, and 51 of 120 ANA-positive patients were extractable nuclear antigen-positive [22]. Moreover 36 of 106 tested patients were anti-Scl-70 positive [22]. Anticentromere antibodies [43,44] are specific for the limited subtype of the disease, but it is rarely observed in the pediatric population. Anticardiolipin antibodies occur in one-third of the patients, but the clinical relevance of this finding is still unclear. A new clinical parameter, the brain natriuretic peptide, is established, which correlates with the degree of pulmonary hypertension [45 47]. Another interesting clinical parameter is the endothelin-1, which also correlates well with pulmonary hypertension [44]. Mortality was relatively low in the cohort of 135 jSSc patients; 8 of 135 patients died [21] after a mean disease duration of 24 months (12 96 months). The patients with fatal outcome had a higher rate of pulmonary (75%/49%), cardiovascular (100%/41%), renal (50%/10%), and central nervous system (38%/14%) involvement when compared to patients with a nonfatal outcome. In the case series, 12 of the 53 patients died. In this collection of cases, the mean duration from disease onset to death was 22.5 months (4 120 months), showing a similar outcome when compared to the survey. The patients with fatal outcome showed also a higher proportion of pulmonary (75%/46%), cardiovascular (75%/15%), and renal (42%/5%) involvement as well as Raynaud’s syndrome (83%/54%) when compared to the nonfatal group. If the data regarding mortality are summarized, it can be revealed that most patients died in the first 4 years of their disease, and 12 of the 20 deaths occurred even in the first 24 months. In the other cohort [48] the outcome of 127 of the 153 patients were known, 15 patients

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representing 11.8% of patients deceased, 10 of them from cardiac failure. Death occurred in the mean 4.6 years after disease onset (range 0.3 18.8 years).

DIAGNOSTIC INVESTIGATIONS The diagnosis of jSSc is a primarily a clinical diagnosis. To reach the diagnosis it is important to carefully examine the patient and ascertain a good medical history. There are specific examination methods to evaluate singleorgan involvement [49].

Radiological Cardiopulmonary Involvement The gold standard to evaluate pulmonary fibrosis is high-resolution computed tomography [50], where an even scoring method exists for the radiologic changes and the baseline finding predicts future changes [51,52]. To evaluate pulmonary hypertension, the cardiac echo is a screening tool, and to define patients with pulmonary hypertension before starting treatment for this involvement, a right-heart catheter is still needed [34,52]. Gastrointestinal Involvement The most frequent gastrointestinal involvement causes esophageal dysmotility, which can be visualized on a barium swallow or with an esophagus scintigraphy. The changes further distal on the gastrointestinal system are visualized with barium/gastrograffin follow-up as with gastroscopy and colonoscopy [53]. Abdominal ultrasonography is a helpful noninvasive method to gain some information. Renal Involvement Abdominal ultrasound with Doppler can visualize the renal blood flow.

Functional Raynaud’s Phenomenon Nailfolds capillaroscopy with an othoscope can be done in every medical office. A more sophisticated method is to examine the changes with the microscope, eventually with the video microscopy, with qualitative and quantitative evaluation of the pattern of the capillary nailfold changes [25]. The changes are age-specific [26 28]. Video capillaroscopy is the most sensitive way to explore capillary changes, but it is not widely available. Thermography is a fancy method to demonstrate the vasoconstriction after cold stimulation, but it is not routinely used in clinical practice [54,55].

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Skin The modified Rodnan skin score is the method to evaluate the skin thickening, not the tethering; it has a significant intraobserver variation [30]. The skin thickening is scored from 0 to 3, with 3 as the highest score. It evaluates 17 body areas. One study, which evaluated the applicability of this method in healthy children, suggested some modification of the scoring if it is applied in children [56]. Musculoskeletal Involvement The evaluation of the swollen and limited joints is part of the clinical examination, as the evaluation of the presence of the tendon friction rub. To assess the muscle strength, the Childhood Myositis Assessment Scale [57] is available, which is validated for dermatomyositis. Cardiopulmonary Involvement A noninvasive method to evaluate the cardiopulmonary fitness of the patients is the 6-minute walk test [58]; it is evaluated in children with arthritis [59] and in a two healthy cohorts from the United Kingdom [60] and China [61] with different age-specific norms. It needs cooperation of the patient, so it may be that under the age of 7 years it is useful. There is more experience with this evaluation in children with primary pulmonary hypertension, where the decreased mobility caused by the joint contractures and muscle weakness as a cofounder does not exist. The pulmonary function tests with the measurement of the obstructive and restrictive parameters and including the carbon monoxide diffusion capacity, which is especially sensitive for interstitial changes, are useful noninvasive methods for the evaluation of pulmonary involvement. The change of these parameters correlate with the survival in adult patients [62]. The bronchoalveolar lavage is used routinely in adults for the assessment of the inflammatory activity; 3 4% polys or any eosinophils define the presence of alveolitis. The pediatrician would apply this method only if the changes on high-resolution computed tomography are not clearly differentiated between infection and disease activity (with agreement of the Juvenile Inceptions Cohort working group). Renal Involvement Regular assessment of blood pressure, body weight, and serum creatinine is the best screening tool for renal involvement.

Biochemistry/Serology/Immunology Laboratory tests can help to make the diagnosis, but not all patients have specific laboratory changes to support the diagnosis. Sedimentation rate is

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mostly normal. The immunoglobulines can be elevated. In the case of active vasculitis, Factor VIII antigen level is elevated. It is important to determine the ANAs and anti-Scl-70 and anticentromere antibodies [43] and other extractable nuclear antigen (ENA) subtypes. The specific antibodies correlate with the subtype of jSSc and with certain organ involvement [44,63]. Anticardiolipin antibodies can be positive in 30% of the cases.

Evaluation of the Severity of the Disease There is no validated measure to grade the severity of jSSc, but there is a proposed one [64] that presents a pediatric version of the Medsger Disease Severity Score. There are validated measures for adults with SSc—the Medsger Disease Severity Scale [65]—which can be partially helpful to get a feeling for the severity of the disease. The Disease Activity Criteria [66,67] scores mostly assess the damage rather than the activity of the disease and do not respond very well to improvement. The recently developed composite response index from Khannaa et al. [67a], represents an index that can be applied in clinical trials to assess the response to an effective medication; this was applied in the tocilizumab Phase II trial. Recently the evaluation of the quality of life is gaining importance to judge the severity of the disease [68], and for the pediatric population, the Child Health Questionnaire can be helpful. A specific instrument for pediatric patients with jSSc is not developed yet. For the functional assessment the disability score of the Child Health Assessment Questionnaire can be used, although it was not specifically validated for jSSc.

DIFFERENTIAL DIAGNOSIS There is a large list of diseases that can have components of systemic scleroderma. One that can resemble SSc is scleredema, which is a progressively indurated edema on the neck, shoulder girdle, proximal parts of the extremities, and face. The induration regress over 12 18 months, but contrary to SSc the hands are not involved. Sclermyxedema, another SSc-like condition, is characterized by aggregated lychenoid papules that form confluent plaques causing extensive thickening and hardening of the skin with accentuation of the skin folds. It involves the upper extremities, neck, upper trunk, and face, becoming progressively generalized. The main difference of SSc is that here, the skin is not bound and tight to the underlying tissue. Some endocrine disorders as hypothyroidism and juvenile insulin-dependent diabetes, and some metabolic disorders like phenylketonuria and porpyhria cutanea tarda can cause scleroderma-like changes. Rare disorders like Werner’s syndrome and progeria, restrictive dermatopathy, and congenital fascial dystrophy (stiffskin syndrome) resemble SSc. Pansclerotic morphea or generalized morphea, which is a subtype of localized scleroderma, can have a similar presentation

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to SSc. Patients after bone marrow transplantation can evolve graft-versushost disease, where the late changes are scleroderma-like; these patients evolve joint contractures in 60% of the cases, and some of them acquire Sjo¨gren’s syndrome as well.

TREATMENT There are unfortunately no therapy options that offer healing of the disease. All controlled studies were conducted in adult patients. It can be differentiated between immunosuppressive therapy, which tries to control and stop the disease globally or to control a certain organ involvement, and some that are just supportive/palliative, which are aimed to help specific problems that are part of the disease. Some therapies have global as well as organ-specific effects. The EULAR guidelines first published in 2009 summarize the evidence for treatment and were recently updated (the current version is submitted). Two biologics, rituximab [69] and tocilizumab [69], are very promising; the Phase III data is pending. The recently published controlled trial for autologous stem cell transplantation presents an effective therapeutic option for fast progressive disease when it is applied early in the disease course [70]. There are current guidelines for adults regarding treatment of pulmonary hypertension [71]. Physiotherapy plays an important role to decrease joint contracture, to keep up stamina. Occupational therapy support can help to handle the daily problems of life caused by the disease.

KEY POINTS jSSc is a rare autoimmune disease of childhood, with a progressive course, and with a potentially fatal outcome. We have a new proposed classification system for jSSc that will help to make the diagnosis earlier in the disease course, and we have a new proposed disease severity score for jSSc. The clinical presentation of jSSc differs from the adult disease; limited subtype and CREST syndrome are rare. It is important to evaluate the patients regularly for internal organ involvement, to introduce the therapy as early as possible (see the protocol or the juvenile scleroderma inception cohort at www. juvenile-scleroderma.com). There is no causal therapy for jSSc, but there is a great deal of progress in the treatment of pulmonary hypertension and adult SSc. Autologous stem cell transplantation and some of the new biologics seem to be very promising. The survival of jSSc patients after 5 years of 90 95% is significantly better than for adult patients.

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[37] Meune C, Allanore Y, Devaux JY, Dessault O, Duboc D, Weber S, et al. High prevalence of right ventricular systolic dysfunction in early systemic sclerosis. J Rheumatol 2004;31 (10):1941 5. [38] Hughes M, Lilleker JB, Herrick AL, Chinoy H. Cardiac troponin testing in idiopathic inflammatory myopathies and systemic sclerosis-spectrum disorders: biomarkers to distinguish between primary cardiac involvement and low-grade skeletal muscle disease activity. Ann Rheum Dis 2015. [39] Roberts CG, Hummers LK, Ravich WJ, Wigley FM, Hutchins GM. A case-controlled study of the pathology of oesophageal disease in systemic sclerosis (scleroderma). Gut 2006. [40] Rhew EY, Barr WG. Scleroderma renal crisis: new insights and developments. Curr Rheumatol Rep 2004;6(2):129 36. [41] Heijstek MW, Bast BJEG, Wulffraat N. Overlap syndromes in children presenting with the Sicca syndrome, a diagnositc challenge. Ped Rheum Online J 2005;3(1). [42] Houghton K, Malleson P, Cabral DA, Petty R, Tucker L. Primary Sjo¨gren’s syndrome in children and adolescent: are proposee diagnositc criteria applicable? J Rheumatol 2005;32:2225 32. [43] Cepeda EJ, Reveille JD. Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol 2004;16(6):723 32. [44] Castelino FV, Varga J. Current status of systemic sclerosis biomarkers: applications for diagnosis, management and drug development. Exp Rev Clin Immunol 2013;9(11):1077 90. [45] McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126(1 Suppl.):78S 92S. [46] Nasser N, Bar-Oz B, Nir A. Natriuretic petides and heart disease in infants and childres. J Ped 2005;147:248 53. [47] Avouac J, Meune C, Chenevier-Gobeaux C, Borderie D, Lefevre G, Kahan A, et al. Cardiac biomarkers in systemic sclerosis: contribution of high-sensitivity cardiac troponin in addition to N-Terminal Pro-Brain natriuretic peptide. Arthritis Care Res (Hoboken) 2015;67(7):1022 30. [48] Martini G, Vittadello F, Athreva BH, Lehman TJ, Foeldvari I, Russo R, et al. Mortality in juvenile systemic sclerosis: data from the padua international database of 153 patients. Arthritis Res Ther 2005;52:S533. [49] Ong VH, Brough G, Denton CP. Management of systemic sclerosis. Clin Med 2005;5:214 19. [50] Seely JM, Jones LT, Wallace CA, Sherry DD, Effmann EL. Systemic sclerosis: using high-resolution CT to detect lung sisease in children. AJR 1998;170:691 7. [51] Hoffmann-Vold AM, Aalokken TM, Lund MB, Garen T, Midtvedt O, Brunborg C, et al. Predictive value of serial high-resolution computed tomography analyses and concurrent lung function tests in systemic sclerosis. Arthritis Rheumatol 2015;67 (8):2205 12. [52] Gopal DM, Doldt B, Finch K, Simms RW, Farber HW, Gokce N. Relation of novel echocardiographic measures to invasive hemodynamic assessment in scleroderma-associated pulmonary arterial hypertension. Arthritis Care Res (Hoboken) 2014;66 (9):1386 94.

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[53] Jaovisidha K, Csuka ME, Almagro UA, Soergel KH. Severe gastrointestinal involvement in systemic sclerosis: report of five cases and review of the literature. Semin Arthritis Rheum 2005;34(4):689 702. [54] Schuhfried O, Vacariu G, Lang T, et al. Thermographic parameters in the diagnosis of secondary Raynaud’s phenomenon. Arch Phys Med Rehabil 2000;81:495 9. [55] Caramaschi P, Biasi D, Canestrini S, Martinelli N, Perbellini L, Carletto A, et al. Evaluation of finger skin temperature in scleroderma patients cyclically treated with iloprost. Joint Bone Spine 2006;73(1):57 61. [56] Foeldvari I, Wierk A. Healthy children have a significantly increased skin score assessed with the modified Rodnan skin score. Rheumatology 2006;45:76 8. [57] Huber AM, Feldman B, Rennebohm RM, Hicks JE, Lindsley C, Perez MD, et al. Validation and clinical significance if the Childhood Myositis Assessment Scale for assessment of muscle function in the juvenile idiopathic inflammatory myopathies. Arthritis Rheum 2004;50:1595 603. [58] Garofano RP, Barst RJ. Exercise testing in children with primary pulmonary hypertension. Pediatr Cardiol 1999;20(1):61 4; discussion 5. [59] Lelieveld OTHM, Takken T, van der Net J, van Weert E. Validity of the 6-minute walking test in juvenile idiopathic arthritis. Arthritis Care Res 2005;53:304 7. [60] Lammers AE, Hislop AA, Flynn Y, Haworth SG. The 6-minute walk test: normal values for children of 4 11 years of age. Arch Dis Child 2008;93(6):464 8. [61] Li AM, Yin J, Yu CCW, et al. The six-minute walk test in healthy children: reliability and validity. Eur Respir J 2005;25:1057 60. [62] Nihtyanova SI, Schreiber BE, Ong VH, Rosenberg D, Moinzadeh P, Coghlan JG, et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol 2014;66(6):1625 35. [63] D’Aoust J, Hudson M, Tatibouet S, Wick J, Canadian Scleroderma Research G, Mahler M, et al. Clinical and serologic correlates of anti-PM/Scl antibodies in systemic sclerosis: a multicenter study of 763 patients. Arthritis Rheumatol 2014;66(6):1608 15. [64] La Torre F, Martini G, Russo R, Katsicas MM, Corona F, Calcagno G, et al. A preliminary disease severity score for juvenile systemic sclerosis. Arthritis Rheum 2012;64 (12):4143 50. [65] Medsger TA, Silman AJ, Steen VD, et al. A disease severity scale for systemic sclerosis development and testing. J Rheumatol 1999;26:2159 67. [66] Valentini G, Bencivelli W, Bombardieri S, et al. European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria. Ann Rheum Dis 2003;62:901 3. [67] Valentini G, D’Angelo S, Della Rossa A, Bencivelli W, Bombardieri S. European Scleroderma study group to define disease activity criteria for systemic sclerosis. IV. Assessment of skin thickening by modified Rodnan skin score. Ann Rheum Dis 2003;62:904 5. [67a] Khanna D, Berrocal VJ, Giannini EH, Seibold JR, Merkel PA, Mayes MD, et al. The American College of rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol 2016;68 (2):299 311.

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[68] Johnson SR, Hawker GA, Davis A. The Health Assessment Questionnaire disability index and scleroderma Health Assessment Questionnaire in scleroderma rials: an evaluation of their measurement properties. Arthritis Care Res 2005;53:256 62. [69] Elhai M, Meunier M, Matucci-Cerinic M, Maurer B, Riemekasten G, Leturcq T, et al. Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis 2013;72 (7):1217 20. [70] van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014;311(24):2490 8. [71] Hemnes AR. Pulmonary arterial hypertension treatment guidelines: new answers and even more questions. Chest 2014;146(2):239 41.

Chapter 13

Autoinflammatory Disorders in Children G. Elizabeth Legger1 and J. Frenkel2 1

Department of Paediatric Rheumatology and Immunology, University Medical Centre Groningen, Groningen, The Netherlands, 2Department of General Paediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands

ABBREVIATIONS AD ADA2 AGS APLAID AR CAPS CINCA CRMO CRP DIRA DITRA ESR FCAS FMF HIDS IL MWS NOMID PAPA PFAPA PLAID PRAAS SAA SAPHO SAVI

autosomal dominant adenosine deaminase 2 Aicardi
Goutieres syndrome autoinflammation and PLCγ 2-associated antibody deficiency and immune dysregulation autosomal recessive cryopyrin-associated periodic syndrome chronic infantile neurological cutaneous articular syndrome chronic recurrent multifocal osteomyelitis C-reactive protein deficiency of IL-1 receptor antagonist deficiency of the IL-36 receptor antagonist erythrocyte sedimentation rate familial cold autoinflammatory syndrome familial Mediterranean fever hyper IgD syndrome interleukin Muckle
Wells syndrome neonatal onset multisystem inflammatory disease pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome periodic fever with aphthous stomatitis, pharyngitis, and adenitis PLCG2-associated antibody deficiency and immune dysregulation proteasome-associated autoinflammatory syndrome serum amyloid A synovitis acne pustulosis hyperostosis and osteitis STING-associated vasculopathy with onset in infancy

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INTRODUCTION Autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation. These include monogenetic and multifactorial conditions and are the result of exaggerated activation of innate immunity in response to trivial stimuli [1
3]. In contrast to autoimmune diseases there are no high-titer autoantibodies or autoantigen-specific T cells because the acquired immune system is not affected, although patients with autoinflammation might have a dysregulated adaptive immune system. In 2006, McGonagle et al. proposed an immunological disease continuum with, on one side, the monogenetic autoinflammatory diseases, and on the other side, the monogenetic autoimmune diseases, and in the middle, the mixed patterns of diseases and polygentic diseases [4]. In the past years, it becomes more clear that there are also disorders with both immunodeficiency and autoinflammation like HOIL-1 deficiency and ADA2 deficiency [5,6]. Many autoinflammatory disorders are characterized by recurrent episodes of fever alternating with more or less prolonged periods of disease remission and are defined as periodic fever syndromes. The fever episodes are usually accompanied by additional systemic and localized inflammatory symptoms involving joints, skin, eyes, gut, or serosal surfaces [7]. Pathophysiology, symptoms, and treatment of these disorders often overlap, but there are also quite characteristic features that can aid diagnosis. For a rapidly expanding number of these disorders, a causative gene could be identified. Other autoinflammatory diseases are characterized by signs of localized and systemic inflammation, but without prominent fever. These include the granulomatous diseases like sarcoidosis and Blau syndrome but also diseases with signs of sterile skin inflammation like DIRA and DITRA and noninfectious bone inflammation like CRMO and SAPHO, discussed elsewhere. In most autoinflammatory diseases, including the systemic form of juvenile idiopathic arthritis (sJIA), the cytokine interleukin-1 (IL-1) plays a pivotal role [8]. In recent years it become clear that there are many more mechanisms that play a role in autoinflammation, such as protein misfolding, the endoplasmatic reticulum stress response, and proteases, but also new players, including growth factor-like protein with a role in macrophage differentiation [9] (Table 13.1). In this chapter, the clinical presentation and recent progress in elucidating the underlying pathophysiology and the current treatment will be described for the more common hereditary autoinflammatory disorders. Multifactorial disorders such as sarcoidosis, sJIA, CRMO, and PFAPA syndrome will fall beyond the scope of this chapter. Like Blau syndrome these will be discussed elsewhere.

TABLE 13.1 Molecular Classification of Monogenic Autoinflammatory Diseases Disease

Gene

Protein

Mode of Inheritance

Mutation Type

Mechanism(s) of Disease

FMF

MEFV

Pyrin

AR

Controversial

Inflammasome activation IL-1β release

TRAPS

TNFRSF1A

TNFRSF1A

AD

Gain of function

Unfolded protein response ER stress MAPK activation Increased production of mROS

HIDS

MVK

Mevalonate kinase

AR

Loss of function

Shortage of isoprenoid compounds Activation of the small GTPase Rac1 Inflammasome activation IL-1β release

CAPS

NLRP3

NLRP3

AD

Gain of function

Inflammasome activation IL-1β release

PAPA

PSTPIP1

PSTPIP1

AD

Gain of function

Inflammasome activation

Majeed syndrome

LPIN2

Phosphatidate phosphatase LPIN2

AR

Loss of function

Loss of phosphatidate phosphatase activity leads to decreased inhibition of proinflammatory signaling

NLRP12 syndrome

NLRP12

NLRP12 (also known as NALP12)

AD

Loss of function

Decreased inhibition of NF-κB Increased processing of caspase 1 and IL-1 release (Continued )

TABLE 13.1 (Continued) Disease

Gene

Protein

Mode of Inheritance

Mutation Type

Mechanism(s) of Disease

DIRA

IL1RN

IL-1Ra

AR

Loss of function

Decreased inhibition of IL-1α/β signaling

DITRA

IL36RN

IL-36Ra

AR

Loss of function

Decreased inhibition of IL-36 signaling

HOIL-1 deficiency

RBCK1

RBCK1 (also known as HOIL-1)

AR

Loss of function

Decreased activation of NF-κB Enhanced sensitivity to IL-1

APLAID

PLCG2

PLCγ2

AD

Gain of function

Decreased autoinhibition in PLCγ2 signaling

PRAAS

PSMB8

Immunoproteasome subunit β5i

AR

Loss of function

Impaired degradation of ubiquitinated proteins Cellular stress

ADA2 deficiency

CECR1

ADA2

AR

Loss of function

Impaired differentiation of macrophages and endothelial cells

SAVI

TMEM173

STING

AD

Gain of function

Increased STING-induced interferon activation by TBK1 and IRF-3 phosphorylation

NLRC4-associated autoinflammatory syndromes

NLRC4

NLRC4

AD

Gain of function

Inflammasome activation

Abbreviations: FMF, Familial Mediterranean Fever; TRAPS, TNF receptor-associated periodic syndrome; HIDS, Hyper IgD periodic fever syndrome; PAPA, Pyogenic arthritis pyoderma acne syndrome; DIRA, deficiency of IL-1Ra; DITRA, deficiency of IL-36Ra; APLAID, autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation; PRAAS, proteasome-associated autoinflammatory syndrome; SAVI, STING-associated vasculopathy with onset in infancy; ADA2, adenosine deaminase 2; ER, endoplasmic reticulum; HOIL-1, haemoxidized IRP2 ubiquitin ligase 1; IL-1Ra, IL-10 receptor antagonist; IL-10R, IL-10 receptor; IL-36Ra, IL-36 receptor antagonist; IRF-3, interferon regulatory factor 3; MAPK, mitogen-activated protein kinase; mROS, mitochondrial reactive oxygen species; NOD2, nucleotide-binding oligomerization domaincontaining protein 2 (also known as CARD15); PLC, phospholipase C; PSTPIP1, PEST phosphatase-interacting protein 1 (also known as CD2BP1); STING, stimulator of interferon genes protein; TBK1, TANK-binding kinase 1; TNFRSF1A, TNF receptor superfamily member 1A. Source: Adapted from Martinon F, Aksentijevich I. New players driving inflammation in monogenic autoinflammatory diseases. Nat Rev Rheumatol 2015;11(1):11
20.

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DIFFERENTIAL DIAGNOSIS Inflammation is the hallmark of the autoinflammatory syndromes. The first diagnostic step, therefore, is to examine the patient (during an attack) and to document an acute phase response (leukocytosis, granulocytosis ESR, CRP, ferritin). The differential diagnosis for inflammation in children is broad. The most common causes of fever in childhood are (viral) infections, but malignancies, autoimmune diseases, immunodeficiencies, and metabolic or endocrine disorders should be excluded. A careful history should be taken for occult infections, such as urinary tract infections or upper airway infections. A comprehensive physical examination should be performed to search for infections but also for specific signs like lymphadenopthy, skin problems, apthous stomatis, arthritis, and hepatosplenomegaly. A complete blood count with differential should be included. MRI, PET scan, or even biopsies may be indicated to rule out infection and malignancy in some cases. If a patient has true autoinflammatory episodes, one of the periodic fever syndromes should be considered. In some cases, the clinical findings, such as age of onset, length of attacks, precipitating factors, associated symptoms, and family history, are adequate to distinguish a known periodic fever syndrome. This is true for many cases of CAPS, TRAPS, HIDS, and PAPA (Table 13.2). In patients with clinical findings consistent with HIDS, urine mevalonate during an episode or the finding of strongly elevated serum IgD may provide additional support for this diagnosis. However, in many patients there is no straightforward diagnostic route. Rather the combination of epidemiology, signs, symptoms, and disease course should lead to a tentative diagnosis, which may then be supported by genetic testing. Genetic testing for many of these genes is available at several (commercial) laboratories internationally and increasingly dozens of genes can be tested simultaneously. A major factor for diagnosis in many centers is ethnic background. In patients of Armenian, Turkish, Arab, or Sephardic Jewish extraction, FMF is so prevalent that a clinical diagnosis will suffice. When the presentation is not typical of FMF, initial MEFV testing may be warranted. A problem arises when no tentative clinical diagnosis can be made or when the tentative diagnosis is not supported by genetic testing. In such cases we might analyze other periodic fever genes. In cases where only the generation of the identified patient is affected it is important to consider recessive as well as dominant (possibly de novo) diseases. If consecutive generations are affected, autosomal dominant disease genes should be tested initially. The yield of genetic testing, other than to confirm a tentative diagnosis, is usually very low [10]. Unfortunately, there are also cases for each of the known disorders in which a patient has classic presentation, but exhaustive genetic screens are negative (between 20% and 50% of patients with NOMID, FMF, or HIDS). With the identification of targeted therapies for many of these disorders, a therapeutic trial might become another diagnostic approach for these patients.

TABLE 13.2 Clinical Characteristics of the Most Common Autoinflammatory Syndromes Familial Mediterranean Fever

Hyper IgD Periodic Fever Syndrome

TNF Receptor-Associated Periodic Syndrome

Cryopyrin-Associated Periodic Syndrome

Pyogenic Arthritis Pyoderma Acne Syndrome

Inheritance

AR

AR

AD

AD

AD

Gene

MEFV

MVK

TNFRSF1A

CIAS1

PTSTPIP1

Ethnic background

Armenian, Turkish, Jewish, Arab

Dutch, French, German, among others

Worldwide (more frequent in Scottish/Irish)

Worldwide

Worldwide

Variable

Onset

Childhood ( . 90%)

Infancy

Variable

Neonatal

Duration of attacks

12
72 h

3
5 days

Days to weeks

,24 h

Symptoms Vomiting

+

Diarrhea

+

+

+

++

+/


++

+/


Abdominal pain

++

Peritonitis

++

Pleuritis

+

++

Acute scrotum

+

++

Rash

+ (Erysypelas-like, Henoch
Schonlein purpura)

++ (Pleiomorphic)

++ (Migrating erythematous plaques)

++ (Nonpruritic urticaria)

++ (Acne conglobata, pyoderma gangrenosum)

Aphtosis

+

Pharyngitis

+

Eye signs

Periorbital edema, conjunctivitis

Sensorineural hearing loss Joint symptoms

++ Mainly monoarthritis

Headache Muscle aches

Conjunctivitis, uveitis, papillitis

+

Lymphadenopathy

Arthralgias, arthritis

Arthralgias

Varying from mild arthralgias to destructive arthropathy large joints

+

++

++

Rare

++

+

++

+

+

Splenomegaly

+

+

+

+

Amyloidosis

+

Rare

+

+

Suggestive test results

Favorable response to colchicine

Raised serum IgD, IgA, elevated urinary mevalonic acid

CSF pleiocytosis, elevated CSF pressure

Destructive purulent monoarthritis

Sterile purulent joint aspirate

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TREATMENT IN GENERAL The aims of treatment in autoinflammatory diseases are to reduce symptoms of disease activity and prevent permanent sequelae such as kidney failure, deafness, blindness, joint damage, or short stature. Drugs of choice vary per disease. In 2014, Piram et al. defined an activity index for hereditary recurrent fever syndrome (AIDAI), which can be used to evaluate the level of disease activity and response to therapy and thus to assess drug efficacy in standardized assessments across trials [11].

DISORDERS PRIMARILY AFFECTING IL-1 FAMILY CYTOKINE REGULATION Cryopyrin-Associated Periodic Syndromes Prevalence/Epidemiology Cryopyrin-associated periodic inflammatory diseases include FCAS, MWS, and NOMID (also known as CINCA). These are all dominantly inherited. Previously considered as distinct disorders, they are now thought of as a spectrum of one systemic inflammatory disease with varying severity, with FCAS being the mildest condition and CINCA/NOMID the most severe. CAPS is a very rare disease. It is estimated that there are 1
2 cases out of 1 million inhabitants in the United States and 1/360,000 in France. However, many patients are diagnosed very late or not at all. Therefore the real prevalence is likely to be higher [12]. Etiology/Pathogenesis FCAS, MWS, and CINCA/NOMID are all associated with a gain-of-function mutation of the NLRP3 gene (also called CIAS1). This gene encodes for the protein NLRP3, also known as cryopyrin. Cryopyrin contains an N-terminal PYRIN domain, a central NACHT domain with a nucleotide-binding site, and a carboxy-terminal leucine-rich repeat (LRR) [13
15]. Cryopyrin interacts with apoptotic speck protein (ASC), leading to activation of caspase 1 and subsequent release of IL-1, as well as activation of nuclear factor κB (NF-κB), which results in the release of many proinflammatory cytokines such as IL-6. All the mutations identified to date in FCAS, MWS, and CINCA/NOMID are gain-of-function mutations. They are almost all localized in exon 3 (http://fmf.igh.cnrs.fr/ infevers/), irrespective of disease severity [1,16
18]. This exon encodes for the NACHT domain and its flanking protein regions. Rare mutations have been described in the LRR region [13]. There does appear to be some genotype
phenotype correlation [19]. Only 60% of patients with clinical presentation of FCAS, MWS, or CINCA/NOMID have mutations of the CIAS1 gene. This suggests genetic heterogeneity.

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FIGURE 13.1 Urticaria-like rash in NOMID patient.

Clinical Manifestations Cryopyrin-associated periodic inflammatory syndromes are all characterized by early onset of recurrent episodes of fever with remarkable systemic inflammation, a characteristic nonpruritic urticarial skin rash (Fig. 13.1) with perivascular polymorphonuclear cell infiltrates in skin biopsy, and a broad spectrum of joint manifestations ranging from arthralgias in mild form to recurrent arthritis and permanent arthropathies in severe diseases. Sensorineural hearing loss can develop with increasing age in MWS and CINCA/NOMID. Neurological involvement is observed in CINCA/NOMID and is due to chronic aseptic meningitis with neutrophil granulocytosis in the cerebrospinal fluid (CSF). Familial Cold Autoinflammatory Disease Patients with FCAS experience recurrent episodes of urticaria-like rash, fever, and arthralgias precipitated by generalized cold exposure. Additional symptoms suffered during attacks include conjunctivitis, sweating, drowsiness, headache, extreme thirst, and nausea. The symptoms usually develop 1
2 hours after cold exposure, peak approximately 6
8 hours later, and resolve in less than 24 hours. Most of the patients describe a correlation between the severity of the crisis and the intensity of cold exposure. Attacks are more frequent in winter, on damp and windy days. Relatively mild exposures such as air-conditioned rooms can precipitate episodes. Many patients have daily rash and fatigue that peak in the evening and resolve by morning, regardless of cold exposure. Disease onset is often at birth with neonatal rash, and 95% of patients experience symptoms by 6 months of age. Amyloidosis is rare in FCAS [20].

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Muckle
Wells Syndrome The course of the disease varies from typical recurrent attacks of inflammation very similar to those observed in FCAS but without defined triggers to more permanent symptoms with periods of exacerbation. Attacks may be precipitated by cold exposure, but also heat, stress, exercise, or fatigue. Fever is not always present. Joint manifestations can be mild with short episodes of arthralgias but recurrent episodes of synovitis, affecting predominantly large joints, have been observed. Conjunctivitis is frequently noticed. Renal disease and hearing loss are ultimately seen in .50% of untreated patients. AA amyloidosis, due to chronic inflammation, is the main complication and develops in adulthood in 20
40% of patients. Focal neurological involvement has not been reported in MWS. Headache and papilledema have been reported in some cases [21]. Mild forms of MWS are close to FCAS and more severe phenotypes overlap with CINCA/NOMID. The age of onset is variable from childhood to adulthood. Severe disease activity was documented in 19 patients (59%). Predictors of severe MWS identified at the time of diagnosis are female sex and hearing loss [22]. CINCA/NOMID CINCA/NOMID is the severe phenotype in this spectrum of diseases. Urticaria are usually present at birth or during the first months of life. Fever is intermittent, and can be absent or very mild in some cases. Bone and joint involvement vary in severity. In approximately two-thirds of the patients, joint manifestations are limited to arthralgia or transient nonerosive arthritis during flare-ups. In one-third, however, joint abnormalities are severe. The metaphyses and epiphyses of long bones are affected, resulting in marked bony overgrowth, deformity of the joints, chronic pain, and loss of function. The knees, ankles, wrists, and elbows are most commonly affected in a symmetric pattern. Abnormalities of the central nervous system (CNS) are present in almost all patients and are due to chronic aseptic meningitis. Chronic headaches, sometimes with vomiting, and papilledema are frequently noted. Spastic diplegia and epilepsia may develop. Progressive cognitive impairment occurs in severely affected patients. Chronic increased intracranial pressure often leads to late closure of the anterior fontanel, macrocrania, frontal bossing, and saddle back nose. Ocular disease consists of anterior uveitis in half and posterior uveitis in another 20% of affected patients. Optic atrophy can develop. Progressive to perceptive deafness is frequently observed [23,24]. Diagnostic Investigations Patients suffering from CAPS have elevated acute phase reactants and neutrophil granulocytosis during attacks. In MWS and NOMID patients acute phase reactants may be chronically elevated and anemia of chronic illness is common. CSF examination in NOMID usually reveals a raised opening

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FIGURE 13.2 Radiographic appearance of arthropathy in NOMID/CINCA syndrome. Courtesy of Dr A.M. Prieur.

pressure pleiocytosis and elevation of CSF protein. Radiological manifestations in CINCA/NOMID patients with hypertrophic arthropathies are distinctive with overgrowth and irregular ossification of metaphysis and epiphysis of long bones (Fig. 13.2). Involvement of the internal auditory organ can be visualized on MRI and audiometry can document sensorineural hearing loss.

Treatment Treatment, until recently, has been limited to avoidance of cold exposure and to nonsteroidal anti-inflammatory drugs (NSAIDs) for FCAS patients, and high-dose steroids for more severe FCAS, MWS, and NOMID patients. IL-1 blockade with anakinra, canakinumab, and rilonacept all are very effective in the treatment of CAPS [25
27].

Deficiency of IL-1 Receptor Antagonist DIRA, the deficiency of the IL-1 receptor antagonist (IL-1RA), is an autosomal recessive disease caused by mutations in the encoding gene IL1RN. The symptoms usually present around birth with multifocal osteomyelitis, periostitis, and pustulosis and can lead to live threatening systemic inflammation. The absence of IL-1RA permits overactivity of both IL-1α and IL-1β. IL-1α is expressed in skin and is a potent osteoclast activator. In addition to its proinflammatory effects, it also acts as an

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autocrine growth factor. Its expression profile in skin and bone differs from that of IL-1β [28]. The prominent role of IL-1 cytokines in the development of skin and bone manifestations in affected patients suggests a role for IL-1 in the pathophysiology of other autoinflammatory bone disorders such as CRMO and SAPHO. The deficiency can be corrected with the recombinant IL-1 receptor antagonist anakinra, leading to a rapid and complete clinical response [29,30].

DITRA DITRA is an autosomal recessive autoinflammatory disease characterized by repeated flares of diffuse erythematous pustular rash (Fig. 13.3), fever, and systemic inflammation. Age at onset is variable. It is caused by an IL-36 receptor antagonist deficiency as a result of a loss of function mutation in the IL36RN gene. IL-36α, IL-36β, and IL-36γ, three cytokines belonging to the IL-1 family, exert their actions by binding to the IL-36 receptor. Ligand binding to this receptor enables the recruitment of the IL-1 receptor accessory protein, leading to signal transduction involving activation of nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases. The IL-36 receptor antagonist (IL-36Ra) also binds to the IL-36 receptor, which blocks binding by the agonist ligands but fails to recruit accessory protein and therefore does not lead to biologic activity. IL-36Ra antagonist and the three agonists IL-36α, IL-36β, and IL-36γ are highly expressed in epithelial tissues such as the skin, trachea, and esophagus [31]. Although IL-1RA does not bind to the IL-36 receptor, some patients seem to respond well to treatment with anakinra [32,33]. Etanercept has been effective in when IL-1 blockade fails.

FIGURE 13.3 Palmoplantar pustulosis and psoriatiform squamous eruption in an infant with DITRA.

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NLRC4-Associated Autoinflammatory Syndromes Gain-of-function mutations in NLRC4, encoding the cytoplasmic danger receptor NLRC4, have been identified in patients with autoinflammation with infantile enterocolitis (AIFEC, MIM#616050). In addition to severe infantile enterocolitis, these patients have maculopapular rash hepatosplenomegaly and episodes of hemophagocytosis (macrophage activation syndrome, MAS) [34,35] as described mutations in the same gene leading to infantile onset of high fevers, urticariform rash (Fig. 13.4), arthralgias, and myalgias, known as FCAS4 (MIM# 616115). The incidence of these autosomal dominant NLRC4-related diseases is unknown. The NLRC4 protein normally functions as a component of an inflammasome formed in response to gram-negative bacterial components, activating caspase 1. In this disorder caspase 1-mediated IL-18 generation is prominent, with very high concentrations detectable in patient sera. IL-1 blockade has been reported to be effective clinically, although IL-18 concentrations remain elevated.

NLRP12-Associated Periodic Syndrome/Familial Cold Autoinflammatory Syndrome 2 In 2008 Jeru et al. discovered a mutation in the NLRP12 gene in 10-year-old monozygotic twin brothers presenting with fever episodes during 2
10 days several times a month accompanied by arthralgias and myalgias, bilateral sensorineural hearing loss, urticarial rash, and headache. In general the

FIGURE 13.4 Maculopapular rash in a toddler with NLRC4-related autoinflammatory disease.

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clinical presentation is variable but resembles CAPS. Episodes seemed to be triggered by exposure to cold [36,37]. NLRP proteins are part of the larger family of nod-like receptor (NLR) proteins characterized by a Leucin Rich Repeat (LRR) domain, a nucleotidebinding oligomerization (NOD) domain, and an N-terminal adaptor domain. In humans, at least 22 NLR family members have been found to play a central role in the regulation of inflammation and cell death [38]. Other NLR genes involved in human pathology are NLRC4 (involved in another autosomal dominant autoinflammatory disease; see later), NRLP7 in hydatidiform mole, NRLP1 in vitiligo-associated autoimmune diseases, CIITA in bare lymphocyte syndrome and multiple sclerosis, and NOD2 in Crohn’s disease and Blau syndrome. The nucleotide sequence of NLRP12 is highly similar to that of NLRP3, with 58% identity, which contains mutations identified in patients with FCAS, MWS, and CINCA [37]. The mechanisms underlying NLRP12-associated disorders varies according to the nature of the disease-causing mutation. Missense mutations are associated with a gain of function of caspase 1 processing, while nonsense and splice site mutations lead to a loss of function of NF-κB inhibition [37,39]. The mode of inheritance is autosomal recessive. NLRP12 is an extremely rare disease and only a few cases have been described. Treatment used in these patients are corticosteroids, antihistamines, and NSAIDs. Anakinra initially induced significant improvement but the effect decreased in time [40].

DISORDERS INDIRECTLY AFFECTING IL-1 FAMILY CYTOKINE REGULATION Hyper IgD Syndrome Prevalence/Epidemiology HIDS (MIM#260920) is an autosomal recessive disease, mostly affecting people of Caucasian origin. It is a rare disorder with an estimated 200 patients worldwide. The disease is relatively common in the Netherlands, where carrier frequency approaches 1:350 [41]. Etiology/Pathogenesis In 1999, mutations in the gene that codes for mevalonate kinase (MVK) was found to be the cause of HIDS [42,43]. So far, approximately 107 mutations have been described that lead to documented HIDS or to the more severe phenotype of MVK deficiency, known as mevalonic aciduria (http://fmf.igh. cnrs.fr/infevers/). Two missense mutations are most prevalent: I268T and V377I, accounting for the vast majority of patients [44]. Mevalonate kinase is an enzyme in the cholesterol biosynthesis pathway. Besides cholesterol, this pathway produces a number of other nonsterol end products such as farnesyl and geranylgeranyl groups, which can be covalently attached to

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specific proteins, including proteins of the Ras superfamily. Although patients with HIDS have only 1
7% residual activity of mevalonate kinase [43], plasma cholesterol levels in these patients are within the normal range. How the metabolic defect leads to the clinical manifestations of hyper IgD is unclear, but evidence is now emerging that the shortage of specific isoprenylated proteins can induce IL-1β-mediated inflammation [45].

Clinical Manifestations The recurrent fever attacks that are characteristic of HIDS usually return every 3
6 weeks and last for 3
5 days. They are almost always accompanied by painful cervical lymphadenopathy (Fig. 13.5) and often by abdominal pain, vomiting, and diarrhea [44,46]. A variety of other symptoms including headache, skin rashes, mucosal ulcers, myalgia, and arthralgia may also occur. Colitis and macrophage activation syndrome are rare but severe complications (Fig. 13.6). A profound mevalonate kinase deficiency, known as mevalonic aciduria, can, in addition, be accompanied by developmental delay, dysmorphic features, tapetoretinal degeneration, ataxia, cerebellar atrophy, and psychomotor retardation [47,48]. In reality, a phenotypic continuum exists between these extreme phenotypes [46,49]. Ninety percent of HIDS patients will experience their first fever attack within the first year of life, but the fever episodes tend to become less frequent and less severe with age. Fever episodes can be provoked by a variety of triggers, including vaccinations, infections, or minor trauma, but most often such a trigger cannot be identified [50]. When fever has subsided, malaise and arthritis may take days longer to resolve. Between attacks, patients are well and thrive normally. Long-term sequelae include AA amyloidosis, which has been reported in about 5% of patients.

FIGURE 13.5 Cervical lymphadenopathy in mevalonate kinase deficiency.

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FIGURE 13.6 Monoarthritis in mevalonate kinase deficiency.

Diagnostic Investigations As the name implies, many patients develop elevated serum immunoglobulin D levels, but how this relates to the clinical disease is poorly understood. Since up to 30% of patients with MVK mutations have normal levels of IgD, it is likely that elevated IgD is an epiphenomenon. Patients may also have elevated serum IgA [51]. Urine mevalonic acid concentrations are consistently raised during fever episodes, but may be normal in between. In addition, patients exhibit an acute phase response with leukocytosis, and high levels of SAA and CRP [50,52].

Treatment NSAIDs are helpful in reducing severity of attacks, but rarely induce disease remission. Corticosteroids improve symptoms to a varying degree in the majority of patients, but are poorly suited as maintenance therapy to prevent attacks due to side effects. Statins have been reported to be effective in a small trial [53], but in clinical practice statins have little value and may even worsen disease activity [40]. Colchicine is usually ineffective. Etanercept has been reported to be effective in some patients [54], but in most reported patients the effect was limited [40]. IL-1 blockade with anakinra during attacks reliably improves symptoms to a varying degree and can fully control attacks in some patients. Both anakinra and canakinumab have been reported to be able to reduce the frequency and severity of attacks when used as maintenance therapy [55]. Very severely affected patients have undergone allogeneic stem cell transplantation resulting in complete remission of inflammatory activity [56].

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Familial Mediterranean Fever Prevalence/Epidemiology FMF (MIM#249100) is the most prevalent of the hereditary autoinflammatory diseases, probably affecting more than 100,000 patients worldwide. It is autosomal recessive and affects mostly people from the Mediterranean area, including Armenians, Arabs, Turks, and Sephardic Jews. The carrier rate varies among these populations and the disease prevalence reaches frequencies of 1/500
1/1000 [57,58]. By migration it has now also spread to Northern and Western Europe, Australia, and the Americas. Etiology/Pathogenesis The gene responsible for FMF, the MEFV gene, encodes a 781-amino acid protein known as pyrin [3]. Pyrin is expressed predominantly in innate immune cells such as neutrophils, monocytes, and dendritic cells [59]. The exact function of pyrin is poorly understood. It is composed of at least five domains that mediate interactions with several proteins related to inflammation [60]. It shows structural similarity to NLRs. These are cytoplasmic receptors for endogenous and exogenous, especially microbial, danger signals [61,62]. Pyrin might serve a similar function. The most notable domain of pyrin is the N-terminal PYRIN domain. This domain can interact with a similar PYRIN domain on ASC, the apoptosis-associated speck-like protein with a caspase-recruitment domain (CARD). ASC is a central component of inflammasome complexes through interactions of its PYRIN and CARD domains with NLRP proteins and inflammatory caspases, respectively [63]. Active caspase 1 is essential for the proteolytic activation of IL-1β and IL-18. In FMF gain-of-function mutations cause activation of inflammasome leading production of proinflammatory cytokines. Another interesting finding was that pyrin interacts with tubulin and colocalizes with microtubules suggesting a rationale for current highly efficacious treatment of the disease using colchicine, a microtubule-stabilizing agent [64]. Since its discovery in 1997, more than 300 sequence variants have been described for the MEFV gene but only 14 occur commonly in FMF (E148Q, E167D, T267I, P369S, F479L, I591T, M680I, I692del, M694I, M694V, K695R, V726A, A744S, R761H); 80% are in exon 10 and the others in exons 2, 3, and 5 (http://fmf.igh.cnrs.fr/infevers/). The M694V mutation is the most frequently encountered mutation and usually associated with the most severe phenotype and early onset of the disease [58,65]. Both patients homozygous and compound heterozygous for M694V and to a lesser extent all patients with homozygous mutations in positions 680
694 on exon 10 are at increased risk for severe disease including the development of amyloidosis [66,67]. The common E148Q variant is of uncertain pathogenic significance, since it is frequently encountered in healthy individuals, and usually is not associated with FMF in the absence of other MEFV mutations [68].

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FIGURE 13.7 Characteristic erysipelas-like erythema in familial Mediterranean fever.

Clinical Manifestations Most patients suffer from recurrent fever attacks (usually 1
3 days), with acute monoarthritis and/or serositis, affecting the peritoneum, pleura, pericardium, or scrotum. Some patients display an erysipelas-like rash (Fig. 13.7) and a few develop chronic erosive arthritis. However, in childhood, recurrent abdominal pain may rarely be the only manifestation of FMF [69,70]. Disease onset is usually in childhood, with 75
89% of patients having their first attack before the age of 20 years. Frequency of attacks can vary from several times per week to once every few months or even years [71,72]. Laboratory Investigations During fever episodes there are elevated markers of acute phase response: ESR, SAA protein, and CRP; complement and plasma fibrinogen are elevated and there is granulocytosis [70,73]. Between attacks, patients are well, even though they may continue to have increased acute phase reactants. Risk of AA Amyloidosis Both genetic and environmental factors seem to play a role in the disease pathogenesis. Prolonged elevation of serum amyloid A protein and frequent attacks (at least 2 per month) predisposes to AA systemic amyloidosis in which SAA deposition occurs in several organs leading to organ failure. The risk of amyloidosis is higher in carriers of M694V allele though the mechanisms of this possible link are still unclear [3,65,74,75]. On the other hand a study in 1974 of 100 Armenian FMF patients living in the United States showed no cases of amyloidosis although M694V was demonstrated to be the most frequent MEFV mutation [76]. In an international registry, the country of residence was the most important risk factor for amyloidosis.

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Homozygosity for M694V was the second most important risk factor in Armenians, Israelis, and Arabians, but its association with AA amyloidosis was less significant in Turkish patients and undetectable among other ethnicities [77]. Three hundred and forty-six FMF pediatric patients were enrolled in the Eurofever registry. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation, and positive family history [78]. In conclusion, subjects homozygous for M694V who do not report symptoms should be evaluated and followed closely. For individuals with two pathogenic mutations for FMF who do not report symptoms close follow-up should be started if there are other risk factors for AA amyloidosis (such as the country, family history, and persistently elevated inflammatory markers, particularly SAA protein) [68].

Diagnosis FMF is a clinical diagnosis, which can be supported but not excluded by genetic testing [68]. Several sets of criteria have been proposed in the past years. The Tel Hashomer criteria is the most widely used diagnostic criteria for adults (Table 13.3) [79]. Recently new criteria have been proposed for children. In 2009, Yalcinkaya et al. showed that the Tel Hashomer criteria were very successful in diagnosing FMF patients, but that the specificity was low (54.6%) in children [80]. The duration of the attacks in children seem to be somewhat shorter than in adults. Furthermore, the child is often not able to express the severity and location of the pain and the chest pain is not always unilateral in children. They proposed a new set of criteria for children with FMF. A drawback of this study was that it was confined to a group of Turkish children. The response to colchicine therapy used to be a major diagnostic criterion, but may not be practical for ethnic groups where other periodic fever diseases are more frequent [80]. Genetic testing may support the

TABLE 13.3 Tel Hashomer Criteria for Diagnosis of Familial Mediterranean Fever Major Criteria

Minor Criteria

Recurrent fever with arthritis and/or serositis

Recurrent fever attacks

AA amyloidosis in the absence of a predisposing illness

Erysypelas-like erythema

Favorable effect of colchicine

FMF in first-degree relatives

Definite diagnosis: 2 major or 1 major and 2 minor criteria Probable diagnosis: 1 major and 1 minor criteria

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diagnosis, but in up to one-third of patients, one or both MEFV alleles are normal [81,82]. Beside that there are patients with FMF mutations without any clinical signs of the disease.

Treatment Colchicine is so effective in the treatment of FMF that the response to colchicine is used as one of the major Tel Hashomer criteria [73]. Colchicine prevents inflammatory attacks in B60% of the patients and significantly reduces the number of attacks in another 20
30% and effectively prevents the development of AA amyloidosis [83]. The recommended colchicine dose in young children based on pharmacokinetics in pediatric patents with FMF is 0.6 mg/day for children 2
6 years, 0.9 mg/day in children 7
12 years of age, and 1.2 mg in patients 12 years and older. In countries where the available tablets contain 0.5 mg of colchicine this would translate to 0.5 mg/day for children 2
6 years, 1 mg/day in children 7
12 years of age and 1.5 mg in patients 12 years and older [84]. In severe cases the dose can be increased up to 2 mg/day. A period of at least 3 months of stable colchicine dose is advised before adjusting the dose [85]. The main side effects are diarrhea, abdominal pain, and transient elevation of transaminases. In order to minimize gastrointestinal side effects, a 50% lower starting dose may be given and the daily dose can be divided over two to three times a day. For pain relief during attacks NSAIDs can be used. Colchicine efficacy differs between patient groups depending on genotype and environmental factors. Patient homozygote for M694V seem to be less responsive [86]. In some patients colchicine fails, due to either lack of efficacy or intolerable side effects. Since IL-1 plays a pivotal role in FMF, anti-IL seems to be a good approach to treat colchicine-resistant FMF patients [85]. Case studies have shown that anakinra and canakinumab are both effective [40,87,88]. Another IL blocker, rilonacept, significantly decreases the number of attacks in 14 colchicine-resistant FMF patients without relevant adverse events [89]. A randomized trial of canakinumab in FMF patients who have failed colchicines is currently evaluated.

Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne Syndrome Prevalence/Epidemiology PAPA, previously described as the “streaking leucocyte factor” disease [90], was recognized and redescribed in 1997 by Lindor et al. [91]. Families described thus far are of European descent, but the number of documented cases remains very small. PAPA syndrome is an autosomal dominant disease, with a presumed complete penetrance.

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Etiology/Pathogenesis The affected gene, PSTPIP1, encodes CD2 antigen-binding protein 1 (CD2BP1), also known as proline/serine/threonine phosphatase-interacting protein 1 (PSTPIP1) [92,93] (http://fmf.igh.cnrs.fr/infevers). The protein has been shown to interact with the Mediterranean fever protein, pyrin [94], and has been proposed to be a component of a pyrin-inflammasome-producing IL-1β [95]. Indeed, patient cells secrete increased amounts of IL-1β [96]. Clinical Manifestations PAPA is characterized by recurrent inflammation of joints, skin, and muscle. During episodes of arthritis patients may present with fever. Ulcerative lesions (pyoderma gangrenosum) occur in the skin, often on the lower limbs or at sites of minor trauma or surgery. Patients also suffer from severe cystic acne starting in adolescence and persisting into adulthood, and from destructive arthritis [91,92]. Onset of the disease is in early childhood, but additional symptoms, like insulin-dependent diabetes mellitus, can develop at older ages. Diagnostic Investigations During episodes patients may have elevated white blood cell counts and erythrocyte sedimentation rate [97,98]. Biopsies and joint aspirates usually show massive neutrophil influx. Treatment Treatment of PAPA can consist of isotretinoin, for treatment of acne, usually in combination with steroids. Glucocorticoids, both intraarticular and oral, have been reported to be efficacious [99]. Alternative therapies include anti-TNFα therapy with either infliximab or etanercept [98] (PMID:20661073) [96]. Several patients have been successfully treated with the IL-1 receptor antagonist anakinra during attacks [100] (PMID:25362725) and one patient with canakinumab [101]. Despite this anecdotal evidence IL-1 inhibition is probably not as effective a strategy in PAPA as for CAPS, and thus raises the possibility that PSTPIP1 mutations may have additional pathophysiologic effects. PAPA can lead to pronounced disfigurement. In addition, the severe acne and the scarring resulting from it can cause psychological damage like anxiety and depression. Prognosis is mostly determined by the development of diabetes mellitus and/or renal failure [91]. Other Disease Related to Mutations in the PSTPIP1 Gene The rare syndrome of hyperzincemia and hypercalprotectinemia (HZ/HC) is an autosomal dominant disorder characterized by neonatal onset of inflammation. Patients have fever, skin rash, hepatosplenomegaly, and may have lymphadenopathy, arthralgias, or arthritis as well as failure to thrive. Anemia

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and thrombopenia are common. Patients are consistently granulocytopenicopenic, often due to antineutrophil autoantibodies. Unsurprisingly, acute phase proteins are raised, but the striking feature of HZ/HC is the massive elevation of the serum calprotectin MRP8/14 and of serum zinc levels. The disorder is caused by a mutation (usually p.E250K) in PSTPIP1, leading to enhanced affinity of the encoded protein for pyrin. Serum levels of several cytokines including IL-1β, IL-2, IL-8, IL-18, and IL-22 were shown to be elevated. The mainstay of treatment are corticosteroids and immunosuppressants. Some patients respond to IL-1 blockade, some to anti-TNF-α monoclonals, and tocilizumab was effective in the one patient tried [102].

Majeed Syndrome Majeed syndrome is a rare autosomal recessive disorder characterized by the triad of chronic early onset recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and a neutrophilic dermatosis often accompanied by recurrent fever. It is caused by gain-of-function mutations in LPIN2. This gene encodes for the protein phosphatidate phosphatase LPIN2. Loss of function of this protein leads to decreased inhibition of proinflammatory signals. Long-term outcome is poor although treatment with IL-1 blockade seems promising [103,104].

Autosomal Recessive Systemic Juvenile Idiopathic Arthritis Mutations in both alleles of the LACC1-gene, encoding multicopper oxidoreductase, were identified in Saudi children presenting with earlyonset sJIA [105]. The phenotype includes spiking fevers, maculopapular rash, and polyarthritis, but other features of sJIA such as serositis and hepatosplenomegaly were not prominent. The disorder is reportedly highly therapy-resistant although the effect of IL-1 blockade is not yet known.

PROTEIN FOLDING DISORDERS TNF Receptor-Associated Periodic Syndrome Prevalence/Epidemiology TRAPS was first reported as Familial Hibernian Fever in 1982 in a large family of Irish and Scottish descent [106], but it has now been described in more than 20 families from a wide variety of ethnic groups [107,108]. Although more than 100 patients with TRAPS have been described, the exact prevalence is unknown. TRAPS has an autosomal dominant inheritance mode. The mutations described to date differ in penetrance. Individuals with low penetrance variants may be completely asymptomatic, suffer from atypical inflammatory symptoms, or display the classical features of TRAPS [107].

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Etiology/Pathogenesis TRAPS results from mutations in the TNFRSF1A gene [2]. It encodes TNFRSF1A, the 55 kDa receptor for TNF. The TNFRSF1A gene consists of 10 exons. Approximately 142 mutations have now been described that lead to an altered protein sequence, with most mutations being present in exons 2, 3, and 4. The most common TNFRSF1A variant is R92Q followed by T50M [109] (http://fmf.igh.cnrs.fr/infevers/). TRAPS-associated mutations exclusively affect the extracellular domains of the receptor [107]. The exact pathogenesis of inflammation in TRAPS is unknown. Some mutations lead to impaired shedding of membrane-bound TNFR, resulting in lower levels of soluble TNF-receptor, the natural antagonist of TNF-α. More importantly, intracellular trafficking of the mutant TNF-receptor is impaired leading to its retention in the endoplasmatic reticulum. The overload of these misfolded proteins leads to an inflammatory response including the generation of IL-1β [1,2,107,110
117]. Clinical Manifestations The clinical presentation of TRAPS varies widely. The age of onset is between a few weeks and 63 years of age, but most patients have their first symptoms in childhood [108,109]. There is little evidence of a significant effect of age or genotype on disease features at presentation [109]. Like FMF, TRAPS is characterized by periodic fever attacks, but these last days to weeks and recur two to six times a year. Fever attacks may start unprovoked, but can also be set off by emotional stress, minor infections, or vigorous exercise. Clinical features during attacks include conjunctivitis; pericarditis; migratory rash (Fig. 13.8); prominent myalgias; monoarthritis, mostly of the lower

FIGURE 13.8 Migratory rash in TRAPS patient. Courtesy of Dr. E. Hoppenreys.

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limbs; abdominal pain; and erythematous swelling of eyelids, limbs, fingers, and/or ears. The abdominal pain may be due to serositis, which can also involve other serosal surfaces, including the testicular tunica vaginalis. Focal neurological signs are a rare feature of the disease [118,119]. AA amyloidosis develops in about 10% of the patients at a median age of 43 years [109].

Diagnostic Investigations During episodes of fever there is a clear acute phase response: leukocytosis, elevation of CRP, SAA, and ESR [118,120], and even in symptom-free intervals such inflammatory responses may be detected. Between attacks, patients may have reduced serum levels of sTNFRSF1A [2]. However, diagnosis depends on the identification of TNFRSF1A mutations on DNA analysis. Treatment TRAPS can be treated with NSAIDs and glucocorticoids to alleviate the symptoms, but these drugs do not affect the frequency of attacks or the development of amyloidosis. The efficacy of etanercept has been shown in single patients and/or in case studies of patients of different ages with fully penetrant TRAPS phenotypes, as evidenced by decreased frequency of attacks and/or decreased severity of disease [121
123]. However a decrease in responsiveness over time and etanercept-resistant patients have also been reported [124,125]. Remarkably, the administration of other anti-TNF agents, such as infliximab or adalimumab, may lead to clinical worsening [126]. Anakinra has recently been shown to prevent disease relapses in the short-term, and to induce a prompt and stable disease remission. Its longterm efficacy and safety in patients with and without amyloidosis have also been recently described. Canakinumab also appeared highly effective and is currently evaluated in a randomized controlled trial [127
129].

Proteasome-Associated Autoinflammatory Syndrome Autosomal recessive mutations in proteasome subunit-type 8 (PSMB8) can cause a disease spectrum currently known as PRAAS. It was first described in 1939. Since then, several syndromes, such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Nakajo
Nishimura syndrome (NNS), joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP) syndrome [130] have been used to categorize patients with diseases within the same spectrum. Common clinical features of PRAAS include periodic fever, skin eruptions, progressive lipodystrophy, muscular atrophy/myositis, and hepatosplenomegaly. CANDLE syndrome is characterized by onset during the first year of life, recurrent fevers, purpuric skin lesions, violaceous swollen eyelids,

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arthralgias, progressive lipodystrophy, hypochromic or normocytic anemia, delayed physical development, and increased levels of acute phase reactants. Variable clinical features include hypertrichosis, acanthosis nigricans, and alopecia areata [131]. NNS is characterized by a pernio-like rash on the hands and feet, nodular erythema with infiltration and induration, repetitive spiking fever, long clubbed fingers and toes with joint contractures, progressive partial lipomuscular atrophy and emaciation mainly in the upper body, hepatosplenomegaly, and basal ganglia calcification [132,133]. JMP syndrome is a disease characterized by progressive lipodystrophy, hypergammaglobulinemia, and debilitating joint contractures that are worse in the feet and hands [131]. Interestingly, fever is absent in JMP syndrome, and joint contracture is not prominent in CANDLE syndrome. The mutated gene, PSMB8, encodes the inducible b5i subunit of a proteasome (http://fmf.igh.cnrs.fr/infevers). Proteasomes are evolutionarily conserved cylindrical structures that are critical for protein degradation. The immunoproteasomes have an important role in maintaining cell homeostasis by removing accumulating proteins marked for degradation from the cells. Cellular stress such as infection or radiation leads to type I interferon (IFN)-induced production of reactive oxygen species and newly synthesized proteins. Failure to process/degrade ubiquitinated proteins will increase cellular sensitivity to apoptosis. Defects in immunoproteasome function may lead to accumulation of damaged proteins, resulting in more cellular stress and a vicious circle of increased IFN signaling [134]. The prognosis for PRAAS patients is grim because no effective treatment has been found. Oral glucocorticosteroids reduce some of the acute inflammatory responses. Various antirheumatic and immunosuppressive drugs including IL-1 receptor antagonist anakinra, IL-6 receptor antagonist tocilizumab, and TNF-α inhibitor had either no effect or resulted in transient clinical improvement. Blocking the IFN pathway with janus kinase (JAK) inhibitors might be a target for treatment in these patients [132].

INTERFERONOPATHIES Probably all nucleated cells can produce IFN in response to virus infection. The pathway starts with recognition of viral pathogen-associated molecular patterns by pattern recognition receptors. This stimulates intracellular transduction pathways leading to de novo IFN transcription. The secreted IFNs act in both an autocrine and paracrine manner through binding to a type I IFN receptor leading to intracellular signaling via the JAK
STAT pathway and the induction of hundreds of IFN-stimulated genes, the majority of which have unknown functions. Aberrant stimulation or unregulated control of the IFN system can lead to inappropriate and/or excessive IFN output.

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In some inflammatory diseases like Aicardi
Goutieres syndrome and SAVI but also in SLE and familial chilblain lupus, an upregulation of type I IFN seems to play a central role in the pathogenesis [135].

STING-Associated Vasculopathy With Onset in Infancy In 2014 Liu et al. discovered that mutations in exon 5 of TMEM173 gene can cause an autoinflammatory disease characterized by early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. The TMEM171 gene encodes the stimulator of interferon genes (STING), and gain-of-function mutations in this gene causes elevated transcription of interferon genes like IFNB1 in peripheral blood mononuclear cells, causing an increased production of type I IFNs. The synthesis and release of IFNs and their binding to interferon receptor further upregulate STING and the transcription of other proinflammatory cytokine genes in a positive feedback loop. JAK inhibition blocks the loop in vitro and may offer a treatment strategy [136].

Aicardi
Goutieres Syndrome AGS is a genetically determined inflammatory disorder that particularly affects the brain (vasculitis lesions) resulting in microcephaly, spasticity, and psychomotor retardation, and the skin (vasculitis). It is a severe disease that can lead to childhood death in about 35% of the cases. Although some children are affected in utero and display features of illness at birth, most infants with AGS appear to experience the onset of disease in the first 12 months after birth. It is a genetically heterogeneous disease that can result from mutations in the TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR genes and is consistently associated with an IFN signature [137].

AUTOINFLAMMATION WITH IMMUNODEFICIENCY HOIL-1 Deficiency HOIL-1 deficiency is a autosomal recessive disease characterized by chronic systemic autoinflammation, invasive pyogenic bacterial infections, and amylopectin-like deposits in muscle. It is caused by a loss of function mutation in RBCK1/HOIL-1. The protein HOIL-1 is a component of the linear ubiquitination chain assembly complex (LUBAC). Mutations in this protein result in impairment of LUBAC stability. LUBAC is involved in the NF-κB pathway. The consequences of human HOIL-1 deficiencies for IL-1β responses differs between cell types leading to a disease with signs of both autoinflammation and immunodeficiency. HOIL-1-deficient human fibroblasts display impaired NF-κB activation, resulting in impaired NF-κB-driven gene transcription and

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cytokine production in response to TNF and IL-1β, which might be the basis of the immunodeficiency. By contrast, the mononuclear leukocytes, particularly monocytes, of these patients are hyperresponsive to IL-1β, resulting in autoinflammation [6,138].

PLCγ2 Mutations APLAID is an autosomal dominant inherited inflammatory disease characterized by recurrent skin lesions, bronchiolitis, and nonspecific pneumonitis, arthralgia, ocular inflammation, enterocolitis, and mild immunodeficiency, manifested by recurrent sinopulmonary infections and by paucity of circulating antibodies. Lymphocyte phenotyping reveals a near complete absence of class-switched memory B cells. The skin lesions include recurrent eruptions of erythematous plaques and vesiculopustular lesions and the frequent evolution of skin lesions into cellulitis. A dense interstitial and perivascular inflammatory infiltrate in the dermis is composed of lymphocytes, histiocytes, eosinophils, and much karyorrhectic nuclear debris. It is caused by a gain-of-function missense mutation in PLCG2 encoding phospholipase Cγ2, an enzyme with a critical regulatory role in various immune and inflammatory pathways. The APLAID-associated p.Ser707Tyr mutation disrupts the highly conserved C-terminal copy of a tandem pair of autoinhibitory SH2 domains, causing increased production of intracellular IP3 and increased release of intracellular calcium. The disease was refractory to treatment with NSAIDs and partially responsive to steroids in two patients [139].

PLCG2-Associated Antibody Deficiency and Immune Dysregulation PLAID is caused by genomic deletions in PLCG2 characterized by cold urticaria, autoimmunity, atopy, and humoral immune deficiency, resulting in recurrent sinopulmonary infections. Deletions of PLCG2 cause diminished receptor-mediated activity at physiologic temperatures in B cells and natural killer cells with enhanced spontaneous signaling in mast cells and B cells at subphysiologic temperatures The cold-induced signaling in mast cells leads to the characteristic cold urticaria observed in all patients with PLAID [140].

ADA2 Deficiency Recently Zhou et al. discovered that autosomal recessive loss of function mutations in CECR1 are associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis combined with a mild immunodeficiency [5]. Three unrelated children presented with intermittent fevers, recurrent lacunar strokes, elevated levels of acute phase reactants, livedoid rash,

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hepatosplenomegaly, and hypogammaglobulinemia. Navon et al. presented that recessive mutations in CECR1 can cause polyarteritis nodosa vasculopathy with a highly varied clinical expression [141]. CECR1 encodes for the ADA2 protein. ADA2 has partial structural homology with ADA1. Both proteins convert adenosine to inosine and 20 -deoxyadenosine to 20 -deoxyinosine, but the affinity of ADA2 for adenosine is lower than that of ADA1 by a factor of approximately 100. Whereas ADA1 is largely intracellular, ADA2 is secreted. ADA1 deficiency is known to cause severe combined immunodeficiency disease (SCID) [142], which is associated with the toxic intracellular accumulation of deoxyadenosine nucleotides. Patients with ADA2 deficiency only have a mild immunodeficiency that is most profound in B cells. They have significantly diminished ADA2 activity in plasma whereas ADA1-specific activity is preserved. ADA2 is a growth factor for endothelial and normal leukocyte development and differentiation. ADA2 deficiency may compromise endothelial integrity while polarizing macrophage and monocyte subsets toward proinflammatory cells [5]. Since neither CECR1 expression nor the ADA2 protein is detectable in cultured human endothelial cells, reduction of ADA2 activity may also indirectly result in endothelial damage via a neutrophil-driven process [143]. Treatment is directed to prevention of recurrent infections with antibiotic prophylaxis and/or immunoglobulin substitution. Inflammation might be treated with anti-TNF or anti-IL-1 antibodies. Anticoagulants are given to prevent strokes. Hematopoetic stem cell transplantation might prevent vasculopathy and resolve hypercoagulability [144,145].

Sideroblastic Anemia With Immunodeficiency, Fevers, and Developmental Delay Recently Chakraborty et al. described a syndromic form of congenital sideroblastic anemia (CSA) associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), caused by partial loss of function mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs [146].

KEY POINTS G

G

G

The autoinflammatory syndromes are a distinct group of disorders characterized by generalized inflammation in the absence of microbial pathogens, autoreactive T cells, or autoantibodies. Clinically, these syndromes can be recognized by the presence of periodic fever episodes, accompanied by systemic inflammatory symptoms involving joints, skin, eyes, or abdomen. Since many of the autoinflammatory syndromes are hereditary, genetic testing can aid diagnosis. However, in many patients a genetic diagnosis cannot be established.

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To diagnose a patient presenting with periodic fever, a combination of clinical characteristics such as age of onset, length of attacks, precipitating factors, associated symptoms, and family history should be documented as well as genetic screening of the appropriate genes.

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34. [141] Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 2014;370(10): 921
31. [142] Franco R, Pacheco R, Gatell JM, Gallart T, Lluis C. Enzymatic and extraenzymatic role of adenosine deaminase 1 in T-cell-dendritic cell contacts and in alterations of the immune function. Crit Rev Immunol 2007;27(6):495
509.

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[143] Belot A, Wassmer E, Twilt M, Lega JC, Zeef LA, Oojageer A, et al. Mutations in CECR1 associated with a neutrophil signature in peripheral blood. Pediatr Rheumatol Online J 2014;12 44-0096-12-44. eCollection 2014. [144] van Montfrans J, Zavialov A, Zhou Q. Mutant ADA2 in vasculopathies. N Engl J Med 2014;371(5):478. [145] Van Eyck Jr L, Hershfield MS, Pombal D, Kelly SJ, Ganson NJ, Moens L, et al. Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency. J Allergy Clin Immunol 2015;135(1) 283
7.e5. [146] Chakraborty PK, Schmitz-Abe K, Kennedy EK, Mamady H, Naas T, Durie D, et al. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood 2014;124(18):2867
71.

Chapter 14

Periodic Fever With Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) M. Hofer Pediatric Immunology and Rheumatology of Suisse Romande, CHUV, University of Lausanne, Lausanne, Switzerland

INTRODUCTION Fever is a common symptom in children, and is usually secondary to an infection. In case of repetitive fever episodes with similar clinical manifestations, the treating physician should consider an inflammatory cause. In the Western countries, the most frequent cause of recurrent autoinflammatory flares is periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome [1]. In 1987, Marshall et al. described 12 cases of young children with periodic fever, pharyngitis, cervical adenitis, and oral aphtosis [2]. In 1989, the term PFAPA was coined by Thomas et al., and a set of diagnostic criteria was proposed (modified Marshall criteria) [3]. Since then, many studies of PFAPA patients have been published including patients with disease onset in late childhood or adulthood [4].

CLINICAL PRESENTATION The main clinical features are described in the modified Marshall diagnostic criteria (Table 14.1) [2]. The patient shows regularly recurrent fever episodes accompanied by at least one of the three cardinal symptoms (aphthous stomatitis, pharyngitis, and cervical adenitis). In about half the patients, a clear periodicity of the flares is described, at least during the first phase of the disease. In a series of 301 PFAPA patients, pharyngitis was the most

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TABLE 14.1 Diagnostic Criteria Used for PFAPA I. Regularly recurring fevers with an early age of onset (,5 years of age) II. Constitutional symptoms in the absence of upper respiratory infection with at least one of the following clinical signs: (1) aphthous stomatitis, (2) cervical lymphadenitis, (3) pharyngitis III. Exclusion of cyclic neutropenia IV. Completely asymptomatic interval between episodes V. Normal growth and development

frequent cardinal symptom (90%) followed by cervical adenitis (78%) and oral aphtosis (57%), which was less frequent than abdominal symptoms (59%) [5]. About 44% of the patients presented a complete cluster (all three cardinal symptoms), and this phenotype was more frequent in patients with disease onset after 5 years of age. Pharyngitis was exsudative in less than the half of the affected patients, and cervical adenitis was usually bilateral. Several others symptoms have been described during the fever episodes, mainly of abdominal and osteoarticular origin, and headache. Typically, PFAPA patients present fever flares with a temperature above 39 C during 3 6 days and with a periodicity of 2 8 weeks. Patients may present a very predictable periodicity (up to 50%) [6,7] but some authors consider it as essential for the diagnosis. The exclusion of other diseases with a similar clinical presentation, like cyclic neutropenia or monogenic autoinflammatory disease (MAID), is part of the diagnostic criteria. Two aspects are essential for the diagnosis: first, the patients should be asymptomatic in between the fever episodes, and they usually have negative inflammatory markers [8]; second, the disease should not affect the child’s growth and development [2]. Disease onset is usually before the age of 5 years as stated in the diagnostic criteria. However, clinically typical PFAPA phenotype may also be found later and even in adulthood [5,9].

EPIDEMIOLOGY Since the first description in 1987, many series of PFAPA patients were published with more than 1000 patients described. From an international web-based registry, the authors could report the clinical characteristics of 301 patients and delineate three different phenotypes based on the presence of a complete cluster, the age at onset, and the need for genetic testing [5]. In a paper on the Eurofever database, the cohort of PFAPA patients was the largest described with 361 patients after familial Mediterranean fever (FMF) [1]. The incidence of PFAPA syndrome was evaluated in a Norwegian study at 23 new cases per 100,000 children, which is higher than the incidence of juvenile idiopathic arthritis measured in

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Norway (15/100,000) [10]. PFAPA syndrome has been described worldwide and a predominance among certain ethnicities has not been reported up to now.

DIAGNOSIS Pediatricians rely on their own clinical experience to diagnose PFAPA, but no validated sets of classification criteria have been established yet. Moreover, no specific diagnostic tests are available to confirm the diagnosis. Repetitive fever flares with a similar clinical presentation and at least one of the cardinal symptoms (pharyngitis, cervical adenitis, oral aphtosis) are very suggestive for the diagnosis. Often parents know when the episode will begin because of the periodicity of flares or presence of prodromal symptoms preceding fever. Blood tests will consist of inflammatory markers, which should be elevated during the fever and normal outside the flares; and of tests to exclude the differential diagnoses suggested by the clinic [11]. Like many other immunological diseases, PFAPA syndrome is an exclusion diagnosis and several infectious, oncological, and immunological diseases should be considered in the diagnostic work-up. The main differential diagnoses are listed in Table 14.2, and the investigations should be adapted to the particular presentation of the patient. Cyclic neutropenia is a classical differential diagnosis especially in patients with strict periodicity of the flares, but it is a very rare disease. Repetitive blood tests to measure the neutrophil count are proposed to exclude cyclic neutropenia. It is important to exclude the MAID, notably mevalonate kinase deficiency (MKD), before making the diagnosis of PFAPA syndrome [7,12]. The measurement of mevalonic aciduria during the fever flares is proposed for the diagnosis of MKD; this test should be performed on urine transported frozen to the laboratory to avoid the degradation of the molecule and a false negative result. Genetic analysis is not indicated in all patients and will be mainly proposed in case of an atypical presentation or evolution over the time, and in case of persisting systemic inflammation TABLE 14.2 Differential Diagnosis of PFAPA Syndrome Recurrent viral upper respiratory tract infections Immunodeficiency, cyclic neutropenia Hematooncologic diseases Behc¸et’s disease, Crohn’s disease, systemic-onset juvenile idiopathic arthritis Monogenic autoinflammatory disease: FMF, MKD, TRAPS, CAPS

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outside the fever flares. A score based on the clinical presentation has been proposed to select the patients with high risk of MAID [7,12]. The interpretation of the genetic testing should always be done in correlation with the clinical findings. Heterozygous variants with low penetrance may be found on both the TNFRSF1A and NLRP3 genes in patients with a classical PFAPA phenotype. The R92Q mutation is more often associated with typical symptoms of PFAPA than with a TRAPS (TNF receptor-associated periodic syndrome) phenotype and the outcome of R92Q positive patients is often milder than for TRAPS patients [11]. Similarly, NLRP3 variants (Q705K, V198M) were found in PFAPA patients [8], but also in CAPS (cryopyrin-associated periodic syndrome) patients with mild symptoms [13]; the significance of these variants in patients with clinical PFAPA is still a matter of debate. The absence of inflammation between the fever attacks (normal serum amyloid A) is reassuring, and may allow the physician to observe the evolution of the patient before further investigation. Due to the absence of specific markers for the disease, the delay from disease onset to diagnosis is often long, mainly because recurrent fever flares will be first considered as repetitive viral infections, especially in young children. Since PFAPA patients are followed by pediatricians or general practitioners, awareness of this disease should be raised among these specialties to reduce the diagnostic delay. This point is essential for parents of PFAPA patients, who report their suffering due to long-term recurring fever episodes without recognition of the cause. Different sets of criteria were used to diagnose PFAPA syndrome in the patients described in the literature [5]. None of them were validated mainly because of the lack of a gold standard. Most authors use the Marshall modified criteria (Table 14.1), but with a modified third criterion in order to consider the exclusion of MAID and not only cyclic neutropenia. Some aspects of these criteria are controversial: whether a strict periodicity of flares is mandatory, whether cases with age at onset after 5 years are still PFAPA patients, whether minor symptoms like oral aphtosis are allowed outside the fever flares [4]. A new classification based on the opinion of a large panel of experts and confirmed on a large cohort of PFAPA patients is currently under investigation and should bring some improvement in the diagnosis of PFAPA soon.

PATHOGENESIS Little is known about the pathophysiology of PFAPA syndrome as the exact etiology is currently unknown. Recurrent fever accompanied by pharyngitis and the cure after tonsillectomy initially suggested an infectious etiology. However, the periodicity, the presence of recurrent aphtosis, and the response to steroids but not to antimicrobial agents strongly suggest an inflammatory origin [14]. The similarity of the clinical presentation between

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the episodes, the absence of specific autoantibodies, and the increase of circulating neutrophils evoke an activation of innate immunity like that seen in autoinflammatory diseases [8,15]. Tonsillectomy has been reported to be an efficient treatment to induce a remission placing tonsils as the hypothetical origin of the flares [16,17]. However, histological findings showed chronic inflammation only with lymphoid, follicular, interfollicular immunoblastic hyperplasia, focal histocytic clusters, fibrosis, and keratinizing debris [17]. Tonsils from PFAPA patients may contain a different microbial flora compared to other causes of pharyngitis as recently suggested [18]; these microbes could be a trigger for the autoinflammatory flare. Analyses of cytokine profile in serum of PFAPA patients during flares and in asymptomatic periods have shown elevated levels of IL-6, and in vitro stimulation of peripheral blood mononuclear cells isolated from patients during a flare have an increased response to lipopolysaccharides leading to an increased secretion of TNF-α, IL-6, and IL-1β [16,19]. Moreover, gene expression analysis of whole blood cell extracts showed an overexpression of complement, IFN-inducible, and IL-1-related genes during fever flares compared with afebrile intervals and healthy controls. The good response of a few PFAPA patients after anti-IL-1 treatment with anakinra reinforces the role of IL-1β in fever induction during acute PFAPA episodes [19]. Altogether these data suggest that PFAPA syndrome may be due to a dysregulation of the innate immunity. Even if no monogenic mutation has been found for PFAPA [20], some studies have reported a positive familial history, arguing for a genetic background in this syndrome [21]. A recent published paper described an increased frequency of known mutations in the NLRP3 gene involved in inflammasome-dependent caspase-1 activation leading to IL-1β secretion, especially of the Q705K variant [8]. The exact implication of this variant, which has an incomplete penetrance and is present in about 5% of the healthy population [22], is still unknown, but it could represent a risk factor involved in autoinflammatory syndromes. Heterozygous variants of the MEFV gene were described in up to 50% of the PFAPA patients from countries where FMF is prevalent [23,24]. These carriers showed shorter duration for the episodes of fever, and lower rates of periodicity and oral aphtae. In our Swiss study, 4/57 patients were heterozygous for the E148Q variant, whose role is still controversial [8]. In a recent study, we did not observe any unique mutation in all the affected individuals analyzed, indicating the absence of a monogenic etiology and suggesting a possible oligogenic inheritance [20].

TREATMENT Achieving remission of the disease should be the main goal of the treatment of PFAPA syndrome. Due to the spontaneously favorable evolution over time, effective treatment should induce remission significantly faster than the

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natural course of the disease. No medical or surgical treatment has so far shown evidence in this direction [25]. Thus, the therapy is currently focused on the rapid control of febrile episodes and increasing the interval between the flares. The efficacy of the different treatments proposed to PFAPA patients is evaluated in a paper comparing the effect of treatments described retrospectively in the Eurofever database as compared to the data of the literature [26]. To control the fever, paracetamol is relatively ineffective, while nonsteroidal anti-inflammatory drugs allow partial control of the symptoms. The administration of a single dose of steroids (prednisone 1 2 mg/kg) early during the fever episode allows resolution of symptoms within a few hours of taking in a large majority of cases; sometimes a second dose after 24 hours is necessary. The main drawback of this treatment is that the following flare may come earlier in about half of patients [27]. This one-time treatment is generally well tolerated but it lacks studies to evaluate the potential adverse events in case of long-term treatment. Since IL-1β has been shown to play a role in the pathogenesis of PFAPA, anakinra, an IL-1 antagonist (IL-1RA), has been used in a few cases to control inflammation [19]. This treatment is still anecdotal, mainly because a single dose is easier to administer and better tolerated than a subcutaneous injection (Table 14.3). Cimetidine, a histamine H2 receptor antagonist used in the treatment of peptic ulcer and with immunomodulatory effects was used for the treatment of PFAPA, but it showed low efficiency of about 28%, which is comparable to a placebo effect. There are no randomized trials at present and its effectiveness in the PFAPA syndrome remains doubtful [16,28]. Tasher et al. were able to show in a retrospective study that colchicine, the main treatment of FMF, is able to significantly reduce the number of attacks [29]. Due to good tolerability, this treatment can be offered to patients with short intervals between attacks and a significant impact on everyday life. Several studies have reported the beneficial effect of tonsillectomy that could induce complete remission in 27 100% of the patients depending on the study [28,30 34]. However, a recent metaanalysis showed limited evidence with only two randomized trials [25]. The selection of patients for some of these studies may be questioned since a proportion of the patients TABLE 14.3 Treatment of PFAPA Syndrome NSAIDs

Moderate efficacy to control the fever

Prednisone (single dose)

Stop the flare within a few hours

Colchicine

Decrease of the number of attacks

Tonsillectomy

Induction of remission

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did not meet the diagnostic criteria for PFAPA and postoperative follow-up was often short [35]. The effectiveness of tonsillectomy in PFAPA syndrome remains to be clarified. Actually, we propose tonsillectomy if the impact of the disease on the child’s quality of life is important with a relative failure of the medical treatment [25]. PFAPA syndrome has a good prognosis without long-term damage and usually resolves during childhood with remission after a median of 4.5 years following the first episode [6,27,36]. Other authors mention that the episodes will decrease in intensity with time and the interval between two flares will increase. In rare cases PFAPA syndrome may persist into adulthood [9]. The burden of PFAPA is mainly related to the impact of chronic recurring inflammatory symptoms on daily life of the child and its family. The elevated number of days of illness per year may perturbate the social and work life of the parents and the school performance of the child [4,30].

CONCLUSION PFAPA syndrome is benign cause of recurrent fever, which needs to be recognized and treated early. A better understanding of the pathogenesis of the disease is essential to facilitate the diagnosis through specific biomarkers of disease and to develop new treatments. Randomized trials are expected to increase the evidence regarding the effectiveness of treatment used and assess if they are able to induce remission significantly faster than the natural course of the disease.

REFERENCES [1] Toplak N, Frenkel J, Ozen S, Lachmann HJ, Woo P, Kone-Paut I, et al. An international registry on autoinflammatory diseases: the Eurofever experience. Ann Rheum Dis 2012;71:1177 82. [2] Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr 1987;110:43 6. [3] Thomas KT, Feder Jr. HM, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr 1999;135:15 21. [4] Hofer MF. Syndrome PFAPA: Ce que nous a appris la cohorte Europe´enne. PFAPA syndrome: what we have learned from the European cohort. Rev Rhum Ed Fr 2012;79:38 41. [5] Hofer MF, Pillet P, Cochard M, Berg S, Krol P, Kone-Paut I, et al. International PFAPA syndrome cohort: evaluation of the diagnostic criteria in 301 patients. Rheumatology 2014;53:1125 9. [6] Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, et al. Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr 1999;135:98 101. [7] Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S, Zulian F, et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics 2009;124:e721 8.

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[8] Kolly L, Busso N, von Scheven-Gete A, Bagnoud N, Moix I, Holzinger D, et al. Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1beta production. J Allergy Clin Immunol 2013;131:1635 43. [9] Padeh S, Stoffman N, Berkun Y. Periodic fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) in adults. Isr Med Assoc J 2008;10:358 60. [10] Førsvoll J, Kristoffersen EK, Oymar K. Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a population-based study. Acta Paediatr 2013;102:187 92. [11] Pelagatti MA, Meini A, Caorsi R, Cattalini M, Federici S, Zulian F, et al. Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene. Arthritis Rheum 2011;63:1141 50. [12] Gattorno M, Sormani MP, D’Osualdo A, Pelagatti MA, Caroli F, Federici S, et al. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum 2008;58:1823 32. [13] Schuh E, Lohse P, Ertl-Wagner B, Witt M, Krumbholz M, Frankenberger M, et al. Expanding spectrum of neurologic manifestations in patients with NLRP3 low-penetrance mutations. Neurol Neuroimmunol Neuroinflamm 2015;2:e109. [14] Long SS. Syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)—what it isn’t. What is it? J Pediatr 1999;135:1 5. [15] Brown KL, Wekell P, Osla V, Sundqvist M, Sa¨vman K, Fasth A, et al. Profile of blood cells and inflammatory mediators in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. BMC Pediatr 2010;10:65. [16] Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr 2010;99:178 84. [17] Peridis S, Koudoumnakis E, Theodoridis A, Stefanaki K, Helmis G, Houlakis M. Surgical outcomes and histology findings after tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. Am J Otolaryngol 2010;31:472 5. [18] Lantto U, Koivunen P, Tapiainen T, Glumoff V, Hirvikoski P, Uhari M, et al. Microbes of the tonsils in PFAPA (Periodic Fever, Aphtous stomatitis, Pharyngitis and Adenitis) syndrome—a possible trigger of febrile episodes. APMIS 2015;123:523 9. [19] Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA, et al. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci USA 2011;108:7148 53. [20] Di Gioia SA, Bedoni N, von Scheven-Gete A, Vanoni F, Superti-Furga A, Hofer M, et al. Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Sci Rep 2015;5:10200. [21] Cochard M, Clet J, Le L, Pillet P, Onrubia X, Gueron T, et al. PFAPA syndrome is not a sporadic disease. Rheumatology 2010;49:1984 7. [22] Sahdo B, Fransen K, Asfaw Idosa B, Eriksson P, Soderquist B, Kelly A, et al. Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome. PLoS One 2013;8:e75457. [23] Cazeneuve C, Genevieve D, Amselem S, Hentgen V, Hau I, Reinert P. MEFV gene analysis in PFAPA. J Pediatr 2003;143:140 1. [24] Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R. MEFV, TNF1RA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int 2010;30:633 6.

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[25] Burton MJ, Pollard AJ, Ramsden JD, Chong LY, Venekamp RP. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev 2014;9:CD008669. [26] Ter Haar N, Lachmann H, Ozen S, Woo P, Uziel Y, Modesto C, et al. Treatment of autoinflammatory diseases; results from an international registry and a literature review. Ann Rheum Dis 2013;72:678 85. [27] Tasher D, Somekh E, Dalal I. PFAPA syndrome: new clinical aspects disclosed. Arch Dis Child 2006;91:981 4. [28] Licameli G, Lawton M, Kenna M, Dedeoglu F. Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. Arch Otolaryngol Head Neck Surg 2012;138:902 6. [29] Tasher D, Stein M, Dalal I, Somekh E. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr 2008;97:1090 2. [30] Garavello W, Pignataro L, Gaini L, Torretta S, Somigliana E, Gaini R. Tonsillectomy in children with periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome. J Pediatr 2011;159:138 42. [31] Pignataro L, Torretta S, Pietrogrande MC, Dellepiane RM, Pavesi P, Bossi A, et al. Outcome of tonsillectomy in selected patients with PFAPA syndrome. Arch Otolaryngol Head Neck Surg 2009;135:548 53. [32] Renko M, Salo E, Putto-Laurila A, Saxen H, Mattila PS, Luotonen J, et al. A randomized, controlled trial of tonsillectomy in periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. J Pediatr 2007;151:289 92. [33] Licameli G, Jeffrey J, Luz J, Jones D, Kenna M. Effect of adenotonsillectomy in PFAPA syndrome. Arch Otolaryngol Head Neck Surg 2008;134:136 40. [34] Wong KK, Finlay JC, Moxham JP. Role of tonsillectomy in PFAPA syndrome. Arch Otolaryngol Head Neck Surg 2008;134:16 19. [35] Hofer MF. Letter to the editor. Cured by tonsillectomy: was it really a PFAPA syndrome? J Pediatr 2008;153:298. [36] Wurster VM, Carlucci JG, Feder Jr. HM, Edwards KM. Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr 2011;159:958 64.

Chapter 15

Chronic Recurrent Multifocal Osteomyelitis and Related Disorders P.J. Ferguson University of Iowa Carver College of Medicine, Iowa City, IA, United States

INTRODUCTION Chronic recurrent multifocal osteomyelitis (CRMO) was first described in 1972 by Giedion and colleagues as subacute and chronic symmetric osteomyelitis [1]. The hallmark of the disease is sterile osteomyelitis affecting one or more osseous sites. Many have a personal or family history of psoriasis, inflammatory bowel disease, or inflammatory arthritis, suggesting shared pathogenesis. Clinical and scientific data support classifying CRMO as an autoinflammatory disorder and evidence suggests a genetic component to disease susceptibility. There are two human Mendelian forms of the disease and several animal models of CRMO. Immune dysregulation is present in all models of the disease, with interleukin (IL)-1 pathway dysregulation central to the pathogenesis in the Mendelian models of the disease. Dietary modulation is associated with disease protection in the chronic multifocal osteomyelitis (CMO) mouse and is associated with alterations in the intestinal microbiome. The role of diet, the microbiome, and genetics in sporadic cases of CRMO remains to be defined.

NOMENCLATURE Sterile osteomyelitis is the key feature of the autoinflammatory disorders that affect the bone. In childhood, the most common autoinflammatory bone disorder is chronic recurrent multifocal osteomyelitis (CRMO) or chronic nonbacterial osteomyelitis (CNO) [2]. The term CNO takes into account milder presentations of the disease, which can be unifocal and nonrecurrent. Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is the diagnostic label most often utilized by adult rheumatologists for patients Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00015-3 © 2016 Elsevier B.V. All rights reserved.

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with sterile bone inflammation [3]. Additional terms including pustulotic arthroosteitis syndrome [4], chronic nonbacterial osteitis [5], chronic sclerosing osteomyelitis of Garre [6], chronic symmetric osteomyelitis [7,8], and diffuse sclerosing osteomyelitis [9] have been used in the literature for phenotypically similar patient populations. For this chapter, we will use the term CRMO except when referencing adult-specific literature, in which case we will use the term SAPHO syndrome.

PREVALENCE AND EPIDEMIOLOGY There is limited data on the prevalence and incidence of CRMO and SAPHO syndrome. It is a rare disorder. Most reported cases are from Scandinavia, Western Europe, Canada, and the United States, but there is a worldwide distribution. Caucasian race is most often reported in the literature but all races and ethnicities can be affected. A nationwide incidence survey conducted in Germany from 2006 to 2008 determined the annual incidence at 0.4 per 100,000 children [10].

ETIOLOGY AND PATHOGENESIS Immune Dysregulation and Possible Triggers There is innate immune system dysregulation in CRMO with elevated proinflammatory cytokines documented by several investigators in both CRMO and SAPHO syndrome [5,11
13]. Hofmann et al. documented decreased IL-10 secretion from lipopolysaccharide-stimulated CNO monocytes accompanied by attenuated extracellular-signal regulated kinase 1/2 activity [12]. Attenuation of Sp1 and reduced histone H3 serine-10 phosphorylation was found, suggesting that epigenetic factors play a role in the decreased IL-10 gene expression. Decreased IL-10 production could disrupt the pro- and anti-inflammatory cytokine balance leading to increased proinflammatory (tumor necrosis factor (TNF)-α and IL-6) cytokine production [12,13]. The proinflammatory cytokine IL-1β has also been implicated in disease pathogenesis. This is best illustrated in DIRA (deficiency of the interleukin-1 receptor antagonist) in which the lack a functional IL-1 receptor antagonist results in unfettered signaling through the IL-1 receptor I (RI) leading to systemic inflammation accompanied by early onset chronic multifocal osteomyelitis and cutaneous pustulosis [14,15]. Pharmacologic blockade of IL-1 with the recombinant IL-1 receptor antagonist (anakinra) results in prompt and dramatic clinical improvement in affected individuals [14,15]. IL-1β also is an important cytokine in Majeed syndrome based on the clinical response to biologic therapy in which blockade of IL-1β, but not TNF-α, results in

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prompt control of the systemic and bone inflammation [16]. There are reports of aberrant IL-1 mediated signaling in both nonsyndromic cases of CRMO and in adults with SAPHO syndrome [17,18], and there are a few reports of patients with CRMO or SAPHO improving on IL-1 blocking agents [17,19]. Studies in murine models of CRMO also support a central role of IL-1β in sterile bone inflammation. Cmo mice that also lack key IL-1 pathway genes demonstrate that bone disease is an IL-1β dependent disease that occurs independent of the Nlrp3 inflammasome. Cmo mice that lack a functional IL-1 RI are protected from disease, yet cmo mice that lack the key inflammasome components Nlrp3, Asc, or caspase-1 develop disease similar to cmo controls [20,21]. Neutrophils have been implicated as the innate immune system source of biologically active IL-1β [20]. This evidence supports the role of the innate immune system in CRMO, yet what triggers immune system activation remains unclear. In the vast majority of CRMO and SAPHO cases, bone inflammation occurs in the absence of an identifiable microbe or trigger. Cultures of the bone are typically sterile, antibiotic therapy is rarely accompanied by clinical improvement, and antiinflammatory medications improve the condition [2,17,22
25]. Yet, there are reports of typical CRMO and SAPHO cases that had positive bone cultures for various organisms. It is unclear if the organisms were contaminants or pathogens [22,26
39]. Girschick et al. studied 12 CRMO/CNO biopsies for the presence of bacterial ribosomal DNA by polymerase chain reaction (PCR) using universal 16S ribosomal DNA primers and found no microbial signature [2]. However, in the SAPHO syndrome literature, Propionibacterium acnes has emerged as a potential trigger. Assmann et al. reported the culture results from a cohort of 21 SAPHO patients and found that 66% (14 of 21) of bone biopsies from this cohort of patients grew P. acnes [38,39]. Reviews of the literature found 42% of 90 SAPHO bone cultures were P. acnes positive [38,40]. P. acnes can activate the innate immune system using both tolllike receptor (TLR)-9, as well as TLR-9 independent pathways [41,42] and may lead to inflammasome activation [43]. Additional studies are needed to determine the role of P. acnes and IL-1 in CRMO/CNO and SAPHO. The microbiome may play an important role in sterile bone inflammation. Lukens et al. demonstrated that dietary manipulation can profoundly alter the inflammatory bone phenotype in cmo mice. They fed cmo mice a high fat diet and observed nearly complete protection from disease accompanied by alterations in the microbiome with a skewing of the gut microbes away from inflammation-associated microbes such as Prevotella and toward enrichment of good bacterial species including Lactobacillus [44]. They went on to demonstrate that cmo mice fed the protective diet had lower levels of pro-IL-1β compared to diseased cmo mice fed the standard low fat chow [44]. Fecal transplants from old diseased cmo mice into young prediseased cmo mice accelerated disease suggesting that the microbiome drives the

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autoinflammatory bone disease in this model [44]. Further investigations are needed to determine the dietary component(s) that are responsible for disease protection and to determine if dietary changes can be protective in humans with CRMO.

Genetics Although most cases of CRMO are sporadic, multiple lines of evidence support a genetic contribution to the development of CRMO. There are reports of affected sib pairs and affected parent-child duos [5,45
47], and B30
50% of individuals with CRMO have a first- or second-degree relative with psoriasis, inflammatory bowel disease, or inflammatory arthritis [5,25,48,49]. There is a reported CRMO susceptibility locus on chromosome 18q21.3-18q22, which was detected by transmission disequilibrium test analysis of 27 trios of German heritage, yet no mutations were found in the candidate genes in the region that included RANK [50]. This locus has not been validated in an independent cohort. Hofmann et al. reported an association with polymorphisms in the IL-10 promotor in CRMO patients but when assessed in vitro, CNO monocytes did not display a high IL-10 secreting phenotype, which is what would be predicted based on the association [11]. There are monogenic human and animal models of CRMO. Large breed dogs, particularly Weimaraners, develop a disease called hypertrophic osteodystrophy, which can be accompanied by pustulosis and Crohn’s disease [51,52]. This disease clusters in litters and in specific breeds supporting a genetic etiology [51]; genetic dissection of this model is ongoing. There are several mouse models of CRMO in which bone inflammation is due to autosomal recessive mutations in proline-serine-threonine phosphatase interacting protein-2 (Pstpip2) [53,54], including the cmo mice. These mice develop severe multifocal sterile osteomyelitis, skin inflammation, and extramedullary hematopoiesis [53] that is a hematopoietically driven, innate immune system disease dependent on intact IL-1 mediated signaling [20,55]. Interestingly, the inflammatory bone phenotype can be modulated by diet [44]. And finally, there are two autosomal recessive human disorders that have CRMO as a subphenotype including Majeed syndrome, which is due to mutations in LPIN2 and deficiency of the IL-1 receptor antagonist (DIRA), which is due to mutations in IL1RN [14,15,56]. IL-1 pathway dysregulation is present in murine cmo, Majeed syndrome, and DIRA [14,16,20,21].

MENDELIAN AUTOINFLAMMATORY BONE DISORDERS Majeed Syndrome (OMIM #609628) In 1989 and 2001, Dr. Majeed described six affected individuals from two unrelated families that presented with early onset CRMO, dyserythropoietic

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anemia with or without the neutrophilic dermatosis Sweet syndrome [57,58], recognizing it as a new syndrome [57,58]. All affected children have early onset (prior to 2 years of age) severe chronic multifocal osteomyelitis. The distribution of the bone lesions is similar to nonsyndromic cases of CRMO; however, the CRMO in Majeed syndrome is more severe [16,57
60]. Dyserythropoietic anemia has been reported in all patients with Majeed syndrome ranging from transfusion-dependent to quite mild [16,57
60]. The anemia is hypochromic and microcytic, which differentiates it from the better known forms of congenital dyserythropoietic anemias (CDA). Despite a neutrophilic dermatosis being part of the classic triad of Majeed syndrome (along with CRMO and CDA), Sweet syndrome has been reported in only two Majeed syndrome patients [57
59]. Other reported manifestations include recurrent fevers, delayed puberty, failure to thrive, hepatosplenomegaly, and neutropenia shown in Table 15.1 [16,56
58,60]. All have moderate to marked elevations in inflammatory markers including C-reactive protein and erythrocyte sedimentation rate [16,56
58,60]. Majeed syndrome remains an exceedingly rare disease and has only been reported in nine individuals from four unrelated consanguineous families [16,57,58,60]. The molecular basis of Majeed syndrome was discovered in 2005 when homozygous deleterious mutations in LPIN2 were found in six affected individuals from two unrelated kindreds [57
59]. Subsequently, three affected individuals from two additional unrelated families have been reported in the literature [16,60]. Each of the four families have a private mutation [16,56,60]. To date the penetrance is 100% but no genotype/phenotype correlations can be made due to the small number of affected children. There are two additional cases in the literature that may have had Majeed syndrome. One is a child reported by Edwards et al. who presented at 23 months of age with CRMO and Sweet syndrome with reportedly a normal bone marrow [61]. The other was reported by Vermylen et al. with CRMO diagnosed at 5 years followed by hepatosplenomegaly with dyserythropoietic anemia diagnosed at age 13 years [62]. LPIN2 encodes the phosphatidate phosphatase (PAP) LIPIN2, a molecule important in glycerolipid biosynthesis [63
66]. One of the reported Majeed syndrome associated mutations (S734L) has been shown to disrupt PAP activity in vitro suggesting that the loss of PAP function contributes to disease pathogenesis [67]. Despite the evidence that lipid metabolism is affected in Majeed syndrome, no lipid abnormalities have been detected in the blood of the affected individuals who have been tested [60]. Lipin1, another member of the LIPIN family of proteins, have been shown to be involved in autophagy [68,69], but this has not been shown for Lipin2. LIPIN2 appears to be an anti-inflammatory molecule as its absence in Majeed syndrome causes a systemic inflammatory disease. In vitro data supports this statement as Valdearcos et al. showed that LIPIN2 reduces the inflammatory response of macrophages exposed to excessive saturated fatty acids [70].

TABLE 15.1 Majeed Syndrome Clinical Features

Recurrent fever

A1

A2

A3

A4

B1

B2

C1

D1

D2

+

+

+

+

+++

+++

+

2

+

Failure to thrive

+

+

+

+

+

+

2

NR

NR

CRMO

+

+

+

+

+

+

+

+

+

1 year

19 months

9 months

1 month

3 weeks

9 months

15 months

6 months

3 months

LE long bones

+

+

+

+

+

+

+

+

+

UE long bones

+

+

+

+

+

+

+

+

+

Feet

2

2

2

2

2

+

+

2

2

Spine

2

2

2

2

2

2

2

2

2

Age at onset

Other

Hands

Hands

Ribs

Hands Φ

Osteo

Osteo

Osteo

NR

NR

NR

ND

Osteo

ND

Objective joint swelling

+

+

+

NR

+

+

+

2

+

Hepatosplenomegaly

+

+

+

+

+

NR

+

2

2

m ESR/CRP

+++

+++

+++

+++

++

+++

+++

+++

+++

Microcytic anemia

+

+

+

+

+

+

+

+

+

Transfusion Rx

+

+

+

+

+

+++










Dyserythropoiesis on BM

Bone bx

+

+

+

+

+

+

+

+

+

Neutropenia

NR

NR

NR

NR

NR

NR

+

2

2

Neutrophilic dermatosis

+

+

2

2

2

2

2

2

2

NR, not reported; Φ, granulomatous inflammation; 2 not present. 1 present or mildly elevated. 11 moderately elevated. 111 markedly elevated.



anemic but MCV not reported.

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The long-term outcome of Majeed syndrome in the prebiologic age is poor [58]. Many of the children have been treated with nonsteroidal antiinflammatory drugs (NSAIDs) or chronic corticosteroids and have had poor growth and have developed joint contractures resulting in significant disability [58]. However, the recent report by Herlin et al. demonstrates the ability to control the systemic and osseous inflammation with therapeutic agents that block IL-1β, offering hope for improved long-term outcomes [16] and suggesting that Majeed syndrome maybe an inflammasomopathy.

Deficiency of the Interleukin-1 Receptor Antagonist (OMIM #612852) DIRA is a potentially life-threatening disease that is due to marked cytokine dysregulation stemming from mutations in IL1RN that result in either the absence of, or defective production of the IL-1 receptor antagonist (IL-1RA) [14,15]. Although not recognized as a distinct syndrome until 2005, it is likely that the child described over a decade earlier by Prose et al. had the same syndrome [71]. The child had severe persistent bone disease and diffuse pustulosis unable to be fully controlled with corticosteroids [71]. The child’s parents were unaffected. Subsequently, two groups described nine additional affected children, all of whom had bone and skin inflammation associated with homozygous loss of function mutations in IL1RN [14,15]. Since that time several additional cases have been reported [72
78]. The disease is autosomal recessive with 100% penetrance. The absence of IL1RA results in unfettered IL-1 signaling with subsequent amplification of proinflammatory molecular pathways [14,79]. The result in humans is a severe inflammatory disease with early onset (typically in the first weeks of life), which if unrecognized and treated is potentially fatal [14]. The affected children can present with or without fever and nearly all have early onset CRMO, cutaneous pustulosis, and marked systemic inflammation [14,15,72
76,78]. Multifocal sterile osseous lesions, typically involving the clavicles, ribs, vertebra, and long bones have been reported in all but one affected child [14,72
78]. A Turkish patient reported by Ulusoy et al. developed pustulosis at 1 year but had no other symptoms until 12 years of age when she developed joint swelling without radiographic evidence of osteitis or periostitis [77]. The pustular skin rash can be quite mild or extensive but is present in nearly all affected individuals at some point [14,15,72
77]. Other associated features include central nervous system vasculitis, interstitial lung disease, venous thrombosis, cardiomyopathy, conjunctival injection, episcleritis, arthritis, and hypotonia [14,15,72
78]. Nearly half of DIRA patient are born near-term premature and failure to thrive is common [14,15,74,75,77,78]. Fortunately, there is a highly effective treatment for DIRA; the recombinant IL-1 receptor antagonist (anakinra) is the treatment of choice as it allows the replacement of the very protein that these infants

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are missing [14,15,72
76,80,81]. Within days of initiation of treatment, the skin clears and the inflammatory markers normalize and within months, the bone lesions heal [14]. One child with cutaneous inflammation, episcleritis, and inflammatory arthritis was treated with canakinumab with resolution of these symptoms and improvement of inflammatory markers suggesting that these features are mediated primarily via IL-1β rather than IL-1α [77].

CLINICAL MANIFESTATIONS OF NONSYNDROMIC CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS The average age of onset is around 9
10 years (peak B7
12 years old) with girls being affected more than boys; however, males may have more severe disease [2,5,22,24,49]. The disease predominantly affects children and when the disease occurs in adults, it is typically called SAPHO syndrome [82]. Bone pain is the cardinal clinical feature [5,22,24,29,83]. The pain can have an insidious, subacute, or acute onset. Fever is present in up to 33% of patients [24,25,49,84]. The pain is typically worse at night and may disrupt sleep. Swelling and warmth overlying the affected bone may be present or there may be no objective findings. Visual or palpable bony enlargement may be present, particularly if the clavicle or mandible is involved [85]. The disease may be unifocal at presentation but for the vast majority, the disease becomes multifocal and is symmetric in up to 40% [5,24,49]. Typically, there are intermittent exacerbations with periods of remission, but the disease course may be chronic and persistent [22,24,49,86]. Any bone can be involved but the metaphyseal regions of the long bones, clavicles, vertebral bodies, and pelvis are the most frequently affected sites [2,5,22,24,25,49,87,88]. Pain typically localizes to the area(s) of bone involvement, but lesions can be asymptomatic and pain can be referred. Joint pain and swelling may be present, which may be due to secondary soft tissue inflammation adjacent to active bone lesions or may be due to synovitis [2,89]. Overall, affected individuals look well and given that the physical exam can be completely normal and laboratory studies can be normal, the diagnosis is often delayed for months to years [49,83]. Individuals may present with bony deformity such as with pathologic fracture (Fig. 15.1) kyphosis, scoliosis, leg length discrepancy, or premature epiphyseal closure [22,49,90
92]. Extraosseous manifestations occur in B25%; most commonly palmoplantar pustulosis, psoriasis vulgaris, Crohn’s disease, or inflammatory arthritis [83,93]. A family history of psoriasis, inflammatory bowel disease, or inflammatory arthritis is present in 30
50% of affected individuals [5,48,49].

Associated Inflammatory Disorders Many individuals with CRMO also have a personal history of inflammatory disorders of the skin, intestine, joints, or other tissues. The strongest association is between CRMO and inflammatory skin conditions including

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FIGURE 15.1 Pathologic fracture in CRMO. This child had a large osteolytic lesion in the right distal femur as his presenting feature of CRMO. His course was complicated by a pathologic fracture sustained 5 months after presenting with a limp. The osteolytic lesion and fracture of the femur are seen on plain film and MRI (A). Two years later, the fracture has healed but the inflammatory lesion, although much improved, continues to demonstrate evidence of residual inflammation on MRI (B).

palmoplantar pustulosis [49,91,94
98], psoriasis vulgaris [49,91,98,99], severe acne [49,91,100,101], generalized pustulosis [71], pyoderma gangrenosum [22,102,103], Sweet syndrome [57,61,104,105], and panniculitis [91]. Inflammatory bowel disease occurs in approximately 10% of individuals with CRMO, most often Crohn’s disease, but ulcerative colitis and celiac disease also occur [5,22,26,49,106
115]. Inflammatory arthritis occurs in up to 80% of individuals with CRMO, most often with inflammation in the joint adjacent to a bone lesion but synovitis distant from sites of osteitis can also occur [2,4,5,22,49,91]. Other associations include vasculitis (ANCA positive and Takayasu arteritis) [22,116
118], juvenile dermatomyositis [25,87,119,120], uveitis [25,91], sclerosing cholangitis [22,26], Still disease [19], and tumoral calcinosis [121].

DIAGNOSTIC TESTING There is no diagnostic laboratory test for CRMO and although many affected individuals may have mild to moderate elevations of acute phase proteins, these may be completely normal [5,24,91,122] or quite elevated [49]. Serum TNF-α is elevated in some but this test is not routinely ordered [5]. Autoantibodies if detected are typically in low titer or they are absent [48,49]. HLA-B27 is not strongly associated with the disease [49]. Radiographic investigations are vital in establishing a diagnosis of CRMO. Plain films often show osteolytic lesions with surrounding sclerosis with or without hyperostosis but they may be completely normal (especially early in disease) [89,123]. Osteolytic lesions surrounded by sclerosis in the

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FIGURE 15.2 Clavicular involvement in CRMO. A 13-year-old girl presented with isolated swelling of the left clavicle. Three years later the diagnosis of CNO was established. At that time, there was an osteolytic expansile clavicular lesion with surrounding sclerosis. The lesion is shown on plain film (A), CT (B), 3-dimensional CT (C), and partial healing demonstrated on plain film approximately 2 years later (D).

metaphyseal regions of the long bones is the most common finding although the epiphysis and diaphysis can also be involved [89,123]. Clavicular involvement, when present, usually involves the medial third of the clavicle presenting as an expansile lesion with osteolytic areas intermixed with sclerosis (Fig. 15.2) [85,89,124]. Overtime, significant hyperostosis of the clavicle may occur [89,124]. On plain films vertebral body lesions may present as destructive lytic lesions, erosion of the endplates, or overt vertebral body collapse resulting in vertebra plana or a wedge-shaped segment (Fig. 15.3) [89,123,125,126]. Any site in the pelvis can be involved but are often at the joint surfaces (including the sacroiliac joint) or subchondroses, which may have an expansive appearance or may appear only as areas of increased sclerosis [22,27,84,125]. Whole-body imaging, preferably by MRI

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FIGURE 15.3 Vertebral body damage in CRMO. A child with CRMO demonstrates residual vertebral body damage with endplate deformities most marked at T7 and T8 (arrow) on plain films (left and center) while the corresponding MRI on the right shows the deformities but no residual inflammation (normal STIR signal in T7 and T8).

rather than technetium bone scan, is important during the initial diagnostic evaluation as well as to follow disease activity, gauge response to treatment, and to demonstrate both symptomatic as well as asymptomatic lesions [127,128]. Decreased signal intensity on T1-weighted images accompanied by increased signal intensity on T2-weighted and STIR images is typical for active lesions. MRI can also provide information about the presence of synovitis and the extent of soft tissue inflammation associated with bone lesions [89,129]. Bone biopsy with histologic assessment of an active lesion is a frequent part of the work up in CRMO. It is most useful in helping to rule out malignancy, infection, histiocytic disease and other disorders in the differential diagnosis. Jansson et al. developed and tested a scoring system designed to help determine whether a bone biopsy is needed to establish a diagnosis [130]. A normal blood cell count; symmetric bone lesions; lesions with marginal sclerosis; absence of fever; vertebral, clavicular, or sternal location of lesions; more than one lesion; and C-reactive protein level $ 1 mg/dL were all supportive of the diagnosis of CRMO [130]. The composite score for a diagnosis of CRMO based on these predictors ranged from 0 to 63. A score of $ 39 had a positive predictive value of 97% and a sensitivity of 68% [130]. Histologic findings in the bone are in keeping with those seen in bacterial osteomyelitis except that microbial stains are negative. A range of inflammatory cells can be seen from predominantly neutrophilic, to predominantly lymphocytic, to a mixed picture [24,28,29,122,131]. Noncaseating granulomas,

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increased number and size of osteoclasts, multinucleated giant cells, necrotic bone, new bone formation, and fibrosis have all been reported [28,122,131].

DIFFERENTIAL DIAGNOSIS Infectious osteomyelitis is high on the differential diagnosis. Bone biopsy with cultures and stains are important in differentiating infectious versus sterile osteomyelitis, and is especially important in unifocal disease, with high inflammatory markers and in a child with fever. Infection with fastidious organisms including mycobacteria and organisms such as Kingella can be difficult to culture. Multifocal disease and/or the presence of a personal or family history of psoriasis, inflammatory arthritis, or Crohn’s disease may help support the diagnosis as CNO/CRMO. Immune deficiency with infectious or sterile osteomyelitis may also mimic CRMO [132]. Malignant conditions can mimic CRMO including leukemia, lymphoma (including primary intraosseous lymphoma), Ewing sarcoma, neuroblastoma, Langerhans cell histiocytosis, and Rosai-Dorfman, among others [133
136]. Laboratory studies that may help identify malignancy include uric acid, LDH, a pathologist review of the blood smear, and urine catecholamines. Biopsy of the bone remains the gold standard to help rule out malignancy. Disorders of phosphate metabolism including both hyper- and hypophosphatasia have been associated with a CRMO-like phenotype. Dr. Majeed was the first to report association of CRMO-like phenotype with tumoral calcinosis [121]. Subsequently, two other groups have reported similar cases [137,138]. One case, an 8-year-old child, had presented with bilateral elbow swelling due to soft tissue calcification. Laboratory analysis revealed hyperphosphatemia with normal vitamin D, parathyroid hormone levels, and renal function. Histopathologic analysis of the bone removed from the elbows showed multinucleated giant cells, fibroblasts, and amorphous calcification surrounded by chronic inflammation [138]. Hyperphosphatemic familial tumoral calcinosis (HFTC) was suspected and the child was found to harbor a homozygous loss of function mutation in GALNT3 (p.R126X), a gene known to cause HFTC [138,139]. Subsequently, the child developed painful multifocal bone lesions and biopsy of other bone lesions demonstrated medullary fibrosis, chronic inflammatory infiltrate, and new bone formation, which phenotypically resembled CRMO [138]. GALNT3 encodes a glycosylating enzyme that is important in maintaining homeostasis of phosphate metabolism [139,140]. Hypophosphatasia (OMIM # 241510) has also been associated with CRMO initially by Girschick et al. and then by others [141,142]. Hypophosphatasia is an inborn error of metabolism due to inactivating mutations in ALPL (also known as TNSALP) that encodes the tissue nonspecific isoenzyme of alkaline phosphatase [142,143]. Children with hypophosphatasia have abnormal bone mineralization with ricket-like bone deformities, predisposition to fracture,

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dental abnormalities, and difficulties with renal calcification [143]. Whyte et al. reported two children with hypophosphatasia who developed multifocal bone lesions with lucency, osteosclerosis involving the metaphyseal regions of the bones with associated edema on MRI phenotypically similar to CRMO [142]. Beck et al. investigated if patients with hypophosphatasia have bone lesions consistent with CRMO by performing whole-body MRI on four children with the childhood form of hypophosphatasia [144]. They found that hyperemia and edema in the metaphyses of the long bones in all four children in a pattern that mimics the whole-body MRI findings in CRMO [144].

TREATMENT Treatment of CRMO is empiric and there are no approved medications for the condition. Nonsteroidal anti-inflammatories remain the first line of treatment. Although the vast majority obtain some relief of their symptoms on NSAIDs, most continue to have symptoms [2,5,24,25,84,85,145]. Beck et al. performed a prospective study of NSAIDs in CRMO and found that 100% of children with CRMO and inflammatory arthritis had active arthritis at 3 months and 50% continued to have active arthritis after 6 months of NSAID treatment. Nearly one-third with vertebral body involvement developed pathologic vertebral body fracture when treated with NSAID monotherapy for 12 months [146]. This study suggests that NSAID monotherapy is inadequate treatment in individuals with comorbid inflammatory arthritis and in those with vertebral body involvement. It is unclear what the best course of treatment is for lesions that are asymptomatic but that demonstrate evidence of disease activity on MRI. Lesions in the spine, mandible, and perhaps the pelvis pose a higher risk for long-term permanent damage so a more aggressive approach may be needed. As long as the lesions are in areas at low risk for long-term damage then observation may be reasonable. Second-line therapy is needed for those with persistent pain associated with radiologic evidence of active disease and for those with continued disease activity in areas at higher risk of permanent deformity or damage. Individuals with CRMO may develop a chronic pain syndrome so it is important to document radiologic evidence of active disease before escalating therapy. Second-line treatment agents included methotrexate, sulfasalazine, corticosteroids, bisphosphonates, and TNF inhibitors. Corticosteroids reduce pain and inflammatory markers in most but the side effects prevent this from being a viable long-term treatment option. There is evidence that nonbiologic disease-modifying antirheumatic drugs such as methotrexate and sulfasalazine may provide improvement but lead to clinical remission in only about 20% [25]. A TNF inhibitor or bisphosphonate (most often pamidronate) are increasingly being used in patients with CRMO who fail NSAIDs. There are more than 70 case reports or case series

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documenting response to bisphosphonates [86,91,92,147
162]. Most are retrospective in nature with at least one prospective study and several quantitating bone lesions by whole-body MRI before and after bisphosphonate treatment. Review of case reports and case series suggests that approximately 70
80% of individuals treated with bisphosphonates improve with many reporting prompt pain relief [163]. Radiographic improvement assessed by MRI may occur within a few months after treatment. Miettunen et al. performed a prospective open-label study of pamidronate administered monthly or quarterly until there was resolution of disease by MRI. The time to radiologic resolution was 2
12 months (mean of 6 months) [150]. In a retrospective review of 11 patients using a dose of 1 mg/kg (maximum 60 mg/dose) for 3 consecutive days given every 3 months for 1 year, Roderick et al. reported a good or moderately good response to pamidronate in 73% of patients as defined by improvement on MRI [161]. TNF inhibitors have also been used as second-line agents in CRMO. There are no large case series. Overall, the response is mixed with about two-thirds documenting clinical improvement and the rest reporting no improvement [163]. Infliximab and adalimumab appear to be the preferred agents although improvement with etanercept has also been reported [49,86,91,108,147,151,152,154,164
169]. Zhao et al. have advocated a more aggressive approach to treatment using methotrexate and infliximab in combination with zoledronic acid [92]. There is very limited information on the use of IL-1 inhibitors or other biologics in CRMO.

PROGNOSIS Prognosis is mixed. The literature suggests that most children have multiple recurrences occurring over several years with ultimate resolution and most have no long-term sequelae [22,170]. However, increasingly there are reports of more severe and persistent disease. Kaiser et al. and Gikas et al. reported that 49% and 67.5% of their cohorts, respectively, had a chronic persistent course instead of a chronic recurrent course [91,171]. Jansson et al. studied 17 individuals with CRMO for at least 10 years’ duration and found radiologically active lesions in more than 50% of patients assessed by whole-body MRI [86]. Others have reported a more prolonged course of disease activity with only the minority achieving prolonged clinical remission [49,170
172]. Long-term sequelae include pathologic fractures (Fig. 15.1), vertebral collapse, residual hyperostosis, chronic arthritis, evolution into spondyloarthropathy, and clinically significant leg length discrepancies [2,5,22,24,30,49,86,90,116,170,173]; difficulty with employment, school performance, and psychologic disturbance have also been reported [22,90,170].

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42 PubMed PMID: h12375195i. Epub 2002/10/11. Wirbelsaulenmanifestationen der chronischen rekurrierenden multifokalen Osteomyelitis (CRMO). ger [127] Fritz J. The contributions of whole-body magnetic resonance imaging for the diagnosis and management of chronic recurrent multifocal osteomyelitis. J Rheumatol 2015;42 (8):1359
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32 PubMed PMID: h18841069i. Epub 2008/10/09. eng [135] Al-Saad K, Thorner P, Ngan BY, Gerstle JT, Kulkarni AV, Babyn P, et al. Extranodal Rosai
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8 PubMed PMID: h16211443i. Epub 2005/10/08. eng [136] Girschick HJ, Zimmer C, Klaus G, Darge K, Dick A, Morbach H. Chronic recurrent multifocal osteomyelitis: what is it and how should it be treated? Nat Clin Pract 2007;3 (12):733
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81 PubMed PMID: h17763293i. Die chronisch-rezidivierende multifokale Osteomyelitis und die tumorose Kalzinose—assoziierte Erkrankungen? [138] Demellawy DE, Chang N, de Nanassy J, Nasr A. GALNT3 gene mutation-associated chronic recurrent multifocal osteomyelitis and familial hyperphosphatemic familial tumoral calcinosis. Scand J Rheumatol 2015;44(2):170
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31 PubMed PMID: h21788901i. Epub 2011/07/27. eng [149] Miettunen PMH, Kaura D, Abou Reslan WF, Kellner JD. Effective treatment of chronic recurrent multifocal osteomyelitis (CRMO) with IV pamidronate. Arthritis Rheum 2004;50:S537. [150] Miettunen PM, Wei X, Kaura D, Reslan WA, Aguirre AN, Kellner JD. Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J 2009;7:2 PubMed PMID: h19138427i. PubMed Central PMCID: 2631594. Epub 2009/01/14. eng [151] Eleftheriou D, Gerschman T, Sebire N, Woo P, Pilkington CA, Brogan PA. Biologic therapy in refractory chronic non-bacterial osteomyelitis of childhood. Rheumatology 2010;49(8):1505
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5 author reply 5. PubMed PMID: h19187751i. Epub 2009/02/04. eng [157] Yamazaki Y, Satoh C, Ishikawa M, Notani K, Nomura K, Kitagawa Y. Remarkable response of juvenile diffuse sclerosing osteomyelitis of mandible to pamidronate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104(1):67
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12.

Chapter 16

Kawasaki Disease J. Anton1 and R. Cimaz2 1

Pediatric Rheumatology Unit, Hospital Sant Joan de De´u, Universitat de Barcelona, Barcelona, Spain, 2A. Meyer Children’s Hospital and University of Florence, Florence, Italy

INTRODUCTION Kawasaki disease (KD) is an acute febrile systemic vasculitis that affects small and medium-sized vessels usually occurring in children younger than 5 years [1]. It is the most frequent cause of pediatric acquired heart disease in North America, Europe, and Japan [2]. The etiology remains unknown, although epidemiological and clinical features strongly suggest an infectious cause in genetically predisposed subjects. There is an activation of immune system and marked production of many proinflammatory cytokines and chemokines by activated cells [3]. The disease is self-limited but when coronary arteries are involved, sudden death in the acute phase and myocardial ischemia are life-threatening complications. Administration of intravenous immunoglobulins (IVIGs) in the first 10 days after disease onset has significantly reduced the risk of cardiac damage, from 20% to 35% of untreated patients up to 5%, and the mortality rate to approximately 0.1% in the United States and Japan [4]. KD is a systemic vasculitis and all blood vessels may eventually be involved, and aneurysms and thrombotic occlusion may develop in other arteries, mainly the brachial and internal iliac arteries, but also in axillary, subclavian, celiac, mesenteric, femoral, aorta, and renal arteries [5,6]. In the acute phase, high-dose IVIG (2 g/kg) has been proven to prevent coronary artery aneurysms (CAAs) when given within 10 days from the onset of fever. However, 10 20% of KD patients do not respond to IVIG and require additional treatment. In refractory cases, corticosteroids have shown to induce defervescence and prevent coronary artery lesions without severe effects [7,8]. Infants younger than 6 months often display an atypical or incomplete disease, being difficult to differentiate with other infantile febrile illnesses with rash [9].

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00016-5 © 2016 Elsevier B.V. All rights reserved.

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EPIDEMIOLOGY The prevalence of KD differs substantially among countries. It is more prevalent in Asian countries, especially in Japan, although it is reported in more than 60 countries and in all continents and is increasingly recognized in many resource-limited countries [10]. In Japan, the annual incidence has increased to 265 per 100,000 children under 5 years old [11]. The prevalence in Korea, Hong Kong, and Taiwan are half, third, and third of that in Japan, respectively [12]. In North America, Australia, and Europe, the current incidence of KD is 4 25/100,000 children under 5 years. In these regions, the incidence increased until the last decade, partly probably due to a higher awareness and better diagnoses, when it appears to have largely plateaued. Most European countries report an incidence ,16/100,000 (3.6 6.9 cases per 100,000) [10]. In the United States the data suggest an incidence between 17.5/100,000 and 20.8/100,000 [13], while in Ontario, Canada, it increases to 27.5/100,000 [14]. In Hawaii, where around half the population is of Asian ancestry, the incidence, though higher than in the United States, is lower than in Japan. That supports the assumption that both genetic predisposition and environmental factors are critical in KD. Moreover, distinct seasonality has been described in different countries. In Japan, peaks in January and July have been reported while in mainland United States, Canada, and Europe peaks are more common in winter months, although KD must be present at any time during the year. KD mainly affects children aged 1 5 years (85%) with an average age of approximately 2 years. It is more common in boys than in girls with a male/female ratio of 1.6 to 1 [15]. The peak incidence age is lower in Japanese (9 11 months) than in North American children (2 years) with a few cases at the extreme ages of childhood, and in young adulthood [15]. In adults, KD usually has an atypical onset and seems to occur more frequently in patients with human immunodeficiency virus [16]. KD in infants younger than 6 months is rare, and these children are possibly at high risk of CAA [9].

ETIOLOGY The etiology of KD remains unknown despite almost 50 years passing since its first report [17]. An infectious origin or trigger is suspected and previous studies have proposed several viral or bacterial candidates, but no one has been determined as the proper cause of the disease [15]. Besides, no correlation has been found among the presence or absence of any specific agent at disease onset and the response to treatment or the outcome of coronary disease [18]. The peak incidence in early childhood and the virtual absence in adulthood suggest that a microbe causing an asymptomatic infection in most individuals could be a possible trigger, with acquired immunity by adulthood. Moreover, the rarity of illness in infants in the first months of life

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supports passive protection by maternal antibodies. The clinical pattern of KD (fever, exanthema, conjunctivitis, lymph node enlargement, and mucositis) closely resembles a bacterial or viral infection of childhood such as scarlet fever. Among other common infantile febrile diseases, adenoviral infection is characterized by prolonged fever, conjunctivitis, lymphadenopathy, and mucous membrane changes, high erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) and may closely mimic KD, especially in infants [19,20]. It has been suggested that variations in the normal intestinal flora induced by environmental factors induce a hyperimmune reaction in children who are genetically susceptible [21]. Recently markedly increased amounts of Streptococcus spp. have been observed in the gut microbiota of acute phase KD patients and it is thought that this difference in microbiota composition might be related to KD pathogenesis [22]. In a challenging study, analyses of the three major KD epidemics in Japan, major nonepidemic interannual fluctuations of KD cases in Japan and San Diego, and the seasonal variation of KD in Japan, Hawaii, and San Diego, reveal a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific [23]. Although similar associations have not been observed in other areas, like Canada [24], an association with northern desert winds in Chile has been reported [25]. These results suggest that the environmental trigger for KD could be a wind-borne agent originated in China. Recently air sampling of the troposphere has shown a high density of spores from Candida albicans [26]. In fact exposure to the C. albicans water-soluble fraction has been shown to induce vasculitis and coronary arteritis in animal models of KD [27], as has exposure to the Lactobacillus bacterial cell wall [28], and immunization with bacillus Calmette-Gue´rin [29]. The high incidence in some Asian countries (Japan, China, Korea, etc.) and the increased risk in siblings of cases suggest that host genetic factors are important in the pathogenesis of KD. Genome-wide association studies for susceptibility genes in the pathogenesis of KD, IVIG resistance, and the development of coronary arterial lesions has pointed to several plausible loci. In the largest study to date, involving 2173 individuals with KD and 9383 controls from 5 independent sample collections, 2 variants exceeded genome-wide significance: a nonsynonymous polymorphism in a high affinity receptor for immunoglobulin G (FCGR2A) and variants in the region of the T-cell regulator ITPKC 8 (inositol 1,4,5-trisphosphate 3-kinase C) [30]. ITPKC variant (rs28493229) has functional consequences, markedly enhancing [Ca2+], acting as negative regulator of T-cell activation through the Ca2+/nuclear factor of activated T cells (NFAT) signaling pathway, and it is thought that the C allele may contribute to immune hyperreactivity in KD [31]. The involvement of the FCGR2A locus may have implications for understanding immune activation in KD pathogenesis and the mechanism of

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response to IVIG, currently the main treatment in these patients. A metaanalysis suggests that the H131R polymorphism in the FCGR2A gene might be associated with susceptibility to KD in Asians [32]. Other potential susceptibility genes including genetic polymorphisms of CASP3, the transforming growth factor-β signaling pathway, B lymphoid tyrosine kinase, KCNN2, and an imbalance of T helper type 17 cells (Th17)/regulatory T cells (Treg) have been proposed [33]. KD has some similarities to toxin-mediated diseases, both from a clinical and from an immunological point of view. The role of one or more superantigens capable of stimulating large numbers of T cells produced by certain strains of Staphylococcus or Streptococcus has been the subject of several investigations with conflicting results and no general agreement [34].

PATHOGENESIS One of the most accepted theories about pathogenesis in KD suggests that the disease may be caused by an infectious agent, probably a virus, which is inhaled by a genetically susceptible host. This nonidentified agent infects medium-sized ciliated bronchial epithelial cells, it is engulfed by tissue macrophages, and it starts an innate immune response with subsequent infiltration of macrophages, antigen-specific T lymphocytes, and IgA plasma cells. The presence of IgA plasma cells in arterial tissues from patients with KD and the antigen-driven IgA response directed at cytoplasmic inclusion bodies in tissues of these patients supports these theories [35,36]. Activation of the immune system is an evident characteristic of KD, and concentrations of proinflammatory cytokines and chemokines are being studied in patients with KD [3]. Many studies of cytokine networks in KD show an increase in inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-2, IL-6, IL-8, and chemokines such as monocyte chemotactic protein-1, although mechanisms that induce aberrant immune function or overexpression of inflammatory cytokines are not clear [37]. It has been suggested that Th17/Treg imbalance is involved in KD pathogenesis. Th17 cells play a critical role in the development of autoimmunity and allergic reactions by producing IL-17, while CD4+ CD25+ Tregs have an anti-inflammatory role. IL-17 induced by Th17 cells have proinflammatory properties and act on inflammatory cells, thereby inducing expression of cytokines and chemokines and resulting in tissue inflammation [38]. Initially, activated inflammatory cells, particularly monocytes, macrophages, T cells, and, later in the disease, platelets adhere to the endothelial cells that line medium-sized elastic arteries. The endothelium expresses surface molecules that allow leukocytes and platelets to adhere and some of the adherent inflammatory cells penetrate the vessel wall. Local expression of mediators attracts further inflammatory cells and increase vessel permeability.

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Other mediators contribute to destruction of the extracellular matrix, leading to vessel dilatation, and subsequent smooth muscle proliferation in the media contributes to later pathology. The predilection for the coronary artery damage is not understood, but it may partly reflect local flow dynamics [15]. Coronary arteritis due to KD develops on days 6 8 after onset. All layers of arteries are inflamed around day 10 after onset. Arterial dilatation starts around day 12 after onset. Usually inflammation subsides around day 40 [12]. Three linked processes underlying the arteriopathy have been proposed in KD vasculopathy: necrotizing arteritis, subacute chronic vasculitis, and luminal myofibroblastic proliferation [39]. Necrotizing arteritis begins at the luminal endothelium, driven by neutrophil-mediated necrosis of the intima, media, and part of the adventitia. It is essentially complete in the first 2 weeks after fever onset, but large saccular aneurysms can be formed. These rarely rupture, but more commonly fill with layers of thrombus, potentially resulting in worsening ischemia or myocardial infarction. Thrombus layers adjacent to the residual adventitia can calcify, and thrombi might recanalize. Subacute chronic vasculitis, and luminal myofibroblastic proliferation also starts during the first 2 weeks of disease, but persist for months and years. Subacute chronic arteritis begins in the adventitia and progresses toward the lumen. The infiltrate consists of lymphocytes, plasma cells, and eosinophils. Subacute chronic arteritis usually leaves some intact media and can result in fusiform arterial dilatation. Finally, luminal myofibroblastic proliferation involves proliferation of medial smooth muscle cell-derived myofibroblasts and build-up of their matrix products, potentially resulting in progressive arterial stenosis with or without thrombosis [40].

CLINICAL MANIFESTATIONS The typical clinical manifestations of KD are high fever lasting more than 5 days without reasonable explanation and unresponsive to antibiotics and four or more of the five principal clinical features: (1) bilateral nonexudative bulbar conjunctivitis, (2) cervical nonsuppurative lymphadenopathy, usually bilateral (with at least one lymph node larger than 1.5 cm), (3) polymorphous exanthema, which affects predominantly the trunk, often erythematous, maculopapular rash, but occasionally scarlatiniform or erythroderma (but no bullous or vesicular), (4) changes in lips and oral cavity (erythema, fissured lips, redness of oral and pharyngeal mucosa, strawberry-like tongue), and (5) changes in extremities (early stage: erythema of palms and soles, edema of the hands and feet; subacute phase: periungueal peeling of fingers and toes around second and third weeks of disease). Figs. 16.1 16.4 are representative examples of such manifestations. Symptoms are not all present at onset and evolve over the first 10 days then gradually resolving in most children. Even in absence of the specific treatment fever usually resolves in 2 4 weeks.

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FIGURE 16.1 Exfoliative desquamation of foot.

FIGURE 16.2 Morbilliform macular trunk rash in an infant.

Other clinical findings besides the classical diagnostic criteria are common and may help in the diagnosis, like gastrointestinal manifestations (vomiting, diarrhea, abdominal pain) seen in one-third of patients, marked irritability (reflecting an aseptic meningitis), urethritis, or jaundice [2,41]. The presence of uveitis can provide additional support to the diagnosis in patients with incomplete KD, and ocular evaluation with slit-lamp examination has been recommended to be included as a part of the work-up of any

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FIGURE 16.3 Strawberry-like tongue in an infant.

FIGURE 16.4 Reddening and cracking of the lips in an infant.

suspected patient [42,43]. Other findings such as sensorineural hearing loss, transient or permanent, and facial paralysis are more rare [3]. Arthritis and arthralgia may be observed in the acute phase and in the convalescent phase, and affect both small and large joints [44]. Those patients who have been vaccinated with Bacille Calmette-Guerin develop induration and erythema at the site where it was administered [45]. For the diagnosis of complete KD, fever of 5 days duration plus four of the five principal criteria are required, or the presence of fever with less than four principal criteria if CAA are detected on echocardiogram or

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TABLE 16.1 Kawasaki Disease: Diagnostic Criteria Fever: Duration of 5 days and the presence of at least four of the principal features 1. Conjunctivitis

Bulbar, nonsuppurative, bilateral

2. Lymphadenopathy

Cervical .1.5 cm, usually unilateral

3. Erythematous rash

Polymorphous, nonvesicular, or bullous

4. Changes in lips and oral mucosa

Red cracked lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosa

5. Changes of extremities

Acute phase: Erythema of palms, soles; edema of hands, feet Subacute phase: Periungueal peeling of fingers, toes in weeks 2 and 3

Kawasaki disease may be diagnosed with fever at least 5 days and less than 4 or the principal criteria if coronary artery aneurysms are detected by echocardiography or angiography. In the presence of . 4 principal criteria, Kawasaki disease diagnosis can be made on day 4 of illness. Experienced clinicians who have treated many Kawasaki disease patients may establish diagnosis before day 4.

angiography (Table 16.1) [46]. In the 2006 EULAR (European League Against Rheumatism)/PReS (Pediatric Rheumatology European Society) endorsed consensus criteria for the classification of childhood vasculitides perineal desquamation was added to the criterion describing changes in the extremities [1]. Recurrence of skin peeling after the disease recovery does not mean recurrence of the disease and does not require IVIG retreatment, as it may be also observed in a number of other conditions caused by infectious agents and their toxins [47].

Atypical and Incomplete Kawasaki Disease Incomplete KD patients are those with suspected KD who do not fulfill the diagnostic criteria, and whose diagnosis is made based on coronary artery abnormalities. The term atypical KD should be reserved for patients who have symptoms that are not common in classical KD, such as fever for more than 5 days along with, for example, renal impairment, acute surgical abdomen (eg, appendicitis, acute pancreatitis), neurological manifestations (eg, seizures, facial palsy), or pleural effusion. The characteristic clinical findings may not develop or may develop over time [2]. An early diagnostic and starting treatment before day 10 of disease decrease significantly the risk of artery aneurysms. There have been proposals to add laboratory tests and minor clinical signs in diagnosing children with KD [48,49].

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LABORATORY FINDINGS Laboratory findings are not specific for KD, as they are shared by other acute inflammatory febrile diseases. Early in the course of illness all parameters of inflammation are increased, namely ESR, CRP, white blood cell (WBC) and neutrophil counts. Platelet count is normal in the acute phase and markedly increases at the end of the second week, reaching 1,000,000 mm21 [3] in the most severe cases. A low platelet count may be detected in approximately 10% of patients in the acute phase and may correlate with a poor prognosis. About 50% of patients develop anemia with hemoglobin concentrations ,2 SD below the mean for age. Urinalysis may show leukocytes and erythrocytes but no bacteria. Cerebral fluid contains increased numbers of WBC, mainly lymphocytes, as expression of aseptic meningitis. Hyponatremia frequently occurs in patients displaying a more aggressive disease; its pathogenesis remains unclear although several mechanisms have been postulated, including the syndrome of inappropriate antidiuretic hormone secretion [50]. In several patients liver enzymes and bilirubinemia are significantly elevated; jaundice and hydrops of gallbladder are relatively uncommon, and abdominal ultrasound may be helpful in detecting this complication, which may support in the acute phase the diagnosis of atypical or incomplete KD [51]. In the subacute phase changes of serum lipid profiles are detected, with increased levels of triglycerides and low-density lipoproteins, and reduced high-density lipoproteins that usually normalize within a few weeks after IVIG therapy. An abnormal serum lipid profile after several years of KD has been described. The most reported abnormal lipid profile in individuals with a previous history of KD is decreased serum HDL-C level; however, other studies did not show these differences [52]. A specific laboratory test for the diagnosis of KD does not exist. However, serum levels of NT-proBNP have been postulated as a useful marker for the diagnosis of KD. The plasma NT-proBNP level was elevated in patients with KD in the acute phase, whereas it was only mildly elevated in febrile control patients. Moreover, it seems that serum levels of NTproBNP can be used in the prediction of a patient’s sensitivity to IVIG treatment [53,54].

TREATMENT The current treatment regimen in any patient with definite or suspected KD includes IVIG (2 g/kg) as a single infusion over 8 12 hours and aspirin (ASA) (50 100 mg/kg in four divided doses) [2]. The prevalence of coronary artery abnormalities is dependent on IVIG dose but independent from that of ASA [55]. In patients with cardiac compromise who may not tolerate the fluid challenge associated with a single infusion, divided doses over several days may be appropriate. IVIG should be administered as soon as the disease is suspected, and possibly within the first 10 days from the onset of fever. However,

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in presence of persistent signs of inflammation IVIG must be given even in patients who are diagnosed later than 10 days from onset. After the acute phase has resolved and platelet count rises, the dose of ASA is reduced to 3 5 mg/kg per day as inhibitor of platelet function. In the absence of cardiac complications, low-dose aspirin is maintained for at least 6 8 weeks until a follow-up ultrasound rules out coronary involvement. Long-term treatment is required in children with coronary alterations up to normalization of aneurysms, and long-life therapy is needed if they persist [2]. Around 9 23% of patients do not respond to a single dose of IVIG. Patients are considered to have refractory disease if they develop or continue to have a fever within 36 hours of the IVIG infusion. In these children a second infusion of IVIG (2 g/kg) is advised [2]. There is no agreement about how to treat the small group (3 4%) still remaining febrile. No efficacy data exist today to support administering a third dose of IVIG therapy [56]. For those unresponsive, there are other optional therapies that have been effective in series of cases. An initial report of the use of corticosteroids reported a high rate of coronary alterations [57]. However it was an uncontrolled, nonrandomized study, with small sample size and without comparison of baseline characteristics (including echocardiography). Since then several studies have shown that additional IVIG combined with steroids appears to be safe in acute KD unresponsive to initial IVIG treatment [7]. Moreover, another study shows that IV methylprednisolone followed by prednisone may prevent coronary artery lesions without severe effects [8]. In 2013 a metaanalysis that analyzed nine clinical studies concluded that IVIG plus corticosteroids as initial treatment reduced the risk of coronary aneurysms in KD [58]. Nowadays the question is if we must give steroids to all KD patients, or if we must give them only to those patients refractory to initial treatment (after the first or second dose IVIG failure). That means adding steroids to IVIG in all the patients, or adding them only to those patients in whom we expect a bad response to initial treatment (those with higher risk of coronary artery aneurisms). Different predictive models designed to evaluate the possibility of IVIG resistance have been proposed, including the Kobayashi score [59], the Egami score [60], and the Sano score [61]. For those still unresponsive, treatments with anti-TNF have been suggested (etanercept, and mostly infliximab) [62]. Cyclosporine has been proposed as a third-line treatment in IVIG-resistant patients [63]. Recently anakinra, an IL-1 receptor antagonist, has reported as a treatment in severe refractory KD patients [64,65]. In children with aneurysms the American Heart Association’s (AHA) guidelines for KD diagnosis and treatment divide risk and the therapeutic management into five categories. Risk level I: no coronary abnormalities at any time of KD, risk level II: transient coronary artery ectasia or dilatation, risk level III, isolated (solitary) small to medium-sized (3 6 mm) CAA in one or more coronaries, risk level IV: one or more large ( . 6 mm) or giant

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(.8 mm) CAAs and/or multiple or complex aneurysms without obstruction, and risk level V: coronary artery obstruction and/or myocardial ischemia [2]. A metaanalysis of the published long-term follow-up studies of children treated with anticoagulation therapy and aspirin or aspirin alone demonstrates a significantly lower incidence of death in children with giant CAA treated with warfarin plus aspirin as compared to those treated with aspirin alone. Furthermore, there was a significantly lower incidence of coronary artery occlusion in patients treated with warfarin plus aspirin as compared to those treated with aspirin alone, and a significantly lower incidence of myocardial infarction [66]. In children with severe cardiac sequelae surgical options (eg, percutaneous transluminal coronary angioplasty, coronary bypass grafting, and cardiac transplantation) also need to be considered.

Vaccinations Passively acquired antibodies administered with IVIG may interfere with the serologic response to active immunization. So, it is recommended to defer live-attenuated vaccines after IVIG administration. However there is no clear consensus about the appropriate time interval. In Japan, an interval of 6 7 months is recommended while the International Guidelines of the Advisory Committee on Immunization Practices and the American Academy of Pediatrics advise measles vaccination after an interval of more than 11 months post-IVIG. However several studies suggest postponing the MMR vaccination to at least 9 months after IVIG administration [67,68].

FOLLOW-UP All patients with typical or suspected KD have to be closely monitored with electrocardiogram (ECG) and echocardiography. ECG can reveal arrhythmia, myocardial dysfunction, and ischemia. Echocardiography is useful in detecting pericardial effusion, valvular inflammation and regurgitation, and coronary artery dilatation and aneurysms, which may be revealed by ultrasound also in peripheral arteries [6]. After baseline echocardiography during the acute phase of illness, the 2004 AHA recommendations advise repeating echocardiography at 2 weeks and at 6 8 weeks after illness [2]. In children with transient coronary artery alterations, ultrasound control up to normalization is recommended, although most of cardiac complications repair without further abnormalities; the coronary damage as first revealed by the wall brightness may progress to either ectasia or aneurysms [69]. Patients with persistent or remodeled coronary aneurysms after KD are at risk of complications including thrombosis or stenosis leading to myocardial infarction, and require a follow-up by cardiologists. Moreover, a review of acute coronary syndrome in 50 Japanese adults with a history of aneurysms due to prior KD pointed to the persistent risk of thrombosis also in arterial

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segments with regressed aneurysms, so these patients remain having an increased risk for thrombosis and should be followed closely [70]. In contrast to aneurysms (diameter of coronary lumen $ 4 mm) that may regress in size and restore over time, giant aneurysms (GAs) (diameter of coronary lumen $ 8 mm) rarely improve, becoming stenotic in up one-third of patients. In these cases myocardial ischemia may develop, leading to myocardial infarction and sudden death even in early adulthood [2,71]. Therefore GAs, a potential risk for rupture in the acute phase or subsequent thrombosis due to the stasis of blood flow and the procoagulant endothelial surface of inflamed vessels, are major concerns in KD and raise the dilemma of long-term anticoagulation in children, especially in infants [72]. There are conflicting studies regarding whether or not patients with KD are at risk of accelerated atherosclerosis. The vasculopathy of KD appears to be different from that of atherosclerosis; however, some authors suggest that statins could have benefits in these patients [73]. It is unclear also if these patients even without coronary involvement have vascular stiffening in the aorta and arteries [73].

Cardiac Imaging Echocardiography still remains the gold standard in the early cardiac assessment of KD children and in detecting CAA of proximal right and left coronary arteries. CAA are diagnosed by echocardiography during the acute or subacute phase of the disease. CAA are traditionally classified according to the definitions of the Japanese Ministry of Health: a luminal diameter of .3 mm in children ,5 years of age, .4 mm in children $ 5 years of age, or a diameter 1.5 times the size of an adjacent segment or an irregular lumen in children $ 5 years of age. A GA is defined as an aneurysm with an internal diameter of $ 8 mm or a diameter .4 times that of an adjacent segment in children $ 5 years old [12]. However, adjustments for body-surface area, z-scores, seem a better indicator of any serious enlargement. Using this approach, a z-score of $ 2.5 is considered an aneurysm and a z-score of $ 10 is a GA [74]. Besides echocardiography, other methods are needed in order to better visualize in detail the entire coronary artery system. There are no evidencebased guidelines for cardiovascular assessment of KD patients [75]. But two consensus guidelines for follow-up of KD patients with CAA have been published, one by the AHA in 2004, and one by the Japanese Circulation Society (JCS) in 2014 [2,12]. The AHA advises for children with small to medium aneurysms an annual routine follow-up and biennial stress testing with myocardial nuclear perfusion scans. If there are large and/or multiple or complex aneurysms within one artery, the AHA recommends an invasive coronary angiography to be performed routinely 6 12 months after the disease onset and repeated if the noninvasive stress test or clinical signs suggest

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myocardial ischemia [2]. The JCS recommends for those patients with small aneurysms at 30 days after the disease onset to perform an echocardiogram and ECG every 3 months until the dilatation has disappeared. For those patients with medium-sized aneurysms they propose an ECG (with exercise), and echocardiography until dilatation is no longer observed. And for those patients more than 10 years after onset, they propose a magnetic resonance coronary angiography, or if not possible, a multidetector row computed tomography [12]. Both guidelines recommend for those patients with large CAA a follow-up in a risk-stratified manner with additional imaging modalities. In the last years other techniques have been proposed such as cardiac MRI (that provides clinically relevant information about myocardial ischemia, infarction, inflammation, and function), low-dose radiation CT angiography with prospective ECG triggering (that permits to diagnose all CAA detected with ultrasound plus the more distal aneurysms and dilatations) [76], or CT calcium scoring. CT calcium scoring, a technique without intravenous contrast that measures calcification in the coronary arteries, has been proposed as a useful technique for risk-stratification, but exact clinical implication of small coronary artery calcifications is still unknown [77].

OUTCOME The recurrence rate in Japanese children is higher, up to 3.6%, than in Caucasians, less than 1%. Patients with a family history of KD accounted for 1.6% of all patients [12]. The second episode of KD carries a higher risk of coronary damage [78]. Siblings of patients with KD have a significantly greater chance of acquiring the disease than do children in the general population [79]. Japanese patients with a family history of KD were more likely to have a more aggressive disease, being more prone to develop recurrent KD, to receive additional doses of IVIG, and to have CAA [80]. In the Japanese 2009 2010 nationwide survey cardiovascular sequelae included coronary dilatation in 1.90%, aneurysms in 0.78%, valvular lesions in 0.29%, GA in 0.22%, coronary stenosis in 0.03%, and myocardial infarction in 0.02%. The incidence rate of GA was about threefold higher in males than in females. Nonvascular complications include bronchitis/pneumonia in 2.58%, severe myocarditis in 0.16%, encephalitis/encephalopathy in 0.09%, tachyarrhythmia in 0.07%, and macroscopic hematuria in 0.04% [81]. Patients less than 1 year of age and those older than 9 years of age were more likely to have coronary artery abnormalities than were patients diagnosed between 1 and 4 years of age. Patients diagnosed between the ages of 5 and 9 years were at the lowest risk. Patients at both extremes of the age spectrum were more likely to present with less than four of the classic KD features. Although the increase of coronary risk in children younger than 6 months is more likely related to pathophysiological factors and in children older than 9 years with delays in the diagnosis and appropriate treatment [82].

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The risk of coronary aneurysms is highest among children who are male, those at the extreme of age, those who have persistent fever despite treatment with IVIG, and those not treated with IVIG after 10 days since disease onset [83]. It is not clear, as some authors suggest, whether early treatment (between 4 and 7 days since onset of fever) could be related with a better outcome. Regarding adult patients, although the mortality rate for young adults without cardiac sequelae look the same as the general population, young adults with cardiac sequelae have a higher mortality rate [84]. There are concerns about vascular health in KD patients after several years. Recently a study in North American children and young adults demonstrated that KD patients whose maximum CA dimensions were either always normal or mildly ectatic have normal vascular health indexes (endothelial function, intima-media thickness of the right common carotid artery and the left common carotid artery, fasting lipid profile, and C-reactive protein) [85].

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[46] Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, Kiyosawa N, et al. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int 2005; 47(2):232 4. [47] Michie C, Kinsler V, Tulloh R, Davidson S. Recurrent skin peeling following Kawasaki disease. Arch Dis Child 2000;83(4):353 5. [48] Burns JC, Glode´ MP. Kawasaki syndrome. Lancet 2004;364(9433):533 44. [49] Simonini G, Rose CD, Vierucci A, Falcini F, Athreya BH. Diagnosing Kawasaki syndrome: the need for a new clinical tool. Rheumatology 2005;44(8):959 61. [50] Lim GW, Lee M, Kim HS, Hong YM, Sohn S. Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion in Kawasaki disease. Korean Circ J 2010;40(10): 507 13. [51] Falcini F, Resti M, Azzari C, Simonini G, Veltroni M, Lionetti P. Acute febrile cholestasis as an inaugural manifestation of Kawasaki’s disease. Clin Exp Rheumatol 2000;18(6):779 80. [52] Mostafavi SN, Barzegar E, Manssori NS, Kelishadi R. First report on the lipid profile late after Kawasaki disease in Iranian children. Int J Prev Med 2014;5(7):820 4. [53] Ye Q, Shao WX, Shang SQ, Zhang T, Hu J, Zhang CC. A comprehensive assessment of the value of laboratory indices in diagnosing Kawasaki disease. Arthritis Rheumatol 2015;67(7):1943 50. [54] Lin KH, Chang SS, Yu CW, Lin SC, Liu SC, Chao HY, et al. Usefulness of natriuretic peptide for the diagnosis of Kawasaki disease: a systematic review and meta-analysis. BMJ Open 2015;5(4):e006703. [55] Terai M, Shulman ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Pediatr 1997;131(6):888 93. [56] Saneeymehri S, Baker K, So TY. Overview of pharmacological treatment options for pediatric patients with refractory Kawasaki disease. J Pediatr Pharmacol Ther 2015;20(3): 163 77. [57] Kato H, Koike S, Yokoyama T. Kawasaki disease: effect of treatment on coronary artery involvement. Pediatrics 1979;63(2):175 9. [58] Chen S, Dong Y, Yin Y, Krucoff MW. Intravenous immunoglobulin plus corticosteroid to prevent coronary artery abnormalities in Kawasaki disease: a meta-analysis. Heart 2013;99(2):76 82. [59] Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 2006;113:2606 12. [60] Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr 2006;149:237 40. [61] Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, et al. Prediction of nonresponsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr 2007;166:131 7. [62] Research Committee of the Japanese Society of Pediatric Cardiology; Cardiac Surgery Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease. Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version). Pediatr Int 2014;56(2):135 58.

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[80] Uehara R, Yashiro M, Nakamura Y, Yanagawa H. Clinical features of patients with Kawasaki disease whose parents had the same disease. Arch Pediatr Adolesc Med 2004; 158:1166 9. [81] Nakamura Y, Yashiro M, Uehara R, Sadakane A, Tsuboi S, Aoyama Y, et al. Epidemiologic features of Kawasaki disease in Japan: results of the 2009 2010 nationwide survey. J Epidemiol 2012;22:216 21. [82] Manlhiot C, Yeung RS, Clarizia NA, Chahal N, McCrindle BW. Kawasaki disease at the extremes of the age spectrum. Pediatrics 2009;124(3):e410 15. [83] Kavey RE, Allada V, Daniels SR. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 2006;114(24):2710 38. [84] Nakamura Y, Aso E, Yashiro M, Tsuboi S, Kojo T, Aoyama Y, et al. Mortality among Japanese with a history of Kawasaki disease: results at the end of 2009. J Epidemiol 2013;23(6):429 34. [85] Selamet Tierney ES, Gal D, Gauvreau K, Baker AL, Trevey S, O’Neill SR, et al. Vascular health in Kawasaki disease. J Am Coll Cardiol 2013;62(12):1114 21.

Chapter 17

IgA Vasculitis (Henoch Scho¨nlein Purpura), Polyarteritis Nodosa, Granulomatous Polyangiitis (Wegener Granulomatosis), and Other Vasculitides S. Ozen and Y. Bilginer Department of Pediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey

INTRODUCTION Vasculitis is the inflammation of blood vessels. This inflammation is characterized by the infiltration of the vessel wall with inflammatory cells. The vasculitis syndromes present their features according to the vessel size they affect. In some vasculitic syndromes only one vessel size is affected whereas all sizes can be affected in some, such as Behc¸et’s disease. Focal lesions may cause aneurysm formation whereas segmental lesions may cause stenosis or occlusion [1]. The consequence of the inflammation of the vessel leads to infarction, ischemia, or hemorrhage or dysfunction of the affected tissue. The inflammatory mediators induce further compromise. Vasculitis may be primary or secondary to another associated disease or condition such as the vasculitis of systemic lupus erythematosus (SLE) or a vasculitis secondary to meningococcemia [2]. Primary vasculitides will be the primary focus of this chapter. Vasculitis in children is overall more frequent than in adults. However, the most common vasculitic syndromes in children are the self-limited vasculitides such as IgA vasculitis (IgAV) (Henoch Scho¨nlein purpura (HSP)) and Kawasaki disease. The distribution of vasculitides may vary with geographical Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00017-7 © 2016 Elsevier B.V. All rights reserved.

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distribution, as is the case in adult cases. Evidence from the adult rheumatology literature suggests that environmental factors may be responsible for this distribution and that this reflects the interplay between environment and genes [3].

CLASSIFICATION For more than 50 years, rheumatologists have tried to decide on the best classification criteria for the vasculitic syndromes. The most widely used set of criteria used in adults has been the ACR (American College of Rheumatology) criteria for classification. These criteria have not been validated in children and they are based on adult experience only. In 2005, a pediatric set of criteria was suggested with the endorsement of EULAR (European League against Rheumatism) and PRES (Pediatric Rheumatology European Society), with the participation of members of the ACR (American College of Rheumatology) and ESPN (European Society of Pediatric Nephrology) [4]. This paper defines a working classification of childhood vasculitides as well as a set of criteria for the common vasculitis syndromes seen in childhood. These criteria have subsequently been validated in a large pediatric registry. Finally the EULAR/ PRINTO/PRES (Ankara 2008) criteria for Henoch Scho¨nlein purpura (HSP), childhood polyarteritis nodosa (PAN), childhood Wegener granulomatosis (WG), and childhood Takayasu arteritis (TA) have been published and hence have been used by the pediatric community [5]. The Chapel Hill nomenclature criteria has recently been revised (Table 17.1).This chapter will discuss the common vasculitides of childhood in this context and present the new classification criteria for these four vasculitides with the new terminology. Kawasaki Disease will be presented elsewhere.

COMMON VASCULITIDES IN CHILDREN IgA Vasculitis/Henoch Scho¨nlein Purpura IgAV (HSP) is the most common form of vasculitis of childhood in many geographical areas [6]. It is a syndrome characterized by palpable purpura, arthritis and/or arthralgia, abdominal pain, and glomerulonephritis. It is a small vessel vasculitis, mediated by immunoglobulin-A containing immune complexes (Table 17.1).

Epidemiology IgAV (HSP) is predominantly a disease of childhood. It has an incidence of 10.2 20.4 per 100,000 children [7 9]. In a study from United Kingdom the incidence was 70.3 per 100,000 in the 4- to 6-year age group [7]. Although it is rare in children younger than 2 years, it has been reported in patients as

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TABLE 17.1 2012 Revised International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides [2] Large vessel vasculitis Giant cell arteritis Takayasu arteritis

Medium vessel vasculitis Kawasaki disease Polyarteritis nodosa

Small vessel vasculitis Antineutrophil cytoplasmic antibody-associated vasculitis Granulomatosis with polyangiitis (Wegener’s) Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis Immune complex small vessel vasculitis Antiglomerular basement membrane disease Cryoglobulinemic vasculitis IgA vasculitis (Henoch Scho¨nlein) Hypocomplementemic urticerial vasculitis (anti-C1q)

Variable vessel vasculitis Behc¸et’s disease Cogan’s syndrome

Single organ vasculitis Cutaneous leukocytoclastic angiitis Cutaneous arteritis Primary central nervous system vasculitis Isolated aortitis Others

Vasculitis associated with systemic disease Vasculitis associated with probable etiology Source: Modified from Ref. [2].

young as 6 months [7,10,11]. Ninety percent of patients are younger than 10 years of age [10]. Male-to-female ratio was 1.5:1.0 in the series reported by Saulsbury [12] and Calvino et al. [13].

Etiology and Pathogenesis IgAV (HSP) is often preceded by an upper respiratory tract infection, and a wide variety of pathogens including streptococci have been implicated in the

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etiology [14]. Insect bites, exposure to drug and dietary allergens, subtle abnormalities in complement function, and immune complex clearance may play a role in the pathogenesis of IgAV (HSP) [15,16]. Saulsbury has suggested that aberrantly glycosylated immunoglobulin A1 has a role in the pathogenesis of IGAV (HSP) [17]). Patients who are predisposed to inflammation may well be more inclined to develop IgAV (HSP). This was suggested in a study from Turkey where the incidence of IgAV (HSP) in patients with familial Mediterranean fever—an autoinflammatory condition—was 2.7%, much higher than reported elsewhere [18].

Clinical Manifestations Diagnosis depends on the characteristic features of the disease: the typical nonthrombocytopenic palpable purpura (present in almost all), abdominal pain reflecting the gastrointestinal involvement (in 63 100% of the patients), arthralgia and/or arthritis (in 47 84% of the patients), and renal involvement (in 37 51% of the patients) [14,19]. According to ACR criteria, a patient is said to have IgAV (HSP) if at least two of the following criteria are present: (1) age # 20 years, (2) palpable purpura, (3) bowel angina, (4) wall granulocyte on biopsy; with a diagnostic sensitivity of 87.1% and specificity of 87.7% in adults [19]. These criteria have been revised based on the experience in childhood cases (Table 17.2). The rash is most manifest on pressure-bearing areas and extensor surfaces, especially the lower extremities and buttocks (Fig. 17.1). The typical skin finding is a palpable purpura. The lesions may range from petechiae to large echymoses to hemorrhagic bullae, and may progress in color from red to purple to brown. Cutaneous edema of the scalp and extremities is also quite typical. Arthritis and arthralgia usually affect the large joints such as knees, ankles, elbows, and wrists. Gastrointestinal involvement may precede other manifestations, and may rarely lead to intussusception, perforation, and gangrene. TABLE 17.2 EULAR/PRINTO/PRES (Ankara 2008) Henoch Scho¨nlein Purpura Criteria Purpura or petechiae (mandatory) with lower limb predominance (for purpura with atypical distribution a demonstration of an IgA deposit in a biopsy is required) and at least one of the four following criteria: Abdominal pain Histopathology Arthritis or arthralgia Renal involvement Source: From Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/ PRES criteria for Henoch-Scho¨nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;69(5):798 806.

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FIGURE 17.1 Typical purpura of Henoch Scho¨nlein purpura.

The spectrum of renal involvement ranges from microscopic hematuria and proteinuria to nephritic and/or nephritic syndrome, hypertension, and acute or chronic renal failure (see later). Other rare manifestations are isolated central nervous system (CNS) vasculitis, seizure [20], coma and hemorrhage [21], ataxia [22], neuropathy [23], pulmonary hemorrhage [24], carditis [25], and scrotal involvement [26].

Diagnostic Investigations There are no specific laboratory tests and the diagnosis is mainly a clinical one. There may be a moderate leukocytosis with a left shift. Acute phase reactants are usually mildly elevated. Serum IgA may be increased and some may have circulating immune complexes [27]. C1q, C3 and C4 levels, and antineutrophil cytoplasmic antibodies (ANCAs) are usually normal. Renal involvement often manifests as hematuria and/or proteinuria. In 5 10% of the patients the involvement is severe resulting in hypoalbuminemia and abnormal renal function test, and necessitating immunosuppression [28]. Renal biopsy is helpful in differentiating the severe renal disease from other causes: IgA deposition in the glomerular mesangium is the hallmark of IgAV (HSP) nephritis. In patients with severe abdominal pain, an ultrasound is helpful to delineate whether there is an intussusception or perforation. Stool should be examined for occult or frank blood.

Differential Diagnosis IgAV (HSP) must be differentiated from immune thrombocytopenic purpura, systemic lupus erythematosus, hemolytic-uremic syndrome, poststreptococcal glomerulonephritis, disseminated intravascular coagulopathy, and other types of vasculitis.

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Treatment The optimal management of gastrointestinal and renal involvement has not yet been determined [28]. Joint complaints respond well to nonsteroidal anti-inflammatory drugs (NSAIDs). Cutaneous manifestations are often selflimited; however they may have a relapsing pattern. Early morbidity is determined by the gastrointestinal vasculitis. The family should be cautioned against severe gastrointestinal involvement, such as frank bleeding that may be a sign of intussusception. For severe gastrointestinal involvement uncontrolled studies favor a short course of oral corticosteroids. In a randomized, double-blind, placebo-controlled study the treatment group (n = 21) received oral prednisone, 2 mg/kg per day for 1 week, with weaning over a second week, while the placebo group (n = 19) received an identical-appearing placebo [29]. There was no statistically significant difference in the rate of acute gastrointestinal complications (2/21 in prednisone group vs 3/19 in placebo group). However, two children in the placebo group did experience intussusceptions compared with none in the prednisone group. It is worth noting, however, that steroids can also mask symptoms of such intestinal complications Urinary findings such as hematuria and mild proteinuria do not require immunosuppressive treatment but should be followed closely. Clinical features of rapidly progressive glomerulonephritis and/or nephrotic range proteinuria necessitate a biopsy: .50% crescentic glomerulonephritis leads to renal failure in 50% of patients with IgAV (HSP) [27]. Thus in these patients an intensive approach with corticosteroids and oral cyclophosphamide (CYC) for 3 months has been suggested [30,31]. We do not have evidence-based data on the use of steroids in this most common vasculitis. There are no studies proving the use of steroids for mild renal disease [27]. The protective role of steroids is also debatable [19,32]. In a prospective study by Mollica et al. [32], patients without signs of nephropathy upon initial presentation entered into the study. A total of 84 patients received prednisone (1 mg/kg per day per os for 2 weeks), and 84 patients did not receive steroids. The patients were followed for 24 36 months. None of the 84 patients treated with steroids and 10 (11.9%) of the 84 control patients developed nephropathy 2 6 weeks after the acute episode. The difference in the prevalence of nephropathy between the two groups was highly significant (p , 0.001). On the other hand, in the series reviewed by Saulsbury [19], a total of 50 patients had no evidence of acute renal involvement; of these 50 patients, 20 were treated during the acute phase of the illness with corticosteroids, while 30 never received corticosteroid therapy. Delayed nephritis .3 weeks following an initial normal urinalysis occurred in 4 of 20 (20%) patients who received prior corticosteroid treatment, and in 6 of 30 (20%) patients who were not treated, thus failing to show a benefit of steroid treatment.

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We still need more data to decide on the role of therapy in this potentially self-limited disease. However, uncontrolled studies and expert opinion may suggest the following algorithm: G

G

Oral steroids (short course) indicated for: severe gastrointestinal involvement less than 50% crescent in severe clinical renal involvement testis involvement Steroids plus CYC indicated for: more than 50% crescent in severe clinical renal involvement CNS, pulmonary vasculitis.

Recently a European initiative (SHARE) has been working on developing recommendations for the management of all childhood vasculitides, which is hoped will guide pediatricians in their practice. Early morbidity and mortality is associated with gastrointestinal, CNS, and pulmonary involvement, whereas late morbidity is associated with renal involvement [27]. In a long-term study by Ronkainen et al. [33] (mean follow-up, 24.1 years), patients with significant glomerulonephritis at onset had a 4.7-fold risk of developing a poor renal outcome as compared to patients with mild abnormalities. Women were at a 2.5-fold risk for a poor renal outcome. Seventy percent of women developed pregnancy complications of hypertension and decreased renal function.

POLYARTERITIS NODOSA Jennette et al. [34] have defined PAN as necrotizing inflammation of medium- or small-sized arteries without glomerulonephritis or vasculitis in arterioles, capillaries, and venules. The criteria for PAN in childhood proposed by Brogan et al. [35] and Ozen et al. [36] were modifications of the ACR criteria [37]. Both criteria lack the presence of ANCA, which has emerged as an important marker for the disease, and were not based on a large consensus. Pediatricians have recently suggested revised criteria, where a typical angiogram finding and/or a biopsy showing small-to-medium-sized artery necrotizing vasculitis are mandatory criteria [5] (Table 17.3). The aforementioned group also defined cutaneous polyarteritis by the presence of subcutaneous nodular, painful, nonpurpuric lesions with or without livedo reticularis, with no systemic involvement (except for myalgia, arthralgia, and nonerosive arthritis), and where a skin biopsy shows necrotizing nongranulomatous vasculitis. Tests for ANCA are negative. Cutaneous polyarteritis is often associated with serologic or microbiologic evidence of streptococcal infection. No formal classification criteria were proposed beyond this definition of a clinical syndrome.

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TABLE 17.3 EULAR/PRINTO/PRES (Ankara 2008) Childhood Polyarteritis Nodosa (PAN) Criteria A child is classified as having childhood PAN if he/she has a systemic illness and has the presence of one of the following as a mandatory criterion: Biopsy showing small and mid-size artery necrotizing vasculitis Angiographic abnormalities (aneurysms or occlusions)  should include angiography if MRA is negative AND one of the five following criteria: Skin involvement Myalgia/muscle tenderness Hypertension Peripheral neuropathy Renal involvement G G

Source: From Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/ PRES criteria for Henoch-Scho¨nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;69(5):798 806.

Epidemiology PAN is rare in childhood. It occurs with approximately equal frequency in boys and in girls. The average ages of patients were 9.3 and 7.5 years in two pediatric cases [36,38]. A recent survey of 21 pediatric centers presented 110 patients classified as childhood PAN [39]. The female-to-male ratio was 56:54, and the mean age was 9.05 6 3.57 years.

Etiology and Pathogenesis The cause of PAN is unknown. Infectious agents have been associated especially with the cutaneous and classic form of the disease. The association with streptococcal infection is a remarkable feature that has been described in various pediatric patients [40,41]; this association is less common in adults [42]. On the other hand hepatitis B-associated PAN is now classified as a vasculitis associated with probable etiology [2]. ADA2 deficiency may also cause features that mimic PAN [43]. Microscopic polyangiitis is also a completely separate entity as an ANCA-associated disease.

Clinical Manifestations Children almost always have constitutional symptoms such as malaise, fever, and/or weight loss. Severe myalgia and arthralgia were present in 56 81%, whereas renal involvement was present in 65 80% of cases in the series reported by Fink et al. [44] and Ozen et al. [36]. As discussed in the classification of PAN, a number of patients do not have typical presentations of

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FIGURE 17.2 An angiogram showing aneurysms in systemic polyarteritis nodosa.

microscopic or classic PAN, but have inflammation in varying-sized arteries of skin, musculoskeletal, and other organ systems [45,46] (Fig. 17.2). Cutaneous PAN is characterized by crops of painful skin nodules and livedo reticularis and sometimes nonspecific musculoskeletal findings such as myalgia and arthralgia [42]. There is often a history of preceding streptococcal infection [40,41]. When it affects mid-size vessels, PAN frequently leads to aneurysm formation (Fig. 17.2). The main clinical feature is organ infarction occurring mostly in kidneys and gut. Hypertension due to renal artery aneurysms is a frequent manifestation in childhood patients.

Diagnostic Investigations Patients with PAN frequently have anemia, leukocytosis, thrombocytosis, and almost always elevated erythrocyte sedimentation rate (ESR) and Creactive protein (CRP). On the other hand the acute phase reactants are often normal or mildly elevated in cutaneous PAN. A urinalysis must be obtained in all cases to look for hematuria, proteinuria, and casts. Blood urea nitrogen or creatinine may be elevated. Diagnostic work-up of these patients should also include ANCA [47]. In microscopic PAN, the ANCA predominantly shows a perinuclear pattern of antibody staining using the indirect immunofluorescence technique [45,47]. An ELISA test will frequently show that the autoantibody is directed against myeloperoxidase. On the other hand ANCA is often not present in other

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forms of childhood PAN and if ANCA directed against myeloperoxidase is present, it is at low titer. Thus a negative ANCA would not exclude the diagnosis of childhood PAN. A biopsy of the involved organ system showing necrotizing arteritis or a conventional CT or magnetic resonance angiogram is indicated for definite diagnosis. Angiogram may show aneurysms or nonaneurismal changes: perfusion defects, the presence of collateral arteries, lack of crossing of peripheral renal arteries, and delayed emptying of small renal arteries [35]. The sensitivity and specificity of renal angiographic diagnosis of PAN by the finding of aneurysms was 43% (SE: 10%) and 69% (SE: 14%), respectively [35]. The sensitivity increased to 80%, and specificity fell to 50% for angiogram positivity defined as the presence of at least one of the previous nonaneurismal signs irrespective of the presence of aneurysms. Aneurysms may also be demonstrated on hepatic and mesenteric angiography, and nonaneurismal signs can be found on hepatic, mesenteric, and splenic angiography.

Differential Diagnosis PAN should be suspected in any child with fever of unknown origin, skin rash, myalgia, unexplained pulmonary, cardiovascular, nervous system or renal disease. It should be distinguished from other forms of vasculitis (HSP, WG), sarcoidosis, pulmonary-renal syndromes, relapsing polychonditis, and viral infections.

Treatment Glucocorticoid therapy (prednisone 1 2 mg/kg per day) remains the basis of treatment. In severe organ involvement intravenous pulses of methylprednisolone are indicated. Systemic disease and renal involvement necessitate CYC for induction of remission [48]. In a child the cumulative dose of immunosuppressives remains a major concern. When data from large studies were analyzed, a cumulative dose of up to 200 250 mg/kg was considered safe for most children in terms of gonadal toxicity [49]. This would be roughly equal to 3.5 months of oral CYC at a dose of 2 mg/kg per day. An intravenous route may also be employed. Thus, after 3 months, CYC is switched to azathioprine if remission is achieved. Switching to azathioprine has proved successful in adult studies as well. In the CYCAZAREM trial, patients received oral CYC and prednisolone until remission was achieved, between 3 and 6 months, and were then randomized to continue CYC or azathioprine. There was no difference in relapse rate during 18 months [50]. The efficacy and toxicity of i.v. pulse administration of CYC (0.75 gm/m2) versus daily oral CYC treatment (2 mg/kg per day) were investigated in a prospective, randomized, multicenter study in adult patients with ANCA-associated vasculitis and renal involvement [51]. The cumulative CYC dose was reduced by 57% in patients with i.v. pulse treatment (n = 22)

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compared with patients treated with daily oral therapy (n = 25). Patient survival, remission rate, time of remission, relapse rate, and outcome of renal function were not different between the two treatment groups. However, the rate of leukopenia and severe infections was significantly reduced in the i.v. pulse group compared with the group receiving daily oral treatment. Recent data suggest that mycophenolate mofetil may be a promising alternative for treatment of PAN. A pediatric study is also underway. Mortality has been reported to be as high as 20% in some older childhood series [38,44]. However, in more recent childhood series, the outcome has been substantially better [34,39]. In these patients the beneficial role of penicillin deserves controlled studies. This effect is especially striking in cutaneous PAN. In cutaneous PAN NSAIDs and short courses of low-dose oral corticosteroids have been used. Relapses are frequent. Any constitutional symptom or organ involvement should alert the physician for the development of systemic PAN. We lack an evidence-based treatment for the management of these patients.

GRANULOMATOUS POLYANGIITIS (WEGENER’S GRANULOMATOSIS) Granulomatous polyangiitis (GPA) WG is characterized by a granulomatous vasculitis affecting small-to-medium-sized arteries. Glomerulonephritis accompanied by granulomatous lesions of the upper and lower respiratory tract is a common presentation.

Epidemiology GPA (WG) is rare in childhood. The 5-year incidence was 3.2 cases per 100,000 persons in a large study [52]. In the pediatric age range, it occurs with approximately equal frequency in boys and in girls [53]. On the other hand, in a British study, the female-to-male ratio was 13:4 [54]. The mean age at onset of disease ranged from 6.3 years to 15.4 years [54,55], and 15% of cases of GPA (WG) are initially diagnosed in patients less than 19 years of age [56].

Etiology and Pathogenesis The cause of GPA (WG) is unknown. It is a multifactorial disease as most of the other major vasculitides with a complex genetic predisposition. In a recent study an association has been defined with a region on chromosome 6p21.3, suggesting the need for extensive mapping of this region [57]. The pathogenic role of ANCA in the development of the disease suggests an autoimmune background of GPA (WG). Environmental factors have been highlighted in a

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number of reports, especially those describing the geographic distribution and clusters of the disease. Staphylococcus aureus has been suggested to have a triggering role in its pathogenesis [58]. Autoimmunity, hypersensitivity, allergic reactions, and nasal carriage for S. aureus have been implicated. Recent studies have elegantly demonstrated the role of ANCA in the disease pathogenesis, and are well summarized in a review by Frosh and Foell [59].

Clinical Manifestations Patients frequently present with malaise, fever, sinusitis, epistaxis, and hematuria. Diagnosis according to the ACR criteria requires two out of the four following criteria: (1) nasal oral inflammation, (2) abnormal chest X-ray, (3) microscopic hematuria or red blood cell casts, and (4) granulomatous inflammation on biopsy [60]. The triad of paranasal sinus involvement, pulmonary infiltration, and renal disease is characteristic of GPA (WG) [55]. The EULAR/PRES Endorsed Consensus Criteria for Classification of Wegener granulomatosis revised by pediatricians has introduced minor changes (Table 17.4); one of these was the inclusion of subglottic stenosis since this was a common pediatric feature. Upper respiratory tract symptoms include rhinorrhea, nasal mucosal inflammation, epistaxis, persistent cough, hoarseness, and paranasal sinus pain. Pulmonary involvement (cough, dyspnea, and hemoptysis) occurs in 74% of children [55]. It may be in the form of nodules, fixed infiltrates, or cavities [60] (Fig. 17.3). Multifocal infiltrates with or without small peripheral nodules were the commonest thoracic CT manifestations [61]. The skin disease may be in the form of palpable purpura, papules, vesicles, ulcers, and nodules [55]. Most features in children are similar to those of adults; however, some features such as subglottic stenosis and nasal deformity are more common in children [55]. Blurred vision, eye pain, conjunctivitis, episcleritis, persistent otitis media, myalgia, and arthralgia are also common [62]. CNS and cardiac involvement are less common. In the pediatric series reported by Rottem et al. [55] (23 patients), Stegmayr et al. [63] (10 patients), and Belostotsky et al. [54] (17 patients), upper airway involvement ranged from 58% to 91%, lung involvement from 74% to 87%, kidney involvement from 53% to 100%, eye involvement from 48% to 53%, CNS involvement from 10% to 17%, and skin involvement from 40% to 53%. In patients with kidney involvement the findings range from proteinuria and/ or hematuria to impairment of renal function. If kidney biopsy is performed it characteristically shows necrotizing pauci-immune glomerulonephritis.

Diagnostic Investigations Anemia, thrombocytosis, and marked elevation of ESR or CRP are prominent features. White blood cell counts are usually normal or moderately

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TABLE 17.4 EULAR/PRINTO/PRES (Ankara 2008) Childhood Wegener Granulomatosis Criteria At least three of the following six criteria: Histopathology Upper airway involvement Laryngo-tracheo-bronchial stenoses Pulmonary involvement ANCA positivity Renal involvement Source: From Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/ PRES criteria for Henoch-Scho¨nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;69(5):798-806.

FIGURE 17.3 Pulmonary involvement in Granulomatous Polyangiitis

elevated. Urinalysis reveals hematuria and proteinuria, and renal function tests may be abnormal. Chest CT is often indicated. ANCAs may be cytoplasmic or perinuclear, but usually display a cytoplasmic-staining pattern by immunofluorescence, and is directed against serine proteinase 3 in more than 90% of cases [64,65].

Differential Diagnosis Churg Strauss syndrome, lymphomatoid granulomatosis, and primary angiitis of the CNS are other granulomatous vasculitides. Differential diagnosis includes the other granulomatous vasculitides as well as relapsing

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polychondritis, chronic granulomatous disease, and the pulmonary-renal syndromes such as PAN, Churg Strauss syndrome, Goodpasture syndrome, and SLE.

Treatment Randomized adult studies of the European Vasculitis Group include patients with GPA (WG) along with microscopic polyangiitis cases, in the ANCAassociated vasculitis trials such as the CYCAZAREM study [50]. Treatment is similar to that for patients with microscopic PAN. In children with systemic disease steroids and CYC are used. The number of patients reported so far is too small to establish a standard recommendation for oral versus intravenous pulse CYC [55,63]. Methotrexate may be used in less severe cases [66]. Whether trimethoprim-sulphamethoxazole is able to reduce disease relapse is controversial [67,68]. Recently in controlled adult studies, rituximab has emerged as an alternative to CYC for induction of remission in ANCA-associated vasculitides [69,70]. Both in the RAVE and rituxvas studies, rituximab was comparable to conventional therapy with possible superiority in relapsing patients [69,70]. Leflunomide [71] and mycophenolate mofetil [72] were found to be useful in the maintenance of remission. Plasmapheresis and immunoabsorption have been applied as adjunctive therapy in cases not responding to drug therapy [73,74]. Intratracheal dilation with an intratracheal injection of a long-acting glucocorticoid provides a safe and effective treatment for GPA (WG)-associated subglottic stenosis [75,76]. Prognosis has been dramatically improved with immunosuppressive therapy. However, a significant proportion of patients are still subject to permanent morbidity and mortality from both the disease and treatment [55]. The course is complicated with relapses. Stegmayr et al. [63] have reported that 80% of their young patients relapsed within a period of 4 120 months.

TAKAYASU ARTERITIS TA is a segmental inflammatory arteritis leading to stenosis and aneurysms of large muscular arteries, mainly the aorta and its major branches [77]. Females are affected more than males. Many reports have drawn attention to the association of TA with tuberculosis. According to ACR classification based on adult experience, a patient is classified as having TA if three of the following six criteria are present: (1) age ,40 years, (2) claudication of extremities, (3) decreased brachial artery pulse, (4) blood pressure difference between the two sides .10 mm Hg, (5) bruit over subclavian arteries or aorta, and (6) arteriogram abnormality [78].

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TABLE 17.5 EULAR/PRINTO/PRES Childhood Takayasu Arteritis (Ankara 2008) Criteria Angiographic abnormalities of the aorta or its amin branches and pulmonary arteries showing aneurysm/dilatation (mandatory criterion) plus one of the five following criteria: Pulse deficit or claudication Four limbs blood pressure discrepancy Bruits Hypertension Acute phase reactant Source: From Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/ PRES criteria for Henoch-Scho¨nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;69(5):798 806.

These criteria have also been revised along with the other pediatric vasculitides [5] (Table 17.5).

Epidemiology Although TA is rare in children, it follows IgAV (HSP) and Kawasaki disease in frequency [62]. Twenty percent of cases are younger than 19 years [79]. Female-to-male ratio varies from 4:1 to 2:1 in different series [77,80]. The type of vascular involvement seems to differ according to the geographic area: obstructive lesions seem to be more common in the United States and Western Europe and Japan, whereas aneurysms appear to be more common in South East Asia and Africa [62].

Clinical and Laboratory Features The presenting symptoms are fever, night sweats, anorexia, weight loss, and musculoskeletal symptoms. Symptoms related to hypertension and pulse deficits are common [77]. In the series reported by Jain et al. [80], hypertension was the most common mode of presentation, seen in 83% of patients; 16% of patients had congestive heart failure; left ventricular hypertrophy was present in 54% of patients. Acute phase reactants are elevated. Although plain radiographs may be helpful, diagnosis requires the demonstration of the arteritis and typical findings by magnetic resonance or conventional angiography (Fig. 17.4).

Treatment Corticosteroids are used in acute disease [81]. As in other vasculitides CYC is an effective alternative. Adult and childhood reports have also emphasized

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FIGURE 17.4 Takayasu arteritis demonstrating involvement of aorta.

the use of methotrexate as a steroid-sparing agent [81]. Multiple case series support the use of anti-tumor necrosis factor medications in TA [82]. More recently anti-IL-6 has emerged as a promising alternative for the treatment of TA as well [83]. A positive tuberculin test would justify antituberculous therapy. Subsequent reconstructive surgery and transluminal angioplasty may be employed for the vascular complications.

OTHER RARE VASCULITIDES IN CHILDHOOD Microscopic polyangiitis is a vasculitis with predominantly small-vessel involvement and association with a high titer of myeloperoxidase-ANCA (MPO-ANCA) or positive perinuclear-ANCA (p-ANCA) staining [2,5]. Necrotizing glomerulonephritis was noted to be very common and pulmonary capillaritis as well, often in the absence of granulomatous lesions of the respiratory tract as was suggested by the Chapel Hill Consensus Criteria [2]. Rare childhood series have been reported.

Eosinophilic Granulomatous Polyangiitis (Churg Strauss Syndrome) Churg Strauss syndrome is another ANCA-associated small-vessel vasculitis defined by allergic rhinitis, asthma, peripheral eosinophilia, peripheral neuropathy, pulmonary infiltrations, chronic sinusitis, and biopsy-proven eosinophilic vasculitis. It is very rare in childhood. All childhood-onset patients had peripheral eosinophilia and almost all had asthma [84]. Cardiac, renal, and nervous involvement may also occur. Corticosteroids are the main therapy. Immunosuppressives were added in most reported cases.

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Hypocomplementemic Urticarial Vasculitis (Anti-C1q Vasculitis) In this rare syndrome, children, usually girls, have recurrent episodes of urticaria associated with pruritus and burning. Purpura, papules, vesicles, fever, nausea, vomiting, arthralgia, arthritis, and chest and abdominal pain are other manifestations. It may be associated with SLE, Sjo¨gren’s syndrome, hepatitis B and C, drugs, and sun exposure [6]. The pathogenesis is unknown. Complement levels (C1q, C3, C4) may be decreased. Antihistamines, colchicine, hydroxychloroquine, indomethacin, and dapsone have all been used [85]. Glucocorticoids and other immunosuppressive drugs are required in severe cases.

VARIABLE VESSEL VASCULITIDES Behc¸et’s Disease and Cogan Syndrome have been classified as such since they can affect any vessel size and also the veins. Both of these diseases have unique features with frequent involvement of the eye. Behc¸et’s Disease is especially common among children with an ancestry of the so-called “Silk-road.” The readers are referred to specific reviews on these two diseases [86,87].

SINGLE ORGAN VASCULITIDES Cutaneous Leukocytoclastic Angiitis This is small-vessel vasculitis confined to the skin. Histologically the lesion is a leukocytoclastic angiitis [88]. The definition requires the exclusion of any systemic feature. Treatment is often symptomatic; however, steroids may be indicated although they have not been proven to alter the course of the disease.

Primary Central Nervous System Vasculitis The true incidence of primary CNS vasculitis is not known. Acute severe headache (80%), focal neurologic deficits (78%), motor deficiencies (62%), cranial nerve involvement (59%), and cognitive dysfunction (54%) are the leading presenting features of primary CNS vasculitis in children [89]. Infections, systemic vasculitis, collagen vascular disease, inflammatory bowel disease, sarcoidosis, vascular injury, drugs, and neoplasms are secondary causes of CNS vasculitis in children. Cerebrospinal fluid (CSF) opening pressure may be elevated. In small pediatric series reported by Gallagher et al. [90], Lanthier et al. [91], and Benseler and Schneider [89], 9 out of 11 patients had either pleocytosis or elevated protein CSF levels. MRI is more sensitive than CT for the diagnosis of CNS vasculitis [92]. The combination of normal CSF analysis and a normal brain MRI has a high

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negative predictive value. The most common angiographic feature of pediatric primary CNS vasculitis is arterial vessel stenosis [90]. MR angiography is an alternative diagnostic tool. SPECT and PET may demonstrate perfusion abnormalities. The gold standard for primary CNS vasculitis is a biopsy of the brain and leptomeninges. However large-vessel vasculitis confirmed by angiography may not be associated with small-vessel involvement seen on biopsy. Corticosteroids 6 cyclophosphamide or other immunosuppressives may be useful in children with primary CNS vasculitis. Thromboembolic phenomena, prothrombotic conditions, and poststenotic low-flow conditions may require prophylactic anticoagulation.

SECONDARY VASCULITIDES Since vasculitis is defined as inflammation of the blood vessels, practically any process accompanied by this feature may be termed as secondary vasculitis. Infectious agents may act as triggering factors through various mechanisms such as molecular mimicry, through direct damage, or by immune-mediated damage to the vessel by immune complex deposition or from bystander damage to the blood vessel [93]. Among viral causes hepatitis B- and HIV-associated vasculitis have been described in children [94]. The other causes of secondary vasculitides include malignancy, drugs, and other rheumatic diseases such as systemic lupus erythematosus or dermatomyositis.

REFERENCES [1] Scott DG, Watts RA. Classification and epidemiology of vasculitis. In: Isenberg DA, Maddison PJ, Woo P, Glass D, Breedveld FC, editors. Oxford textbook of rheumatology, 2004. Oxford: Oxford University Press; 2004. p. 934. [2] Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 Revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum 2013;65:1 11. [3] Scott DG, Watts RA. Systemic vasculitis: epidemiology, classification and environmental factors. Ann Rheum Dis 2000;59:161 3. [4] Ozen S, Ruperto N, Dillon M, Bagga A, Barron K, Davin JC, et al. EULAR/PRES Endorsed Consensus Criteria for the classification of childhood vasculitides under review by the ACR. Ann Rheum Dis 2005;65(7):936 41. [5] Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/ PRES criteria for Henoch Scho¨nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 2010;69(5):798 806. [6] Cassidy JT, Pett RE. Leukocytoclastic vasculitis. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB, editors. Textbook of pediatric rheumatology. 5th ed. Philadelphia: Elsevier Saunders; 2005. p. 496.

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[7] Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch Schonlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet 2002;360:1197 202. [8] Yang YH, Hung CF, Hsu CR, Wang LC, Chuang YH, Lin YT, et al. A nationwide survey on epidemiological characteristics of childhood Henoch Scho¨nlein purpura in Taiwan. Rheumatology (Oxford) 2005;44(5):618 22. [9] Dolezalova P, Telekesova P, Nemcova D, Hoza J. Incidence of vasculitis in children in the Czech Republic: 2-year prospective epidemiology survey. J Rheumatol 2004;31: 2295 9. [10] Allen DM, Diamond LK, Howell DA. Anaphylactoid purpura in children. Am J Dis Child 1960;99:833 54. [11] Al-Sheyyab M, El-Shanti H, Ajlouni S, Sawalha D, Daoud A. The clinical spectrum of Henoch Schonlein purpura in infants and young children. Eur J Pediatr 1995;154: 969 72. [12] Saulsbury FT. Henoch Schonlein purpura in children. Report of 100 patients and review of the literature. Medicine (Baltimore) 1999;78(6):395 409. [13] Calvino MC, Llorca J, Garcia-Porrua C, Fernandez-Iglesias JL, Rodriguez-Ledo P, Gonzalez-Gay MA. Henoch Schonlein purpura in children from northwestern Spain: a 20-year epidemiologic and clinical study. Med Baltimore 2001;80:279 90. [14] Bagga A, Dillon MJ. Leukocytoclastic vasculitis. In: Cassidy JT, Petty RE, editors. Textbook of pediatric rheumatology. 4th ed. Philadelphia: WB Saunders Co; 2001. p. 569. [15] Stefansson Thors V, Kolka R, Sigurdardottir SL, Edvardsson VO, Arason G, Haraldsson A. Increased frequency of C4B Q0 alleles in patients with Henoch Schonlein purpura. Scand J Immunol 2005;61:274 8. [16] Motoyama O, Iitaka K. Henoch Schonlein purpura with hypocomplemen-temia in children. Pediatr Int 2005;47:39 42. [17] Saulsbury FT. Henoch Schonlein purpura. Curr Opin Rheumatol 2001;13:35 40. [18] Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcınkaya F, et al. Familial Mediterranean fever: FMF in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 2005;84(1):1 11. [19] Mills JA, Michel BA, Bloch DA, Calabrese LH, Hunder GG, et al. The American College of Rheumatology 1990 criteria for the classification of HSP. Arthritis Rheum 1990;33(8):1114 21. [20] Lewis IC, Philpott MG. Neurological complications in the Schonlein Henoch syndrome. Arch Dis Child 1956;31:369 71. [21] Bakkaloglu SA, Ekim M, Tumer N, Deda G, Erden I, Erdem T. Cerebral vasculitis in Henoch Schonlein purpura. Nephrol Dial Transplant 2000;15:246 8. [22] Bulun A, Topaloglu R, Duzova A, Saatci I, Besbas N, Bakkaloglu A. Ataxia and peripheral neuropathy: rare manifestations in Henoch Schonlein purpura. Pediatr Nephrol 2001;16:1139 41. [23] Kaplan JM, Quintana P, Samson J. Facial nerve palsy with anaphylactoid purpura. Am J Dis Child 1970;119:452 3. [24] Besbas N, Duzova A, Topaloglu R, Gok F, Ozaltin F, Ozen S, et al. Pulmonary haemorrhage in a 6-year-old boy with Henoch Schonlein purpura. Clin Rheumatol 2001;20:293 6. [25] Imai T, Matsumoto S. Anaphylactoid purpura with cardiac involvement. Arch Dis Child 1970;45:727 9.

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[26] Mintzer CO, Nussinovitch M, Danziger Y, Mimouni M, Varsano I. Scrotal involvement in Henoch Schonlein purpura in children. Scand J Urol Nephrol 1998;32:138 9. [27] White RHR, Yoshikawa N, Feehally J. IgA nephropathy and Henoch Scho¨nlein nephritis. In: Barratt TM, Avner ED, Harmon WE, editors. Pediatric Nephrology. Baltimore: Lippincott Williams and Wilkins; 1999. p. 691. [28] Szer IS. Henoch Scho¨nlein purpura: when and how to treat. J Rheumatol 1996;23:1661 5. [29] Huber AM, King J, McLaine P, Klassen T, Pothos M. A randomized, placebo-controlled trial of prednisone in early Henoch Scho¨nlein purpura. BMC Med 2004;2:7. [30] Oner A, Tinaztepe K, Erdoga O. The effect of triple therapy on rapidly progressive type of Henoch Schonlein nephritis. Pediatr Nephrol 1995;9:6 10. [31] Flynn JT, Smoyer WE, Bunchman TE, Kershaw DB, Sedman AB. Treatment of Henoch Schonlein purpura glomerulonephritis in children with high-dose corticosteroids plus oral cyclophosphamide. Am J Nephrol 2001;21:128 33. [32] Mollica F, Li Volti S, Garozzo R, Russo G. Effectiveness of early prednisone treatment in preventing the development of nephropathy in anaphylactoid purpura. Eur J Pediatr 1992;151:140 4. [33] Ronkainen J, Nuutinen M, Koskimies O. The adult kidney 24 years after childhood Henoch Schonlein purpura: a retrospective cohort study. Lancet 2002;360:666 70. [34] Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37:187 92. [35] Brogan PA, Davies R, Gordon I, Dillon MJ. Renal angiography in children with polyarteritis nodosa. Pediatr Nephrol 2002;17:277 83. [36] Ozen S, Besbas N, Saatci U, Bakkaloglu A. Diagnostic criteria for polyarteritis nodosa in childhood. J Pediatr 1992;120:206 9. [37] Lightfoot Jr RW, Michel BA, Bloch DA, Hunder GG, Zvaifler NJ, McShane DJ, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 1990;33:1088 93. [38] Dillon MJ. Vasculitis syndromes. In: Woo P, White PH, Ansell BM, editors. Paediatric rheumatology update. Oxford: Oxford University Press; 1990. p. 227. [39] Ozen S, Anton J, Arisoy N, Bakkaloglu A, Besbas N, Brogan P, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children. J Pediatr 2004;145:517 22. [40] David J, Ansell BM, Woo P. Polyarteritis nodosa associated with streptococcus. Arch Dis Child 1993;69:685 8. [41] Bont L, Brus F, Dijkman-Neerincx RH, Jansen TL, Meyer JW, Janssen M. The clinical spectrum of post-streptococcal syndromes with arthritis in children. Clin Exp Rheumatol 1998;16:750 2. [42] Dillon M. Primary vasculitis in children. In: Maddison PJ, Isenberg DA, Woo P, Glass DN, editors. Oxford textbook of rheumatology. Oxford: Oxford University Press; 1998. p. 1402. [43] Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Stone DL, et al. Early onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014;370 (10):911 20. [44] Fink CW. Polyarteritis and other diseases with necrotizing vasculitis in childhood. Arthritis Rheum 1977;20:378 84.

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[45] Bakkaloglu A, Ozen S, Baskin E, Besbas N, Gur-Guven A, Kasapcopur O, et al. The significance of antineutrophil cytoplasmic antibody in microscopic polyangitis and classic polyarteritis nodosa. Arch Dis Child 2001;85:427 30. [46] Watts RA, Jolliffe VA, Carruthers DM, Lockwood M, Scott DG. Effect of classification on the incidence of polyarteritis nodosa and microscopic polyangiitis. Arthritis Rheum 1996;39:1208 12. [47] Wong SN, Shah V, Dillon MJ. Antineutrophil cytoplasmic antibodies in Wegener’s granulomatosis. Arch Dis Child 1998;79:246 50. [48] Besbas N, Ozen S, Saatci U, Topaloglu R, Tinaztepe K, Bakkaloglu A. Renal involvement in polyarteritis nodosa: evaluation of 26 Turkish children. Pediatr Nephrol 2000;14:325 7. [49] Latta K, von Schnakenburg C, Ehrich JH. A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Pediatr Nephrol 2001;16:271 82. [50] Jayne D. Update on the European vasculitis study group trials. Curr Opin Rheumatol 2001;13:48 55. [51] Haubitz M, Schellong S, Gobel U, Schurek HJ, Schaumann D, Koch KM, et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective, randomized study. Arthritis Rheum 1998;41:1835 44. [52] Cotch MF, Hoffman GS, Yerg DE, Kaufman GI, Targonski P, Kaslow RA. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum 1996;39:87 92. [53] Orlowski JP, Clough JD, Dyment PG. Wegener’s granulomatosis in the pediatric age group. Pediatrics 1978;61:83 90. [54] Belostotsky VM, Shah V, Dillon MJ. Clinical features in 17 paediatric patients with Wegener granulomatosis. Pediatr Nephrol 2002;17:754 61. [55] Rottem M, Fauci AS, Hallahan CW, Kerr GS, Lebovics R, Leavitt RY, et al. Wegener granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr 1993;122:26 31. [56] Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488 98. [57] Szyld P, Jagiello P, Csernok E, Gross WL, Epplen JT. On the GPA (WG) associated region on chromosome 6p21.3. BMC Med Genet 2006;7:21. [58] Mayet WJ, Marker-Hermann E, Schlaak J, Meyer Zum Buschenfelde KH. Irregular cytokine pattern of CD4+ T lymphocytes in response to Staphylococcus aureus in patients with Wegener’s granulomatosis. Scand J Immunol 1999;49:585 94. [59] Frosch M, Foell D. Wegener granulomatosis in childhood and adolescence. Eur J Pediatr 2004;163:425 34. [60] Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990;33:1101 7. [61] McHugh K, Manson D, Eberhard BA, Shore A, Laxer RM. Wegener’s granulomatosis in childhood. Pediatr Radiol 1991;21:552 5. [62] Lindsley CB, Laxer RM. Granulomatous vasculitis, giant cell vasculitis and sarcoidosis. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB, editors. Textbook of pediatric rheumatology. 5th ed. Philadelphia: Elsevier Saunders; 2005. p. 539.

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[63] Stegmayr BG, Gothefors L, Malmer B, Muller Wiefel DE, Nilsson K, Sundelin B. Wegener granulomatosis in children and young adults. A case study of ten patients. Pediatr Nephrol 2000;14:208 13. [64] Specks U, Wheatley CL, McDonald TJ, Rohrbach MS, DeRemee RA. Anticytoplasmic autoantibodies in the diagnosis and follow-up of Wegener’s granulomatosis. Mayo Clin Proc 1989;64:28 36. [65] Nolle B, Specks U, Ludemann J, Rohrbach MS, DeRemee RA, Gross WL. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener granulomatosis. Ann Intern Med 1989;111:28 40. [66] Gottlieb BS, Miller LC, Ilowite NT. Methotrexate treatment of Wegener granulomatosis in children. J Pediatr 1996;129:604 7. [67] de Groot K, Reinhold-Keller E, Tatsis E, Paulsen J, Heller M, Nolle B, et al. Therapy for the maintenance of remission in sixty-five patients with generalized Wegener’s granulomatosis. Methotrexate versus trimethoprim/sulfamethoxazole. Arthritis Rheum 1996;39:2052 61. [68] Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole: co-trimoxazole for the prevention of relapses of Wegener’s granulomatosis. Dutch CoTrimoxazole Wegener Study Group. N Engl J Med 1996;335:16 20. [69] Stone JH, Merkel PA, Splera R, Seo P, Langfors CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363 (3):221 32. [70] Jones RB, Furuta S, Tervaert JW, Hauser T, Luqmani R, Morgan MD, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomized trila. Ann Rheum Dis 2015;74(6):1178 82. [71] Metzler C., Fink C., Lamprecht P., Gross W.L., Reinhold-Keller, E., Maintenance of remission with leflunomide in Wegener’s granulomatosis. Rheumatology (Oxford) 2004;43:315 20. [72] Langford CA, Talar-Williams C, Sneller MC. Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis. Arthritis Rheum 2004;51:278 83. [73] Guillevin L, Pagnoux C. Indications of plasma exchanges for systemic vasculitis. Therap Apher Dial 2003;7:155 60. [74] Matic G, Michelsen A, Hofmann D, Winkler R, Tiess M, Schneidewind JM, et al. Three cases of c-ANCA-positive vasculitis treated with immunoadsorption: possible benefit in early treatment. Ther Apheresis 2001;5:68 72. [75] Langford CA, Sneller MC, Hallahan CW, Hoffman GS, Kammerer WA, Talar-Williams C, et al. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener’s granulomatosis. Arthritis Rheum 1996;39:1754 60. [76] Staepperts I, Van Laer C, Deschepper K, Van de Heyning P, Vermeire P. Endoscopic management of severe subglottic stenosis in Wegener’s granulomatosis. Clin Rheumatol 2000;19:315 17. [77] Hall S, Barr W, Lie JT, Stanson AW, Kazmier FJ, Hunder GG. Takayasu arteritis. A study of 32 North American patients. Medicine (Baltimore) 1985;64:89 99. [78] Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990;33:1129 34. [79] Ishikawa K. Survival and morbidity after diagnosis of occlusive thromboaortopathy: Takayasu’s disease. Am. J. Cardiol. 1981;47:1026 32.

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[80] Jain S, Sharma N, Singh S, Bali HK, Kumar L, Sharma BK. Takayasu arteritis in children and young Indians. Int J Cardiol 2000;75(Suppl. 1):S153. [81] Hoffman GS, Leavitt RY, Kerr GS, Rottem M, Sneller MC, Fauci AS. Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 1994;37:578 82. [82] Comarmond C, Plaisier E, Dahan K, Mirault T, Emmerich J, et al. Anti-TNF-alpha in refractory Takyasu’s arteritis: cases series and review of the literature. Autoimmun Rev 2012;11(9):678 84. [83] Tombetti E, Franchini S, Papa M, Sabbaddini MG, Baldissera E. Treatment of refractory Takayasu arteritis with tocilizumab: 7 Italian patients from a single referral center. J Rheumatol 2013;40(12):2047 51. [84] Louthrenoo W, Norasetthada A, Khunamornpong S, Sreshthaputra A, Sukitawut W. Childhood Churg Strauss syndrome. J Rheumatol 1999;26:1387. [85] Mehregan DR, Hall MJ, Gibson LE. Urticarial vasculitis: a histopathologic and clinical review of 72 cases. J Am Acad Dermatol 1992;26:441 8. [86] Singer O. Cogan and Behcet syndromes. Rheum Dis Clin North Am 2015;41(1):75 91. [87] Ozen S, Eroglu FK. Pediatric onset Behcet disease. Curr Opin Rheumatol 2013;25 (5):636 42. [88] Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997;337:1512 23. [89] Benseler S, Schneider R. Central nervous system vasculitis in children. Curr Opin Rheumatol 2003;16:43 50. [90] Gallagher KT, Shaham B, Reiff A, Tournay A, Villablanca JP, Curran J, et al. Primary angiitis of the central nervous system in children: 5 cases. J Rheumatol 2001;28:616 23. [91] Lanthier S, Lortie A, Michaud J, Laxer R, Jay V, deVeber G. Isolated angiitis of the CNS in children. Neurology 2001;56:837 42. [92] Stone JH, Pomper MG, Roubenoff R, Mille TJ, Hellmann DB. Sensitivities of noninvasive tests for central nervous system vasculitis: a comparison of lumbar puncture, computed tomography, and magnetic resonance imaging. J Rheumatol 1994;21:1277 82. [93] Ozen S. Vasculopathy, Behcet’s syndrome, and familial Mediterranean fever. Curr Opin Rheumatol 1999;11(5):393 8. [94] Athreya BH. Vasculitis in children. Pediatr Clin North Am 1995;42:1239 61.

Chapter 18

Pediatric Antiphospholipid Syndrome ˇ 1 and R. Cimaz2 T. Avcin 1

Department of Allergology, Rheumatology and Clinical Immunology, Children’s Hospital Ljubljana, University Medical Center, Ljubljana, Slovenia, 2A. Meyer Children’s Hospital and University of Florence, Florence, Italy

INTRODUCTION Antiphospholipid syndrome (APS) is a multisystem autoimmune disease characterized by vascular thrombosis, recurrent fetal loss, thrombocytopenia and other clinical manifestations in the presence of persistent circulating antiphospholipid antibodies (aPL). APS is considered as the most common acquired hypercoagulation state of autoimmune etiology and may occur as an isolated clinical entity (primary APS) or in association with an underlying systemic disease, particularly systemic lupus erythematosus (SLE). The features of APS have been increasingly recognized in children and since aPL-related thrombosis can affect any organ, pediatricians of different subspecialties must be aware of this syndrome and associated complications [1,2].

PREVALENCE OF ANTIPHOSPHOLIPID ANTIBODIES Antiphospholipid antibodies is an umbrella term used to describe a heterogeneous group of autoantibodies directed against negatively charged phospholipids or phospholipid-binding plasma proteins. The most useful aPL for identifying patients with APS are anticardiolipin antibodies (aCL), anti-β2 glycoprotein I antibodies (anti-β2GPI), and lupus anticoagulant (LA) [3].

Healthy Children aPL can be found in a high percentage of children without any underlying disorder. Such naturally occurring aPL are usually present at low levels and could be the result of previous infections or vaccinations that are common in the pediatric population. The estimated frequency of aCL in healthy children Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00018-9 © 2016 Elsevier B.V. All rights reserved.

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ranges from 3% to 28%, which is higher than in the normal adult population [4 6]. The frequency of anti-β2GPI in healthy children ranges from 3% to 7% and high levels of anti-β2GPI seems to be relatively more frequent in preschool children than in adolescents and healthy adults [5,6]. It has generally been assumed that naturally occurring aCL are not associated with thrombotic events, but it is prudent to perform a follow-up determination after a time interval of at least 12 weeks to exclude persistent positive test. LAs have also been described in apparently healthy children and are usually found incidentally in preoperative coagulation screening as prolonged activated partial thromboplastin time (aPTT). In a prospective study of 80 asymptomatic children with incidentally found positive LA none of the children experienced clinically relevant complications during a mean follow-up of 2.9 years, and over half had normalization of aPTT values [7]. Age-dependent differences in immune responses are also important considerations when evaluating results of aPL testing in apparently healthy children. For example, there is growing evidence of postnatal synthesis of anti-β2GPI in infants that have preferential specificity for domains IV/V of the β2GPI molecule and seem to have low thrombosis risk [8,9]. The production of anti-β2GPI in infants may be associated with the exaggerated immune response to nutritional antigens or infections and not with an autoimmune disease.

Systemic Lupus Erythematosus SLE is the autoimmune disease where aPL occurs in highest percentage. The reported frequencies of aPL in childhood-onset SLE have ranged from 19% to 87% for aCL, from 27% to 48% for anti-β2GPI, and from 10% to 62% for LA, respectively [10 16]. This wide variability in the frequency of aPL reported in childhood-onset SLE may be due to differing sensitivities of assays and heterogeneity in the patient population regarding the disease duration, clinical features, and disease activity. A metaanalysis of the published studies of aPL in children with SLE yielded a global prevalence of 44% for aCL, 40% for anti-β2GPI, and 22% for LA [17]. A variety of clinical features have been reported to be present in aPLpositive children with SLE including arterial and venous thromboses, different neurological manifestations, and autoimmune cytopenias. In a retrospective cohort study of 149 children with SLE, thromboembolic events occurred in 13 patients who were all positive for LA [18]. The reported incidence of thrombosis was 54% in LA-positive children with SLE [18]. Additionally, LA were reported as the strongest predictor of the risk of thrombotic events in a nonselected group of 58 children with SLE [19]. Some pediatric studies demonstrated significant association of persistently positive aPL with SLE disease activity and long-term damage suggesting that aPL can modify the clinical expression and long-term outcome of childhood-onset SLE [15,20].

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Other Diseases The presence of aCL was reported in 7 53% of children with juvenile idiopathic arthritis (JIA), usually as a single positivity without the presence of anti-β2GPI or LA [21 23]. Most studies in JIA found no association between the presence of aPL and disease activity, and no clinical manifestations of APS were observed. Limited prothrombotic potential of aPL observed in JIA patients could be partially explained by low frequency of anti-β2GPI and LA, which are reportedly more specific for thrombosis than aCL [23]. The presence of circulating aPL have been demonstrated in a variety of other pediatric autoimmune and nonautoimmune diseases, including Henoch Scho¨nlein purpura, Behc¸et disease, polyarteritis nodosa, immune thrombocytopenic purpura, hemolytic uremic syndrome, rheumatic fever, and malignancies [1,24]. In most of these conditions aPL-related clinical manifestations are unusual, and the significance of aPL needs further confirmation.

Infections and Vaccinations There is growing evidence that various viral and bacterial infections can induce aPL, which are usually transient and not associated with thrombotic events [25,26]. aPL were most commonly described in patients with varicella, cytomegalovirus, parvovirus B19, human immunodeficiency virus, streptococcus, mycoplasma pneumonia, and gram-negative bacteria [25]. The majority of postinfectious aPL differ immunochemically from those seen in patients with autoimmune diseases and do not require the presence of β2GPI for their binding to cardiolipin [27,28]; however, this distinction has been found not to be absolute [29]. Because most children suffer from frequent viral and bacterial infections, a high percentage of incidental aPL positivity might be expected in the pediatric population [30,31]. Since postinfectious aPL tend to be transient, all positive aPL values should be verified on at least two occasions, preferably at a time when the child has not had a recent infection. The risk of APS manifestations with postinfectious aPL is not completely absent, however, and there is a growing list of infectious agents as triggering factors for APS. There have been isolated pediatric case reports of thromboembolic events associated with mycoplasma pneumonia infection, which is a common cause of community-acquired pneumonia in children [32,33]. Another common infectious cause in children, varicella-zoster virus, was described in pediatric cases with thrombosis [34,35] and in association with a distinct clinical entity purpura fulminans after chickenpox infection linked to the presence of LA and acquired protein S deficiency [36].

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aPL apparently can be induced also by vaccinations. In healthy children transitory induction of aPL was observed following hepatitis A vaccination [37] and in children with JIA following influenza vaccination [38]. aPL following vaccinations were only transient in the majority of cases and no case of APS was described so far in an apparently healthy person.

EPIDEMIOLOGY OF ANTIPHOSPHOLIPID SYNDROME The actual prevalence of APS in the pediatric population is difficult to estimate since there are no validated criteria and diagnosis rests on the extension of adult guidelines and clinical judgment. Current consensus criteria for the classification of APS in the adult population designate patients who suffered from vascular thrombosis or recurrent fetal losses, accompanied by elevated titers of aCL, anti-β2GPI, or LA [39] (Table 18.1). APS in children has been largely reported in patients with thromboses and less frequently in TABLE 18.1 Preliminary Criteria for the Classification of Antiphospholipid Syndrome [39] Clinical criteria 1. Vascular thrombosis One or more clinical episodes of arterial, venous, or small-vessel thrombosis, in any tissue or organ. 2. Pregnancy morbidity One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation. One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or eclampsia, or placental insufficiency. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation.

Laboratory criteria 1. Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma Must be present in medium or high titer (ie, .40 GPL or MPL, or .99th percentile) on two or more occasions, at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay. 2. Anti-β2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma Must be present in titer .99th percentile, on two or more occasions, at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay. 3. Lupus anticoagulant in plasma Must be present on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis. APS is considered to be present if at least one of the clinical criteria and one of the laboratory criteria are met.

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association with neurological or hematological manifestations [24,40,41]. Recurrent fetal losses, which represent one of the most important clinical criteria in adults, are not applicable for the pediatric population and it is likely that current consensus criteria may fail to recognize significant groups of pediatric patients with APS. Metaanalysis of observational studies that investigated the association of aPL and first onset of thromboembolism in children showed persistent aPL positivity in 1 22% of arterial and 2 12% of venous thrombotic events [42]. Data from large pediatric registries suggest that primary, isolated APS accounts for 38 50% of pediatric patients with APS [24,41], and some children that present with primary APS may develop overt SLE during followup [24,43].

ETIOLOGY AND PATHOGENESIS There is good evidence that aPL can be pathogenic rather than a simple serological marker for APS, but the exact mechanisms by which these antibodies induce thrombosis remain to be clearly defined [44,45]. The so-called twohit model of thrombosis associated with aPL suggests that aPL per se are unable to trigger the coagulation cascade, and proposes that an initiating first-hit injury disrupts the endothelium, while a second hit potentiates thrombus formation. There is growing evidence that inflammatory stimuli are essential for triggering thrombosis, while tissue distribution of the major antigenic target (β2GPI) and the fine epitope specificity and avidity of antiβ2GPI antibodies may influence the type and occurrence of clinical manifestations [45 47]. Multiple pathogenic mechanisms have been proposed to explain the prothrombotic nature of aPL including the activation of cellular components (endothelial cells, platelets, monocytes, and neutrophils), activation of the coagulation cascade, inhibition of the fibrinolytic system, inhibition of natural anticoagulants (activated protein C, antithrombin, and the annexin A5 anticoagulant shield), and activation of the complement system. At present, it cannot be discerned whether one dominant mechanism is responsible for venous, arterial, or small-vessel thrombosis. Pathogenic mechanisms involved in pediatric APS have not been thoroughly investigated, but it is generally assumed that they are similar to adults. Additional factors that have particular relevance in the pediatric population include different concentrations of plasma procoagulant and anticoagulant proteins, increased incidence of infections, routine immunizations, and immaturity of the immune and other organ systems. Endothelial cell activation is likely the consequence of the cross-link of β2GPI with its receptor annexin II. aPL bind to the β2GPI, and through a signaling pathway involving myeloid differentiation factor 88 (MyD88), p38 mitogen-activated protein kinase (p38MAPK), and nuclear factor κB

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(NF-κB) activation, the endothelial cell becomes activated, increasing expression of the adhesion molecules (ICAM-1, VCAM-1, and E-selectin), and the coagulation protein, tissue factor [48]. Furthermore, receptors of the innate immunity, in particular toll-like receptor 4 (TLR-4), have been shown to mediate in vivo endothelial cell activation after aPL binding to β2GPI expressed on the cell membrane [49]. It has been suggested that polymorphisms of TLR-4 may determine the extent of the inflammatory response triggered by infectious agents and contribute to the assessment of thrombosis risk in aPL-positive patients [50]. The central importance of platelets in the development of arterial thrombosis and cardiovascular disease is well established. β2GPI-antibody complexes can bind to apolipoprotein E receptor 2 (ApoER2) and glycoprotein Ib α (GPIbα) receptors present on platelets, and this binding mediates the activation of platelets and the induction of thromboxane A2 synthesis. Activated platelets release a cationic protein, platelet factor 4, which can in turn facilitate dimerization of β2GPI, further promoting the formation of pathogenic immune complexes on platelet surface [51]. Currently, it is not known whether dysregulated platelet activation only accounts for the arterial thrombotic events or that it also explains the venous thromboembolic events associated with APS. In monocytes, aPL upregulate tissue factor expression and adhesion molecule expression, and the production of interleukins (IL)-1, IL-6, and IL-8 via phosphorylation of p38MAPK and the activation of NF-κB and MEK/ ERK kinases. These monocyte effects of aPL are likely important in preactivating endothelial cells to a prothrombotic phenotype. Antigen-antibody complexes made of aPL and the surface membrane phospholipids to which they are directed can activate complement promoting both inflammation at sites of antibody deposition and thrombus formation. It has been demonstrated that pregnancy morbidity in APS may be due not only to placental thrombosis but also to placental inflammation due to complement activation and to impairment of trophoblast function. aPL can interfere with anticoagulant effects of protein C and protein S systems in two different ways, including inhibition of the activation of protein C mediated by interference with thrombin and thrombomodulin, and acquisition of activated protein C resistance and protein C and/or S deficiency [52]. Because of the physiological role of the protein C and protein S systems, this finding can explain the higher risk for venous but not for arterial thrombosis.

CLINICAL MANIFESTATIONS Classical clinical features of APS in the adult population include vascular thromboses and recurrent fetal losses [39]. Besides these classical features, the clinical spectrum has broadened considerably over the last years, and

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thrombocytopenia, hemolytic anemia, livedo reticularis, cardiac valve disease, multiple-sclerosis-like syndrome, transverse myelitis, chorea, and migraine have been reported as well [2,53]. Most of the clinical features that can occur in adults with aPL have also been described in children, but there clearly are differences in the frequency of specific clinical events, since children generally do not have prothrombotic risk factors present in adults (such as atherosclerosis, cigarette smoking, hypertension, oral contraceptives, pregnancy). Among the 121 children with APS enrolled in the international pediatric APS registry (Ped-APS Registry), venous thromboses were more frequent in female adolescents with SLE and arterial ischemic cerebral events in younger children [24]. Of note, more than 40% of pediatric patients with APS were found to have an additional inherited prothrombotic risk factor, namely deficiencies of protein C, protein S, Factor V Leiden, prothrombin G20210A heterozygosity, and 677TT MTHFR polymorphism [24,40].

Thromboses Vascular occlusion in APS may involve arteries and veins at any level of the vascular tree and in all organ systems [1,24,40,41]. Analysis of the 121 children with aPL-related thrombosis included in the Ped-APS Registry revealed that 60% of pediatric APS patients presented with venous thrombosis, 32% with arterial thrombosis, 6% with small-vessel thrombosis, and 2% with mixed arterial and venous thrombosis [24]. The most frequently reported association with aPL is deep and superficial venous thrombosis in the lower extremities, which may be complicated by pulmonary embolism in some cases. Deep vein thrombosis in the lower extremities represented 40% of all cases included in the Ped-APS Registry, followed by cerebral sinus vein thrombosis in 7% and portal vein thrombosis in 3% [24]. Venous thrombosis also can affect vessels such as superior and inferior vena cava, renal, mesenteric, adrenal, hepatic, and retinal veins (Table 18.2). Arterial thrombosis most often involves the cerebrovascular circulation, with most patients presenting with stroke or transient ischemic attacks. Other reported sites of arterial thrombosis include peripheral, retinal, coronary, renal, mesenteric, and hepatic arteries (Table 18.3). Digital ischemia and renal thrombotic microangiopathy represented the most common small-vessel thromboses among pediatric APS patients [24,41].

Catastrophic Antiphospholipid Syndrome Catastrophic APS is an uncommon, potential life-threatening variant of APS characterized by aggressive microvascular occlusive disease involving multiple organs, mainly kidney, lung, central nervous system, heart, and skin [54,55]. Diagnosis of catastrophic APS is based on clinical involvement of at least three organ systems over a short period of time (less than 1 week) with

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TABLE 18.2 Venous Thrombosis Manifestations Associated With Antiphospholipid Antibodies in Children Vessel Involved (Organ)

Clinical Manifestations

Limbs

Deep vein thrombosis

Skin

Livedo reticularis, chronic leg ulcers, superficial thrombophlebitis

Large veins

Superior or inferior vena cava thrombosis

Lungs

Pulmonary thromboembolism, pulmonary hypertension

Brain

Cerebral venous sinus thrombosis

Eyes

Retinal vein thrombosis

Liver

Budd Chiari syndrome, enzyme elevations

Adrenal glands

Hypoadrenalism, Addison’s disease

TABLE 18.3 Arterial Thrombosis Manifestations Associated With Antiphospholipid Antibodies in Children Vessel Involved (Organ)

Clinical Manifestations

Limbs

Ischemia, gangrene

Brain

Stroke, transient ischemic attack, acute ischemic encephalopathy

Eyes

Retinal artery thrombosis

Kidney

Renal artery thrombosis, renal thrombotic microangiopathy

Heart

Myocardial infarction

Liver

Hepatic infarction

Gut

Mesenteric artery thrombosis

Bone

Infarction

histopathological evidence of small-vessel occlusion and serological confirmation of the presence of aPL [56,57]. Thrombosis of large vessels is less common in catastrophic APS, but may occur together with small-vessel occlusion.

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Data of 45 pediatric cases included in the catastrophic APS international registry revealed that a majority of patients had primary APS (69%) and 87% of patients developed catastrophic APS as initial presentation without any previous history of thrombosis [55]. Underlying infection was the most common precipitating factor present in 61% of pediatric cases compared to 26% in adult patients with catastrophic APS. Thrombocytopenia was found in more than 70% of pediatric patients with catastrophic APS and was one of the characteristic features [55]. The reported mortality rate in pediatric patients with catastrophic APS was between 26% and 33% [24,55]. A separate subset of APS termed microangiopathic antiphospholipid-associated syndrome was proposed to emphasize different conditions affecting the microvasculature that might also demonstrate aPL positivity, such as hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, malignant hypertension, and related syndromes [58]. The presence of aPL has been demonstrated in the classic pediatric hemolytic-uremic syndrome with acute renal failure due to widespread glomerular thrombosis [59,60]. The pathogenic role of aPL in these clinical conditions characterized by thrombotic microangiopathic hemolytic anemia remains controversial and patients may exist in whom the presence of aPL positivity just reflects the induction of aPL as an immune response to the endothelial damage or preceding infection [61]. Other possible causes need to be considered in these patients including inherited defects in complement genes (eg, complement factors H, I, B, and membrane cofactor protein), acquired autoantibodies against complement regulatory proteins, deficiency of von Willebrand factor cleaving protease (ADAMTS13), and inherited prothrombotic disorders [62 64].

Hematological Manifestations There are well-documented associations between aPL and hematological abnormalities, such as thrombocytopenia, autoimmune hemolytic anemia, and less commonly, leucopenia [24,53]. Hematological manifestations were reported in 38% of pediatric patients with confirmed thrombotic APS [24]. Isolated thrombocytopenia was seen in 8 9% and thrombocytopenia associated with autoimmune hemolytic anemia (Evans’ syndrome) in 12 16% of patients with pediatric APS [24,41]. Leucopenia, lymphopenia, autoimmune hemolytic anemia, and bleeding disorders were also reported in pediatric APS [24,41]. Thrombocytopenia is usually mild (with platelet counts greater than 50 3 109/L) and clinically benign; however, there are a few reports of children with severe aPL-related thrombocytopenia causing major bleeding [65]. In a cohort study of 42 children with immune thrombocytopenic purpura elevated concentrations of IgG aCL were found in 78% and anti-β2GPI in all chronic cases, while increased serum levels of IgG aCL were observed only in 27% and anti-β2GPI in 13% of children with acute immune thrombocytopenic purpura. Children with aPL who present with isolated

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hematological manifestations need closer follow-up because of risk for the development of future thrombosis or progression to overt SLE [43,66]. Although the presence of LA confers an increased risk for thrombosis, this antibody has been occasionally associated with a severe bleeding diathesis. This complication, termed the acquired LA-hypoprothrombinemia syndrome, is usually preceded by a viral infection and has been attributed to the presence of antiprothrombin antibodies that could cause rapid depletion of plasma prothrombin [67]. A review of 74 cases with this syndrome revealed that 50% of patients developed severe bleeding, while the mortality rate was below 5%. The acquired LA-hypoprothrombinemia syndrome most commonly occurs in young adults and was described also in several pediatric cases [68 70]. The thrombosis risk in this syndrome may strongly increase during treatment due to the improvement of plasma prothrombin level.

Neurological Manifestations The most common neurological complications of APS are ischemic stroke and cerebral venous sinus thrombosis, both caused by thrombotic occlusion of cerebral vessels. aPL were found to be significant prothrombotic risk factor for arterial and venous ischemic cerebral events [71,72] and screening of all children with ischemic stroke for aPL seems to be justified. The association between aPL and recurrent stroke risk is more controversial. In a prospective observational study including 185 children with arterial ischemic stroke or transient ischemic attack no difference was found in recurrence rates between the aCL-positive and aCL-negative groups, but the aCL-positive children were more likely to receive antithrombotic treatment, which might decrease their recurrence risk [73]. Several other neurological manifestations have been linked to aPL such as chorea, seizures, transverse myelopathy, migraine, cerebral ataxia, transient global amnesia, and psychosis [74]. These manifestations are not fully explained by the procoagulant effect of aPL and there are some experimental data that support possibility of nonthrombotic, immune-mediated mechanisms of neurological impairment associated with aPL [75 78]. The most common nonthrombotic neurological manifestations in children included in the Ped-APS Registry were migraine headache (7%), chorea (4%), and seizures (3%) [24]. Chorea has been described as an isolated clinical manifestation in children with aPL or in association with SLE [74,79,80]. The association between childhood seizure disorder and aPL has been reported in two prospective studies [81,82]. There has been controversy concerning a possible association of aPL and migraine, which has not been confirmed in a prospective study in an unselected group of children with migraine [83]. Elevated levels of aPL were reported also in children with autism spectrum disorders and were linked with more impaired behaviors such as lethargy, irritability, and stereotypy [84].

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Other Manifestations Dermatological manifestations of aPL have not been extensively investigated in childhood, but in clinical practice many aPL-positive children present with chronically cold hands and livedo reticularis (Fig. 18.1). aPL were found in 21% of children with primary or secondary Raynaud’s phenomenon [85]. Several other dermatological manifestations have been associated with APS, including skin ulcers due to multiple small vessel occlusions (Fig. 18.2), cutaneous necrosis, digital gangrene, superficial thrombophlebitis, and nailfold infarcts [86 88]. The most common skin disorders in children included in the Ped-APS Registry were livedo reticularis (6%), Raynaud’s phenomenon (6%), and skin ulcers (3%) [24].

FIGURE 18.1 Livedo reticularis in an adolescent girl with systemic lupus erythematosus and antiphospholipid antibodies.

FIGURE 18.2 Chronic leg ulcers in a child with systemic lupus erythematosus and positive antiphospholipid antibodies.

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Echocardiographic studies have disclosed heart valve abnormalities resembling Libman-Sacks endocarditis in 11% of adult patients with APS [53], but the frequency of this complication in pediatric APS seems to be significantly lower. The APS-associated nephropathy characterized by hypertension, acute renal failure, proteinuria and poorer renal function was reported in 16% of Thai patients with childhood-onset SLE who underwent renal biopsy [89]. aPL were also associated with hepatic, digestive, and adrenal manifestations resulting from occlusive vascular disease of intraabdominal vessels. Skeletal involvement might be an underrecognized manifestation of APS, which presumably develops as a consequence of microvascular thrombosis leading to bone microinfarcts, osteonecrosis, as well as fractures. An increased risk of developing avascular necrosis of bone in the absence of previous steroid administration has been reported in adult patients with aPL [90]. aPL have been implicated also in the pathogenesis of other osteoarticular disorders such as nontraumatic fractures, bone marrow necrosis, and Perthes’ disease [91 93].

Neonatal Antiphospholipid Syndrome Neonatal APS is a rare clinical entity characterized by neonatal thrombotic disease due to the transplacental passage of maternal aPL [94]. While women with aPL show a high incidence of obstetric and fetal complications, the aPL-related thrombosis in their offspring seems to be exceedingly rare. The low frequency of neonatal aPL-related thrombosis has been attributed to the lack of the most known second-hit risk factors in infants, and to a low transplacental passage of IgG2 subclass of aPL, which are responsible for most clinical pathogenicity [95]. Data from the European registry of babies born to mothers with APS showed that aPL-related clinical manifestations developed only in 2/134 (1%) neonates; both patients developed thrombocytopenia, but there were no cases of thrombosis [96]. During the long-term follow-up, 4/134 (3%) children included in the registry developed behavioral abnormalities including autism spectrum disorders, hyperactivity, language delay, and learning disabilities suggesting possible neurodevelopmental abnormalities [96,97]. The mechanism of neurodevelopmental abnormalities in these children could be related to prematurity or exposition to transplacentally transferred maternal aPL in utero. Isolated cases of neonatal thromboses associated with transplacentally acquired aPL were most commonly described in cerebral vessels and abdominal organs [94,98]. Special concern is needed particularly when dealing with aPL-positive infants who are exposed to other acquired thrombotic risk factors (ie, central vascular catheters, sepsis, prematurity, congenital heart disease, traumatic delivery), and possibly inherited prothrombotic disorders (ie, deficiencies of antithrombin, protein C, protein S, factor V Leiden, prothrombin 20120A gene mutation, polymorphism of MTHFR gene) [2,94,98].

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A subgroup of patients with de novo neonatal APS was described based on neonatal presentation of thrombosis, persistently positive aPL in a child, and negative aPL in the mother or cord blood. All de novo cases were found to have an additional acquired or inherited thrombotic risk factor, and no recurrence of thrombotic events was reported during the long-term follow-up period [99].

DIAGNOSTIC INVESTIGATIONS The presence of aPL should be investigated in every child presenting with thrombosis or clinical features that are very suggestive of APS, such as chorea, unexplained thrombocytopenia, hemolytic anemia, and livedo reticularis. Determination of aPL may provide clinically relevant information also in children with other aPL-associated clinical features, including various neurological and dermatological manifestations. In a child with SLE, it is recommended to perform aPL testing at the time of diagnosis and then at least once yearly as part of routine screening [1,100,101]. aPL are detected by a variety of laboratory tests and multiple tests should be used in diagnosing APS, because patients may be negative according to one test but positive according to another. In the cohort of children included in the Ped-APS registry, the presence of aCL was detected in 81%, antiβ2GPI in 67%, and LA in 72% of patients, respectively [24]. Thirty-three percent of children included in this cohort were positive for all three aPL subtypes and 67% tested negative for one or more of the aPL subtypes, emphasizing the importance of routine testing for multiple aPL subtypes in clinical practice. Determination of complete aPL profile is important also for stratification of thrombosis risk and identification of high-risk patients with multiple (particularly triple) aPL positivity [102]. Persistent positivity of aPL is of major importance for diagnosing APS and a time interval of at least 12 weeks between tests was suggested to demonstrate persistence [39]. The most sensitive test for aPL is the aCL test, which uses enzyme-linked immunosorbent assay to determine antibody binding to solid plates coated with either cardiolipin or other phospholipids. The specificity of aCL for APS increases with titer and is higher for the IgG than for the IgM isotype [3,103]. The observation that many aCL are directed at an epitope on β2GPI led to the development of anti-β2GPI immunoassays, which have improved specificities over the aCL test [104,105]. Evidence suggests that IgG antibodies directed against domain I of β2GPI are more strongly associated with thrombosis than those detected using the standard anti-β2GPI assay [106,107]. The LA test is a functional assay measuring the ability of aPL to prolong in vitro phospholipid-dependent clotting reactions such as the aPTT, the Russell viper venom time, or the kaolin clotting time [108]. In vivo, however, the presence of LA is paradoxically associated with thrombotic events rather than with bleeding. Inadequate data exist as to the clinical

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utility of other aPL assays for antibodies to prothrombin, phosphatidylethanolamine, anionic phospholipids other than cardiolipin, IgA isotype of aCL and anti-β2GPI, and the annexin A5 resistance test [39,109]. Thrombosis must be confirmed by objective validated criteria. Imaging studies are aimed to detect thrombosis in the target organ with the use of ultrasound, lung scanning, magnetic resonance arteriography/venography, or conventional angiography. For histopathologic confirmation of small vessels occlusions, thrombosis should be present without significant evidence of inflammation in the vessel wall.

DIFFERENTIAL DIAGNOSIS Given the spectrum of clinical manifestations, differential diagnosis of APS is very broad and depends on target organ involvement. Characteristic of pediatric thrombosis is a requirement to have multiple risk factors that lead to abnormal clotting [110]; therefore, all children presenting with aPL-related thrombotic event should receive a broad investigation for congenital prothrombotic states (protein S, protein C, antithrombin, total cholesterol, triglycerides, homocystein, factor V Leiden, prothrombin G20210A mutation, polymorphism of MTHFR gene) and acquired prothrombotic risks (infection, surgery, immobilization, trauma, malignancy, congenital heart disease, nephrotic syndrome, systemic vasculitis, central venous line). Testing for inherited prothrombotic disorders may be particularly important for early recognition of pediatric APS patients with highest risk for recurrent thrombosis that may benefit with intensified and prolonged anticoagulation therapy. Differentiation of isolated aPL-related thrombocytopenia from classic idiopathic thrombocytopenic purpura is important to indicate closer follow-up because of risk for the development of future thrombosis or progression to SLE [43,111]. Neurological manifestations of aPL should be distinguished from idiopathic neurological conditions, neuropsychiatric involvement in systemic autoimmune diseases, Sydenham chorea, multiple sclerosis, infections, intoxications, and other causes [112,113]. Catastrophic APS should be distinguished from severe SLE vasculitis, sepsis, hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, heparin-induced thrombocytopenia, macrophage activation syndrome, and disseminated intravascular coagulation [1,57,114].

TREATMENT Treatment in patients with positive aPL is focused on prevention of thrombosis in aPL carriers without previous thrombosis (primary thromboprophylaxis) and prevention of recurrent thrombosis in patients with APS who already had a thrombotic event (secondary thromboprophylaxis). A strict control of other prothrombotic risk factors should be accomplished, such as

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hypertension, obesity, and dyslipidemia. The optimal management of adolescents with aPL also should include the avoidance of smoking and use of oral contraceptives.

Primary Thrombosis Prophylaxis Asymptomatic children, in whom aPL were incidentally found, only rarely develop thrombotic complications [7]. Because of the low thrombosis risk, it is generally assumed that these children do not need any prophylactic treatment. There is considerable controversy as to whether prophylactic treatment is indicated in children who have never had thrombosis but fulfills the laboratory criteria for APS including persistently positive aCL in moderate to high titers, anti-β2GPI, and/or LA [39]. Because of the increased risk of bleeding during play and sports in children, which might outweigh the possible but unproven benefit of low-dose aspirin, it is generally recommended that asymptomatic children with aPL do not need long-term prophylactic treatment. The final decision should be individualized and based on the aPL profile (eg, presence of multiple aPL subtypes) and the presence of additional inherited or acquired prothrombotic risk factors. Prophylaxis with low molecular weight heparin administered subcutaneously should be considered to cover high-risk situations, such as prolonged immobilization or surgery [115]. Hydroxychloroquine, which has modest anticoagulant properties, may be protective against the development of thrombosis in aPL-positive patients with SLE [115 117]. Aspirin at low dose has also been used as prophylaxis in aPL-positive children with autoimmune diseases and in particular to prevent arterial thromboses, although there is no evidence yet that aspirin may provide protection against thrombosis in pediatric patients.

Secondary Thrombosis Prophylaxis Treatment of the acute thrombotic event in children with APS is no different from that of thrombosis arising from other causes. Patients are anticoagulated with unfractionated or low-molecular weight heparin followed by oral anticoagulants. There is general agreement that long-term anticoagulation is needed in children who experienced an aPL-related thrombosis to prevent recurrences, but there is no consensus about the duration and intensity of this therapy. Metaanalysis of secondary thromboprophylaxis in adult patients with definite APS suggests prolonged anticoagulation at a target INR of 2.0 3.0 in patients with first venous events and above 3.0 for those with recurrent and/ or arterial events [115,118]. Another large study has demonstrated that either low-dose aspirin or moderate intensity warfarin with INR between 1.4 and 2.8 are acceptable for adult patients with aPL and a first episode of ischemic stroke [119,120]; however, most patients included in this trial had only low levels of aCL and did not meet classification criteria for APS.

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Patients included in the Ped-APS Registry were treated according to the decision of their physician and all patients with venous thrombosis received long-term anticoagulation, but only 40% of patients with arterial thrombosis received anticoagulation therapy with or without concomitant antiaggregation therapy [24]. In spite of the long-term anticoagulation, 19% of pediatric patients with initial venous thrombosis and 21% of patients with initial arterial thrombosis developed recurrent thrombotic events, which is higher than reported in adult APS patients (3 16%) [53,121,122]. Given that the risk of recurrence might be lower in aPL-positive children compared with adults, and considering the higher risk of hemorrhage during play and sports, it was suggested to perform moderate intensity anticoagulation therapy targeted at an INR of 2.0 3.0 in pediatric patients who have experienced an aPL-related thrombosis [1]. In the Canadian study in pediatric SLE patients none of the LA-positive patients who were maintained in the target INR range of 2.0 3.0 developed a second thrombotic event [18]. In the absence of controlled trials, the optimal type and duration of treatment cannot be determined. An improved understanding of the pathogenic mechanisms by which aPL induced thrombosis has suggested also some innovative treatments such as oral direct thrombin inhibitor, antifactor Xa inhibitors, antiplatelet drugs, statins, complement inhibitors, peptide therapy, and B-cell inhibition [123]; however, there are no available data in the pediatric population.

Treatment of Catastrophic Antiphospholipid Syndrome The risk of recurrent thrombosis is extremely high in patients with catastrophic APS, therefore, their treatment must be complex and include elimination of possible precipitating factors, treatment of the ongoing thrombotic events, and suppression of the excessive cytokine storm [124,125]. Treatment of known precipitating factors includes prompt use of antibiotics if infection is suspected, excision of necrotic tissues, and aggressive treatment with steroid pulses and cyclophosphamide if in presence of an SLE flare. Treatment of the ongoing thrombosis needs to be aggressive with full doses of heparin and attempts to achieve a rapid reduction of aPL titers by intravenous immunoglobulin or, alternatively, plasma exchange. Combined treatment regimen with anticoagulants, corticosteroids, plasma exchange, and/or intravenous immunoglobulin was associated with the highest survival rate also in a recent series of pediatric catastrophic APS patients [55]. Rituximab was successfully used in 15/20 (75%) adult patients with refractory catastrophic APS [126].

Treatment of Neonatal Antiphospholipid Syndrome There are no uniform guidelines for the therapeutic approach in infants with neonatal APS [94,98]. Infants with stroke usually received only symptomatic

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treatment for the seizures, with or without antiaggregation, and infants with venous or disseminated thrombotic events received additional anticoagulation, thrombolytic therapy, and/or exchange transfusion. Children born to mothers with APS exceedingly rarely develop aPLrelated thrombotic events in the perinatal period, but may exhibit a higher percentage of neurodevelopmental changes including language delays and learning disabilities on a long term; therefore, it is recommended to include regular neuropsychological assessments during their clinical follow-up [97,127 129].

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Pediatrics in Systemic Autoimmune Diseases anticardiolipin antibodies are at risk for clinical manifestations related. Br J Rheumatol 1995;34:873 81. Seaman DE, Londino AV, Kwoh CK, Medsger TA, Manzi S. Antiphospholipid antibodies in pediatric systemic lupus erythematosus. Pediatrics 1995;96:1040 5. Berube C, Mitchell L, Silverman E, David M, Saint Cyr C, Laxer R, et al. The relationship of antiphospholipid antibodies to thromboembolic events in pediatric patients with systemic lupus erythematosus: a cross-sectional study. Pediatr Res 1998;44:351 6. Avcin T, Benseler SM, Tyrrell PN, Cucnik S, Silverman ED. A followup study of antiphospholipid antibodies and associated neuropsychiatric manifestations in 137 children with systemic lupus erythematosus. Arthritis Rheum 2008;59:206 13. Ahluwalia J, Singh S, Naseem S, Suri D, Rawat A, Gupta A, et al. Antiphospholipid antibodies in children with systemic lupus erythematosus: a long-term clinical and laboratory follow-up status study from northwest India. Rheumatol Int 2014;34:669 73. Avcin T, Silverman ED. Antiphospholipid antibodies in pediatric systemic lupus erythematosus and the antiphospholipid syndrome. Lupus 2007;16:627 33. Levy D, Massicotte M, Harvey E, Hebert D, Silverman E. Thromboembolism in paediatric lupus patients. Lupus 2003;12:741 6. Male C, Foulon D, Hoogendoorn H, Vegh P, Silverman E, David M, et al. Predictive value of persistent versus transient antiphospholipid antibody subtypes for the risk of thrombotic events in pediatric patients with systemic lupus erythematosus. Blood 2005;106:4152 8. Descloux E, Durieu I, Cochat P, Vital Durand D, Ninet J, Fabien N, et al. Paediatric systemic lupus erythematosus: prognostic impact of antiphospholipid antibodies. Rheumatology (Oxford) 2008;47:183 7. Caporali R, Ravelli A, De Gennaro F, Neirotti G, Montecucco C, Martini A. Prevalence of anticardiolipin antibodies in juvenile chronic arthritis. Ann Rheum Dis 1991;50:599 601. Serra CR, Rodrigues SH, Silva NP, Sztajnbok FR, Andrade LE. Clinical significance of anticardiolipin antibodies in juvenile idiopathic arthritis. Clin Exp Rheumatol 1999;17:375 80. Avcin T, Ambrozic A, Bozic B, Accetto M, Kveder T, Rozman’ B. Estimation of anticardiolipin antibodies, anti-beta2 glycoprotein I antibodies and lupus anticoagulant in a prospective longitudinal study of children with juvenile idiopathic arthritis. Clin Exp Rheumatol 2002;20:101 8. Avcin T, Cimaz R, Silverman ED, Cervera R, Gattorno M, Garay S, et al. Pediatric antiphospholipid syndrome: clinical and immunologic features of 121 patients in an international registry. Pediatrics 2008;122:e1100 7. Avcin T, Toplak N. Antiphospholipid antibodies in response to infection. Curr Rheumatol Rep 2007;9:212 18. Shoenfeld Y, Blank M, Cervera R, Font J, Raschi E, Meroni P-L. Infectious origin of the antiphospholipid syndrome. Ann Rheum Dis 2006;65:2 6. Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA. A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus 1992;1:75 81. McNally T, Purdy G, Mackie IJ, Machin SJ, Isenberg DA. The use of an anti-beta 2glycoprotein-I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis. Br J Haematol 1995;91:471 3.

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[100] Sen ES, Beresford MW, Avˇcin T, Ramanan AV. How to use lupus anticoagulants. Arch Dis Child Educ Pract Ed 2013;98:52 7. [101] Avcin T, Cimaz R, Meroni PL. Recent advances in antiphospholipid antibodies and antiphospholipid syndromes in pediatric populations. Lupus 2002;11:4 10. [102] Pengo V, Ruffatti A, Legnani C, Testa S, Fierro T, Marongiu F, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011;118:4714 18. [103] Pierangeli SS, Harris EN. A protocol for determination of anticardiolipin antibodies by ELISA. Nat Protoc 2008;3:840 8. [104] Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa M-C. Variability of anti-beta2 glycoprotein I antibodies measurement by commercial assays. Thromb Haemost 2005;94:665 72. [105] Reber G, Boehlen F, de Moerloose P. Technical aspects in laboratory testing for antiphospholipid antibodies: is standardization an impossible dream? Semin Thromb Hemost 2008;34:340 6. [106] de Laat B, Pengo V, Pabinger I, Musial J, Voskuyl AE, Bultink IEM, et al. The association between circulating antibodies against domain I of beta2-glycoprotein I and thrombosis: an international multicenter study. J Thromb Haemost 2009;7:1767 73. [107] de Groot PG, Urbanus RT. The significance of autoantibodies against β2-glycoprotein I. Blood 2012;120:266 74. [108] Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/ Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009;7:1737 40. [109] Bertolaccini ML, Amengual O, Atsumi T, Binder WL, de Laat B, Forastiero R, et al. “Non-criteria” aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010. Lupus 2011;20:191 205. [110] Yang JYK, Chan AKC. Pediatric thrombophilia. Pediatr Clin North Am 2013;60:1443 62. [111] El-Bostany EA, El-Ghoroury EA, El-Ghafar EA. Anti-beta2-glycoprotein I in childhood immune thrombocytopenic purpura. Blood Coagul Fibrinolysis 2008;19:26 31. [112] Ferreira S, D’Cruz DP, Hughes GRV. Multiple sclerosis, neuropsychiatric lupus and antiphospholipid syndrome: where do we stand? Rheumatology (Oxford) 2005;44:434 42. [113] Freeman H, Patel J, Fernandez D, Sharples P, Ramanan AV. Fitting and flailing: recognition of paediatric antiphospholipid syndrome. Arch Dis Child Educ Pract Ed 2014;99:28 36. [114] Golan TD. Lupus vasculitis: differential diagnosis with antiphospholipid syndrome. Curr Rheumatol Rep 2002;4:18 24. [115] Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Derksen R, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011;20:206 18. [116] Jung H, Bobba R, Su J, Shariati-Sarabi Z, Gladman DD, Urowitz M, et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 2010;62:863 8.

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Chapter 19

Behc¸et’s Disease I. Kone´-Paut Department of Pediatric Rheumatology, National Reference Center for Auto-Inflammatory Disorders, Biceˆtre University Hospital, Le Kremlin Biceˆtre, France

DEFINITION/CLASSIFICATION Behc¸et’s disease (BD) is a systemic inflammatory disease for which both autoinflammatory and autoimmune mechanisms may explain the pathogenesis. BD features include a vasculitis affecting all types and sizes of vessels and classified in the variable vessels vasculitis according to the classification adopted by the 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides [1]. There is no satisfactory definition of the disease; it is recognized only on a clinical basis with main clinical characteristics such as recurrent oral aphthosis (ROA), genital ulceration, and uveitis belonging to the former description of the disease by the Turkish dermatologist Huluci Behc¸et, whose name was given to the disease [2]. Other associated symptoms are numerous and may potentially involve all organs [3 5]. Even some of them appear as characteristic of BD, a considerable overlap exists between BD and both the spondyloarthropathy-related and the autoinflammatory conditions, and also with some immunodeficiency and malignant diseases [6,7]. As a result making the diagnosis, essentially on exclusion, can take several years. Many attempts, at least 15, have tried to provide an accurate classification of BD in adult patients. The international study group for BD had proposed the association of recurrent oral ulceration, at least thrice a year, as mandatory criteria associated with at least two other criteria among a list of cutaneous and ocular symptoms that gave a sensitivity of % and a specificity of % to make a diagnosis (Table 19.1) [8]. Classifications including oral ulcers as mandatory could exclude 5% of patients; in addition, other important involvement like the nervous system and the vessels may contribute in a decrease of both its sensitivity and specificity. Accordingly, new international criteria for BD have been recently published for which a score of 4 points or more may consider the diagnosis (Table 19.1) [9]. The applicability of these

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00019-0 © 2016 Elsevier B.V. All rights reserved.

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TABLE 19.1 International Classifications Criteria for Behc¸et’s Disease [8,9] Criteria of the International Study Group for Behc¸et’s Disease Recurrent oral aphthosis (mandatory) plus at least two of the following: Genital ulceration (or aphthosis) (at least 3 episodes per year, observed by a physician) Skin lesions Ocular lesions (erythema nodosum, necrotic folliculitis, papulopustular lesion) Positive pathergy test (Posterior, total uveitis or retinal vasculitis)

International Criteria 2014 Clinical Manifestations

Scoring System

Oral aphthosis

2

Genital ulceration

2

Ocular signs (anterior uveitis, posterior uveitis, retinal vasculitis)

2

Skin lesions (pseudo-folliculitis, skin aphthosis, erythema nodosum)

1

Neurological manifestation

1

Vascular signs (arterial thrombosis, large vein thrombosis, phlebitis, or superficial phlebitis)

1

Positive pathergy test (additional criteria)

1

Behc¸et’s disease diagnosis is made if the score is $4.

criteria in current practice outside clinical trials is questionable given that in most cases the diagnosis will rely on a combination of factors including the physician’s level of expertise in BD, the patient’s sex, country of origin, and age, as well as in some cases the pathology of a lesion. In addition, at disease onset, and particularly at the pediatric age, the number of symptoms may be too few to apply any classification to a single patient. An international group of experts has proposed a preliminary consensus classification of BD in children, yet unpublished, using a prospective cohort of pediatric BD patients (PEDBD) [10].

ETIOLOGY/PATHOGENESIS BD is a complex disease both on the clinical and on the pathogenesis levels. Formerly considered as an infectious condition due to a virus, the concepts have

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evolved to a disorder resulting in a deregulation of inflammation driven by both the innate and the adaptive. Ubiquitous microbial pathogen or their antigens (related to herpes simplex virus, streptococci, staphylococci, or Escherichia species) and heat-shock proteins may stimulate the innate immune system of BD patients through Toll-like receptors (TLRs), especially TLR2 and TLR4 [11]. In addition, like in other autoinflammatory diseases, flares of BD may be triggered by emotional stress, fatigue, and traumas. Conversely improvement of dental and periodontal hygiene has been associated with a decrease of oral ulcerations [12]. A major phenomenon in BD is the hyperactivity of neutrophils, T-helper (Th)-1, and Th-17 natural killer (NK) cells, the main result of which is the critical overproduction of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-17 [4]. The involvement of pathogens in individuals with genetic susceptibility is widely believed in BD, especially in those carrying the HLA-B51 tissue antigen.

GENETICS The genetic background of BD is suspected from years due to its peculiar geographic distribution, its association with the antigen HLA-B51, and the observation of familial cases and genetic anticipation [13,14]. Familial aggregation has been reported higher in pediatric BD, in accordance with a high genetic component [15]. Progress in its understanding has demonstrated that along with its clinical presentation, BD is a genetically complex disease. The association of the HLA-B51 with BD reaches 40 80% in countries where the disease is prevalent. Mahr et al. performed a metaanalysis on the predictive value of HLA-B51 determination using data from 2896 BD patients and 11,078 controls. Overall, the Odd Ratio (OR) for the presence of BD was 6.04 (95% CI 4.96 7.35) in HLA-B51-positive individuals. However, regional differences were observed, with a higher OR in the Middle East (6.93) and Southern Europe (7.65) compared to Northern Europe (4.91) [16]. Another association with HLA A2 (6) has been reported in several countries. Whole-genome screening analyses in the Turkish population have confirmed the association of BD with the HLA-B51 as the strongest, but also at a lesser extent with IL-10, IL23R/IL12, the antigen HLAA26, and Mediterranean fever MEFV genes [17,18]. An epigenomewide study was performed to investigate potential DNA methylation abnormalities in BD [19]. The results provided strong evidence that epigenetic modification of cytoskeletal dynamics underlies BD pathogenesis.

EPIDEMIOLOGY BD is associated with the old “silk road” trade route in the Far East, Middle East, and Mediterranean. The highest prevalence is observed in Turkey (80 370.0 per 100,000), in the Druze population of Israel (146 per 100,000),

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in Northern China, in Iran (100 per 100,000), and in the Turkish German population (77 per 100,000) [20 22]. The disease presentation is influenced by both the country of origin and the country of residence [23 25]. For example in Germany the disease appears more often in people of Turkish, Lebanese, and Greek origins than in the Germany-native population [23]. In the United States, BD is more severe in people originating from countries of high prevalence of BD. Some clinical features show marked regional differences in terms of both frequency and severity, like eye disease more prevalent and severe in Mediterranean countries and gastrointestinal disease more prevalent in the Far East. A variation by gender has been reported also in numerous countries but as a whole its distribution is equal. BD more frequently affects males in Mediterranean countries but more frequently females in Japan and Korea. In addition the gender is an important influence on clinical manifestations; that is, genital aphthosis and erythema nodosum being more frequent in females, uveitis and papulopustular lesions in males [26,27]. The usual age for the disease is 30 40 years but the disease may occasionally start and may be completed before the age of 16 years in 4 26% of cases [10,14,28 34]. Although the first symptoms of BD occur at a mean age of 8 years, it is usually recognized at a mean age of 14 years (Table 19.2) [10].

CLINICAL MANIFESTATIONS The clinical manifestations of BD are more recurrent than chronic, reflecting their link to acute inflammation. The onset of disease is insidious with few symptoms separated by months or years.

Fever Episodes of fevers have been variously reported in adults with BD and are associated strongly with vascular, neurological, or joint involvement [28,34]. Recurrent fevers could be more frequent (43%) in children with BD, and in young children also observed in association with attacks of oral aphthosis in a clinical feature resembling periodic fever, aphthosis pharyngitis, and adenitis (PFAPA) syndrome [35].

Mucocutaneous Lesions ROA is the initial manifestation of 70 90% of pediatric BD and present in almost all patients with BD (95%). Lesions may involve any part of the oral mucosa including lips and usually disappear without scarring. The typical lesion is round, with a sharp, erythematous border, and the surface is covered with a yellowish pseudo-membrane [4]. Patients usually present with oral aphthae (minor . major . herpetiform), which may be the only manifestation

TABLE 19.2 Respective Frequencies of Clinical Symptoms in Pediatric and Adult Behc¸et’s Disease Pediatric Series

N 5 patients

Adult Series

Karincaoglu [33]

Krause [32]

Kone´-Paut [14]

Alpsoy E [5]

Krause [32]

33

19

65

661

34

Oral aphthosis

100

100

96

100

100

Genital aphthosis

82

31.6

70

58.3

88.2

89.5

92

Cutaneous signs

82.4

Erythema nodosum

52

36.8

40

44.2

26.5

Pseudo-folliculitis

51

8/19

58

55.4

ND

Pathergy test

37

41.2

37.8

57.1

35

47.4

60

29.2

Approximately 50%

42.1

36

Ocular signs Anterior uveitis Posterior uveitis

47.1

10.5

8.8

Arthralgia/arthritis

40

47.4

56

33.4

17.6

Gastrointestinal

4.8

36.8

14

1.6

11.7

Neurological

a

7.2

26.3

15

3

5.8

Vascular

9.6

10.5

15

4.4

26.5

Family history of Behc¸et’s disease

19

ND

15

ND

ND

Age first symptom

12.3 (1 16)

6.9 6 3.9 y

8.4 (0 16)

ND

30.4 6 8 y

a

Other than headaches.

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FIGURE 19.1 Perianal ulceration and cutaneous aphthae in a girl with Behc¸et’s disease.

of disease for an average of 6 7 years before the second major manifestation is apparent [36,37]. Other causes of ROA are common in childhood and must be ruled out as possible. ROA is also frequent in young patients outside a systemic disorder like BD [35]. Important clues for BD is their morphology, usually minor, the increase of their recurrence with time, and the association of genital ulceration or aphthosis. Genital lesions are generally painful, and located on the vulva or scrotum. Other locations on the penis and in the perianal area occur more likely in childhood than in adult BD (Fig. 19.1). They are usually larger and deeper than oral aphthosis (OA) and have an irregular margin [4]. The presence of scar is remarkable and is a useful clue for eventual retrospective evaluation. The skin of patients with BD is irritable at puncture, minor trauma, and shaving. The pathergy phenomenon has been described as a pustula obtained 24 48 hours after intracutaneous injection or needle prick (24 gauges), in BD patients, more likely in Mediterranean and adult patients than in children [8]. Acneiform, folliculitis-like, and papulopustular lesions on the back and lower extremities are the most common skin lesions often occurring in combination (Fig. 19.2). Erythema nodosum is more often observed in female patients, is usually painful, and appears on the front of the legs. Other nodular lesions may correspond to superficial vein thrombosis. Sweet syndrome like lesions, pyoderma gangrenosum, and necrotizing vasculitis are more exceptional [4].

Ocular Lesions Posterior or total uveitis, frequently bilateral accompanied with retinal vasculitis, macular edema, and papillitis are the most typical of BD. The frequency of uveitis varies considerably among countries (60 80%) and is generally lower in pediatric cases (34%) [10,14,30]. Young males are significantly more affected

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FIGURE 19.2 Papulopustular lesions in Behc¸et’s disease.

than females [10,14,31]. Anterior uveitis with hypopion was part of the first descriptions of BD but appears finally less characteristic of this disease than posteye involvement. In a Tunisian retrospective survey of 62 patients (111 eyes), panuveitis (68 eyes, 61.3%), and posterior uveitis (38 eyes, 34.2%) were the most common forms, followed by anterior uveitis (5 eyes, 4.5%). Retinal vasculitis was found in 89 eyes (80.2%). Most common complications included posterior synechiae (32.4%), cataract (31.5%), and cystoid macular edema (19.8%) [38]. Similar findings were observed in adult and childhood uveitis from several case series [39,40]. The course of BD-associated uveitis may be very severe, especially in male patients who are significantly more frequently affected than female patients, with definite impairment of visual acuity secondary to optic atrophy [31]. Data from the PEDBD registry at a mean of 5 years of follow-up showed that visual acuity was decreased ,1/10 in 16.6% (26/156) of patients, which represented 33.3% (26/78) of patients with ocular involvement (unpublished). This finding underlines the severity of uveitis in male children with BD. Interestingly, the frequency of extraocular manifestations has been found to be lower than that in the general Behc¸et disease population [39].

Neurological Lesions Neurological involvement occurs in 5.3 59% of adult patients [41]. Headache, a common and disabling symptom in BD, may be associated with a variety of neurologic syndromes (in 5 31% of cases) and ocular inflammation, or may present as an isolated feature [42]. The PEDBD study showed 68 (43.59%) patients with chronic headaches (unpublished). Headaches should be not considered as neuroBD (NBD) if they are not associated to a neurologic symptom, a cerebrospinal fluid (CSF) or MRI abnormality, and if they may be related to a cause other than BD [43]. The onset of NBD may be either acute or progressive; in rare cases (5%) NBD can be the initial presentation of BD [44]. NBD can be

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distinguished in parenchymal (due to inflammatory lesions of the spinal cord and the brain) and vascular (cerebral venous sinus thrombosis and intracranial or extra cranial aneurysms). Parenchymal lesions of encephalomyelitis are generally acute. Patients present with acute headaches, bilateral papilledema, and hemiparesis accompanied with signs of brainstem involvement (ataxia, pyramidal and extrapyramidal syndrome, epilepsy, and cranial nerve involvement) [41]. The NBD lesions are mainly located at the mesodiencephalic junction and the brainstem, with typical features consisting of small scattered inflammatory lesions detected on MRI with contrast enhancement during their acute phase, and peripheral edema. These features are not specific and look like multiple sclerosis especially if they are the first manifestation of BD (5% of cases). Other lesions include pseudo-tumor cerebri, revealed by progressive headaches, lethargy, bilateral papilledema, and sixth nerve palsy; and myelitis (spinal cord involvement). Other lesions unclassified as parenchymal or vascular are observed such as inflammatory meningitis, myositis (myopathy), and peripheral neuropathy. Chronic NBD includes various neuropsychiatric disturbances such as cognitive impairment, memory loss, depression, anxiety, pseudo-bulbar syndrome, and definite sensitive and motor deficits. The long-term outcome of parenchymal BD is poor. In the large series of 115 patients by Noel et al., after a median follow-up of 73 months (IQR 59 102 months), 29 patients (25.2%) became dependent (were unable to perform activities of daily living) or died. Factors independently associated with poor outcome were paresis at onset (OR 6.47 [95% CI 1.73 24.23]) and location of inflammatory lesions at the brainstem on MRI (OR 8.41 [1.03 68.43]). The outcome of children with NBD is also severe and on 12 patients reported by Metreau Vastel et al., 9 had sequelae and 8 had difficulties in learning. Six stopped at middle school level [41,43].

ARTICULAR FEATURES Joint problems in BD are usually minor, limited to inflammatory arthralgia in a few joints (knees, ankles, elbows, and wrists) and run acute and recurrent course. In a large series of patients from Morocco, monoarthritis and oligoarthritis were seen in 16.17% and 11.76% of cases, respectively, and polyarthritis involving the large limb joints and the small joints of the hands and feet in 17.05% of cases [44]. In the PEDBD study, joint symptoms were present in 50% (78/156) of definite BD patients. Axial arthritis was reported in 16.67% (26/156), and peripheral arthritis in 47.44% (74/ 156) (unpublished). These data are in accordance with that reported in adults. Association with HLA B27 spondylarthropathy is seen in 2% of patients [44].

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GASTROINTESTINAL INVOLVEMENT In children with BD, isolated abdominal pain is frequently reported [10,14]. True colitis is extremely rare and raises the challenging question of another cause of inflammatory colitis, for example, Crohn’s disease or ulcerative colitis. The existence of gastrointestinal BD is debated in Western countries whereas it can reach 40% in Japan and Korea [4]. The most common intestinal symptoms of BD are diarrhea (bloody or not bloody), nausea, vomiting, weight loss, and abdominal pain. The most common location is the ileocecal and the colon region, however the whole digestive tract may be involved, except the rectum very occasionally. The evolution is generally more severe than in other inflammatory bowel diseases, often requiring surgery due to abscess and perforation.

VASCULAR INVOLVEMENT BD vasculitis, so-called “variable,” may affect any type of vessels but predominantly the veins. The venous and arterial wall lesions attract cytokinergic and neutrophilic reactions. Activated neutrophils get excessive production of superoxide anion radicals and lysosomal enzymes that induce lesions of the vessel’s wall. Endothelial damage with aneurysm formation cause local blood flow abnormalities. Endothelial dysfunction, release of von Willebrand factor, platelet activation, enhanced thrombin and fibrin generation, antithrombin deficiency, and impaired fibrinolysis enhance thrombosis associated with BD. Venous thrombosis is a predominant feature of BD, which has been integrated in international criteria. If the condition per se is a risk for vascular activation, mal patients are predominantly affected (SR 6/1) and many patients may cumulate other factors of thrombophilia such as anticardiolipin antibodies and protein C deficiency [45]. Involvement of the lower extremities (tibial, femoral, and iliac vessels) are the most common but may affect many different sites including the inferior and superior vena cava, pulmonary artery, suprahepatic vessels (Budd Chiarri), and cardiac cavities [4,45]. In adults 27.7 35.4% of patients with vascular BD have recurrent vascular events in follow-up [46]. In our PEDBD cohort, venous thrombosis occurred in 15.38% (24/156) of patients, arterial thrombosis in 2.56% (4/156), and arterial aneurysms in two patients (unpublished). In the Turkish BD population, new vascular event development risk is 23.0% at 2 years and 38.4% at 5 years [46]. Vasculitis of the pulmonary arteries is usually revealed by hemoptysis (79% of cases) followed by cough, fever, dyspnea, and pleuritic chest pain and leads to aneurysm and thrombus formation evolving to stenosis or permanent occlusion [47]. Of importance, in a large series of Seyahi et al., 91% of the patients had active disease outside the lungs when they presented with pulmonary artery involvement [47]. In addition, peripheral venous thrombosis was present in 36 of 47 (77%) patients,

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and intracardiac thrombi in 12 of the 36 (33%) patients. After a mean follow-up of 7 years, 12 of 47 (26%) patients were dead, especially those with the larger aneurysms.

PULMONARY INVOLVEMENT Beside pulmonary artery involvement, several other lesions have been reported; multiple pulmonary parenchymal lesions such as nodules, consolidations, and cavities are part of this involvement as well. Pleural effusions are usually associated with nodular lesions. Mediastinal lymphadenopathy may appear and disappear in follow-up. In all cases, ruling out pulmonary infection is a necessity [47].

CARDIAC INVOLVEMENT Valsalva sinus aneurysms and aortitis are the most frequently reported cardiovascular complications, with BD particularly involving the root of the aorta. Coronary aneurysms may be asymptomatic, or may manifest with acute coronary syndrome. All cardiac tunics may be inflammatory. Pericarditis is the most common, manifesting as recurrent, constrictive tamponade or small asymptomatic pericardial effusion. Intracardiac thrombus is occasionally seen more often in the right ventricle. Heart failure is due to cardiomyopathy, which can be ischemic, nonischemic, or inflammatory in nature [48].

URINARY AND NEPHROLOGICAL INVOLVEMENT Orchitis, epididymitis, urethritis and sterile cystitis are seldom reported. The nephrological involvement is not exceptional but generally mild. The vascular disease comprises thrombosis, stenosis, and aneurysms of the renal arteries leading to arterial hypertension. BD-associated diseases include several types of glomerulonephritis, crescentic glomerulonephritis and IgA nephropathy being the most common [49]. Tubulo interstitial nephropathy is rare. AA amyloidosis has decreased with time and better management of BD.

OUTCOME AND PROGNOSIS The course of BD is unpredictable and marked by acute and remission periods. In adults the disease is very active during the third decade of life; they decrease in severity and frequency after 10 years of evolution. Functional sequellae are observed in 30% of patients and are related to neurological and visual impairments (loss of vision, encephalopathy, and paralysis). Vascular disease is the main cause of mortality in pediatric BD, 5% in an international survey [14]. An analysis of causes of death in French adult patients with BD showed major vessel disease (mainly arterial aneurysm and Budd Chiari

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syndrome) (43.9%), cancer and malignant hemopathy (14.6%), central nervous system involvement (12.2%), and sepsis (12.2%) [50]. The mortality rate at 5 years was estimated 3.3% and associated with younger age (15 25 years), male sex, arterial involvement, and a high number of flares.

DIAGNOSTIC INVESTIGATION The diagnosis of BD is based on a combination of clinical symptoms, which are generally few at onset of the disease. Accurate patient reporting and clinical expertise of lesions are mandatory, whereas no other tests are reliable to BD. During the acute phase of the disease the acute phase reactants (ie, C-reactive protein and erythrocyte sedimentation rate) may not be modified, except in case of serositis or active vasculitis. The utility of searching the HLA-B51 is relatively low and BD cannot be ruled out in the absence of B51. Histological findings of skin lesions may show an accumulation of activated neutrophils and small-vessel vasculitis concordant with but not specific to BD.

DIFFERENTIAL DIAGNOSIS Aphthosis Recurrent aphthous stomatitis (RAS) is a common oral disorder that affects 20% of the general population with familial clustering. The lesions of RAS are not caused by a single factor but appear in a permissive environment, triggered by food hypersensitivity, trauma, stress, or infection. To properly diagnose RAS, it is necessary to exclude other “correctable” causes. The most common of these is the syndrome of PFAPA initially described in 12 children [51]. The disease is characterized by high fevers lasting 5 days, recurring regularly every 3 6 weeks, with symptom-free intervals. The key features are observed in 70 90% of cases and accompanied with abdominal pain, headaches, and nausea. The course is benign since episodes are dramatically resolved with oral steroids or tonsillectomy. The etiology is unknown and most observations are sporadic; however, a genetic component is not excluded. The predictable and stereotypic character of clinical manifestations makes this disease easily recognizable by aware physicians. The hyper IgD syndrome (HIDS) is quite less frequent but young children with either oral or bipolar aphthosis should be taken into consideration. The main presentation is recurrent fever lasting 5 7 days, accompanied by headaches, lethargy, cervical adenitis, abdominal distress, urticarial rash, and transient arthritis. First manifestations of HIDS start during the first year of life and are triggered by infections and immunizations. A high level of serum IgD was previously considered as a hallmark of HIDS [52]. However, increasing case reports have shown that this finding is neither constant nor specific to this disease. Conversely, detection of slight mevalonic aciduria in a febrile patient allows the diagnosis while HIDS is caused by a partial

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mevalonate kinase (MVK) deficiency. Genetic confirmation is available by identifying mutations in the MVK gene on chromosome 12p13. Immunodeficiency, especially neutrophil defects, may reveal by repeated aphthosis. Among them, cyclic neutropenia is the most remarkable in young children manifesting by regular attacks of mucosal ulceration, lymphadenopathy, and infectious colitis with sometimes life-threatening infections. A 21-day oscillation in the peripheral blood neutrophils count ,2 3 106/L (often 0) to near-normal to normal levels correlates with myeloid waves at bone marrow examination. The defect is either sporadic or dominantly inherited and mutations in the gene coding for neutrophil elastase into chromosome 19p13.3 are present in 90% of cases. Mucosal ulceration and infections are efficiently preventable by administration of granulocytes stimulating factor [53]. The other immunological disorders that may induce oral ulceration are chronic granulomatous disease, severe combined immunodeficiency, leukemia, HIV infection, and systemic lupus erythematosus.

Periodic Fever Syndromes BD is a cause of recurrent fever especially in childhood [54]. Well-defined entities to be distinguished are PFAPA syndrome, HIDS, and familial Mediterranean fever (FMF). FMF is the most common recurrent fever syndrome, affecting people from Middle Eastern and Mediterranean countries. First manifestations appear in young age (mean 4 years old) with fever lasting 2 3 days, chills, abdominal and thoracic pain, arthritis (knee, ankle), and myalgia. Erysipela-like erythema over the dorsum of the foot is a hallmark of this disorder. Renal amyloidosis is the most severe complication to be prevented by daily colchicine therapy. Mutations of the MEFV gene on chromosome 16p13.3 are responsible for FMF, and the presence of two (one on each chromosome) is mandatory for the definite diagnosis of this autosomal recessive disease. FMF and BD affect the same populations and share common clinical symptoms. Moreover MEFV mutations are more frequent in BD patients than in the general population, suggesting at least one common factor for autoinflammation in this episodic disease [55].

Neurological Involvement Encephalomyelitis of BD is not specific and must be distinguished from infectious, tumoral, or other inflammatory processes, especially multiple sclerosis, lupus erythematosus, antiphospholipid syndrome, or sarcoidosis [56].

Uveitis Toxoplasmosis is the most common cause of posterior uveitis in childhood, followed by sarcoı¨dosis and BD. The major causes of anterior uveitis are

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herpes infection and spondyloarthropathies. BD-related uveitis is not granulomatous and includes vasculitis of the retina, which is not the case of spondyloarthropathies and of some periodic fever syndromes mimicking BD.

Arthritis Differential diagnoses of BD arthritis in childhood include reactive arthritis, juvenile idiopathic arthritis, and spondyloarthropathies.

TREATMENT The treatment of BD remains difficult, due to the wide variety of clinical manifestations not relying on a unique mechanism. In addition, data provided from evidence-based medicine are very few regarding the efficacy and safety of medications. Treatments for BD are currently used for the major part of them, out of a label of the health authorities. The aim of treatments is to suppress inflammation, immunosuppressive drugs being mandatory for serious involvement; for example, eye, neurological, and vascular disease. In 2008, an international panel of experts addressed nine main recommendations for the treatment of BD; as a whole they are also applicable in pediatric patients with some differences (Table 19.3) [57]. Close communication among the various specialists is essential for successful management.

Mucocutaneous Lesions Colchicine has been used for a long time to treat mucocutaneous lesions. Its efficacy on oral and genital ulcers has not been demonstrated by controlled studies; even colchicine on clinical observations remains a first-line treatment for OA. Pain-relieving treatments and topical measures (steroidal topics) may help during attacks. Minimizing local traumatisms and improvement of dental hygiene may decrease the incidence of attacks of OA. Colchicine is a treatment of choice for erythema nodosum and other nodular lesions. Thalidomide is rapidly effective in severe aphthosis and pseudo-folliculitis with the restriction of nervous toxicity to be carefully monitored in a child [58]. In resistant cases of mucocutaneous lesions other immunosuppressants should be used such as azathioprine, TNFα inhibitors, or interferon α. Apremilast, an oral phosphodiesterase-4 inhibitor, has shown effectiveness for the treatment of mucous lesions and was recently approved by The Food and Drug Administration (FDA) and European Medicines Agency (EMA) after positive results on BD-related OA in a placebo-controlled study [59].

Arthritis NSAIDs and colchicine are the mainstay of treatment in BD-related arthritis. A short course of steroids may be warranted in resistant cases.

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TABLE 19.3 EULAR Recommendations for the Management of Behc¸et’s Disease [57] 1. Any patient with Behc¸et’s disease (BD) and inflammatory eye disease affecting the posterior segment should be on a treatment regime that includes azathioprine and systemic corticosteroids. 2. If the patient has severe eye disease defined as two lines of drop in visual acuity on a 10/10 scale and/or retinal disease (retinal vasculitis or macular involvement), it is recommended that either cyclosporine A or infliximab be used in combination with azathioprine and corticosteroids; alternatively IFNα with or without corticosteroids could be used instead. 3. There is no firm evidence to guide the management of major vessel disease in BD. For the management of acute deep vein thrombosis in BD immunosuppressive agents such as corticosteroids, azathioprine, cyclophosphamide, or cyclosporine A are recommended. 4. For the management of pulmonary and peripheral arterial aneurysms, cyclophosphamide and corticosteroids are recommended. 5. Similarly there are no controlled data on or evidence of benefit from uncontrolled experience with anticoagulant, antiplatelet, or antifibrinolytic agents in the management of deep vein thrombosis or for the use of anticoagulation for the arterial lesions of BD. 6. There is no evidence-based treatment that can be recommended for the management of gastrointestinal involvement of BD. Agents such as sulfasalazine, corticosteroids, azathioprine, TNFα antagonists, and thalidomide should be tried first before surgery, except in emergencies. 7. In most patients with BD, arthritis can be managed with colchicine. 8. There are no controlled data to guide the management of CNS involvement in BD. For parenchymal involvement agents to be tried may include corticosteroids, IFNα, azathioprine, cyclophosphamide, methotrexate, and TNFα antagonists. For dural sinus thrombosis corticosteroids are recommended. Cyclosporine A should not be used in BD patients with central nervous system involvement unless necessary for intraocular inflammation. 9. The decision to treat skin and mucosa involvement will depend on the perceived severity by the doctor and the patient. Mucocutaneous involvement should be treated according to the dominant or codominant lesions present. Topical measures (ie, local corticosteroids) should be the first line of treatment for isolated oral and genital ulcers. Acne-like lesions are usually of cosmetic concern only. Thus, topical measures as used in acne vulgaris are sufficient. Colchicine should be preferred when the dominant lesion is erythema nodosum. Leg ulcers in BD might have different causes. Treatment should be planned accordingly. Azathioprine, IFNα and TNFα antagonists may be considered in resistant cases.

Severe Manifestations High-dose steroids alone or in combination with immunosuppressants (azathioprine, cyclosporine, and cyclophosphamide) remain a mainstay in the therapy when severe clinical manifestations are present (ocular, neurological, gastrointestinal, or vascular) [57]. In addition to these, Gevokizumab, an anti-IL-1 monoclonal antibody, was recently approved for use in severe

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cortico-dependant sight-threatening uveitis [60]. The use of anticoagulants in severe vascular involvement is still a controversy. No studies have proven its utility, and it may increase the risk of aneurysm bleeding in pulmonary artery vasculitis [61].

REFERENCES [1] Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;65(1):1 11. ¨ ber Rezidivierende Aphtose Durch ein Virus Verursachte Geschwu¨re am [2] Behc¸et H. U Mund, am Auge und an den Genitalien. Derm Wschr 1937;105:1152. [3] Shimizu T, Erlich GE, Inaba G, Hayashi K. Behc¸et’s disease. Sem Arthritis Rheum 1979;8:223 60. [4] Sakane T, Takeno M, Suzuki N, Inaba G. Behc¸et’s disease. N Engl J Med 1999;21:1284 91. [5] Alpsoy E, Donmez L, Onder M, Gunasti S, Usta A, Karincaoglu Y, et al. Clinical features and natural course of Behc¸et’s disease in 661 cases: a multicentre study. Br J Dermatol 2007;157(5):901 6. [6] Yazici H, Ugurlu S, Seyahi E. Behc¸et’s disease, is it one condition? Clinic Rev Allerg Immunol 2012;43:275 80. [7] Kone´-Paut I, Sanchez E, Le Quellec A, Manna R, Touitou I. Autoinflammatory gene mutations in Behc¸et’s disease. Ann Rheum Dis 2007;66(6):832 4. [8] International Study Group for Behc¸et’s Disease. Criteria for diagnosis of Behc¸et’s disease. Lancet 1990;335:1078 80. [9] International Team for the Revision of the International Criteria for Behc¸et’s Disease (ITR-ICBD). The International Criteria for Behc¸et’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014;28(3):338 47. [10] Kone´-Paut I, Darce-Bello M, Shahram F, Gattorno M, Cimaz R, Ozen S, et al. Registries in rheumatological and musculoskeletal conditions. Paediatric Behc¸et’s disease: an international cohort study of 110 patients. One-year follow-up data. Rheumatology (Oxford) 2011;50(1):184 8. [11] Horie Y, Meguro A, Ota M, Kitaichi N, Katsuyama Y, Takemoto Y, et al. Association of TLR4 polymorphisms with Behcet’s disease in a Korean population. Rheumatology (Oxford) 2009;48(6):638 42. [12] Seoudi N, Bergmeier LA, Drobniewski F, Paster B, Fortune F. The oral mucosal and salivary microbial community of Behc¸et’s syndrome and recurrent aphthous stomatitis. J Oral Microbiol 2015;7:27150. [13] Barnes CG, Yazici H. Behc¸et’s syndrome. Rheumatology 1999;38:1171 6. [14] Kone´-Paut I, Yurdakul S, Bahabri SA, Shafae N, Ozen S, Ozdogan H, et al. Clinical features of Behc¸et’s disease in children: an international collaborative study of 86 cases. J Pediatr 1998;132(4):721 5. [15] Kone´-Paut I, Geisler I, Wechsler B, Ozen S, Ozdogan H, Rozenbaum M, et al. Familial aggregation in Behc¸et’s disease: high frequency in siblings and parents of pediatric probands. J Pediatr 1999;135(1):89 93. [16] Maldini C, Lavalley MP, Cheminant M, de Menthon M, Mahr A. Relationships of HLAB51 or B5 genotype with Behcet’s disease clinical characteristics: systematic review and meta-analyses of observational studies. Rheumatology (Oxford) 2012;51(5):887 900.

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[17] Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behc¸et’s disease. Nat Genet. 2010;42(8):698 702. [18] Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, et al. Genomewide association analysis identifies new susceptibility loci for Behc¸et’s disease and epistasis between HLA-B 51 and ERAP1. Nat Genet 2013;45(2):202 7. [19] Hughes T, Ture-Ozdemir F, Alibaz-Oner F, Coit P, Direskeneli H, Sawalha AH. Epigenome-wide scan identifies a treatment-responsive pattern of altered DNA methylation among cytoskeletal remodeling genes in monocytes and CD4T cells from patients with Behc¸et’s disease. Arthritis Rheumatol 2014;66:1648 58. [20] Zouboulis CC, Kotter I, Djawari D, et al. Epidemiological feature of Adamantiades Behcet’s disease in Germany and in Europe. Yonsei Med J 1997;38:411 22. [21] Sibley C, Yasici Y, Tascilar K, Kahn N, Bata Y, Yasici H, et al. Behc¸et syndrome manifestations and activity in the United States versus Turkey—A cross sectional cohort comparison. J Rheumatol 2014;41(7):1379 84. [22] Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM. Epidemiology and clinical characteristics of Behc¸et’s disease in the US: a population-based study. Arthritis Rheum 2009;61(5):600 4. [23] Ko¨tter I, Vonthein R, Mu¨ller CA, Gu¨naydin I, Zierhut M, Stu¨biger N. Behc¸et’s disease in patients of German and Turkish origin living in Germany: a comparative analysis. J Rheumatol 2004;31(1):133 9. [24] Mahr A, Belarbi L, Wechsler B, Jeanneret D, Dhote R, Fain O, et al. Population-based prevalence study of Behc¸et’s disease: differences by ethnic origin and low variation by age at immigration. Arthritis Rheum 2008;58(12):3951 9. [25] Davatchi F, Shahram F, Chams-Davatchi C, Shams H, Nadji A, Akhlaghi M, et al. Behcet’s disease: from East to West. Clin Rheumatol 2010;29(8):823 33. [26] Tursen U, Gurler A, Boyvat A. Evaluation of clinical findings according to sex in 2313 Turkish patients with Behc¸et’s disease. Int J Dermatol 2003;42(5):346 51. [27] Bonitsis NG, Luong Nguyen LB, LaValley MP, Papoutsis N, Altenburg A, Ko¨tter I, et al. Gender-specific differences in Adamantiades Behc¸et’s disease manifestations: an analysis of the German registry and meta-analysis of data from the literature. Rheumatology (Oxford) 2015;54(1):121 33. [28] Toplak N, Frenkel J, Ozen S, Lachmann HJ, Woo P, Kone´-Paut I, et al. An international registry on autoinflammatory diseases: the Eurofever experience. Ann Rheum Dis 2012;71(7):1177 82. [29] Bahabri S, Al Mazyed A, Al Balaa S, El Rhamani A, Al Dalaan A. Juvenile Behcet’s disease in Arab children. Clin Exp Rheumatol 1996;14:331 5. [30] Kim DK, Chang SN, Bang D, Lee ES, Lee S. Clinical analysis of 40 cases of childhood-onset Behc¸et’s disease. Pediatric Dermatol 1994;11:95 101. [31] Pivetti-Pezzi P, Accorinti M, Abdulaziz MA, La Calva M, Torella M, Riso D. Behc¸et’s disease in children. Jpn J Ophtalmol 1995;39:309 14. [32] Krause I, Uziel Y, Guedj D, Mukamel M, Harel L, Molad Y, et al. Childhood Behc¸et’s disease: clinical features and comparison with adult-onset disease. Rheumatology (Oxford) 1999;38(5):457 62. [33] Karincaoglu Y, Borlu M, Toker SC, Akman A, Onder M, Gunasti S, et al. Demographic and clinical properties of juvenile-onset Behc¸et’s disease: a controlled multicenter study. J Am Acad Dermatol 2008;58(4):579 84.

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[34] Seyahi E, Karaaslan H, Ugurlu S, Yazici H. Fever in Behc¸et’s syndrome. Clin Exp Rheumatol 2013;31(3 Suppl. 77):64 7. [35] Cantarini L, Vitale A, Bersani G, Nieves LM, Cattalini M, Lopalco G, et al. PFAPA syndrome and Behc¸et’s disease: a comparison of two medical entities based on the clinical interviews performed by three different specialists. Clin Rheumatol 2015;Feb 10 [Epub ahead of print] [36] Letsinger JA, McCarty MA, Jorizzo JL. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J Am Acad Dermatol 2005;52:500 8. [37] Bang D, Hur W, Lee ES, Lee S. Prognosis and clinical relevance of recurrent oral ulceration in Behcet’s disease. J Dermatol 1995;22:926 9. [38] Khairallah M, Attia S, Yahia SB, Jenzeri S, Ghrissi R, Jelliti B, et al. Pattern of uveitis in Behc¸et’s disease in a referral center in Tunisia, North Africa. Int Ophthalmol 2009;29 (3):135 41. [39] Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, Huseyin Altunbas H, Urgancioglu M. Uveitis in Behc¸et disease: an analysis of 880 patients. Am J Ophthalmol 2004;138(3):373 80. [40] Tugal-Tutkun I, Urgancioglu M. Childhood-onset uveitis in Behc¸et disease: a descriptive study of 36 cases. Am J Ophthalmol 2003;136(6):1114 19. [41] Noel N, Hutie´ M, Wechsler B, Vignes S, Le Thi Huong-Boutin D, Amoura Z, et al. Pseudotumoural presentation of neuro-Behcet’s disease: case series and review of literature. Rheumatology (Oxford) 2012;51(7):1216 25. [42] Vishwanath V, Wong E, Crystal SC, Robbins MS, Filopoulos M, Lipton RB, et al. Headache in Behc¸et’s syndrome: review of literature and NYU Behc¸et’s syndrome centre experience. Curr Pain Headache Rep 2014;18(9):445. [43] Metreau-Vastel J, Mikaeloff Y, Tardieu M, Kone´-Paut I, Tran TA. Neurological involvement in paediatric Behc¸et’s disease. Neuropediatrics 2010;41(5):228 34. [44] Benamour S, Zeroual B, Alaoui FZ. Joint manifestations in Behc¸et’s disease. A review of 340 cases. Rev Rhum Engl Ed 1998;65(5):299 307. [45] Krupa B, Cimaz Z, Ozen S, Fischbach M, Cochat P, Kone´-Paut I. Paediatric Behc¸et’s disease and thromboses. J Rheumatol 2011;38(2):387 90. [46] Alibaz-Oner F, Karadeniz A, Ylmaz S, Balkarl A, Kimyon G, Yazc A, et al. Behc¸et disease with vascular involvement: effects of different therapeutic regimens on the incidence of new relapses. Medicine 2015;94(6):e494. [47] Seyahi E, Melikoglu M, Akman C, Hamuryudan V, Ozer H, Hatemi G, et al. Pulmonary artery involvement and associated lung disease in Behc¸et disease: a series of 47 patients. Medicine (Baltimore) 2012;91(1):35 48. [48] Demirelli S, Degirmenci H, Inci S, Arisoy A. Cardiac manifestations in Behcet’s disease. Intractable Rare Dis Res 2015;4(2):70 5. [49] Ozen S. The “other” vasculitis syndromes and kidney involvement. Pediatric Nephrol 2010;25(9):1633 9. [50] Saadoun D, Wechsler B, Desseaux K, Le Thi Huong D, Amoura Z, Resche-Rigon M, et al. Mortality in Behcet’s disease. Arthritis Rheum 2010;62:2806 12. [51] Marshall GS. Syndrome of periodic fever, pharyngitis and apthous stomatis. J Pediatr 1987;111:307 9. [52] Drenth JPH. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. Nat Genet 1999;22:180 3. [53] Palmer SE, Stephens K, Dale DC. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am J Med Genet 1996;66(4):413 22.

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[54] Majeed HA. Differential diagnosis of fever of unknown origin in children. Cur Opin Rheumatol 2000;2:439 44. [55] Touitou I, Magne X, Molinari N, Navarro A, Quellec AL, Picco P, et al. MEFV mutations in Behc¸et’s disease. Hum Mutat 2000;16(3):271 2. [56] Kone´-Paut I, Chabrol B, Riss JM, Mancini J, Raybaud C, Garnier JM. Neurologic onset of Behc¸et’s disease: a diagnostic enigma in childhood. J Child Neurol 1997;12:237 41. [57] EULAR recommendations for the management of Behcet’s disease. Ann Rheum Dis 2008;67:1656 62. [58] Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behc¸et syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128(6):443 50. [59] Hatemi G, Melikoglu M, Tunc R, Korkmaz C, Ozturk BN, Mat C, et al. Apremilast for Behcet’s syndrome—a phase 2, placebo-controlled study. N Engl J Med 2015;372:1510 18. [60] Gu¨l A, Tugal-Tutkun I, Dinarello CA, Reznikov L, Esen BA, Mirza A, et al. Interleukin1β-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet’s disease: an open-label pilot study. Ann Rheum Dis 2012;71(4):563 6. [61] Tayer-Shifman OE, Seyahi E, Nowatzky J, et al. Major vessel thrombosis in Behcet’s disease: the dilemma of anticoagulant therapy—the approach of rheumatologists from different countries. Clin Exp Rheumatol 2012;30:735 40.

Chapter 20

Childhood Sarcoidosis C.H. Wouters1,2 and C.D. Rose3,4 1

Department of Microbiology and Immunology, University of Leuven, Pediatric Immunology, Leuven, Belgium, 2Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium, 3 Thomas Jefferson University, Philadelphia, PA, United States, 4duPont Children’s Hospital, Wilmington, DE, United States

INTRODUCTION Definition The term childhood sarcoidosis has been used to designate a chronic inflammatory disease characterized by granulomatous “boggy” polyarthritis and tenosynovitis, uveitis, and rash. Extension of the disease to involve large vessels [1 3] as well as heart, lung, kidney, and liver [4] in different stages of the disease is rare. Childhood sarcoidosis is seen typically in children younger than 5 years of age, and in contrast with the adult form, is associated with a paucity of constitutional symptoms, namely, lymphadenopathy and fatigue. Since its earliest descriptions, it has been recognized that childhood sarcoidosis can present both in a familial form, reported by Edward Blau in 1985 [5], and in a sporadic one, known as early onset sarcoidosis (EOS), described in 1970 by North [6]. Additionally, it is worth remarking that both Blau syndrome (BS) and EOS are highly associated with mutations in the gene coding for nucleotide oligomerization domain (NOD) 2, a highly conserved protein involved in the intracellular mechanisms of the innate immune system. This finding has placed EOS and BS in a select group of rheumatic diseases for which a specific mutation has been described. Interestingly these two are the most “rheumatic” of all, suggesting a particular arthritogenic effect of this mutation.

Nomenclature Despite the histopathologic similarities between adult sarcoidosis and EOS/ BS there is not much connection between these entities neither clinically nor genetically. We follow the pioneering writings of Dr. Miller and agree that

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00020-7 © 2016 Elsevier B.V. All rights reserved.

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the term sarcoidosis should be removed from these forms of pediatric arthritis. It has become clear in recent years that the differences between BS and EOS are probably artificial. The authors prefer BS to refer to this condition regardless of the presence or absence of other affected family members, and to use sarcoidosis for the adult form of the disease, even if it starts in childhood.

History In 1985, two independent reports described families with an autosomal dominant form of granulomatous arthritis. Douglas Jabs described a three-generation family with four affected members. Clinical manifestations included noncaseating granulomatous synovitis, uveitis, cranial neuropathies including sensory hearing loss and transient sixth nerve palsy, but no cutaneous involvement [7]. That same year, Edward Blau reported a four-generation family with 11 affected members. This family exhibited noncaseating granulomatous synovitis and tenosynovitis, granulomatous uveitis (clumpy precipitates), and papulosquamous skin rash with associated dermal noncaseating granulomas [5]. A third family, involving a mother and two daughters, was reported in 1990 with the Blau triad of polyarthritis, iritis, and granulomatous papulosquamous rash, and BS emerged as a distinct clinical entity [8]. Clinically indistinguishable from BS, although lacking the autosomal dominant transmission, EOS was recognized in the 1960s, but the first detailed description is owed to North and colleagues [6]. Over the following years, the phenotype of the disease has been expanded significantly with multiple descriptions [1 3,9 12]. In the mid 1990s, a susceptibility locus was mapped on the original Blau kindred to chromosome 16 positioned at 16p12-21 [13]. In 2001, a mutation in CARD15, also termed Nucleotide Oligomerization Domain protein 2 (NOD2), was found to increase the risk of Crohn’s disease (CD). This locus fell within the susceptibility region mapped by Tromp for BS, and since CD is a granulomatous disease, Miceli-Richard and colleagues tested this candidate gene in four French Blau families [14]. Three distinct mutations within the nucleotide binding domain (NBD) of CARD15 were found and proven different from the ones found for CD, which are located in the leucin reach repeat (LRR) domain of the same protein [15,16]. Recent molecular work by two independent research teams has demonstrated the BS mutation of CARD15 in sporadic early onset granulomatous arthritis, confirming that BS and EOS are the same disease [17,18]. Currently BS is considered part of the group of hereditary autoinflammatory diseases and the number of described NOD2 mutations is increasing. The Infevers database keeps an updated catalog on the mutations as they become published in the literature [19].

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EPIDEMIOLOGY Few population-based studies of BS are available. In the Danish Sarcoid Registry, between 1979 and 1994 only 48 confirmed cases out of 5536 reported had onset before age 15 and only 3 before age 5 [20]. Of these three, two were twins, and although family history is not provided, we could assume autosomal dominant inheritance in this case. According to this study the adult form of sarcoidosis presenting in the pediatric age has an incidence of 0.29/100,000 person-years and PGA (pediatric granulomatous arthritis; familial and sporadic) has an incidence of 0.06/100,000 person-years [21]. In an attempt to investigate the clinical features of BS/EOS, a North American registry was initiated by Petty and Lindsley between 1991 and 1993 including 18 biopsy-confirmed patients from 7 countries. Of these, 17 had polyarthritis and 10 had uveitis. This registry was expanded to 53 in a consecutive report, and interestingly 11 of the reentries had a first-degree affected relative. Although prevalence figures cannot be extrapolated from this study, a ratio of 1 to 5 between familial and sporadic cases is suggested [22]. As expected from an autosomic dominant trait, the disease is equally distributed among genders with no phenotypic variability in relationship to sex. Most patients with a sporadic form develop symptoms before age 5 and over two-thirds of patients with a familial form present within the first 2 years of life. There is no racial predominance nor phenotypic variation by race or ethnicity, and the disease seems to be distributed worldwide with cases reported throughout the Americas, Europe, Australia, and Asia. To date there has been no relationship between phenotype and mutation variants but new mutations are being described, raising the possibility of genotype/phenotype correlations to be found in the near future.

ETIOLOGY/PATHOGENESIS The CARD15 gene encodes a 1040 amino acid protein comprised of 2 N-terminal caspase recruitment domains (CARDs), 1 NACHT or nucleotide binding site (NBS) domain, and C-terminal LRRs. To date, multiple different genetic mutations leading to amino acid substitutions in or near the NBS/ NACHT domain of NOD2 have been documented in affected patients with either the familial or the sporadic presentations of the disease [14,23,24]. Of those, R334W (substitutes arginine to glutamine at position 334), and R334Q (arginine to tryptophan at position 334), are the most prevalent. The location of these mutations is different from the CD mutations that have been found at or near the LRR region of CARD15 [15]. Conversely, work with adult sarcoidosis did not support a gene defect in NOD2 [25,26] underlining the distinction between adult and EOS. The NOD2 protein and its homolog NOD1 are members of a growing family of NOD cytosolic proteins implicated in inflammation and apoptosis.

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The NOD domain was first found in apoptotic protease activating factor-1 (APAF-1) and its nematode homolog CED-4, which are two essential regulators of programmed cell death. Most NOD-family members contain three distinct functional domains, an amino-terminal effector-binding domain, a centrally located NOD, and a carboxy-terminal ligand-recognition domain. Within the family of NOD proteins, NOD2 is mostly known for its major role in binding to RIP2 and NF-κB activation although a role in apoptosis has been shown as well, often using overexpression systems [27,28] (Fig. 20.1).

FIGURE 20.1 The majority of NOD proteins are composed of variable amino-terminal effector-binding domains, a centrally located NOD that mediates self-oligomerization, and a carboxyl-terminal ligand-recognition domain. WDRs, WD40 repeats; IPAF, ICE-protease activating factor; PYD, pyrin domain; NAIP, neuronal apoptosis inhibitory protein; BIR, baculovirus inhibitor-of-apoptosis factor; DC, dendritic cell; CIITA, MHC class II transactivator; AD, activation domain; X, putative effector-binding domains with no known homology; TIR, toll/interleukin-1 receptor domains; α/c, α-helix/coiled-coil rich; DT, DEFCAP/TUCAN expanded homology domain; WRKY, zinc finger-like domain found in plant W-box-binding transcription factors. Adapted with permission from Ref. [27].

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The CARD domain structure is highly conserved across species and has an important role in the mediation of NF-κB activation, which results from CARD CARD interactions between CARD15 and a pivotal downstream kinase protein RIP2 (receptor-interacting protein 2, also known as RICK and CARDIAK). RIP2 mediates the activation of NF-κB through the common inhibitor of NF-κB kinase (IKK) complex and promotes caspase activation, leading to the secretion of proinflammatory cytokines. The NACHT domain, also referred to as NOD or NBS domain, mediates selfoligomerization, which is required for the activation of downstream effector molecules [28,29]. The LRR region is structurally related to the LRR regions of the toll-like receptors (TLRs), which are molecules of the innate immune system indispensable for the “sensing” of molecular motifs specific to pathogens, such as lipopolysaccharide (LPS). Whereas the ligand for NOD1 is LPS, recent studies have shown that the moiety recognized by NOD2 is actually muramyl dipeptide (MDP), a building block of peptidoglycan found in both gram-positive and gram-negative bacterial cell walls [28] (Fig. 20.2). NOD2 is expressed constitutively in monocytes, granulocytes, and dendritic cells as well as in Paneth cells in the villous crypts of the small intestine, which are of epithelial origin. Its expression can be induced by proinflammatory cytokines in cultured intestinal epithelial cells [9 12]. The mutations in NOD2 associated with CD are found near or in the LRR region [15,16]. These mutations are loss-of-function variants since they result in a defective ability of NOD2 to sense peptidoglycan. Given that the response of NOD2 to peptidoglycan is the activation of an inflammatory cascade, the effect of these mutations in predisposing to inflammatory disease seems counterintuitive, although work in this area is evolving. The gene variants associated with BS involve residues located in the NOD domain and act as constitutively active NOD2 mutants, that is, gain-of-function variants. This is consistent with the autosomal dominant nature of the disease. The NOD domain is critically involved in oligomerization and activation of NOD2, suggesting that these mutations may increase function by stabilizing the active conformation of the protein [23] although these findings have not been replicated yet (Fig. 20.3). The pathologic hallmark of BS is the presence of noncaseating epitheloid cell granulomata indistinguishable morphologically from those seen in sarcoidosis. This pathologic feature has not been biologically linked with NOD2. Experience in sarcoidosis led to the understanding that granulomas are the result of an exaggerated immune-inflammatory response against an undefined antigen. They consist of a central cluster of monocyte/ macrophages in various states of activation, epitheloid cells, and multinucleated giant cells, surrounded by a rim of CD4+ T cells and scattered CD8+ T cells and plasma cells [30,31]. Recent investigations in adult sarcoidosis have identified several cytokines and chemokines secreted in

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Peptidoglycan

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NOD2

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RICK

NF-κB activation, caspase activation Apoptosis Secretion of pro inflammatory cytokines (TNF, IL-1β)

CARD

Inflammatory responses

Kinase domain NOD FIGURE 20.2 NOD1 and NOD2 proteins recognize bacterial-derived LPS and peptidoglycan molecules through their LRR domains. Signaling through NOD1 and NOD2 is mediated through the kinase RICK, which interacts with NOD1 and NOD2 through CARD CARD interactions. RICK mediates NF-κB activation through the common inhibitor of NF-κB kinase (IKK) complex (not shown) and promotes caspase activation that leads to the secretion of proinflammatory cytokines. Adapted with permission from Ref. [28].

situ, and clarified mechanisms leading to recruitment and activity of lymphocytes and monocytes at sites of granuloma formation. In the early phase infiltrating CD4+ T cells show a dominant Th1-type profile with elevated mRNA and protein levels of interferon (IFN)-γ and interleukin (IL)-2, which act as local growth factors. Sarcoid macrophages express IL-12, which is known to stimulate proliferation of activated T cells and differentiation of Th1 cells. Several chemotactic stimuli like IL-16 and IL-8 as well as monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1α (MIP-1α) seem to cooperate with the

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Peptidoglycan

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Leu1007 fsinsC

NOD2

Gly908Arg Arg334Trp, Arg334Gn

Arg702Trp

RICK

Absent or decreased signaling

Uncontrolled signaling

Pediatric granulomatous arthritis Chron’s disease FIGURE 20.3 NOD variants that are associated with Crohn’s disease (Leu1007fsinsC, Gly908Arg, Arg702Trp) are located near or in the leucine-rich repeats. These variants are defective in their response to bacterial peptidoglycan, resulting in absent or decreased signaling. NOD2 mutations associated with Blau syndrome (Arg334Trp, Arg334Gln) are located in the nucleotide binding oligomerization domain and are activating mutations that lead to uncontrolled signaling in the absence of a ligand. Adapted with permission from Ref. [28].

recruitment of CD4+ T cells and monocytes [30,31]. A second mechanism responsible for the accumulation of inflammatory cells at the site of granuloma formation appears to be the in situ proliferation of both T cells and macrophages by the local release of cytokines and growth factors [30]. An increased expression of proinflammatory cytokine genes IL-1, tumor necrosis factor (TNF)-α, and IL-6 by cells inside granulomas was shown by in situ hybridization and immunohistologic techniques [31]. Finally, the continuous formation and persistence of immune granulomas may also reflect an abnormal regulation of apoptosis within the granulomatous structure through the chronic overexpression of TNF-α, IL-15, and IFN-γ (via the expression of P21WAF1) and the upregulation of a number of apoptosisrelated gene products, including growth factors and the Bcl-2 family of genes [31,32]. A morphologic and immunohistochemistry study on remnant biopsy tissue from patients with BS from the registry was performed by the authors and compared with histologic material from the tissue bank

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of patients with CD carrying a NOD2 mutation. The BS granulomas appeared highly organized and emperipolesis was observed. The cytokine profile was different from the one observed in CD and a role for IL-17 was suggested by the findings [33]. Whereas the aforementioned data undoubtedly add to the understanding of cellular interactions governing the formation and maintenance of granuloma in adult sarcoidosis, the relationship between CARD15/NOD2 mutations and granulomatous inflammation remains to be elucidated. Apart from its major role in the mediation of NF-κB activation, CARD15 has been shown to enhance apoptosis and apoptotic caspase activation using only overexpression systems [27,28]. One is tempted to hypothesize that granuloma formation in BS patients reflects both increased proinflammatory activity and defective monocyte apoptosis. Experiments to study this rather attractive theory are underway. Interestingly, altered neutrophil apoptosis was found to contribute to formation of granuloma in chronic granulomatous disease [34]. The investigation of inflammatory and apoptotic events in BS patients with CARD15 mutations will be a major subject of future research in the field. At last, due to the cytoplasmic localization of CARD15 and its potential participation in various signaling complexes it will be important to determine the array of proteins with which NOD2 interacts.

CLINICAL MANIFESTATIONS The description that follows encompasses the so-called classic form of the disease as described originally by Blau and Jabs [5,7] for the familial form, by North [6] for the sporadic disease, and expanded by later reports [1 3,9 12]. It should be noted that the spectrum of pediatric granulomatous diseases and of rheumatic conditions associated with granulomatous synovitis is much more complex. We will describe briefly the nonclassical forms as disease variants since it appears that this group does not share the genetic mutations in NOD2 observed in the majority of individuals with the classic form.

Classic Form: Onset The most common initial manifestation of the disease is the classic tan-colored cutaneous rash (vide infra) followed within 6 months by a symmetrical polyarthritis. Eye disease tends to appear in the second year of the illness. Slightly less commonly, the disease starts with polyarthritis and rash simultaneously and very rarely the three core manifestations (polyarthritis, dermatitis, and uveitis) are present at onset. An International Registry of Blau Syndrome was coordinated by the authors of this chapter and incepted in

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Distribution of onset type

10

5

0 Skin

Joints

UNK.

Simult.

Eyes

FIGURE 20.4 Type of onset among 27 affected individuals with the classic form of the disease (International Registry).

2005. Fig. 20.4 shows distribution of onset in individuals with classical phenotype the largest series existing to date [35]. We have not seen individuals with isolated ocular onset. The average age of onset in the registry was 26 months, with one child presenting as early as 2 months of age and at the other end of the spectrum one female patient starting at 14 years of age. Both genders showed an almost equal representation, as it is expected in an autosomic dominant, single-allele disease.

Classic Form: Articular Involvement The majority of patients present with polyarticular, symmetrical joint involvement either additive (within weeks) or generalized from onset. In the registry 95% of the patients showed polyarticular onset and course. The disease affects large and small joints of hands and feet. Oligoarthritis has been observed as well. The most striking characteristic is the exuberant character of the synovitis which has been described as “boggy” or cystic; however, this pattern was seen in 75% of biopsy-proven, mutation-confirmed cases in the registry. This bogginess is best exemplified in the carpus and tarsus where the physical appearance may resemble a synovial cyst (Fig. 20.5). Morning stiffness is less severe than in rheumatoid arthritis for an equivalent severity of joint inflammation. Similarly, the degree of contracture, pain, and heat detected on the joint examinations tends to be less severe than what one would expect for the degree of swelling (Fig. 20.6). The joints feel spongy and range of motion is relatively preserved. An exception to such rule is the severe contracture in the proximal interphalangeal (PIP) joints of the hands. It is common for those presenting at early age that by late childhood they will exhibit severe PIP contracture of the finger joints (Fig. 20.7). Indeed, this finding earlier led authors to include camptodactyly in the diagnostic triad [9]. Wrist subluxation and ulnar deviation can be seen in adults with longstanding disease (Fig. 20.8).

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FIGURE 20.5 Cyst-like synovitis and ichtyosiform rash.

FIGURE 20.6 Boggy synovitis with relatively preserved range of motion.

FIGURE 20.7 Family with affected mother and two siblings, with development of camptodactyly.

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FIGURE 20.8 Longstanding wrist synovitis with ulnar deviation and camptodactyly.

FIGURE 20.9 Wrist synovitis with camptodactyly and tenosynovitis of extensor digitorum longus.

Involvement of tendon sheaths is characteristic. The involved tendons are thickened upon visual inspection and spongy on palpation. The most commonly affected are the extensor and flexor digitorum, anserinus, tibialis, peroneus, and flexor policis longus (Fig. 20.9). Carpal tunnel symptoms from entrapment are exceptional.

Classic Form: Cutaneous Manifestations Tan-Colored Rash The most common cutaneous manifestation is a characteristic scaly erythematous rash mainly located on the trunk, mostly dorsum, arms, and legs with a predilection for extensor surfaces in the latter two. It can be mildly itchy but is mostly asymptomatic. In itself it is more of a valuable diagnostic clue than an annoyance for the patient. The lesions tend to acquire a tan hue, they are

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FIGURE 20.10 Ichthyosiform skin eruption.

round-shaped, barely palpable, and small (5 7 mm). The rash is usually misdiagnosed as atopic dermatitis but it is more reminiscent of ichthyosis than of eczema (Fig. 20.10). The natural history of the rash is that of exacerbation and quiescence persisting in some patients to adolescence and in other disappearing after a year or two. In the experience of the author, children with 6 10 years of disease will show some evidence of a scaly thickened rash that depicts no erythematous elements and is very reminiscent of mild ichthyosis vulgaris limited to small patches on extensor surfaces.

Erythema Nodosum A few patients with classic disease will develop short-duration episodes of typical nodular rash in the lower extremities, clinically indistinguishable from erythema nodosum. There are no data with regard to the histological features of this particular manifestation.

Classic Form: Ocular Manifestations Very rarely, it will require more than 2 years from disease onset for these children to develop eye disease. Usually presenting as bilateral asymmetrical anterior uveitis, it soon becomes a pan-uveitis, very difficult to control and persistent. Without a doubt the involvement of the eye is the single most important source of disability in this disease. About half of the patients will develop secondary cataracts, and increased intraocular pressure is seen in a third. Posterior involvement with vitritis, retinal vasculopathy, and compromise of the optic nerve can be seen in about 20% with the corresponding sometimes dismal

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visual outcome. The typical clumpy keratic precipitates will alert the experienced ophthalmologists into suspecting this disease. The reader is referred to Lindsley’s description of the biomicroscopic ocular findings in BS [22].

Classic Form: Internal Organ Disease The triad of polyarticular arthritis/tenosynovitis, pan-uveitis, and tan-colored rash (core manifestations) with onset before age 5 combined with the finding of noncaseating granulomatous inflammation in synovium, conjunctiva, and dermis are the basis for the diagnosis of BS. It should be noted, however, that over the years the spectrum of the disease has been expanding with visceral involvement documented in multiple case reports. Granulomatous infiltrates have been seen in the liver [11], kidney [12], lung parenchyma [4], and myocardium [4]. We have observed recently peripheral lymph node involvement in one patient as well. This rather widespread distribution seen in both familial and sporadic cases resembles primary adult sarcoidosis. Bilateral hilar adenopathy, however, has never been described in BS.

Classic Form: Vascular Involvement Early reports of large vessel involvement in BS rather than PGA have been confirmed more recently and in at least one case with documented mutation in CARD15 [36]. Remarkably it is unknown if large vessel involvement is granulomatous as well. Reports of aortic arch and branches mimicking Takayasu’s arteritis [1,37], abdominal aorta [2], and renal arteries [3] with associated malignant hypertension have been documented. Small-vessel and medium-sized-vessel disease may occur but are uncommon. Hypertension without demonstrable large-vessel involvement has been observed in patients with BS [42].

Classic Form: Late Disease A report of late disease [4] described widespread dissemination in autopsybased studies. This report suggests that at least in some cases the disease is associated with mortality. Patients have died with cardiac failure and respiratory failure, and in some cases widespread granulomatous involvement was documented [4].

Other Pediatric Granulomatous Inflammatory Disease Variants: Systemic Granulomatosis, Granulomatous Panniculitis, and Granulomatous Osteitis We have collected in the registry a few children with very early onset of nodular panniculitis associated with granulomatous inflammation documented in the subcutaneous fat tissue biopsy or in other involved organs. These

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patients whose clinical course resembles a severe nonlipodystrophic form of Weber Christian syndrome do not carry mutations in NOD2. Other children present with granulomatous involvement of the reticulo-endothelial system mimicking systemic histiocytosis and also show wild-type NOD2. Uveitis, synovitis, but not tan-colored rash is seen in these children. Finally, monoostotic sarcoid-like osteitis with or without associated synovitis can occur, and again in these children, the wild-type NOD2 has been seen.

Adult-Type Childhood Sarcoid Arthritis Arthritis is not a common manifestation of adult sarcoidosis. Large series report around 5% frequency of true arthritis and 10% of articular symptoms among adults with sarcoidosis [20,21]. Clinicians have recognized two patterns of joint involvement. The most common is an acute arthritis (mainly ankles), associated with erythema nodosum and hilar adenopathy (Loefgren syndrome). These patients are systemically ill, febrile, and experience weight loss. The other rheumatic presentation is a more indolent form of oligoarthritis mainly affecting the knees. This chronic arthritis is similar to rheumatoid arthritis in its erosive potential but oligoarticular. The granulomatous character of the synovitis is unclear. In an early report by Sokoloff and Bunin [38] the disease was described as granulomatous with noncaseating granulomas in the synovial tissue. Later, Palmer and Schumacher performed a systematic investigation with needle biopsy on seven patients with sarcoidosis and arthritis and failed to show granuloma formation in the synovial samples [39]. Adolescents, in particular those of African ancestry, can present with any of these patterns—acute and rheumatoid-like. Occasionally this arthritis is associated with palpable purpura and granulomata in the dermis can be found in association with otherwise classic leukocytoclastic vasculitis. These children are indistinguishable from adult sarcoidosis, presenting all the features of that disease including hilar adenopathy, interstitial pneumonitis, myositis, aseptic meningitis, and white matter disease. Detailed descriptions of adult-type sarcoidosis are beyond the scope of this review.

DIAGNOSTIC INVESTIGATIONS Routine Laboratory Investigations Peripheral blood counts are usually within normal limits except for mild anemia. Patients with systemic granulomatosis can present cytopenias but those are not seen in the classic form of the disease. Unless there is severe renal involvement as seen in the presence of interstitial nephritis the renal chemistries are normal. Despite granulomatous infiltration of the liver, hepatic chemistry can be normal as well.

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Antinuclear antibodies and rheumatoid factors are absent. Elevated angiotensin converting enzyme (ACE) is inconsistent and it lacks the diagnostic and monitoring value seen among adults with sarcoidosis. It should be noted that ACE levels in young children are not very well standardized. Hypercalcemia has been described in both the adult form of the disease and in BS. The sedimentation rate tends to be in the mid-fifties when disease is active but its value [42] as a marker of disease activity has not been well studied in BS.

Pathology The diagnosis rests on the presence of noncaseating giant cell granulomas (Fig. 20.11). Typical skin lesions yield positive results in almost 100% of the cases. In the synovium, however, sampling could affect the sensitivity of the test. In both synovial and cutaneous samples an associated chronic inflammatory infiltrate is characteristic. Involvement of the subcutaneous tissue is seen only in patients with clinical panniculitis, and in those with involvement is lobular rather than septal and is of the nonvasculitic type. As noted before patients with panniculitis have not shown mutations in NOD2. Conjunctival biopsy can yield granulomas when there is follicular/nodular involvement on clinical examination; otherwise, the sensitivity in asymptomatic or diffusely erythematous conjunctiva is low. The granulomas characteristically are those of noncaseating type. Each giant cell represents the fusion of 3 12 macrophages. When the nuclei are lined-up resembling epithelium the lesion is called epithelioid granuloma. There is scarce experience with the histology of the vessel wall in associated large vessel vasculitis except in autopsy-based cases.

Genetic Testing The published frequency of NOD2 mutations was 50% for the familial form [36] and 90% for the sporadic form of BS [17]. In the experience of the authors all classic forms of the disease, either familial or sporadic, have

FIGURE 20.11 Noncaseating multinucleated giant cell granulomata.

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shown mutations in NOD2. Genetic testing has become the standard confirmatory test for BS, yet when “new” mutations are found, histologic confirmation is still recommended.

Imaging Chest films may be necessary to establish the presence of interstitial lung disease. Although there are not evidence-based current recommendations in order to detect mild parenchymal disease, high resolution CT may be necessary when patients become systemically ill. This technique should be used sparingly due to the high radiation exposure involved. Radiologic monitoring of joint involvement is usually not necessary, since the disease is not erosive and only after several years leads to contractures and limitation and it remains nonerosive even later [40]. Vascular imaging may be necessary when large-vessel vasculitis is suspected. CT-angiogram, Doppler sonogram, or magnetic resonance angiography will be selected according to the territory under study and the preference of the center.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of pediatric polyarthritis is vast. Here we include some of the most frequent conditions that can be a challenge for the clinician because of the combination of arthritis and uveitis. It is important to recall that in the familial forms of BS, the index of suspicion will be raised by the presence of family history, albeit there are other causes of familial arthritis as well as occasional patients with juvenile idiopathic arthritis (JIA) and a sibling or a parent with concordant phenotype. The consistent autosomic dominant pattern with high penetrance seen in familial BS is not seen in JIA. We organized the section by the main cardinal manifestations: arthritis, uveitis, and rash.

Arthritis The association of symmetrical polyarthritis with synovial and tenosynovial cysts and development of camptodactyly are the most important distinguishing features between BS and polyarticular JIA. Furthermore, antinuclear antibodies and rheumatoid factor are typically absent in BS. In familial forms of BS, there is an observed element of anticipation, or worsening of symptoms in succeeding generations [9]. A familial occurrence of arthritis and tendinitis can be seen in a subset of JIA called arthritis and enthesitis (previously also known as juvenile spondylarthropathy); however, the arthritic pattern is most often oligoarticular and asymmetrical, and the strong association with HLA B27 are distinguishing features.

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Arthritis and rash with well-demarcated erythematous scaly lesions occurring at the extensor surfaces and with accompanying nail disease are typically seen in psoriatic arthritis. The arthritis in psoriatic arthritis is rarely polyarticular and the rash should not be confused with the ichthyosiform rash of BS. CD may be associated with an extensive list of extraintestinal manifestations including arthritis, uveitis, erythema nodosum, small- and mediumvessel vasculitis and pyoderma gangrenosum, sclerosing cholangitis, and autoimmune hepatitis. The clinician should be aware that particularly in children the intestinal manifestations of the disease may occur years after the arthritis. As depicted in the table, the arthritis of CD is mostly oligoarticular and the only cutaneous manifestation that may be confusing is erythema nododsum. There is an axial pattern of the articular disease with involvement of sacroiliac joints and lower lumbar spine; however, this distribution does not occur in BS. BS and CD are granulomatous diseases but the finding of granulomas in the synovium while exceptional in CD, is the rule in BS. The reader should be reminded that CD and BS share mutations in the NOD2 protein albeit in different domains. Additionally CD has shown associations with allelic variants in different genes, while in PGA, NOD2 is the only protein for which a mutation has been documented. The adult form of sarcoidosis was discussed in some detail in the clinical section. It is usually detected in older children by chest radiography, and the clinical manifestations are characterized by a classical triad of lung, lymph node, and eye involvement, similar to those in adults. Constitutional symptoms, including fatigue, malaise, and fever, are often present. Although visceral involvement has been reported in patients with BS, hilar adenopathy is almost never associated with this disease [4]. Although arthritis, uveitis, and rash can occur in both BS and adult-type sarcoidosis, the clinical pattern of these involvements is different. BS is characterized by progressive polyarthritis causing severe joint deformities, whereas in sarcoidosis either acute arthritis (Loefgren’s syndrome) or a chronic indolent oligoarthritis especially affecting the knees occurs. Erythema nodosum has been reported in both conditions, but is typical of adult sarcoidosis. The tan-colored ichthyosiform rash characteristic of BS has not been reported in patients with sarcoidosis. Whereas the adult form of sarcoidosis is seen mostly in African and Japanese children, BS occurs worldwide and has no racial preference. Despite the striking similarity in pathology between the two conditions (noncaseating granuloma), no NOD2 mutations have been published in studies of adult-type sarcoidosis [21,25] or sarcoidosis-associated uveitis [41]. Table 20.1 summarizes the differential characteristics of chronic inflammatory diseases with arthritis and uveitis in childhood.

TABLE 20.1 Differential Diagnosis of Chronic Pediatric Arthritis With Uveitis Joint Disease Pattern

Tendon Involvement

Uveitis

ANA

HLA B27

Synovial Granuloma

Extraarticular

BS

Polyarticular, boggy, camptodactyly

Intense

Panuveitis; can be severe

Neg

Absent

Yes

Icthtyosiform rash Large vessel disease Hypertension

Polyarticular juvenile idiopathic arthritis

Polyarticular

Variable

Mostly anterior

40%

Absent

No

Subcutaneous nodules

Arthritis and enthesitis

Mostly oligoarticular

Typically at insertion (enthesitis)

Acute anterior; recurrent

Neg

Present (not always)

No

Aortic ring Mucositis E. nodosuma

Psoriatic arthritis

Poly- or oligoarticular

Yes

Rare

40%

Only in axial forms

No

Psoriatic rash Nail disease

Crohn’s arthritis

Oligoarticular (ankle frequent)

Variable

Rare

Neg

Same as normal population

Can be found

Enteritis Pyoderma gangrenosum E. nodosum

Adult sarcoid arthritis

Oligoarticular (ankle frequent)

No

Mostly anterior

Neg

Absent

Can be found

Hilar adenopathy Systemic disease alveolitis E. nodosum

a

Particularly in reactive arthritis.

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Uveitis Uveitis in PGA is chronic, can be anterior, posterior, or panuveitis, and granulomatous or nongranulomatous. The association of chronic uveitis and arthritis can be seen in a number of inflammatory conditions including oligoarticular and polyarticular JIA, psoriatic arthritis, CD, Behc¸et’s disease, and chronic infantile neurologic cutaneous and articular syndrome. Uncommonly, chronic relapsing uveitis is seen in association with acute tubulointerstitial nephritis, known as TINU syndrome. Chronic uveitis also occurs in about one-third of children without additional evidence of other organ involvement. The characteristic biomicroscopic aspect of precipitates in a clumpy, rather than diffuse distribution should alert the ophthalmologist of the possibility of BS; characteristic granulomata may be revealed on a conjunctival biopsy, particularly in the areas of focal disease in the conjunctiva.

Cutaneous Manifestations A scaly erythematous rash may suggest atopic dermatitis (and frequently is diagnosed as such), but the rash of BS usually is nonitching and asymptomatic. The ichthyoses comprise a broad number of scaling diseases mostly generalized and involving all skin layers. A review of the ichtyoses is beyond the scope of this chapter. Erythema nodosum is characterized clinically by subcutaneous tender erythematous nodules. It is seen occasionally in BS and is associated with a multitude of pediatric diseases, some of them also associated with arthritis (eg, adult-type sarcoidosis).

Vasculitis Although reported very rarely, patients with BS may present with cutaneous vasculitis [1,6,10,42], and the granulomatous vasculitides have to be considered in the differential diagnosis. Granulomatosis with polyangeitis (Wegeners) is characterized by a clinical trial of paranasal sinus involvement, pulmonary infiltration, and renal disease with granulomatous involvement of medium-sized arteries and veins and a necrotizing glomerulonephritis. Eosinophilic granulomatous with polyangeitis (Churg Strauss syndrome) is typically associated with severe asthma, fever, eosinophilia, and vasculitis. Granulomatous extravascular and vascular changes may be found. Lymphomatoid granulomatosus is a very rare necrotizing pulmonary vasculitis that can be associated with immunodeficiencies (Wiskott Aldrich syndrome, X-linked lymphoproliferative syndrome), HIV infection, and malignancy. Childhood primary central nervous system vasculitis (cPACNS), previously called granulomatous angiitis, presents as an acquired neurologic deficit and no systemic features. None of these conditions are really

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challenging in the differential diagnosis with BS. Takayasu’s arteritis, although rare in children, is the most common giant cell arteritis of childhood, affecting the aorta and its major branches as well as the pulmonary artery. A Takayasu-like disease has been reported in association with BS and so has a form of abdominal aortitis [1,2,37].

TREATMENT AND PROGNOSIS Compared with an asymptomatic and sometimes naturally disappearing course of the adult form of sarcoidosis in older children, BS is progressive and in many cases causes severe complications, such as blindness, joint destruction, and visceral involvement [4]. There have been no controlled therapeutic studies for patients with granulomatous arthritis. Anecdotal experiences have shown poor response to NSAIDs for the rheumatic symptoms. These authors have reported excellent response to infliximab (5 10 mg/kg every 4 8 weeks) particularly in the sporadic form; however, there is almost always some degree of detectable synovitis particularly in ankles and wrists. The characteristic contractures of the PIP joints tend to be irreversible, although radiologic changes are relatively mild. The only consistently effective measure to reduce synovial hypertrophy is the use of oral corticosteroids, but the side effects of their prolonged use limit their utility. Corticosteroid dependency for either eye or articular disease is common. The sight-threatening pan-uveitis can be extremely severe and multiple immunosuppressive and biologic regimens are being utilized, yet no systematic study has been undertaken so far. Although formal functional studies in BS are not yet available, most patients seem to handle activities of daily living quite well from the articular point of view. There are no reported cases of hip replacements, there is mild joint destruction on conventional imaging, and reported pain is not very significant. Ocular disease on the other hand can be severe. In our prospective cohort study, one-third of patients have moderate to severe disease based upon corrected visual acuity reports. We found no correlation with the type of amino acid substitution on NOD2 or any other predictive feature. Of some concern is the possibility of granulomatous dissemination in patients with BS. An important report has dealt with the question of severity in advanced disease. In a series of sporadic cases [4] terminal involvement of vital organs was observed. We have in our series one mutation-proven patient who had shown involvement of liver, lymph nodes, and lung parenchyma after 16 years of disease so far responsive to corticosteroid therapy. The outcome of the atypical forms including those with panniculitis and involvement of the reticulo-endothelial system, is associated with severe morbidity, and mortality due to vital organ involvement. Early intervention with TNF inhibitors and perhaps IL-1 inhibition may hold the key in the prevention of poor functional outcome.

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KEY POINTS G

G

G

G

BS is highly associated with mutations in the NOD gene, which codes for a protein involved in inflammation and apoptosis. Both the classic clinical symptom triad of BS and the association with a genetic mutation in NOD2 are major distinguishing features with adult sarcoidosis. Although with time expansion of granulomatous inflammation to other disease organs (liver, kidney, blood vessels) has been described, the major cause of morbidity for patients with BS are progressive polyarthritis and sight-threatening uveitis. In view of recent insights into the pathogenesis of BS, biologic treatments directed at the inhibition of proinflammatory cytokines (TNF and IL-1) or more specifically of targets in the NOD2 pathway are promising.

REFERENCES [1] Rose´ CD, Eichenfield AH, Goldsmith DP, Athreya BH. Early onset sarcoidosis with aortitis—“Juvenile Systemic Granulomatosis?” J Rheumatol 1990;17:102 6. [2] Gedalia A, Shetty A, Ward K, et al. Abdominal aortic aneurysm associated with childhood sarcoidosis. J Rheumatol 1996;23:757 9. [3] Gross KR, Malleson PN, Culham G, et al. Vasculopathy with renal artery stenosis in a child with sarcoidosis. J Pediatr 1986;108:724 6. [4] Fink CW, Cimaz R. Early onset sarcoidosis:not a benign disease. J Rheumatol 1997;24:174 7. [5] Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr 1985;107:689 93. [6] North AF, Fink CW, Gibson WM, et al. Sarcoid arthritis in children. Am J Med 1970;48:449 55. [7] Jabs DA, Houk JL, Bias WB, Arnett FC. Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med 1985;78:801 4. [8] Pastores GM, Michels VV, Stickler GB, et al. Autosomal dominant granulomatous arthritis, uveitis, skin rash, and synovial cysts. J Pediatr 1990;117:403 8. [9] Raphael SA, Blau EB, Zhang WH, Hsu SH. Analysis of a large kindred with Blau syndrome for HLA, autoimmunity, and sarcoidosis. AJDC 1993;147:842 7. [10] Rotenstein D, Gibbas DL, Majmudar B, Chastain EA. Familial granulomatous arteritis with polyarthritis of juvenile onset. NEJM 1982;306:86 90. [11] Saini SK, Rose´ CD. Liver involvement in familial granulomatous arthritis (Blau syndrome). J Rheumatol 1996;23:396 9. [12] Ting SS, Ziegler J, Fischer E. Familial granulomatous arthritis (Blau syndrome) with granulomatous renal lesions. J Pediatr 1998;133:450 2. [13] Tromp G, Kuivaniemi H, Raphael S, et al. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16. Am J Hum Genet 1996;59:1097 107. [14] Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet 2001;29:19 20. [15] Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucin-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411:522 603.

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[16] Ogura Y, Bonen D, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2000;411:603 6. [17] Kanazawa N, Matsushima S, Kambe N, et al. Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation. J Invest Dermatol 2004;122:851 2. [18] Rose´ CD, Doyle TM, McIlvain-Simpson G, et al. Blau syndrome mutation of CARD15/ NOD2 in sporadic early onset granulomatous arthritis. J Rheumatol 2005;32:373 5. [19] Touitou I, Lesage S, McDermott M, et al. Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum Mutation 2004;24:194 8. [20] Byg K-E, Milman N, Hansen S. Sarcoidosis in Denmark 1980 1994. A registry based incidence study comprising 5536 patients. Sarcoidosis Vas Dif Lung Dis 2003;20:46 52. [21] Hoffmann AL, Milman N, Byg K-E. Chidhood sarcoidosis in Denmark 1979 1994: incidence clinical features and laboratory results at presentation in 48 children. Acta Pediatr 2004;93:30 6. [22] Lindsley CB, Petty RE. Overview and report on international registry of sarcoid arthritis in childhood. Curr Rheumatol Rep 2000;2:343 8. [23] Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappa B activation:common genetic etiology with Blau syndrome. Blood 2005;105:1195 7. [24] van Duist MM, Albrecht M, Podswiadek M, et al. A new CARD15 mutation in Blau syndrome. Eur J Hum Genet 2005;13(6):742 7. [25] Rybicki BA, Maliarik MJ, Bock CH, et al. The Blau syndrome gene is not a major risk factor for sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:203 8. [26] Schurmann M, Valentonyte R, Hampe J, et al. CARD15 gene mutations in sarcoidosis. Eur Respir J 2003;22:748 54. [27] Inohara N, Chamaillard M, McDonald C, Nunez G. NOD-LRR proteins:role in host microbial interactions and inflammatory disease. Annu Rev Biochem 2005;74:355 83. [28] Inohara N, Nunez G. NODS: intracellular proteins involved in inflammation and apoptosis. Nat Rev 2003;3:371 82. [29] Inohara N, Nunez G. The NOD: a signaling module that regulate apoptosis and host defense against pathogens. Oncogene 2001;20:6473 81. [30] Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol 2000;12:71 6. [31] Agostini C, Meneghin A, Semenzato G. T lymphocytes and cytokines in sarcoidosis. Curr Opin Pulmonol Med 2002;8:435 40. [32] Xaus J, Besalduch N, Comalada M, et al. High expression of P21 WAF1 in sarcoid granulomas:a putative role for long-lasting inflammation. J Leukocyte Biol 2003;74:295 301. [33] Janssen CE, Rose CD, DeHertogh G, Martin T, Badeer-Meunier B, Cimaz R, et al. Morphological and immunohistochemical characteristics of granulomas in the NOD-2related pediatric granulomatous diosorders Blau syndrome and Crohn’s disease. J Allergy Clin Immunol 2012;129:1076 84. [34] Kobayashi SD, Voyich JM, Braughton KR, Whitney AR, Nauseef WM, Malech HL, et al. Gene expression profiling provides insight inot the pathophysiology of chronic granulomatous disease. J Immunol 2004;172:636 43. [35] Martin T, Wouters CH, Meiorin S, Rose´ CD. Pediatric granulomatous arthritis and card 15 mutations: a status report on the international registry. In: Fourth international congress of systemic autoinflammatory diseases, November 2005, Bethesda.

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[36] Wang X, Kuivaniemi H, Bonavita G, et al. CARD15 mutations in familial granulomatosis syndromes: a study of the original Blau syndrome kindred and other families with largevessel arteritis and cranial neuropathy. Arthritis Rheum 2002;46:3041 5. [37] Khubchandani RP, Hasija R, Touitou I, Khemani C, Wouters CH, Rose CD. Blau arteritis resembling Takayasu disease with a novel NOD2 mutation. J Rheumatol 2012;39:1888 92. [38] Sokoloff L, Bunnin JJ. Clinical and pathologic studies of joint involvement in sarcoidosis. N Eng J Med 1959;260:841 7. [39] Palmer DG, Schumacher HR. Synovitis with non-specific histological changes in synovium in chronic sarcoidosis. Ann Rheum Dis 1984;43:778 82. [40] Rose CD, Pans S, Castels I, et al. Blau syndrome: cross-sectional data from a multicenter study of clinical, radiological and functional outcomes. Rheumatology (Oxford) 2014; doi:10.1093/kew/rheumatology437. [41] Martin TM, Doyle TM, Smith JR, et al. Uveitis in patients with sarcoidosis is not associated with mutations in NOD2 (CARD15). Am J Ophthalmol 2003;136:933 5. [42] Rose CD, Arostegui JI, Martin TM, Espada G, Yague J, Scalzi L, et al. NOD-2 associated pediatric granulomatous arthritis (PGA) an expanding phenotype. Arthritis Rheum 2009;60:1797 803. [43] Brescia AM, McIlvain-Simpson G, Rose´ CD. Infliximab therapy for steroid-dependent early onset sarcoid arthritis and Blau syndrome. Arthritis Rheum 2002;46:S313.

Chapter 21

Rheumatic Fever M.T. Terreri and C.A. Len Pediatric Rheumatology Unit, Department of Pediatrics, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil

INTRODUCTION Rheumatic fever (RF) is a late inflammatory, nonsuppurative complication of an upper respiratory tract infection caused by Lancefield Group A β-hemolytic Streptococcus (GAS). It is characterized by involvement of the heart, joints, central nervous system, subcutaneous tissue, and skin. RF and rheumatic heart disease (RHD) remain significant causes of cardiovascular diseases in the world. The most important complications are observed in children and young adults. The economic effects of the disability and premature death caused by RF are felt at both the individual and national levels through higher direct and indirect health-care costs [1].

PREVALENCE The RF distribution is worldwide. A few studies conducted in developing countries report incidence rates ranging from 1.0 to 150 per 100,000 schoolaged children [2]. The prevalence of RHD shows a wide variation between countries, ranging from 0.2 to 77.8 per 1000 [3,4]. The mortality rate for RHD ranges from 0.5 to 8.2 per 100,000 population [5]. A recent report estimates that there are over 15 million cases of RHD worldwide, with 282,000 new cases and 233,000 deaths annually [6]. RF and RHD are the leading causes of cardiovascular death during the first five decades of life [6,7]. In epidemics of streptococcal pharingotonsilitis, 3% of affected individuals develop RF, whereas in endemic situations, this decreases to 0.3% [8]. At least one-third of episodes of acute RF result from unapparent streptococcal infections. Streptococcal skin infections have not been proven to lead to acute RF. It is presumed that chronic streptococcal carrier status does not trigger the development of RF. In Brazil, 24.6% of children presenting with sore throat were found to have GAS pharyngitis [9]. Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00021-9 © 2016 Elsevier B.V. All rights reserved.

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EPIDEMIOLOGY The highest incidence of RF is observed in children between 5 and 15 years old, and it is rare before 4 years old [10]. Only 3 5% of first episodes arise in children younger than 5 years [11]. There is a slight predominance of females and a higher frequency of chorea among girls. There is no racial predisposition; however, it is a prevalent disease in developing countries [12,13]. For the World Health Organization, RF remains a medical and public health problem even in industrialized countries.

ETIOLOGY/PATHOGENESIS There is strong evidence that an autoimmune response to streptococcal antigen mediates the development of RF in a susceptible host. Although RF has been known to be consequent to a streptococcal infection, its pathogenesis is not completely understood. Some factors seem to be important in the disease frequency: 1. Genetic predisposition to the disease, with a higher frequency in some families. 2. Factors related to GAS, such as some serotypes like M1, M3, M5, M6, M14, M18, M19, and M24, are considered to be rheumatogenic. 3. Environmental factors, such as poor living conditions, overcrowding, bad access to health care, and cold regions. Major histocompatibility antigens, potential tissue-specific antigens, and antibodies developed during and immediately after a streptococcal infection are being investigated as potential risk factors in the pathogenesis of the disease. There is a well-known theory of cross-reactivity of molecular mimicry by which the host would promote self-injury due to the presence of common antigenic sequences in human tissues and those of streptococcus [14 16]. Molecular mimicry between streptococcal and human proteins is considered as the trigger that leads to autoimmunity in RF. Heart myosin is one of the most important autoantigens involved in RHD and their peptides were recognized by peripheral and intralesional T-cell clones [17]. Recent evidence suggests that T-cell lymphocytes play an important role in the pathogenesis of rheumatic carditis. It has also been postulated that particular M types of group A streptococci have rheumatogenic potential [18]. Guilherme and Kalil [19] reported that the streptococcal M5 (81 103) region, an immunodominant region, was recognized by both intralesional (valvular) and peripheral T-cell clones (62% and 38%, respectively) [20]. Some studies suggested that abnormal regulation of tumor necrosis factor (TNF)-α production may have a role in the pathogenesis of RF [19,21 23]. Guilherme showed that T cells from all RF patients produce significant

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amounts of TNF-α in response to streptococcal peptides with the highest production attained by the chronic RHD patients [19,21]. A study suggested that carrying a high responder TNF-α G-308A allele may be a genetic factor in increasing the susceptibility to develop RF disease [24]. The most predominant cytokines were TNF-α and interferon (IFN)-γ produced by heart infiltrating mononuclear cells (Th1-type cytokines) and mediators of the heart lesions, and few interleukin (IL)-4-producing cells in the valve tissue that are responsible for the maintenance and progression of the valve lesions. The autoimmune reactions in RHD patients through an analysis of heart infiltrating T-cell repertoire, antigen recognition, and cytokine production induced by specific antigens were described by Fae´ et al. [25]. These authors suggest that mimicry between streptococcal antigen and heart-tissue proteins, combined with high inflammatory cytokine and low IL-4 production, leads to the development of autoimmune reactions and cardiac tissue damage in the RHD patients. Many studies have focused on the role of the superantigen-like activity of M-protein fragments, as well as of the streptococcal pyrogenic exotoxin, in the pathogenesis of RF [26,27]. Superantigenic activation is not limited to the T-cell compartment alone but also to B cells. Aschoff’s nodules represent the pathognomonic lesion of rheumatic carditis, characterized by infiltrate of macrophage, lymphocyte, and complement C3 [28]. The most predominant HLA alleles are from class II. Studies of different HLA-DR loci and ethnicity suggested that the link between susceptibility to RF and class HLA was highly diverse and not linked to one particular allele, but to a susceptibility gene present at, or nearby, the HLA-DR locus [29]. The HLA-DR7 is commonly observed and is associated with the development of valve lesions [30]. Subsequently, it was reported that a B-lymphocyte alloantigen, recognized by the monoclonal antibody, D8/17, and another 70 kD molecule, may be genetically innate markers of an altered immune response to unidentified streptococcal antigens in susceptible subjects [31]. However, further studies carried out in different populations did not corroborate these findings [32,33]. Concluding, initial streptococcal infection in a genetically predisposed host in a susceptible environment leads to the activation of T-cell and B-cell lymphocytes by streptococcal antigens and superantigens, which results in the production of cytokines and antibodies directed against streptococcal carbohydrate and myosin.

CLINICAL MANIFESTATIONS In most cases the onset of clinical manifestations of RF occurs between the second or third week after the streptococcal infection. However, in a few cases it could be earlier.

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Arthritis Arthritis is the most frequent manifestation of RF, occurring in 60 80% of patients in the first attack. Usually it is the presenting complaint and the least specific manifestation. Although the arthritis is typically migratory, transient, and self-limited, polyarticular with pain out of proportion to the inflammatory signs, and present a satisfactory response to anti-inflammatory doses of salicylates, we have to be aware of atypical presentations that might lead to misdiagnosis. These include relatively short latency period, mono- or oligoarthritis, additive pattern, longer duration ($6 weeks), and poor response to salicylates [34,35]. Due to the high prevalence of RF in our country and the lack of a clear distinction between poststreptococcal reactive arthritis and acute RF, we do not consider the diagnosis of poststreptococcal reactive arthritis as a different entity from RF, although other authors think that they are separate conditions with distinct characteristics [36,37].

Carditis Carditis is the second most frequent manifestation of RF, occurring in 40 50% of the patients. Although the endocardium, myocardium, and pericardium may be all affected characterizing a pancarditis, the endocarditis, isolated or not, is the most frequent feature. Nevertheless, the characteristic apical systolic murmur, clinical expression of mitral regurgitation, may be absent in a few patients. The most frequently affected valves are, in the following order, mitral, aortic, tricuspid, and pulmonary. We have to be aware of carditis until the sixth week of acute phase. Some authors have drawn attention to the existence of subclinical carditis, that is, to the rheumatic carditis detected just by Doppler echocardiography [38 40]. Murmurs present during the acute phase do not indicate a permanent valvular defect, and in the majority of cases (60%), they are transient. Mitral stenosis is rare in the pediatric age group, and indicates previous cardiac involvement. Isolated myocarditis or pericarditis should not be labeled rheumatic in origin, when they are not associated with endocardium involvement, and other diagnoses must be considered.

Sydenham’s Chorea This manifestation of RF occurs primarily in children and adolescent females. It is rare in young adults or after the age of 20 years. Although its prevalence is reported between 15% and 20% in most case reports, we diagnosed chorea more frequently, in about 30 35% of the patients [41,42].

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Sydenham’s chorea is characterized by emotional lability, muscle weakness, and uncoordinated abrupt and erratic movements. All muscle groups may be affected but movements of the hands, arms, feet, and legs are most evident. Face, tongue, and lips may also present involuntary movements. Other manifestations include handwriting and speech disturbances. Chorea movements are usually bilateral, decrease with rest, and always disappear during sleep. Neuropsychiatric abnormalities such as obsessive-compulsive disorders have been associated with Sydenham’s chorea [15,43,44]. Higher frequency of major depression, migraine, tics, and hyperactivity with attention deficit in patients with chorea compared with RF patients without chorea and controls were described [43,45 47]. A study showed that patients who had chorea during childhood can exhibit lower cognitive performance in tasks that evaluate attention, speeded information processing, executive functions, and working memory in adult life [48]. Although Sydenham’s chorea has been described as an isolated manifestation of RF, it is associated with carditis and/or arthritis in about 50% of our patients. Recurrent attacks of acute RF in patients who presented chorea in the first episode are usually characterized clinically by chorea [42].

Subcutaneous Nodules This is a very rare manifestation of RF, occurring in less than 3% of our patients. Characteristically they are round, firm, freely movable, painless, varying in size, and occurring on the extensor surfaces of the joints, particularly the elbows, knees, ankles, and knuckles. In most cases they are associated with the presence of carditis, frequently severe carditis.

Erythema Marginatum This is also a rare manifestation of RF, which usually occurs early in the follow-up of a rheumatic attack. This rash is nonpruritic and macular with a serpiginous erythematosous border usually on the trunk or proximal limbs. It is usually associated with carditis.

Other Manifestations Fever and arthralgia are less frequent and nonspecific manifestations of RF. Fever may be a presenting manifestation of RF but usually lasts a few days. Abdominal pain and epistaxis may occur before major manifestations of RF, but they have not been considered a part of the Jones criteria due to the lack of specificity of the symptoms [49].

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DIAGNOSIS Laboratory Tests Although not specific, the laboratory tests are important to detect a recent infection caused by Streptococcus pyogenes, to determine the inflammatory process intensity and to exclude other causes of arthritis such as leukemia and sickle cell anemia. The hemogram can be normal or mild anemia (more intense in cases of carditis), and mild leukocytosis with neutrophilia can be found. Persistent lymphocytosis and severe anemia suggest a differential diagnosis with leukemia. Both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated at the onset of the acute phase and tend to normalize at the end of the second or third week. These tests may be influenced by anti-inflammatory medications. More elevated values of ESR are associated with carditis. Alpha-1-glycoprotein and alpha-2-globulin are elevated later in the acute phase of the disease and remain elevated for a prolonged time. Their levels are not influenced by antiinflammatory medications and they have been used to monitor RF activity. The gold standard for detecting S. pyogenes remains a culture of throat swab. However, in the context of RF it fails in sensitivity due to the latency period that usually lasts 2 or more weeks. On the other hand, neither culture nor rapid antigen detection tests can reliably distinguish between an acute streptococcal infection and a streptococcal carrier with a concomitant viral infection [50]. Therefore, serological tests for streptococcal antibodies (antistreptolysin O, antideoxyribonuclease B) are required and should be undertaken for all suspected cases of acute RF. Although a single elevated antibody titer may be useful for documenting a previous streptococcal infection, it is recommended that an additional test be performed 2 3 weeks after the first test in order to detect the rise of the titer. The most commonly performed and commercially available test is the antistreptolysin-O; however, about 20 25% of the patients with acute RF do not present elevation of its titer. The range of normal values for this test is variable and depends upon the geographical region. Rapid antigen detection tests from throat swabs have the same limitations as cultures with specificity of 95% but lower sensitivity [51].

Diagnosis of Rheumatic Carditis Echocardiography became, in the last years, a key component in the diagnosis of heart disease. Doppler echocardiography is useful in evaluating myocardial function and in diagnosing valvular disease and pericarditis. Echocardiographic findings of valvular lesions in the absence of clinical manifestations of carditis have been well described [38 40]. In order to better characterize the subclinical carditis we performed two prospective and blind studies [52,53]. Aiming to contribute to a better

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understanding of potential of Doppler echocardiography in establishing adequate diagnosis of pathologic valvular regurgitation in acute RF, we evaluated clinically and echocardiographically 56 patients with a first acute episode of the disease and followed them up for 60 months. This study showed that regarding 29 patients with arthritis or chorea presentation without initial clinical carditis, echocardiographic abnormalities were observed in 11 with persistence at late follow-up in 72% of the cases [52]. In an attempt to minimize the possibility of considering physiological regurgitation as pathological we studied the echocardiography in a semiquantitative way and such parameters like mitral variance, mitral flow convergence, and aortic regurgitation were statistically more frequent in patients with clinical and subclinical carditis than in the control group. We also observed that the mitral thickness of patients was larger than in controls [52]. It is important to emphasize that according to the American Society of Cardiology carditis is only considered in the presence of cardiac murmur [54].

Diagnostic Criteria There is no symptom, clinical sign, or laboratory test that is pathognomonic of RF. Definitive diagnosis may be difficult because of the variability of clinical manifestations. Fifty years ago Jones established criteria that are still an important guide for the diagnosis of RF [55]. Since then Jones criteria have been revised five times by the American Heart Association (Table 21.1) [56,57]. Since 1992 these criteria have been considered only for primary episodes of RF [54]. TABLE 21.1 Guidelines for the Diagnosis of an Initial Attack of Rheumatic Fever (Modified Jones Criteria, 1992 [54]) Major Manifestations

Minor Manifestations

Carditis

Clinical

Polyarthritis

Fever

Sydenham’s chorea

Arthralgia

Erythema marginatum

Laboratory

Subcutaneous nodules

Elevated acute phase reactants Erythrocyte sedimentation rate C-reactive protein Prolonged P-R interval on ECG

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Diagnosis of RF is made in the presence of two major manifestations or of one major and two minor manifestations, if supported by evidence of preceding infection with Group A Streptococcus [54]. It is important to emphasize that not all patients with RF fulfill these criteria at onset of disease. In the presence of isolated chorea and indolent carditis a diagnosis of RF can be made without fulfilling other Jones criteria. If a patient presents arthritis as a criterion, arthralgia cannot be considered. The presence of prolonged P-R interval (first-degree heart block) does not predict whether a patient will develop heart disease. Unusual presentation of acute RF with a great range of clinical manifestations that do not fulfill the Jones criteria is responsible for mistakes and delay of diagnosis. It would be worthwhile changing the arthritis concept (not only migratory polyarthritis) in an attempt to include the atypical forms; the echocardiography if utilized with strict criteria could be an accurate instrument to distinguish pathologic from physiologic valvular lesions and therefore to diagnose subclinical carditis; the evidence of streptococcal infections is not always possible and for this reason it would be better to consider it as important evidence for the diagnosis and not as indispensable. Furthermore, the establishment of a score according to the frequency and importance of the manifestations of RF may improve the sensitivity and specificity of the Jones criteria.

Differential Diagnosis Oligo or polyarthritis in the absence of other major manifestations of RF deserves differential diagnosis with many clinical entities. Septic arthritis, including gonococcal arthritis, other reactive arthritides such as Lyme disease, connective tissue diseases, acute lymphoid leukemia and other tumors, and sickle cell disease should be considered. Viral or tuberculous pericarditis, viral myocarditis, bacterial endocarditis, innocent murmurs, congenital heart disease, and connective tissue diseases such as systemic lupus erythematosus or juvenile idiopathic arthritis should be ruled out in the cases of carditis. Although the presence of chorea is highly suggestive of RF, when it is isolated, other diseases need to be excluded like viral encephalitis, systemic lupus erythematosus, and antiphospholipid syndrome.

TREATMENT The management of acute RF consists of elimination of S. pyogenes (primary prevention); treatment of carditis, arthritis, and chorea; and secondary prophylaxis against recurrent infections. The primary prevention of RF is defined as the adequate antibiotic therapy of GAS upper respiratory tract infections to prevent an initial attack of

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acute RF. Streptococcus can be eliminated by a single intramuscular injection of benzathine penicillin G in a dose of 600,000 units for patients ,25 kg or 1.2 million units for those $ 25 kg. Patients with proven penicillin allergy should take erythromycin (30 40 mg/kg per day) in four divided doses for 10 days. Macrolides, amoxicillin/clavulanate, or clindamycin are also alternatives. Oral medications are less effective, mainly due to low compliance and potentially because of variable absorption. It is important to emphasize that sulfa drugs are not effective in eliminating streptococci. Antibiotics should not be administered to GAS carriers, because they are unlikely to spread the microorganism to contacts and they are at a low risk, if any, of developing RF. Carditis is generally treated with corticosteroids in doses of 1 2 mg/kg per day, BID in the first week, and given as a single daily dose thereafter. Its initial dose should be given for 4 6 weeks until clinical and laboratory improvement and subsequently it should be tapered over 8 12 weeks. Successive dose reductions should not exceed 20% of the previous dose. Diuretics, angiotensin-converting enzyme inhibitors are used for the treatment of heart failure. In patients with carditis, a rest period of at least 4 weeks is recommended. Acetyl salicylic acid (ASA) in doses of 80 100 mg/kg per day (maximum of 3 g/day) is recommended for the treatment of arthritis especially due to its efficacy and low cost. Once inflammatory parameters are brought under control, the dose should be reduced to complete 4 8 weeks of treatment. For patients who are intolerant or allergic to ASA, naproxen or other nonsteroidal anti-inflammatory drugs may be used. For patients with associated carditis, treatment with corticosteroids is sufficient. For the treatment of Sydenham’s chorea we recommended haloperidol (initial dose of 1 2 mg/day up to a maximum of 4 5 mg/day), valproic acid (30 40 mg/kg per day), or pimozide (1 6 mg/day) with gradual reduction over the months following disappearance of symptoms. Special attention should be given to side effects of these medications. Although there are no proven benefits of using corticosteroids to treat chorea, prednisone (1 mg/kg per day) may be useful in selected patients with very severe symptoms. Prophylaxis is carried out with benzathine penicillin G, in the same doses used for primary treatment. The recommended interval between doses is 4 weeks, however for populations at high risk, penicillin should be given every 3 weeks [58]. It is recommended that patients who develop RF without carditis should receive prophylaxis until 21 years of age, or for a minimum period of 5 years after the last attack (whichever is longer). Patients who develop mild carditis without sequelae should receive prophylaxis up to 25 years of age, or for a minimum period of 10 years. In the cases of involvement of both mitral and aortic valves, prophylaxis should be maintained indefinitely [59,60]. Penicillin prophylaxis should be continued during pregnancy. Nonadherence to secondary prophylaxis is the main cause of RF recurrence.

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Penicillin allergy is a very rare condition, especially in children under 12 years of age [61 63]. In these cases alternative antibiotics like sulfadiazine can be used. Patients undergoing surgery or dental procedures should receive additional prophylaxis with amoxicillin. Tonsillectomy is not effective in reducing the incidence of RF, and is not recommended for the primary prevention of RF. It does not modify the course of the disease, and it does not alter the frequency of the first attack or recurrences. Vaccines using streptococcal antigens are being developed for use in genetically susceptible individuals. The most promising approaches are Mprotein-based, including those using multivalent type-specific vaccines, and those directed at non-type-specific, highly conserved portions of the molecule [64,65]. New vaccines that contain N-terminal peptides from streptococcal-protective antigen and M proteins of pharyngitis, invasive, and/or rheumatogenic serotypes have being developed and can have significant impact on the overall burden of streptococcal disease [66,67]. No volunteer that received this vaccine developed evidence of rheumatogenicity [68]. Success in developing vaccines may be achieved in the next years, but this success would have to contend with important questions about the safest, most economical, and most efficacious way in which to employ them, as well as their cost-effectiveness in a variety of epidemiologic and socioeconomic conditions [69].

KEY POINTS G

G

G

Rheumatic fever is still a prevalent disease in developing countries, and rheumatic heart disease remains an important cause of cardiovascular disease in the world. Atypical presentation of arthritis and carditis must be considered in the diagnosis of rheumatic fever. Adequate treatment of streptococcal infections in order to prevent rheumatic fever should be a priority for health politics especially in developing countries.

REFERENCES [1] Terreri MT, Ferraz MB, Goldenberg J, Len CA, Hila´rio MO. Resource utilization and cost of rheumatic fever. J Rheumatol 2001;28:1394 7. [2] Joint WHO/ISFC meeting on RF/RHD control with emphasis on primary prevention, Geneva, September 7 9. Geneva: World Health Organization 1994 (WHO Document WHO/CVD 94.1); 1994. [3] Anabwani GM, Bonhoeffer P. Prevalence of heart disease in school children in rural Kenya using colour-flow echocardiograph. East Afr Me´d J 1996;73:215 17. [4] Steer A. Rheumatic heart in school children in Samoa. Arch Dis Child 1999;81:373 4. [5] World Health Statistical Annual. 1990 2000. Geneva: World Health Organization.

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[6] Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal disease. Lancet Infect Dis 2005;5:685 94. [7] Seckeler MD, Hoke TR. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol 2011;3:67 84. [8] Amigo MC, Martinez-Lavin M, Reyes PA. Acute rheumatic fever. Rheum Dis Clin North Am 1993;19:333 50. [9] Rimoin AW, Hamza HS, Vince A, Kumar R, Walker CF, Chitale RA, et al. Evaluation of the WHO clinical decision rule for streptococcal pharyngitis. Arch Dis Child 2005;90:1066 70. [10] Paulo LT, Terreri MT, Barbosa CM, Len CA, Hila´rio MO. Sera´ a febre reuma´tica uma doenc¸a mais grave em pre´-escolares? (Is there rheumatic fever a more severe disease in pre-scholar children?). Acta Reumatol Port 2009;34:66 70. [11] Tani LY, Veasy LG, Minich LL, Shaddy RE. Rheumatic fever in children younger than 5 years: is the presentation different? Pediatrics 2003;112:1065 8. ¨ zer S, Hallioglu O, O ¨ zkutlu S, C [12] O ¸ eliker A, Alehan D, Karago¨z T. Childhood acute rheumatic fever in Ankara, Turkey. Turk J Pediatrics 2005;47:120 4. [13] Ravisha MS, Tullu MS, Kamat JR. Rheumatic fever and rheumatic heart disease: clinical profile of 550 cases in India. Arch Med Res 2003;34:382 7. [14] Khanna A, Nomura Y, Fischetti VA, Zabriskie JB. Antibodies in the sera of acute rheumatic fever patients bind to human cardiac tropomyosin. J Autoimm 1997;10:99 106. [15] Asbahr F, Garvey MA, Snider LA, Zanetta DM, Elkis H, Swedo E. Obsessive-compulsive symptoms among patients with Sydenham chorea. Biol Psychiatry 2005;57:1073 6. [16] Veasy LG, Hill HR. Immunologic and clinical correlations in rheumatic fever and rheumatic heart disease. Pediatr Infect Dis J 1997;16:400 7. [17] Guilherme L, Ramasawmy R, Kalil J. Rheumatic fever and rheumatic heart disease: genetics and pathogenesis. Scand J Immunol 2007;66(2 3):199 207. [18] Bhatnagar A, Grover A, Ganguly NK. Superantigen-induced T cell responses in acute rheumatic fever and chronic rheumatic heart disease patients. Clin Exp Immunol 1999;116:100 6. [19] Guilherme L, Kalil J. Rheumatic fever: the T cell response leading to autoimmune aggresion in the heart. Autoimmun Rev 2002;1:261 6. [20] Guilherme L, Fae´ KC, Oshiro SE, Tanaka AC, Pomerantzeff PM, Kalil J, et al. pyogenesprimed peripheral T cells trigger heart valve lesions. Ann NY Acad Sci 2005;1051: 132 40. [21] Guilherme L, Cunha-Neto E, Tanaka AC, Dulphy N, Toubert A, Kalil J. Heart-directed auto-immunity: the case of rheumatic fever. J Autoimmun 2001;16:363 7. [22] Miller LC, Gray ED, Mansour M, Abdin ZH, Kamel R, Zaher S, et al. Cytokines and immunoglobulin in rheumatic heart disease: production by blood and tonsillar mononuclear cells. J Rheumatol 1989;16:1436 42. [23] Yegin O, Coskun M, Ertug H. Cytokines in acute rheumatic fever. Eur J Pediatr 1997;156:25 9. [24] Sallakci N, Akcurin G, Ko¨ksoy S, Kardelen F, Uguz A, Coskun M, et al. TNF-alpha G-308A polymorphism is associated with rheumatic fever and correlates with increased TNF-alpha production. J Autoimmun 2005;25:150 4. [25] Fae´ KC, Oshiro SE, Toubert A, Chaarron D, Kalil J, Guilherme L. How an autoimmune reaction triggered by molecular mimicry between streptococcal M protein and cardiac tissue proteins leads to heart lesions in rheumatic heart disease. J Autoimmun 2005; 24:101 9.

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[26] Kotb M, Watanabe-Ohnishi R, Wang B. Analysis of the TCR V beta specificities of bacterial superantigens using PCR. Immunomethods 1993;2:33 40. [27] Roberts S, Kosanke S, Dunn TS, Jankelow D, Duran CM, Cunningham MW. Pathogenic mechanisms in rheumatic carditis: focus on valvular endothelium. J Infect Dis 2001;183:507 11. [28] Murphy G. The characteristic rheumatic lesions of striated and non-striated or smooth muscle cells of the heart. Medicine (Baltimore) 1963;42:73 118. [29] Ayoub EM, Barrett DJ, Maclaren NK, Krischer JP. Association of class II human histocompatibility leukocyte antigens with rheumatic fever. J Clin Invest 1986;77:2019 26. [30] El-Hagrassy N, El-Chennawi F, Zaki Mel-S, Fawzy H, Zaki A, Joseph N. HLA class I and class II HLA DRB profiles in Egyptian children with rheumatic valvular disease. Pediatr Cardiol 2010;31:650 6. [31] Kanna AK, Buskirk DR, Williams RC, Gibofsky A, Crow MK, Menon A, et al. Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody. J Clin Invest 1989;83:1710 16. [32] Hila´rio MO, Silva S, Terreri MT, Ferraz H. Expression of the D8/17 B lymphocyte antigen in rheumatic fever patients. Ped Rheumatol Online J 2003;154. [33] Morer A, Vinas O, Lazaro L, Bosch J, Toro J, Castro J. D8/17 monoclonal antibody: an unclear neuropsychiatric marker. Behav. Neurol. 2005;16:1 8. [34] Hila´rio MO, Len C, Goldenberg J, Fonseca AS, Ferraz MB, Naspitz C. Febre reuma´tica: manifestac¸o˜es articulares atı´picas. (“Rheumatic fever: atypical joint manifestations”). Rev Assoc Med Bras 1992;38:214 16. [35] Robazzi TC, Arau´jo SR, Costa SA, Oliveira Junior AB, Nunes LS, Guimara˜es I. Articular manifestations in patients with atypical rheumatic fever. Braz J Rheumatol 2014;64 (4):268 73. [36] Uziel Y, Perl L, Barash J, Hashkes PJ. Post-streptococcal reactive arthritis in children: a distinct entity from acute rheumatic fever. Pediatr Rheumatol 2011;9:32 7. [37] van Bemmel JM, Delgado V, Holman ER, Allaart CF, Huizinga TWJ, Bax JJ, et al. No increased risk of valvular heart disease in adult poststreptococcal reactive arthritis. Arthritis Rheum 2009;60(4):987 93. [38] Figueroa FE, Fernandez MS, Valdes P, Wilson C, Lanas F, Carrion F, et al. Prospective comparison of clinical and echocardiographic diagnosis of rheumatic carditis: long term follow up of patients with subclinical disease. Heart 2001;85:407 10. [39] Hila´rio MO, Andrade JL, Gasparian AB, Carvalho AC, Andrade CT, Len CA. The value of the echocardiography in the diagnosis and follow-up of rheumatic carditis in children and adolescents: a two-year prospective study. J Rheumatol 2000;27:1082 6. [40] Wilson NJ, Neutze JM. Echocardiographic diagnosis of subclinical carditis in acute rheumatic fever. Int J Cardiol 1995;50:1 6. [41] Goldenberg J, Ferraz MB, Hila´rio MO, Fonseca AS, Bastos W, Sachetti S. Increase in incidence of Sydenham’s chorea in Sa˜o Paulo, Brazil. J Tropical Pediatr 1993;39:192 3. [42] Ronchezel MV, Hila´rio MO, Forleo LHA, Len CA, Terreri MT, Vilanova LCP, et al. The use of haloperidol and valproate in children with Sydenham chorea. Indian Pediatr 1998;35:1215 18. [43] Maia DP, Teixeira AL, Cunningham CQ, Cardoso F. Obsessive compulsive behavior, hyperactivity, and attention deficit disorder in Sydenham chorea. Neurology 2005;64:1799 801. [44] Swedo SE. Sydenham’s chorea—a model for childhood autoimmune neuropsychiatric disorders. J Am Med Assoc 1994;272:1788 91.

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[45] Al Teixeira J, Meira FC, Maia DP, Cunningham MC, Cardoso F. Migraine headache in patients with Sydenham chorea. Cephalalgia 2004;25:542 4. [46] Faustino PC, Terreri MT, Rocha AJ, Zappitelli MC, Lederman HM, Hila´rio MO. Clinical, laboratory, psychiatric and magnetic resonance findings in patients with Sydenham chorea. Neuroradiology 2003;45:456 62. [47] Mercadante MT, Busatto GF, Lombroso PJ, Prado L, Rosario-Campos MC, do Valle R, et al. The psychiatric symptoms of rheumatic fever. Am J Psychiatry 2000;157:2036 8. [48] Cavalcanti A, Hilario MO, dos Santos FH, Bolognani AS, Bueno OF, Len CA. Subtle cognitive deficits in adults with a previous history of Sydenham’s chorea during childhood. Arthritis Care Res (Hoboken) 2010;62(8):1065 71. ¨ zdemir O. Two unusual presentations of acute rheumatic fever. [49] Kula S, Olguntu¨rk R, O Cardiol Young 2005;15:514 16. [50] Ayoub EM. Streptococcal antibody tests in rheumatic fever. Clin Immunol Newsl 1982;3:107 11. [51] Roddey Jr OF, Clegg HW, Martin ES, Swetenburg RL, Koonce EW. Comparison of an optical immunoassay technique with two culture methods for the detection of group A streptococci in a pediatric office. J Pediatr 1995;126:931 3. [52] Caldas AM, Terreri MT, Moise´s VA, Silva CM, Len CA, Carvalho AC, et al. What is the true frequency of carditis in acute rheumatic fever? A prospective clinical and Doppler blind study of 56 children with up to 60 months of follow-up. Pediatr Cardiol 2008;29 (6):1048 53. [53] Caldas AM, Terreri MT, Moise´s VA, Silva CM, Carvalho AC, Hila´rio MO. Subclinical rheumatic carditis: the case for utilizing more strict quantitative Doppler echocadiographic criteria. Cardiol Young 2007;17(1):42 7. [54] Dajani AS, Ayoub E, Bierman FZ. Special writing group of the committee on rheumatic fever, endocarditis and Kawasaki disease of the council on cardiovascular disease in the young of the American Heart Association. Guidelines for the diagnosis of rheumatic fever—Jones criteria, 1992 update. J Am Med Assoc 1992;268:2069 73. [55] Jones TD. The diagnosis of rheumatic fever. J Am Med Assoc 1944;126:481 4. [56] Ferrieri P. Proceedings of the Jones criteria workshop. Circulation 2002;106:2521 3. [57] Gewitz MH, Baltimore RS, Tani LY, Sable CA, Shulman ST, Carapetis J, et al. American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation 2015;31(20):1806 18. [58] Dajani A, Taubert K, Ferrieri P, Peter G, Shulman S. Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals. Pediatrics 1995;96:758 64. [59] Dajani AS, Bisno AL, Chung KJ, Durack DT, Gerber MA, Kaplan EL, et al. Prevention of rheumatic fever. A statement for health professionals by the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American Heart Association. Circulation 1988;78:1082 6. [60] Taranta A, Markowitz M. Rheumatic recurrences. In: Taranta M, Markowitz M, editors. Rheumatic fever. 2nd ed. Dordrecht/Boston/London: Kluwer Academic Publishers; 1989. p. 71. [61] Dajani AS. Adherence to physicians’ instructions as a factor in managing streptococcal pharyngitis. Pediatrics 1996;97:976 80.

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[62] Lue HC, Wu MH, Hsieh KH, Lin GJ, Hsieh RP, Chiou JF. Rheumatic fever recurrences: controlled study of 3-week versus 4-week benzathine penicillin prevention programs. J Pediatr 1986;108:299 304. [63] Wood HF, Feinstein AR, Taranta A, Simpson R. Rheumatic fever in children and adolescents. A long term epidemiological study of subsequent prophylaxis, streptococcal infections, and clinical sequelae. III. Comparative effectiveness of three prophylaxis regimens in preventing streptococcal infections and rheumatic recurrences. Ann Internal Med 1964;60(Suppl. 5):31 46. [64] Dale JB. Group A streptococcal vaccines. Pediatr Ann 1998;27:301 8. [65] Beachey EH, Bronze M, Dale JB, Kraus W, Poirier T, Sargent S. Protective and autoimmune epitopes of streptococcal M proteins. Vaccine 1988;6:192 6. [66] Guilherme J, Ferreira FM, Koehler KF, Postol E, Kalil J. A vaccine against Streptococcus pyogenes: the potential to prevent rheumatic fever and rheumatic heart disease. Am J Cardiovasc Drugs 2013;13(1):1 4. [67] Guilherme L, Postol E, Freschi de Barros S, Higa F, Alencar R, Lastre M, et al. A vaccine against S. pyogenes: design and experimental immune response. Methods 2009;49: 316 21. [68] McNeil SA, Halperin SA, Langley JM, Smith B, Warrren A, Sharratt GP, et al. Safety and immunogenicity of 26-valent group A Streptococcus vaccine in healthy adult volunteers. Clin Infect Dis 2005;41:1114 22. [69] World Health Organization Technical Report Series. Rheumatic fever and rheumatic heart disease. 2004;923:1 122.

Chapter 22

Lyme Borreliosis H.-I. Huppertz1,2 and H.J. Girschick3,4 1

Prof.-Hess-Kinderklinik, Klinikum Bremen-Mitte, Bremen, Germany, 2Universita¨tskinderklinik Go¨ttingen, Go¨ttingen, Germany, 3Universita¨tskinderklinik Wu¨rzburg, Wu¨rzburg, Germany, 4 Klinik fu¨r Kinder- und Jugendmedizin, Vivantes Netzwerk fu¨r Gesundheit GmbH, Klinikum im Friedrichshain, Berlin, Germany

INTRODUCTION Lyme disease or Lyme borreliosis (LB) is an infectious multisystem disease. LB is caused by Borrelia burgdorferi, a spirochete. Borrelia burgdorferi organisms can be subdivided into several genotypes, which have been associated with different though overlapping clinical syndromes. LB is transmitted by the vector Ixodes ricinus, a hard tick that is prevalent in many areas of the temperate northern zones including most of Europe and parts of the United States. In some parts of Europe and the United States LB may be among the most frequent infectious diseases with an incidence of 111 per 100,000 or more [1]. Up to 90% of patients with LB have erythema migrans, a mild reddening of the skin at the site of the tick bite that will disappear without intervention after a few days to weeks. The infection can affect the nervous system, joints, heart, eyes, and other organs. Clinical manifestations are classified as early or late. Early manifestations occur a few days to several weeks after infection, while late manifestations occur months to years after infection [2]. Early manifestations are self-limiting and do not cause lasting damage. However, late manifestations may become chronic and lead to organ damage. Clinical manifestations differ in adults and children: in children radiculitis is rare while lymphocytic meningitis with or without cranial nerve palsy is more frequent. Acrodermatitis chronica atrophicans, chronic central nervous system disease, and heart involvement are very rare in children. Arthritis, called Lyme arthritis (LA), is the most frequent late manifestation in children. It is often episodic, but may become chronic and up to 10%

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00022-0 © 2016 Elsevier B.V. All rights reserved.

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of cases are resistant to antibiotic treatment [3]. Risk factors are female gender, age above 10, and treatment with systemic or intraarticular steroids prior to initiation of antibiotic treatment. LB, and in particular LA, has attracted special interest by clinicians and researchers since arthritis due to infection with B. burgdorferi can become chronic. Chronic arthritis following infection with B. burgdorferi has been attributed to several factors including persistent infection or antigenic stimulation, immunopathological reactions to components of B. burgdorferi, and autoimmunity.

PERSISTENT INFECTION At the time of early manifestations, the presence of B. burgdorferi can be verified by isolation of the spirochete or by polymerase chain reaction (PCR) of borrelial genomic and/or plasmid-derived sequences, but this often proves impractical. In otherwise healthy patients with acrodermatitis chronica atrophicans B. burgdorferi could be grown from affected skin up to 10 years after the beginning of the disease showing the remarkable capability of the spirochete to persist in the human body in the presence of an apparently well-functioning immune system. In contrast, B. burgdorferi is rarely isolated from synovial fluid or tissue in patients with LA or from cerebrospinal fluid in patients with late neuroborreliosis. B. burgdorferi may persist in vitro in synovial cells [20]. However PCR may be positive. The spirochete has been demonstrated in synovial tissue, by staining with silver salts or monoclonal antibodies [4]. Interestingly, B. burgdorferi is found in a very low density and it is not clear if these are viable spirochetes or remnants difficult to degrade.

IMMUNOPATHOLOGICAL REACTIONS Borrelia burgdorferi may modulate the immune system. In patients with acrodermatitis chronica atrophicans decreased expression of the major histocompatibility complex (MHC) has been observed on Langerhans cells in contact with B. burgdorferi [5]. Infection may increase or decrease the expression of adhesion molecules on a variety of cell types [6 8]. Borrelia burgdorferi-specific CD4-positive T cells can be isolated from peripheral blood or synovial fluid of patients with LA [9] and the response increases with prolonged disease. The lymphokines secreted by these cells have typical Th1 characteristics [10]. CD8-positive B. burgdorferi-specific T cells have been isolated from children with LA after resolution of arthritis suggesting a regulatory deficiency may contribute to the development of chronic arthritis [11]. Borrelia burgdorferi does not produce toxins and does not harbor lipopolysaccharides, but it contains a variety of lipoproteins that may influence the development of arthritis [12].

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AUTOIMMUNITY Patients with persistent LA have been shown to express MHC class II molecules associated with rheumatoid arthritis (RA), including HLA-DRB1 0401 and  0101 [13]. These patients showed high titers of antibodies against the outer surface protein A (OspA), which is a plasmid-encoded virulence factor located in the outer envelope of the spirochete [14]. After phagocytosis borrelial antigens can be presented by MHC II molecules to T cells [15]. It was shown that the T-cell antigen LFA-1 can stimulate OspA-specific T cells from patients with treatment-resistant LA [16]. Thus LFA-1 might serve as cross-reactive autoantigen by way of molecular mimicry in which initially an immune response is mounted against OspA; then the immune response also affects LFA-1, which leads to the stimulation of the T cells; and finally, the immune response may persist even in the absence of OspA and is directed against LFA-1. However, although conclusive, this hypothesis has not been confirmed subsequently. In an animal model, B-cell tolerance was broken following chronic infection with B. burgdorferi. The immune complexes induced synergistic signaling between B-cell receptor, Toll-like receptors, and T-helper cell [17]. Thus autoimmune reactions and not just molecular mimicry between bacterial and host antigens contribute to the chronic arthritis of LB [18].

CONCLUSIONS LA is an intriguing disease: it is infectious, but the rate of response to antibiotic treatment of about 90% is inferior to that found in other bacterial diseases. LA may also be considered a rheumatic disease, but with a very favorable outcome: there are few or no other rheumatic diseases that remit in 90% of patients after one or two short courses of antibiotics. Moreover, the other 10% of patients have a good chance to reach remission a few months or years later after appropriate antirheumatic treatment including intraarticular steroids and/or methotrexate. Although several theories have been proposed, the mechanisms of the pathogenesis of antibiotic refractory LA remains unknown. In addition, the hope to find clues for understanding the pathogenesis of RA or juvenile idiopathic arthritis (JIA) by better understanding the pathogenesis of LA have not come true so far. Much more research is necessary to achieve that goal. However, at present LA is not a research priority and very little knowledge could be added during the past few years. In contrast alternative medicine is using LB as a platform for attempts called “antiscience” to improve unexplained symptoms usually amenable to multimodal treatment including psychotherapy [19]. However, a better understanding of the pathogenesis of treatment-refractory LA might not only help patients with LA to be treated more effectively. It might also increase our understanding of RA and JIA

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and thereby it might be possible to outline new options for treatment or even prevention that should counter the causative disease process rather than just suppress the inflammatory response as actual pharmacological treatment options do.

KEY POINTS G

G

G

Lyme arthritis is the most frequent bacterial infection associated with arthritis. Chronic Lyme arthritis may be a human model of chronic inflammatory joint disease with a known etiology. Clarification of its pathogenesis may provide clues to the pathogenesis of other chronic inflammatory joint diseases including rheumatoid arthritis and juvenile idiopathic arthritis.

REFERENCES [1] Huppertz HI, Bo¨hme M, Standaert SM, Karch H, Plotkin SA. Incidence of Lyme borreliosis in the Wu¨rzburg area of Germany. Eur J Clin Microbiol Infect Dis 1999;18:697 703. [2] Huppertz HI, Zemel L, Dressler F. Lyme disease. In: Petty RE, Laxer RM, et al., editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2015. p. 551 62. [3] Bentas W, Karch H, Huppertz HI. Lyme arthritis in children and adolescents:outcome 12 months after initiation of antibiotic therapy. J Rheumatol 2000;27:2025 30. [4] Priem S, Burmester GR, Kamradt T, et al. Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but not in synovial fluid from patients with persisting Lyme arthritis after antibiotic therapy. Ann Rheum Dis 1998;57:118 21. [5] Silberer M, Koszik F, Stingl G, Aberer E. Downregulation of class II molecules on epidermal Langerhans cells in Lyme borreliosis. Br J Dermatol 2000;143:786 94. [6] Sellati TJ, Burns MJ, Ficazzola MA, Furie MB. Borrelia burgdorferi upregulates expression of adhesion molecules on endothelial cells and promotes transendothelial migration of neutrophils in vitro. Infect Immun 1995;63:4439 47. [7] Singh SK, Baar V, Morbach H, Girschick HJ. Expression of ICAM-1, ICAM-2,NCAM-1 and VCAM-1 by synovial cells exposed to Borrelia burgdorferi in vitro. Rheumatol Int 2005;24:1 10. [8] Girschick HJ, Meister S, Karch H, Huppertz HI. Borrelia burgdorferi downregulates ICAM-1 on human synovial cells in vitro. Cell Adhes Commun 1999;7:73 83. [9] Huppertz HI, Mo¨sbauer S, Busch DH, Karch H. Lymphoproliferative responses to Borrelia burgdorferi in the diagnosis of Lyme arthritis in children and adolescents. Eur J Pediatr 1996;155:297 302. [10] Yssel H, Shanafelt MC, Soderberg C, Schneider PV, Angola J, Pelty G. Borrelia burgdorferi activates a T helper type 1-like cell subset in Lyme arthritris. J Exp Med 1991; 174:593 601. [11] Busch DH, Jassoy C, Brinckmann U, Girschick HJ, Huppertz HI. Detection of Borrelia burgdorferi-specific CD8+ cytotoxic T cells in patients with Lyme arthritis. J Immunol 1996;157:3534 41.

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[12] Infante-Duarte C, Horton HF, Byrne MC, Kamradt T. Microbial lipopolypeptides induce the production of IL-17 in T helper cells. J Immunol 2000;165:6107 15. [13] Steere AC, Baxter-Lowe LA. Association of chronic, treatment resistant Lyme arthritis with rheumatoid arthriris alleles. Arthritis Rheum 1998;41:S81. [14] Kalish RA, Leong JM, Steere AC. Early and late antibody responses to full length and truncated constructs of outer surface protein A of Borrelia burgdorferi in Lyme disease. Infect Immun 1995;63:2228 35. [15] Filgueiria L, Nestle FO, Rittig M, Joller HI, Groscurth P. Human dendritic cells phagocytose and process Borrelia burgdorferi. J Immunol 1996;157:2998 3005. [16] Trollmo C, Meyer AL, Steere AC, Hafler DA, Huber BT. Molecular mimicry in Lyme arthritis demonstrated at the single cell level: LFA-1 alpha is a partial agonist for outer surface protein A-reactive T cells. J Immunol 2001;166:5286 91. [17] Soulas P, Woods A, Jaulhac B, Knapp AM, Pasquali JL, Martin T, et al. Autoantigen, innate immunity, and T cells cooperate to break B cell tolerance during bacterial infection. J Clin Invest 2005;115:2257 67. [18] Kamradt T, Volkmer-Engert R. Cross-reactivity of T lymphocytes in infection and autoimmunity. Mol Divers 2004;8:271 80. [19] Huppertz HI, Bartmann P, Heininger U, Fingerle V, Kinet M, et al. Rational diagnostic strategies for Lyme borreliosis in children and adolescents: recommendations by the committee for infectious diseases and vaccinations of the German Academy for Pediatrics and Adolescent Health. Eur J Pediatr 2012;171:1619 24. [20] Girschick HJ, Huppertz HI, Ru¨ssmann H, Krenn V, Karch H. Intracellular persistence of Borrelia burgdorferi in human synovial cells. Rheumatol Int 1996;16:125 32.

Chapter 23

Tumor Necrosis Factor Inhibitors in Pediatric Rheumatology V. Gerloni, I. Pontikaki and F. Fantini Unit of Pediatric Rheumatology, Chair and Department of Rheumatology, Gaetano Pini Institute, Milan, Italy

INTRODUCTION The overproduction of the inflammatory cytokine tumor necrosis factor (TNF)-alpha (TNFα) plays a key role in the maintenance of many chronic inflammatory rheumatic diseases, particularly those that depend on the relationship between T cells and macrophages [1]. TNFα has been shown to induce bone reabsorption, to inhibit proteoglycan [2,3] and collagen synthesis [4,5], to induce prostaglandin E2 and collagenase release from synovial cells, and to stimulate fibroblast growth [6]. TNFα also plays a pivotal role in the enhancement of inflammatory cell trafficking into synovium by regulating the expression of adhesion molecules on the endothelial cells [7,8]. It also upregulates the production of other proinflammatory cytokines, such as interleukin (IL)-1 and IL-6, and the expression of their respective receptors [9]. TNFα blockade has been therapeutically achieved through the administration of monoclonal antibodies against TNFα or soluble TNFα receptors. Five anti-TNFα agents have been approved in Europe and the United States for use in adult onset rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis: the fusion protein combining two p75-TNFα receptors with an Fc fragment of human IgG1 (etanercept (Enbrel)); the chimeric, human and murine, monoclonal antibody against TNFα (infliximab (Remicade)); the fully human TNFα monoclonal antibodies (adalimumab (Humira) and golimumab (Simponi)); and the PEGylated Fab fragment of a humanized monoclonal antibody against TNFα (certolizumab (Cimzia)). Two of them, etanercept and adalimumab, are also approved in Europe and the United States for use in polyarticular JIA. Infliximab is approved only for JIA-related uveitis.

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00023-2 © 2016 Elsevier B.V. All rights reserved.

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The monoclonal antibodies, in particular the chimeric antibody infliximab, specifically and potently bind and neutralize not only the soluble TNFα but also its membrane-bound precursor inducing cell lysis by apoptosis; their action mechanism is different and more selective than that of the recombinant p75-TNFα receptor, which inhibits not only TNFα but also TNFβ (lymphotoxin α) and does not cause the cell lysis binding to membrane TNFα. Controlled trials in adults have shown that the TNFα inhibitors significantly reduce symptoms and signs, improve function and quality of life, and reduce radiological damage in RA and related diseases. Concurrent treatment with methotrexate (MTX) appears to enhance the therapeutic response. Since the end of the 1990s, this therapeutic approach was also extended to JIA [10]. The therapeutic approach to JIA is sometimes very troublesome. The progression to erosive chronic polyarthritis, which may occur in all JIA subsets regardless of the type of onset, often results in extreme disability and very poor quality of life. In addition, it remains difficult to control the flares of systemic symptoms in systemic onset subtype (SoJIA) (eg, fever, frequently associated with severe anemia). Many disease-modifying antirheumatic drugs (DMARDs), commonly used in adult RA, have shown a lack of efficacy in several placebo-controlled trials and long-term prospective studies in children with JIA [11 14]. The only treatment that has shown efficacy and safety in a large controlled clinical trial is MTX [15]. Nevertheless, in many cases the lack of efficacy of MTX or development of drug resistance or intolerance has led to trying other therapeutic options, such as salazopyrine [16], cyclosporine A [17], intravenous human immunoglobulins [18] or, in rare cases, a more aggressive approach with autologous stem cell transplantation [19]. However, the beneficial effects of these therapeutic choices are debatable. Prior to the era of anti-TNFα therapies, more than 25% of children with polyarticular and nearly 50% with systemic JIA, at 5 years after onset, had functional limitations. Radiographically evident joint space damage was seen within 1 year of onset in polyarthritis and, by 5 years, two-thirds of polyarticular and systemic patients had damage [20]. Therefore, there has been space in the last 15 years for the more specific and effective new biologic therapies that target specific cytokines, as the TNFα inhibitors.

TNF IN THE PATHOGENESIS OF JIA Although the mechanisms causing the clinical features of JIA (high spiking fever, anemia, joint inflammation, and destruction) are still unknown, indirect evidence suggests that cytokines, such as IL-1, IL-6, and TNFα, may play an important pathogenetic role [21]. Elevation of circulating TNFα was seen only occasionally and in small amounts in JIA [22 24], and no correlation was found between serum concentration of TNFα and parameters of disease activity [22,24,25]. However, it is known that cytokines exert their

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effects mainly at the sites of inflammation [26]. In fact, in JIA the TNFα levels are higher in synovial fluid than in the serum [24] and the cytokine is expressed in synovial fluid mononuclear cells [27]. Moreover, TNFα serum concentration does not differ significantly between the JIA patients and control group, but p55 and p75 soluble receptors (sTNFαR) are significantly elevated in serum from all JIA categories, particularly in those with systemic onset disease, and their levels correlate with disease activity [23,28]. TNFα itself is one of the best inducers of sTNFαR expression [29], and their shedding from the cell surface is believed to be related to TNFα production [30]. Therefore the increased expression of sTNFαR in plasma and in synovial fluid may support the hypothesis that TNFα has a role in the pathogenesis of JIA. Elevations in IL-1, IL-6, and TNFα in patients with systemic episodes of disease, with a rise and fall in circulating TNFα out of phases with fever, were demonstrated [31]. Plasma and synovial fluid TNFα and IL-6 concentrations were found to be significantly increased in the active period of the disease [32]. An imbalance between TNFα and its naturally occurring inhibitors, the soluble receptors (lower sTNFαR/TNFα ratio), might be associated with the increased joint destruction observed in polyarticular disease [33]. Finally, in JIA, synovial tissue and synovial cells overexpress not only TNFα, but also TNFβ (lymphotoxin α) [27,34]. The mechanism of action of the chimeric and human monoclonal antibodies is more selective than that of the recombinant p75-TNFα receptor, which inhibits not only TNFα but also lymphotoxin α.

Anti-TNFα Therapy in JIA The clinical experience on TNFα inhibition in JIA was initially limited to etanercept, the only biological drug approved until 2008 in the United States and in Europe for use in children with active polyarticular JIA despite prior MTX therapy. The RCT (randomized placebo-controlled trial) multicenter American trial on etanercept was published in 2000 [35], the result from the adalimumab RCT study was published in 2006 08 [36 38], and the results of the international RCT on infliximab in 2006 07 [37,39]. Apart from this, the literature was enriched earlier by many case reports [40 48], retrospective studies [49,50], or open prospective studies of small populations [51 56], and by the results of some national registries: the German [57], Italian [58], American [59], Spanish [60], and Dutch [61] ones. The first reported cases of TNFα blockade in JIA [41-45] were cases of SoJIA treated with infliximab. However, most of the subsequent studies refer to experiences with etanercept, with the exceptions of 14 patients treated with infliximab reported in a Finnish study [56], 24 patients of an Italian study [54], and 122 patients of the international RCT study [37,39].

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Both etanercept [35,62] and infliximab [54,56,63] have shown a dramatic clinical benefit in the treatment of patients with active JIA with polyarticular course who did not tolerate or had an inadequate response to MTX. In the majority of patients, the TNF inhibitors not only control the pain [64] and the other symptoms and signs of arthritis but also improve the biochemical measurements of inflammation (ESR and CRP) and the quality of life and are overall well tolerated. Nevertheless, a persistent clinical remission (CR) according to Wallace criteria [65] is a rare event [66 68]. In a followup study, all 11 patients with JIA who discontinued etanercept due to disease remission flared during the follow-up period, nevertheless the disease activity score JIADAS, compared to the time of etanercept initiation, was significantly reduced at etanercept discontinuation as well as at the time of the flare [66]. In a retrospective review, the 82% of 18 nonsystemic JIA patients who achieved clinical remission on medication (CRM) relapsed after treatment withdrawal, and mean time to relapse was 3.04 months (SD 2.03) [69]. Many clinic and biologic factors are studied as possible predictors of anti-TNF therapy response. In an Italian population of 301 JIA patients treated with biological therapy, predictors of discontinuation due to adverse events were female gender and longer disease duration; predictors of discontinuation due to lack or loss of efficacy were SoJIA and polyarthritis FR positive and the use of mAb-antiTNF (vs sTNFR); predictors of discontinuation due to inactive disease were male gender and shorter disease duration [67]. In another retrospective observational study on JIA patients taking etanercept (#105) or infliximab (#104), although infliximab was discontinued more often than etanercept because of adverse events, during a 48-month follow-up the overall treatment survival of etanercept and infliximab as the first biological agent was comparable [70]. In an observational, retrospective study of 41 JIA patients treated with anti-TNF, both etanercept and infliximab performed well, no significant difference in the duration, response, flare, resistance, or adverse effects (AEs) between both drugs were found [68]. In a systematic review, 11 RCT, equal with regard to design and patients’ characteristics related to treatment outcome, were indirectly compared (based on Bucher’s method). Withdrawal trials, which evaluated etanercept, adalimumab, and abatacept in polyarticular course JIA, identified no significant differences in short-term efficacy [71]. The genetic polymorphisms for IL-1B +3954, IL-1RA +2018, TNFα 2238, and TNFα 2308 did not seem to be associated with response to anti-TNF treatment [72]. The 2308G genotype has been associated with a better response to anti-TNFα therapy in JIA patients, confirming adult data [73]. The TNFα 2308 GA/AA and 2238 GA genotypes are associated with a worse prognosis and with a lower response to anti-TNFα drugs [74] High levels of baseline MRP8/14 are associated with good response to anti-TNF treatment, whereas elevated levels at discontinuation are associated with higher chance to flare [75].

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Biological agents are now increasingly prescribed earlier in the disease course and in patients with JIA with lower disease activity, the use of systemic glucocorticoids and synthetic DMARDs before biological agents decreased. These changes are accompanied by better short-term disease outcomes [76]. The early introduction of anti-TNF agents in children with severe JIA, suppressing inflammation and providing a steroid sparing effect, could reduce the risk of osteoporosis [77] and growth failure [78,79], improve significantly Hgb and MCV without use of iron supplementation [80], and improve lipid profile suggesting that it might reduce future atherosclerotic risk [81,82].

Etanercept The open-label data from 69 patients of the etanercept multicenter American trial [35] showed that at the third month of therapy 74% of patients achieved the American College of Rheumatology Pediatric 30 Definition of Improvement (ACR-Pedi-30) [83,84]. In the subsequent RCT of patients who had achieved the ACR-Pedi-30 response, the percentage of patients who withdrew because of disease flare was significantly higher in the group of patients who switched to placebo (81%), as compared with the group of the patients who continued with the active drug (28%). The extended open-label phase of this study demonstrated a sustained clinical efficacy of up to 8 years of continuous etanercept therapy [36,38,62,85]. The conventional pediatric dose of etanercept was 0.4 mg/kg of body weight (maximum dose 25 mg) administered subcutaneously twice a week. However, a pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with JIA showed that 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly regimens generate comparable systemic exposure, likely leading to equivalent clinical outcomes. This has been the basis of the later Food and Drug Administration (FDA) approval of the 0.8-mg/kg once-weekly regimen in pediatric patients with JIA [86]. In the case of lack of efficacy with the conventional dose, the dose can be increased up to 1 mg/kg twice a week [49]. The combination of TNFα antagonists with immunosuppressants generally seems to be beneficial in order to increase the efficacy of therapy. In small studies, etanercept has been proven efficacious and safe when combined with MTX, MTX plus hydroxychloroquine, MTX plus salazopirine and leflunomide [50,52,53,87,88]. There is now extensive experience in clinical practice of the combination therapy of etanercept with MTX; tolerance so far seems not to be problematic. Infliximab Since the first open prospective single-center experiences [54,56], TNFα blockade with the chimeric monoclonal antibody infliximab added to MTX

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also resulted in highly effective and safe treatment of patients with long-lasting active JIA despite previous therapy with MTX and one or more other DMARDs. This resulted in a clinically impressive and statistically significant reduction in disease activity, as assessed by a number of clinical end points and biochemical markers, and was associated with an improvement in some aspects of the quality of life. Already after the first infusions the majority of patients reported an improvement in pain and morning stiffness and a reduction of fatigue. The international RCT [37,39] of infliximab therapy in JIA showed that at week 14 of therapy, with the dose of 3 mg/kg, 63.8% of patients achieved the ACR-Pedi-30 response. By week 16, following crossover from placebo group to infliximab 6 mg/kg (at which time all patients were receiving infliximab), 73.2% of patients achieved an ACR-Pedi-30 response. Also with infliximab, a sustained clinical improvement was demonstrated: by week 52, an ACR-Pedi-50 or ACR-Pedi-70 were reached by 69.6% and 51.8% of patients, respectively. In the pilot clinical experiences in JIA, infliximab was administered, as in adult RA, by i.v. infusions at the conventional dose of 3 mg/kg per infusion at weeks 0, 2, and 6, and every 8 weeks thereafter and was usually added to MTX at the previous well-tolerated dosage. In fact, in the clinical trials in adult RA [89], the combined therapy was proven to be beneficial in order to increase the efficacy of therapy. Moreover, the combined therapy and higher doses of infliximab, up to 10 mg/kg per infusion, seems to be safer reducing the rate of hyperergic infusion reactions (IRs). Similarly, in the controlled study in JIA [37], higher doses of infliximab (6 mg/kg per infusion) proved to be safer than the 3 mg/kg dose in order to reduce the rate of IRs. For these reasons the recommended dose of infliximab for the treatment of JIA is now 6 mg/kg per infusion and the association with MTX is the rule.

Adalimumab The blockade of TNFα with the human monoclonal antibody adalimumab, either alone or combined with MTX, was also shown to rapidly improve signs and symptoms of JIA. The open-label data from 171 patients of the international trial showed with adalimumab (24 mg/m2, maximum dose 40 mg, every other week) after 16 weeks of therapy, the response rates were 83% for ACR-Pedi-30, 74% for ACR-Pedi-50, and 52% for ACR-Pedi-70. In the subsequent RCT of patients who had achieved the ACR-Pedi-30 response, significantly fewer patients receiving adalimumab had disease flares than those who received placebo, regardless of concomitant MTX use [37]. Adalimumab appears to be highly effective in children and adolescents with JIA, either as the first or as a second biologic agent, the treatment is safe, only few patients discontinue therapy due to intolerance [90,91], and its efficacy is similar to that of other anti-TNF agents used to treat JIA [90,92].

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TNFα Blockade in the Treatment of Systemic Onset JIA The efficacy of TNFα blockade in patients with SoJIA soon appeared not to be as satisfactory as in the other nonsystemic JIA International League of Associations for Rheumatology (ILAR) categories [35,51,52,57,93]. In a more recent study, only 11 out of 45 (24%) patients with systemic JIA treated with anti-TNF agents met definition criteria for CRM and only 13% experienced sustained benefit [94]. However, the rate of response appears to vary according to the presence or not of systemic activity (fever and rash) at the time of the treatment. In one study, etanercept was efficacious in the 88% of patients with SoJIA in the first year of treatment, but in children with systemic symptoms at the time of therapy, the improvement was short-lived or the toxicity limited its continuous use. Patients with SoJIA but a nonsystemic chronic polyarticular course show a better response than children with a systemic activity, comparable to the one exhibited by patients with polyarticular JIA [95]. In the patients with SoJIA in active phase who fail to respond to etanercept, the presence of fever/rash was not modified by the treatment when also switched to infliximab [96]. In a different experience [97] TNFα blockade with either etanercept or infliximab resulted as effective in SoJIA as in the other JIA ILAR categories. In fact, most of the SoJIA patients in this study had a longlasting disease and were in a sustained polyarthritic phase without systemic symptoms.

TNFα Blockade in the Treatment of JIA-Associated Chronic Anterior Uveitis In most early experiences, such as a small controlled trial [98], a large survey [99], and a large open prospective study [100], etanercept seems inefficacious in preventing relapses of JIA-associated anterior uveitis (AU) in the population at risk. In general, no sufficient control of ocular inflammation was found with this therapy; on the contrary, infliximab and adalimumab seems to be efficacious for refractory JIA-associated anterior uveitis [101 104, 196, 197]. Infliximab resulted in better clinical responses with less ocular complications, such as new onset or worsening of glaucoma or cataract, than etanercept [40, 105 107, 182]. In a recent study [101] the treatment with anti-TNF was successful in a majority of children with noninfectious uveitis. JIA-associated AU may be especially responsive to anti-TNF therapy. Among 56 retrospectively assessed children with chronic refractory noninfectious uveitis (52% JIA and 75% AU) receiving anti-TNF therapy, the diagnoses of JIA or AU were associated with greater likelihood of success, as was the oligoarticular subtype among JIA cases.

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One-year follow-up data from the Italian Registry have shown that infliximab and adalimumab appear to be both effective and safe for treatment of refractory JIA-associated AU, with a better performance of adalimumab in the medium-term period [108]. In an open-label, multicenter study of 26 children with chronic refractory, noninfectious active uveitis (17 out of 26 were in the contest of JIA), adalimumab used as first anti-TNFα therapy versus adalimumab used after the failure of a previous infliximab, showed higher probability of uveitis remission (p , 0.002) and steroid discontinuation during the first 12 months of treatment (p , 0.04) [109].

TNFα Blockade in the Treatment of Juvenile Spondyloarthropathies TNFα also plays an important role in the pathogenesis of juvenile spondyloarthropathies (JSpA) or enthesitis-related-arthritis (ERA). In keeping with data from adults, anti-TNFα antagonist therapy, either with infliximab or with etanercept, seems safe and rapidly effective in patients with JSpA refractory to nonsteroidal anti-inflammatory drugs: the arthritis and enthesitis significantly improve, the markers of inflammation and the Childhood Health Assessment Questionnaire scores normalize, and there is a reduction in requirements for antirheumatic drugs in most patients. Additionally, the patients noted increased mobility and overall well-being. The improvement was sustained during the 1 2 years of follow-up [110 112]. A recent open-label trial with etanercept has confirmed that this treatment for 12 weeks is effective and well tolerated in children and adolescents with ERA, extended oligoarticular JIA, and psoriatic arthritis, with no unexpected safety findings [113]. Recently, the results of a phase III, multicenter, RCT in patients with ERA treated with adalimumab or placebo for 12 weeks, followed by up to 192 weeks of open-label adalimumab, have been published: adalimumab reduced signs and symptoms of ERA at week 12, with improvement sustained through week 52. The safety profile was consistent with previous adalimumab studies, adverse event (AE) rates were similar between placebo and adalimumab: any AE (53.3% vs 67.7%), serious AEs (0% vs 3.2%), and infectious AEs (20.0% vs 29.0%) [114]. Moreover, TNFα blockade also seems to be efficacious in the treatment of anterior acute uveitis associated with ERA. In fact, in adult patients affected by SpA, treatment with TNFα blockers is associated with a significant decrease in the number of AU flares. This reduction is slightly more marked among patients treated with infliximab [115].

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ADVERSE EVENTS OF TNFα BLOCKADE Biologic drugs, such as TNF inhibitors, refer to genetically engineered drugs that have been designed to modulate a specific aspect of the underlying immune process, thus avoiding generalized immunosuppression, with the hope that such specificity will result in higher efficacy and fewer AEs than traditional cytotoxic DMARDs. However, as use of these agents has increased worldwide during the postmarketing period, infrequent AEs, which were not apparent in RCT required for registration, have emerged [51,100,116]. The neutralization of TNF is associated with an increased risk of certain serious but uncommon AEs, including serious bacterial infections such as tuberculosis (TB) and certain opportunistic infections, malignancy/ lymphoma, congestive heart failure, demyelinating and neurological disorders, injection site reactions or infusion-related systemic reactions, newly induced autoantibodies, and lupus-like disease. However, several of these risks (eg, lymphoma and serious infections) are associated with either the disease per se or the concomitant and previous immunosuppressive treatments [117]. These AEs may be related to blockade of TNF and may therefore represent class effects of these agents. Overall, tolerability of anti-TNF therapy in JIA is good. However, the severity and degree of the risk may not be the same with all three agents. In general, infliximab was discontinued more often than etanercept or adalimumab because of AEs, mainly IRs [67,70]. In 592 patient/years of the German etanercept registry [57], there were 69 reports of AEs in 56 patients. In the USA registry [59] a total of 601 patients (etanercept 403 and MTX 198) were included and the rate of AEs observed with etanercept was very low (21%), exactly the same as was observed with MTX treatment. The anti-TNF blockade was also safe and quite well tolerated in a large Italian experience [67,100]: less than 60% of treatments were complicated with one or more AEs, which contrasts with some adult studies where up to 95% of patients had at least one AE [118]. The AEs observed in pediatric clinical experiences [51,100] usually were not serious, led to discontinuation of treatment in about 20% of the whole population, and all disappeared after discontinuation. Overall, patients with SoJIA seem to be at greater risk for AEs than patients with nonsystemic JIA. The published data on safety after 4 and 8 years show that etanercept also offers an acceptable safety profile in a long-term treatment: in a total etanercept exposure of 318 patient/years, the overall rate of severe AEs (0.12/patient per year) did not increase with long-term exposure. The rate of medically important infections (0.03/patient per year) remained low; one new medically important infection was reported in patients with $ 5 years of etanercept exposure. No cases of TB, opportunistic infections, malignancies, lymphomas, lupus, demyelinating disorders, or deaths were reported [36,38,85].

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Recently, in three tertiary centers in Finland, all AEs in 348 consecutive JIA patients, with a total exposure of 1516 patient/years of biologic therapy, were collected. The most common of the 2902 AEs (191/100 patient/years) observed were mild infections, infusion or injection site reactions, and alanine aminotransferase elevations. The rate of severe AEs was 11.4/100 patient/years on etanercept, 11.8 on infliximab, 10.1 on adalimumab, 15.7 on abatacept, 31.2 on tocilizumab, and 87.5 on rituximab. No cases of malignant neoplasms or TB were detected [119].

Hyperergic Reactions The more frequent AE with etanercept is a transient mild local allergic reaction to the s.c. injection, recorded in up to 39% of JIA patients [35], but about 10% of patients manifested a diffuse cutaneous reaction that required an antihistaminic treatment [35,100,120]. The most common AE with infliximab is the IR, which provokes sensations of thoracic constriction, dyspnea, flushing, and urticaria. This AE can be prevented or attenuated by slowing the infusion velocity and by pretreatment with antihistaminic and steroid drugs. Nevertheless, many patients (20%) failed treatment because of severe IR, relapsing at each infusion despite this pretreatment [100]. In fact, one of the major concerns, limited to the TNFα blockade with the monoclonal antibody infliximab, is the potential formation of human antichimeric antibodies that neutralize the therapeutic agent, limiting its long-term efficacy (silent inactivation) or causing allergic reactions during the infusions [121]. In the international RCT of infliximab plus MTX in polyarticular JIA [37], antibodies to infliximab developed more frequently (37.7% vs 12.2%) with lower (3 mg/kg) rather than with higher (6 mg/kg) doses. Moreover, patients with antibodies to infliximab had a threefold incidence of IRs compared with patients who were negative for these antibodies. The same result was obtained in the first studies of infliximab on adult RA where higher doses and combination with MTX significantly reduced the incidence of IRs to infliximab treatment [89]. The observation that in some cases the IR occurred despite previous medication with antihistamines and steroids, argues against the hypothesis that a true hyperergic mechanism could be responsible for these manifestations. A second hypothesis is that some IRs could be related to an aspecific release of prostaglandin D2, niacin-like effect, as described in the “red man syndrome” [122,123].

Cutaneous Manifestations In JIA patients without a personal or family history of dermatological diseases, receiving treatment with anti-TNFα (infliximab, adalimumab, and etanercept), besides the site injection reactions, other various cutaneous

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manifestations (cutaneous vasculitis, lichen planus, psoriatic palmoplantar pustulosis) have been encountered as AEs [124]. In a JIA patient treated in adulthood with etanercept, a dermatomyositis without muscle involvement was described; the cutaneous manifestation recurred after rechallenge with adalimumab [125]. Cutaneous manifestations could be considered as a paradoxical AE of the anti-TNFα treatment not only in RA but also in JIA.

Neuropsychiatric Manifestations The second most frequent AEs with both treatments are some aspecific signs of central nervous system (CNS) involvement [59,100]. The neuropsychiatric manifestations observed with etanercept ranged from aspecific signs such as headaches (in some cases severe and dose-dependent), vertigo, fatigue, hyperactivity, and nervousness; to more rare cases of pain amplification syndromes, important behavioral alterations such as a severe unusual aggressiveness, or major neuropsychiatric syndromes such as panic, depression, anxiety; and finally to very rare neurological organic signs, such as the described cases of hypoglossal paralysis, optic neuritis, and demyelinating syndromes [35,51,57,62,100,126]. Although exacerbations of multiple sclerosis and other neurological events suggestive of demyelinization have been reported for patients receiving treatment with the anti-TNFα agents etanercept and infliximab, it is not clear whether a causal relationship exists, but in some cases the chronology of clinical events is suggestive. Nevertheless, demyelinating syndromes might persist despite treatment discontinuation, suggesting that anti-TNFα could trigger the demyelinating syndromes, which further evolve independently. The neuropsychiatric AEs observed with infliximab are similar to those observed with etanercept; in some cases these were aspecific and clinically less important, including symptoms such as sleepiness or insomnia, anxiety, transient paresthesia, and fatigue. In other cases the AEs were represented by the classic major psychiatric manifestations: panic attacks, depressive syndromes, and psychoses [100]. In a study in adult RA, the rate of new cases of demyelinating neurological disease in exposed patients was not different from the rate of expected cases [127]. Between Jun. 2005 and Apr. 2008, in a French survey, 33 patients developed demyelinating syndromes after a median of 10.2 months (1.5 39.9) of an anti-TNFα therapy (infliximab (15), etanercept (12), or adalimumab (6)): 22 had CNS and 11 had peripheral nervous system (PNS) involvement. Underlying diseases were 16 RA, 11 ankylosing spondylitis, 4 psoriatic arthritis, 1 JIA, and 1 polymyositis. CNS involvement was encephalic lesions (16), transverse myelitis (8), or retrobulbar optic neuritis (5). Five patients, none children, developed multiple sclerosis. PNS involvement was chronic

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(9 patients) or acute inflammatory demyelinating polyneuropathy (2 patients). Anti-TNF-α was discontinued in 10 patients and 8 received i.v. immunoglobulins. Two patients relapsed after introduction of another anti-TNFα. Overall, a causal relationship between anti-TNFα and demyelinating disorder was considered as probable in 31 patients and definite in 2 who had positive rechallenge [128].

Infections The major concern with the TNFα blockers is their potential proinfective action. In fact, TNFα has immunostimulating functions in vitro [129] and its neutralization in experimental models may increment infections [130]. Indeed, in patients treated with anti-TNFα agents, there is an increased susceptibility to infection by intracellular organisms such as TB, and common infections may present atypically or be more severe; less common are fungal infections. Infliximab appears to be associated with the greatest risk of infection, most likely because of its long half-life (etanercept has a median half-life of 4.8 days, while infliximab has a longer half-life of 8 9.5 days) and the induction of monocyte apoptosis [131]. Most reported infections in children with JIA are mild infections of the upper respiratory or the urinary tract, which were easily managed with antimicrobial therapy. Nevertheless, more serious infection are reported, as 4 musculoskeletal infections among 31 children with JIA being treated with anti-TNFα agents, two of which were secondary to group A beta-hemolytic Streptococcus [132]. The experiences in adult RA and in JIA also reported cases of death for sepsis [133,134] and TB [135]. On the other hand, in adult RA the long-term exposure to the proinflammatory cytokine TNFα seems to impair T-cell responses in vitro and in vivo. This impairment seems to be reversed by anti-TNFα therapy [136]. In fact, in patients with adult RA the incidence of serious infections associated with etanercept and infliximab was low, about 2 3% in etanercept studies of up to 5 years’ duration, and 5% in a survey of more than 10 infliximab trials [137]. Severe infections seem to be more frequent in adult RA than in JIA. Children affected by JIA have less therapeutic options (the only DMARD proven efficacious and safe in a large controlled trial is MTX). For this reason, children are usually treated earlier with anti-TNFα and are less exposed to previous long-lasting immunosuppressant treatments and to immunosuppression due to the persistent uncontrolled disease activity. Infections can be minimized or prevented by screening and careful monitoring and follow-up; most infections respond to appropriate medical treatment. It is recommended that physicians and patients be alert to the development of any new infection so that the appropriate treatment may be promptly started.

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A particular pediatric concern is the immunosuppressive action of biologics in children who are exposed to or develop varicella. In fact, in the multicenter-controlled USA experience [62], three children developed varicella infection during etanercept treatment and two of them needed hospitalization because of severe complications; nevertheless, both children completely recovered. At present it is suggested that, if possible, pediatric patients who are not immune should be vaccinated against varicella at least three months before the start of any anti-TNFα therapy. In the case of nonimmune children who are exposed to or develop varicella while treated with TNFα blockers, the prophylaxis or an aggressive antivaricella treatment should be promptly started. One of the major concerns with the TNFα blockade is the potential reactivation of a silent TB infection. The TB infections are among the most serious AEs, especially given the delays in diagnosis due to their subtle or atypical presentation. This occurs mainly with infliximab due to its capacity to bind to membrane TNFα and to induce cell lysis by apoptosis [138,139]. Two cases of TB arthritis in SoJIA patients treated with etanercept have been described [135,140]; one of them died for this reason. This AE, definitely related to the TNFα inhibition, was frequently observed in the first phase of clinical postmarketing experience in adult RA. It has now quite completely disappeared since the implementation of mandatory screening for TB silent infections, and anti-TB prophylaxis in the case of positive Mantoux test, before the start of therapy with antiTNFα [141 143].

TNF Blockade and Vaccines Administration of live vaccines to patients taking anti-TNF is not recommended, but if possible patients should be brought up to date with all immunizations relevant to their age group before commencement of therapy. In JIA patients, anti-TNF therapy, compared to MTX alone, does not seem to have an additional deleterious effect on short-term and long-term immunogenicity and safety of various vaccines, and no influence on disease activity parameters, as described in the case of the 23-valent polysaccharide pneumococcal vaccine [144], the influenza vaccine [145,146], and meningococcal serogroup C [147].

TNF Blockade and Macrophage Activation Syndrome Macrophage activation syndrome (MAS), which can be considered as secondary hemophagocytic lymphohistiocytosis, is a potentially life-threatening complication of SoJIA. Some case reports have suggested that etanercept may be a useful adjunctive therapeutic agent in refractory MAS, nonresponsive to corticosteroids and cyclosporine [148 150]. Nevertheless, cases of

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MAS in SoJIA during the treatment with both TNFα blockers are reported. In some cases the MAS was a complication of a bacterial or viral infection [56,93,100,151].

New Onset or Worsening of Autoantibody-Mediated Diseases Another concern of TNFα blockade is its potential action to shift the pattern of the immune response from a Th1 to a Th2 response, and thus the possibility of favoring antibody production and the new onset or worsening of autoantibody mediated or allergic diseases. This is true mainly for infliximab due to its long-lasting Th1 suppression. In fact, the TNFα blockade with either infliximab or etanercept, in patients with RA as well as in those with SpA and Crohn’s disease, is clearly associated with the development of autoantibodies such as antinuclear antibodies (ANAs) and/or anti-dsDNA [152]. The mechanism of this phenomenon is not well understood, but the development of these autoantibodies is rarely associated with the development of a lupus-like syndrome. Studies on adult RA have described cases of drug-induced systemic lupus erythematosus (SLE), discoid LE, and cutaneous vasculitis. The anti-TNFα therapy with infliximab, in the case of adult RA and SpA, seems to be more often responsible for the newly induced autoantibodies: newly induced ANA are observed in 60% of SpA and 40% of RA patients, newly induced anti-dsDNA in 70% of SpA and 50% of RA patients, while a lower rate (2 13%) of newly induced autoantibodies is observed with etanercept [152]. In JIA patients, in contrast to adult RA patients, development of new autoantibodies to various nuclear antigens is more rare. Other nonrelevant to rheumatic disease autoantibodies, especially in the presence of a positive family history of autoimmunity, may appear but very rarely they may be related to clinical entities. In the American multicenter RCT [35] and in the subsequent experiences with etanercept in the treatment of JIA, none of the treated patients developed de novo persistent ANA or anti-dsDNA, nor a second autoimmune disease with the rare exception as a case of new onset of insulin-dependent type I diabetes mellitus [153], one case of juvenile SLE [154], one case of proliferative lupus nephritis and leukocytoclastic vasculitis [155]. One case who newly developed anti-dsDNA and another whose autoimmune alopecia relapsed were described out of 14 JIA patients treated with infliximab in Helsinki [56]. In our experience [100], two cases newly developed anti-dsDNA out of 127 etanercept (1.6%) and 7 out of 81 infliximab-treated patients (8.6%), without any clinical manifestation. In the infliximab-treated population, one case with new onset of anti-ENA antibodies (anti-RNP) was also observed. A large panel of autoantibodies (anti-Ro, anti-La, anti-Sm, anti-URNP, anti-Jo1, anti-Scl70, anticentromere, antiribosomal, antihistone, and RF) was tested in 26 JIA patients treated with either infliximab (#12) or etanercept

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(#4) for 2 years and prospectively studied. Six of 26 patients (23%) developed new autoantibodies (SMA, anti-R1, ATA) that persisted for 12 50 months. None developed antibodies to nuclear antigens. In one case only, ATA was associated with the development of Hashimoto’s thyroiditis [156].

New Onset of Inflammatory Bowel Diseases Unexpected and surprising were some cases of new onset of an inflammatory bowel disease (IBD) with abdominal pain and chronic diarrhea (histologically confirmed Crohn’s disease) observed during etanercept treatment in patients affected by long-lasting JIA, who had never previously suffered from chronic abdominal complaints, nor did they present other signs that could raise the suspicion of a preexisting subclinical IBD [51,100,157]. In a French retrospective study [158] intestinal biopsies of eight JIA patients treated with etanercept from 11 to 78 months developed IBD. Gastrointestinal symptoms included abdominal pain, diarrhea, anorexia, anal abscess, and oral ulcers. Five patients presented with Crohn’s disease and three with indeterminate IBD, of whom four had severe pancolitis. CR of IBD was obtained in all after discontinuation of etanercept and initiation of IBD-specific therapy, including infliximab. The Food and Drug Administration Adverse Event Reporting System, between Jan. 2003 and Dec. 2011, reported 158 cases of IBD in RA or juvenile rheumatoid arthritis (JRA) after TNFα inhibitor exposure (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab). In the majority of these cases (71.5%) the TNFα inhibitor exposure was considered a “possible” cause of IBD. A majority (90.91%) of the 40 “probable cases” in JRA were reported with etanercept. There were no “definite” cases of anti-TNF-induced IBD. A weak association between new-onset IBD and TNFα inhibitor therapy in RA patients and a moderately strong association, especially with etanercept exposure, in JRA patients was observed [159]. IBD must be suspected in JIA patients treated with etanercept who develop intestinal symptoms.

Chronic AU Reactivation as AE Another concern with TNFα blockade, mainly with etanercept, is the possible reactivation of chronic iridocyclitis (CIC) in the population at higher risk for this complication (oligoarticular ANA-positive JIA with previous episodes of CIC). Nevertheless, recent data from the biologics in pediatric rheumatology registry [160] showed that few patients developed a first uveitis event while taking etanercept, while the rate is comparable to that with MTX, and conclude that uveitis may not be attributed to be an adverse drug reaction to etanercept.

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Bone Marrow Suppression In contrast with the aspecific immunosuppression of traditional cytotoxic DMARDs, TNFα inhibition is a selective way to suppress a single key point of the immune response. In fact, bone marrow suppression, with leukopenia, thrombocytopenia, or pancytopenia is only rarely described in JIA patients treated with TNFα blockers [51,100]. Malignancies Leukemia and tumors are reported in children and adolescents treated with anti-TNF, with lymphoma accounting for the largest group, and have raised the question about an increased risk for malignancies with TNF blockade. In 2008 the US Food and Drug Administration issued a warning related to the development of malignancies in patients with JIA who had used anti-TNF medications for .2.5 years. More recent data seem to suggest that JIA itself, as in the case of RA, is associated with an increased risk of malignancy and that this risk is not further increased with anti-TNF treatment [161]. The risk of malignancy and lymphoma such as for the case of infections, may be associated with either the disease per se or the concomitant and previous immunosuppressive treatments. We observed one case of thyroid carcinoma in a JIA young adult treated with etanercept, but also previously treated with infliximab and many other DMARDs [100]. Some cases of hepatosplenic T-cell lymphoma have been described in adolescents treated with infliximab for Crohn’s disease [162]. In a nationwide population-based cohort of 2892 Taiwanese children with JIA, followed until a diagnosis of malignancy or up to 8 years, during a 16,114.16 patient/years follow-up, compared with children without JIA, have a threefold increased risk of malignancy, but there was no statistically significant increased risk in JIA patients treated with MTX and/or anti-TNF biologics [163]. TNF inhibitors should be indicated under careful consideration of individual risk factors, such as increased family occurrence of malignancies, or pretreatment with carcinogenic drugs such as cyclophosphamide [164]. More studies are needed to evaluate the baseline occurrence of malignancies in patients with adult RA and JIA and to determine the potential adjunct risk posed by an anti-TNFα therapy.

TNFα-INHIBITORS IN JUVENILE DERMATOMYOSITIS The idiopathic inflammatory myopathies (IIM) in childhood are diseases caused by muscle damage in association with an inflammatory infiltrate. Genetic causes, viral, parasitic, or bacterial infections may play a part in the etiopathogenesis of the IIM. The most common of these autoimmune disorders is juvenile dermatomyositis (JDM). Proximal muscle weakness and

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skin rash are the basic clinical features in JDM; sometimes other organ systems can be involved [165]. Calcinosis is a complication of this disease, which can be troublesome, as it is associated with chronic inflammation [166]. Macrophages and proinflammatory cytokines, including IL-6, IL-1, and TNFα, have been found in the milk of calcium fluid examined from a patient [167]. A long-lasting active disease and the presence of pathologic calcifications have been associated with the A-G polymorphism in the TNFα-308 promoter region (TNFα 308A allele) and the increased TNFα production by peripheral blood mononuclear cells, which may perpetuate the inflammatory response [168]. On this basis, TNFα blockade has been proposed to treat patients that are refractory to conventional immunosuppressive therapies such as corticosteroids, MTX, cyclosporine, and intravenous immunoglobulins [169]. To date, there are some preliminary data concerning the use of TNFα blockers in children affected by chronic JDM. With the use of etanercept in the treatment of five children, there were not encouraging results, but the children treated were not selected on the basis of their TNFα 308A allele [170]. The use of etanercept, combined with the bisphosphonate pamidronate, was mentioned as having benefit in JDM patients with calcinotic skin disease [171]. Nevertheless, in a pilot study on nine patients with refractory JDM, etanercept did not demonstrate appreciable improvement and in some patients disease worsened [172]. In three patients treated with infliximab at the dose of 3 5 mg/kg per infusion a better result on calcinosis was observed: in the first patient there was a retarded progression, in the second and third there was a regression of calcinosis [173]. Major clinical benefit was demonstrated after the initiation of infliximab in other five cases of refractory JDM more recently published [174]. Further investigation of the interaction of the TNFα-308A polymorphism and type I interferon is needed to define the mechanism of TNF blockade in JDM and further controlled studies are required to prove the effectiveness of TNFα blockade in JDM and to predict which patients will respond to this treatment and which will not.

TNFα-INHIBITORS IN OTHER PEDIATRIC RHEUMATIC DISEASES There are a variety of rare systemic inflammatory diseases in which TNF blockade appears promising. Data in adults suggest that several forms of vasculitis appear to be responsive to TNF antagonists, Behc¸et’s disease, polyarteritis nodosa, Wegener granulomatosis, among others. Some of them respond better to infliximab than to etanercept. In adult patients, the TNFα inhibitors (infliximab, etanercept, and adalimumab) has been proven efficacious in evidence-based data, in the

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autoimmune idiopathic uveitis, in the uveitis of Behc¸et’s disease and sarcoidosis [175 179], and in the vasculitides [180]. However, they still have a restricted use in these diseases in childhood. Infliximab is at present looking to be more effective than etanercept in the treatment of refractory autoimmune uveitis. High dose of infliximab has been proven to be a rapidly effective and well-tolerated therapeutic agent in children affected by autoimmune noninfectious refractory uveitis and uveitis of Behc¸et’s disease and sarcoidosis [77,106,107,181]. Moreover, infliximab resulted in better clinical responses with less ocular complications than etanercept [182]. In the field of vasculitides, etanercept has been successfully used in the treatment of one patient with childhood onset refractory polyarteritis nodosa [183] and in many cases of Kawasaki Syndrome [184 186], and infliximab in the treatment of children with rare vasculitic conditions [187]. Etanercept may be effective also in some cases of autoinflammatory diseases or hereditary periodic fever syndromes, even if in these cases an abnormal uncontrolled production of IL-1, on a genetic basis, seems to have a key pathogenetic role, and now the first-choice therapy is usually IL-1 blockade. In the TNF-receptor-associated periodic syndrome (TRAPS), the etanercept has been proven to decrease the severity, duration, and frequency of symptoms and to provide a therapeutic alternative to glucocorticoid therapy [188 190]. However there is variability in the treatment responses among different patients with TRAPS. In a Spanish child the autoinflammatory episodes disappeared with administration of etanercept, but the levels of acute-phase reactants remained increased [189]. In a series of seven patients affected by TRAPS, etanercept did not abolish inflammatory attacks but improved disease activity allowing corticosteroid reduction [191]. On the contrary, the Hyper IgD with periodic fever syndrome caused by mutations in the mevalonate kinase gene has been reported, in case reports, to be not responsive [192] or only partially responsive to etanercept treatment [193]. In the pyogenic sterile arthritis, pyoderma and acne syndrome, the production of TNFα by mononuclear cells was also found abnormally elevated, and the efficacy of etanercept has been reported in a child with several episodes of arthritis unresponsive to glucocorticoids [194]. Finally, etanercept has been reported to induce a dramatic improvement of arthropathy also in the chronic infantile neurological cutaneous articular syndrome [195], even if for this disease anti-IL-1 monoclonal antibody canakinumab is now the only approved biological treatment.

CONCLUSIONS The anti-TNFα agents have dramatically changed the treatment of JIA due to their efficacy and speed of onset. They allow better and faster disease

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control than was previously possible, the rate of response to TNFα inhibitors and the rapidity of response exceeding those of the other DMARDs studied including MTX. The anti-TNFα agents are overall well tolerated and have demonstrated a favorable risk benefit profile. Serious AEs on anti-TNFα therapy in JIA are rare. However, severe infections, including TB, have been reported. These can be largely prevented by appropriate screening. Clearly, comorbidities, long-lasting persistently active disease, and concurrent and previous immunosuppressive therapies all contribute to the risk of infection, malignancy, and other serious AEs. The benefits of anti-TNFα therapy in JIA seem to outweigh these shortcomings, although long-term safety data still need to be established. Given the evidence that TNFα has a primary role in the pathogenesis of JIA, particularly in joint destruction observed in polyarticular disease [33], neutralizing this cytokine earlier in the course of the disease could halt or delay the progression of joint damage and the debilitating consequences of the disease [58]. The early application of these drugs within the window of opportunity in combination with conventional DMARDs seems to produce the best outcomes. Thus, for JIA patients whose disease is not quickly controlled by MTX, therapy with TNFα blockers may be considered as a first-line treatment. Moreover, the therapeutic role of the anti-TNFα agents in many other autoimmune or autoinflammatory rheumatic diseases in childhood has been suggested by several case reports and needs to be evaluated and confirmed in further studies.

KEY POINTS G

G

G G

G

Controlled trials in adults have shown that the TNFα inhibitors significantly reduce symptoms and signs, improve function and quality of life, and reduce radiological damage in rheumatoid arthritis and related diseases. The clinical experience on TNFα inhibition (with etanercept, infliximab, and adalimumab) in children with active polyarticular JIA despite prior MTX therapy, in many open-label trials and in large RCTs, has confirmed that anti-TNFα agents have dramatically changed the treatment of JIA due to their efficacy and speed of onset. However, the persistent clinical remission is until now a rare event. Anti-TNF agents are now increasingly prescribed earlier in the disease course and in patients with JIA with lower disease activity. These changes are accompanied by better short-term disease outcomes. The anti-TNFα agents are overall well tolerated and have demonstrated a favorable risk benefit profile. However, long-term safety data still need to be established.

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[156] Kanakoudi-Tsakalidou F, Tzimouli V, Pratsidou-Gertsi P, Chronopoulou E, Trachana M. The significance of persistent newly developed autoantibodies in JIA patients under long-term anti-TNF treatment. Cytokine 2008;42(3):293 7. [157] Ruemelle FM, Prieur AM, Talbotec C, Goulet O, Schmitz J. Development of Crohn disease during anti-TNF-alpha therapy in a child with juvenile idiopatic arthritis. J Pediatr Gastroenterol Nutr 2004;39(2):203 6. [158] Dallocchio A, Canioni D, Ruemmele F, Duquesne A, Scoazec JY, Bouvier R, et al. Occurrence of inflammatory bowel disease during treatment of juvenile idiopathic arthritis with etanercept: a French retrospective study. Rheumatology (Oxford) 2010;49 (9):1694 8. [159] Krishnan A, Stobaugh DJ, Deepak P. Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis factor-alpha inhibitor therapy for rheumatoid arthritis and juvenile rheumatoid arthritis. Rheumatol Int 2015;35 (4):661 8. [160] Foeldvari I, Becker I, Horneff G. Uveitis events during adalimumab, etanercept, and methotrexate therapy in juvenile idiopathic arthritis: data from the biologics in pediatric rheumatology registry. Arthritis Care Res 2015;67(11):1529 35. [161] Ruperto N, Martini A. Juvenile idiopathic arthritis and malignancy. Rheumatology (Oxford) 2014;53(6):968 74. [162] Thayu M, Markowitz JE, Mamula P, et al. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr 2005;40(2):220 2. [163] Kok VC, Horng JT, Huang JL, Yeh KW, Gau JJ, Chang CW, et al. Population-based cohort study on the risk of malignancy in East Asian children with juvenile idiopathic arthritis. BMC Cancer 2014;14:634. [164] Horneff G, Hospach T, Dannecker G, Fo¨ll D, Haas JP, Girschick HJ, et al. Updated statement by the German Society for Pediatric and Adolescent Rheumatology (GKJR) on the FDA’s report regarding malignancies in anti-TNF-treated patients from Aug. 4, 2009. Zeitschrift fu¨r Rheumatologie 2010;69(6):561 7. [165] Pachman LM. Polymyositis and dermatomyositis in children. Oxford textbook of rheumatology. 3rd ed. Oxford, UK: Oxford University Press; 2004 [chapter 6.8.2]. [166] Ramanan AV, Feldman BM. Clinical features and outcomes of juvenile dermatomyositis and other childhood onset myositis syndromes. Rheum Dis Clin North Am 2002;28:833 58. [167] Mukamel M, Horev G, Mimouni M. New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. J Pediatr 2001;138:763 6. [168] Pachman LM, Liotta-Davis MR, Hong DK, et al. TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications. Arthritis Rheum 2000;43 (10):2368 77. [169] Pilkington CA, Wedderburn LR. Paediatric idiopathic inflammatory muscle disease, recognition and management. Drugs 2005;65(10):1355 65. [170] Miller ML, et al. Experience with etanercept in chronic juvenile dermatomyositis (JDM). Arthritis Rheum 2000;43:1883. [171] Maillard SM, Wilkinson N, Riley P, et al. The treatment of persistent severe idiopathic inflammatory myositis with anti-TNF alpha therapy. Arthritis Rheum 2003;46(Suppl.): S307.

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[172] Rouster-Stevens KA, Ferguson L, Morgan G, Huang CC, Pachman LM. Pilot study of etanercept in patients with refractory juvenile dermatomyositis. Arthritis Care Res 2014;66(5):783 7. [173] Maillard SM, Wilkinson N, Riley P, et al. The treatment of severe idiopathic myositis with anti-TNF therapy. Arthritis Rheum 2002;44(Suppl. 9):S307. [174] Riley P, McCann LJ, Maillard SM, Woo P, Murray KJ, Pilkington CA. Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis. Rheumatology (Oxford) 2008;47(6):877 80. [175] Markomichelakis NN, Theodossiadis PG, Pantelia E, et al. Infliximab for chronic cystoid macular edema associated with uveitis. Am J Ophthalmol 2004;138(4):648 50. [176] Munoz-Fernandez S, Hidalgo V, Fernandez-Melon J, et al. Effect of Infliximab on threatening panuveitis in Behcet’s disease. Lancet 2001;358(9293):1644. [177] Sfikakis PP, Theodossiadis PG, Katsiari CG, et al. Effect of Infliximab on sight-threatening panuveitis in Behcet’s disease. Lancet 2001;358(9278):295 6. [178] Suhler EB, Smith JR, Wertheim MS, et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol 2005;123 (7):903 12. [179] Joseph A, Raj D, Dua HS, et al. Infliximab in the treatment of refractory posterior uveitis. Ophthalmology 2003;110(7):1449 53. [180] Samuels J, Spiera R. Newer therapeutic approaches to the vasculitides: biologic agents. Rheum Dis Clin North Am 2006;32(1):187 200. [181] Kimura Y. Infliximab in refractory Bechet’s disease in children. Pediatr Rheumatol Online J 2003;1(4):141. [182] Saurenmann RK, Levin AV, Rose JB, et al. Tumour necrosis factor α inhibitors in the treatment of childhood uveitis. Rheumatology 2006;45:982 9. [183] Feinstein J, Arroyo R. Successful treatment of childhood onset refractory polyarteritis nodosa with tumor necrosis factor alpha blockade. J Clin Rheumatol 2005;11 (4):219 22. [184] Weiss JE, Eberhard BE, Chowdhury D, et al. Infliximab as a novel therapy for refractory Kawasaki disease. J Rheumatol 2004;31(4):808 10. [185] Zulian F, Zanon G, Martini G, et al. Efficacy of Infliximab in long-lasting refractory Kawasaki disease. Clin Exp Rheumatol 2006;24(4):453. [186] Burns JC, Mason WH, Hauger BS, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 2005;146:662 7. [187] Brik R, Gepstein V, Shahar E, Goldsher D, Berkovitz D. Tumor necrosis factor blockade in the management of children with orphan diseases. Clin Rheumatol 2007;26(10):1783 5. [188] Weyhreter H, Schwartz M, Kristensen TD, Valerius NH, Paerregaard A. A new mutation causing autosomal dominant periodic fever syndrome in a Danish family. J Pediatr 2003;142(2):191 3. [189] Arostegui JI, Solis P, Aldea A, et al. Etanercept plus colchicine treatment in a child with tumour necrosis factor receptor-associated periodic sindrome abolishes auto-inflammatory episodes without normalising the subclinical acute phase response. Eur J Pediatr 2005;164:13 16. [190] Hull KM, Drewe E, Aksentijevich I, et al. The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine (Baltimore) 2002;81(5):349 68. [191] Drewe E, McDermott EM, Powell PT, Isaacs JD, Powell RJ. Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study

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of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients. Rheumatology 2003;42(2):235 9. Marchetti F, Barbi E, Tommasini A, Oretti C, Ventura A. Inefficacy of etanercept in a child with hyper-IgD syndrome and periodic fever. Clin Exp Rheumatol 2004;22 (6):791 2. Arkwright PD, McDermott MF, Houten SM, et al. Hyper IgD syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept. Clin Exp Immunol 2002;130 (3):484 8. Cortis E, De Benedetti F, Insalaco A, et al. Abnormal production of tumor necrosis factor (TNF) alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome. J Pediatr 2004;145(6):851 5. Federico G, Rigante D, Pugliese AL, et al. Etanercept induces improvement of arthropathy in chronic infantile neurological cutaneous articular (CINCA) syndrome. Scand J Rheumatol 2003;32(5):312 14. Simonini G. Substained improvement of refractory chronic uveitis on infliximab treatment. Arthritis Rheum 2005;52(Suppl.):S86. Tynja¨la¨ P, Kotaniemi K, Lindahl P, Latva K, Aalto K, Honkanen V, et al. Adalimumab in juvenile idiopathic arthritis-associated chronic anterior uveitis. Rheumatology (Oxford) 2008;47(3):339 44.

Chapter 24

Other Biological Therapies for Pediatric Rheumatic Diseases A. Santimov1 and A.A. Grom2 1

Department of Pediatrics, Saint-Petersburg State Pediatric Medical University, SaintPetersburg, Russia, 2Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States

INTRODUCTION Inflammation in rheumatic diseases is driven by complex interactions between immune cells that occur through either a direct contact that involves various surface molecules, or soluble mediators such as cytokines. Uncontrolled production of proinflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, or IL-17 can promote pathologic process [1]. In contrast, naturally occurring cytokine inhibitors such as soluble TNF receptors (TNFR) and anti-inflammatory cytokines such as IL-10 can help control inflammation and limit tissue damage. Many proinflammatory cytokines as well as surface molecules involved in cellular interactions leading to increased production of these cytokines have become important therapeutic targets in many rheumatic diseases [1,2]. Selective targeting of specific components of the immune system such as cytokines instead of the use of conventional immunosuppressive drugs broadly affecting many parts of the immune system has the potential to increase efficacy and reduce toxicity. It is usually achieved through the use of biologics.

Biologics and Biosimilars In contrast to traditional drugs, biologics are typically produced in a living system such as bacteria, yeast, or cultured animal cells. Most biologics are very large, complex molecules that are manufactured using recombinant DNA technology. In this process, a recombinant DNA encoding a particular protein is inserted into cultured living cells. When appropriate conditions are

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00024-4 © 2016 Elsevier B.V. All rights reserved.

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provided, these cells start producing this particular protein that then needs to be purified and preserved. A traditional drug is typically produced through chemical synthesis by combining specific chemical ingredients in a defined chemical reaction that can be readily reproduced. In contrast, the living cells used to produce biologics can be sensitive to very minor changes in the manufacturing process. Since even small differences in this process can significantly affect the properties of the finished biologic, it would be difficult or impossible for another manufacturer to reproduce the same biologic. Biosimilars is the term used to describe generic versions of biologic agents. Typically, a biosimilar is required to be comparable with the reference product. In other words there should be no significant differences in the quality, efficacy, and safety of a biosimilar and its reference biologic.

General Properties of Biologics Several strategies to inhibit specific components of the inflammatory response in vivo have been developed [2]: G

G

G

G

G

Recombinant soluble receptors that bind their target cytokines preventing the cytokine’s ability to interact with cell surface receptors Recombinant soluble receptor antagonists that compete with a cytokine for binding to the cytokine’s membrane receptor Neutralizing monoclonal antibodies (mAbs) to cytokines or their receptors Proteins that inhibit the costimulatory signal necessary for T-cell activation mAbs that deplete specific types of immune cells.

Soluble receptors typically have a very short half-life. The addition of the Fc part of human IgG1 to soluble receptors usually prolongs their half-life thus reducing the need for frequent administration. In general, mAbs have higher affinity for a target cytokine and a longer half-life compared with soluble receptors. In case of TNF-inhibiting biologics, it has also been suggested that while soluble receptors bind the target cytokine only when it is free, the mAbs may neutralize the membrane-bound form of the cytokine as well [3]. The mAbs can be chimeric, humanized, or fully human. The term chimeric refers to the antibodies that have both murine and human components. In general, administration of chimeric antibodies is associated with a higher risk of formation of antibodies against the biologic. The formation of such antibodies increases the risk for adverse reactions and may lead to the neutralization of the activity of the biologic.

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Nomenclature Suffixes placed at the ends of the names of biologics often indicate specific information about their structure [4]. For example: G G G G G

“-cept” refers to fusion of a receptor to the Fc part of human IgG1 “-mab” indicates a monoclonal antibody “-ximab” indicates a chimeric mAb “-zumab” indicates a humanized mAb “-umab” indicates a fully human mAb.

COMMONLY USED BIOLOGICS IN PEDIATRIC RHEUMATIC DISEASES The first biologics introduced in clinical practice were TNF-inhibiting agents. They are discussed in detail elsewhere in this textbook.

Proteins That Inhibit Costimulatory Signals Necessary for T-Cell Activation Abatacept Chemistry. Abatacept (CTLA4-Ig) is a soluble fusion protein comprised of the cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) fused with the Fc region of human IgG. This fusion protein disrupts costimulatory signals necessary for T-cell activation [5,6]. To become fully activated, T cells require at least two signaling events. The first one is delivered via their antigen-specific T-cell receptors. The second signal typically involves a non-antigenspecific costimulatory receptor such as CD28 [5]. CD28 is constitutively expressed on T cells and binds to the ligands, CD80 or CD86, on activated antigen-presenting cells. Signaling through CD28 transmits a stimulatory effect, enhancing T-cell activation. CTLA-4 (or CD152) has a structural resemblance to CD28, but transmits an inhibitory signal to T cells and induces anergy. Its affinity to CD80/CD86 is much higher compared with CD28. Abatacept (CTLA4-Ig) interrupts the interaction between CD28 and CD80 or CD86 and thus prevents T-cell activation [7,8]. Approved Indications. Abatacept has been approved for the treatment of adult rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) [8]. The recommended dose of abatacept for patients 6
17 years of age with JIA who weighs less than 75 kg is 10 mg/kg intravenously. Following the initial administration abatacept should be given 2 and 4 weeks after the first infusion and every 4 weeks thereafter. For adult RA patients abatacept can also be administered subcutaneously. Following a single intravenous loading dose, the first 125 mg subcutaneous injection should be given within a day, followed by 125 mg subcutaneous injections once weekly.

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Pharmacodynamics and Pharmacokinetics. In patients with RA after multiple IV doses of 10 mg/kg, serum concentration reaches steady state by approximately day 60. The mean half-life is about 2 weeks (range 8
25 days). Concomitant treatment with methotrexate (MTX), nonsteroidal antiinflammatory drugs, or corticosteroids does not change the clearance [8
10]. Clinical Efficacy. The efficacy and safety of abatacept in JIA has been assessed in a phase III randomized, controlled trial [11] that included an open-label extension phase [12,13]. One hundred and ninety patients with a polyarticular course of JIA were enrolled, including patients with polyarthritis with and without rheumatoid factor, extended oligoarthritis, and systemic JIA (SJIA) without systemic manifestations for at least 6 months. In the first phase, all patients received abatacept 10 mg/kg (maximum 1000 mg/dose) on days 1, 15, 29, 57, and 85. By the end of this lead-in phase, 65% of the subjects were considered responders at least at an American College of Rheumatology (ACR) Pediatric 30 response level, and 13% of the patients attained a status of inactive disease. There were no significant differences in response rates between the various categories of JIA with a polyarticular course. In the double-blind withdrawal phase, the number of patients who developed a flare was significantly lower in the abatacept group compared with the placebo group (20% vs 53%, respectively). The data obtained in the following open-label, longterm, extension period showed that in some patients who did not initially experience a response to abatacept, clinically significant benefits were obtained after longer treatment with additional improvement over time, suggesting that, in some patients, a 4
6 month treatment period may not be necessary to determine how well a patient will respond to abatacept [11,12]. The open-label extension part of the trial showed that long-term abatacept treatment up to 7 years was associated with consistent safety, sustained efficacy, and quality-of-life benefits in patients with JIA. Safety and Tolerability. The safety profile of abatacept is generally good [9
13]. In the described trial, serious infections are seen in about 4% of the patients, including dengue fever, erysipelas, gastroenteritis, herpes zoster, bacterial meningitis, and pyelonephritis. One case of uveitis and four cases of benign neoplasm developed. One patient developed multiple sclerosis. No cases of mycobacterium, opportunistic infections, or malignancies were observed. There were no significant laboratory abnormalities. About 10% of the patients developed new antinuclear antibodies (ANA). The development of double-stranded DNA antibodies was rare. None of those who developed autoantibodies developed autoimmune disease. About 25% of the patients developed antibodies to abatacept or to CTLA-4, but their presence did not influence the efficacy or safety of abatacept.

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Cytokine Inhibitors Interleukin-6 Inhibiting Biologics IL-6 has been implicated in the development of several types of arthritis including RA, SJIA, and polyarticular JIA [14
16]. IL-6 is mainly produced by dendritic cells and macrophages. IL-6 triggers signaling by binding to IL-6 receptor (IL-6R), which is expressed on some leukocytes [15,16]. A soluble form of IL-6R exists in serum. The complex of IL-6 and IL-6R, or the complex of IL-6 and soluble IL-6R binds to gp130, leading to the activation of signaling cascade. IL-6 contributes to JIA and RA pathogenesis via multiple mechanisms. It directly promotes differentiation of proinflammatory Th17 cells and production of other proinflammatory mediators and tissuedegrading enzymes. IL-6 also influences osteoclast differentiation by modulating expression of receptor activator of nuclear factor kappa B ligand [14
16]. The important role for IL-6 in the pathogenesis of SJIA has been suspected since the 1990s [16]. IL-6 is markedly elevated in both peripheral blood and synovial fluid of patients with SJIA, and the levels of IL-6 expression appear to correlate with the overall clinical activity of the disease and such distinctive clinical features as thrombocytosis, microcytic anemia, growth retardation, and osteopenia [17
19]. Furthermore, studies of the unique quotidian fever pattern of SJIA show that IL-6 concentrations rise and fall in concert with the temperature spikes. Tocilizumab Chemistry. Tocilizumab is a humanized mAb that binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R, respectively) and inhibits IL-6-meditaed signaling through these receptors. Approved Indications. Tocilizumab has been approved for treatment of RA, active SJIA, and polyarticular JIA. In the pediatric population it has been approved for patients 2 years and older. For polyarticular JIA, tocilizumab is administered as intravenous infusions every 4 weeks at 10 mg/kg for patients less than 30 kg and 8 mg/kg for patients at or above 30 kg. For SJIA, toclizumab is administered as intravenous infusions every 2 weeks at 12 mg/kg for patients less than 30 kg and 8 mg/kg for patients at or above 30 kg. Clinical Efficacy in SJIA. Two phase III controlled clinical trials of tocilizumab in SJIA have been completed. The first study with a withdrawal design showed that tocilizumab at a dose of 8 mg/kg administered as IV infusions every 2 weeks markedly improved the clinical and laboratory features of SJIA [20]. In the subsequent pivotal double-blind, placebo-controlled international trial (the TENDER trial) [21], 112 SJIA patients, 2
17 years of age, were randomized to receive either tocilizumab (at a dose of 12 mg/kg if the weight was ,30 kg or 8 mg/kg if the weight was equal to or .30 kg) or

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placebo intravenously every 2 weeks for 12 weeks, followed by the openlabel extension phase. At 12 weeks, 71% of patients who received tocilizumab had absence of fever and a JIA-ACR70 response versus 8% of those in placebo group. At the level of adapted pediatric ACR30, the response was achieved in 85% of SJIA patients. A total of 32% of the patients met the criteria for clinically inactive disease. In this trial, tocilizumab was effective in both the systemic as well as the articular symptoms of the disease. The response was sustained in the open-label extension phase. Clinical Efficacy of Tocilizumab in Polyarticular JIA. This was assessed in a three-part, randomized, placebo-controlled, double-blind withdrawal study that included patients who had active polyarticular JIA for $6 months [22]. In the open-label lead-in part of the study, all patients were receiving tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) ,30 kg; 8 mg/kg for BW $ 30 kg). At week 16, 86% of the patients showed ACR30 response and entered the withdrawal part that showed fewer flares in the tocilizumab group. At the end of the withdrawal phase, JIA-ACR70 and JIA-ACR90 response was observed in 65% and 45% of patients receiving tocilizumab. Of note, JIA-ACR70 and JIA-ACR90 response rates were numerically higher in patients receiving MTX than in those not receiving MTX. Safety and Tolerability. Reactions to tocilizumab infusions, including fever and chills, are rare. The most concerning potential side effect with regular therapy is the risk of infection, particularly at the doses used in SJIA. The primary concern is for common bacterial infections with the rate of serious infections exceeding 10
13 per 100 patient/years. Unusual infections, such as tuberculosis, have not been seen frequently with tocilizumab, but they do remain a concern, and screening for prior exposure to TB is recommended before starting tocilizumab therapy. Tocilizumab has been associated with increased cholesterol levels in some patients. Tocilizumab also can cause an increase in liver enzymes or significant neutropenia or thrombocytopenia. Finally, a rare complication seen with tocilizumab use in clinical trials was bowel perforation and gastrointestinal bleeding. Therefore, tocilizumab should be used with caution in patients who may be at increased risk for gastrointestinal perforation. Patients presenting with new onset abdominal symptoms should be evaluated promptly. It is recommended that tocilizumab not be initiated in patients with an absolute neutrophil count (ANC) ,2000 mm3, platelet count below 100,000 mm3, or who have ALT or AST above 1.5 3 ULN (upper limit of normal). After initiation of the treatment neutrophils, platelets, lipids, and hepatic transaminases should be monitored 4
8 weeks after start of therapy and every 3 months thereafter. Since infections have been reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience, dosage modifications may be required.

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Recommended Management of Laboratory Abnormalities Neutropenia If ANC .1000 cells/mm3, maintain the dose. If ANC is 500
1000 cells/mm3, interrupt tocilizumab dosing. When ANC .1000 cells/mm3, resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate. Discontinue tocilizumab if ANC falls below 500 cells/mm3. Thrombocytopenia If platelet count falls in the 50,000
100,000 cells/mm3 range, interrupt tocilizumab dosing. When platelet count is .100,000 cells/mm3, resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate. If platelet count falls in the 50,000 cells/mm3, discontinue tocilizumab. Liver Enzyme Abnormalities Lab Value

Recommendation

. 1 to 3x ULN

Dose modify concomitant DMARDs if appropriate For persistent increases in this range, reduce ACTEMRA dose to 4 mg/kg or interrupt ACTEMRA until ALT/AST have normalized

. 3 to 5x ULN (confirmed by repeat testing)

Interrupt ACTEMRA dosing until ,3x ULN and follow recommendations above for .1 to 3x ULN For persistent increases .3x ULN, discontinue ACTEMRA

. 5x ULN

Discontinue ACTEMRA

It is also recommended to assess lipid parameters approximately 4
8 weeks following initiation of tocilizumab therapy, then at approximately 24 week intervals. Any lipid abnormalities should be managed according to clinical guidelines for the management of hyperlipidemia.

IL-1 Inhibiting Biologics IL-1 family is a group of 11 cytokines. IL-1α and IL-1β are the most studied members, because they were discovered first and play the central role in innate immunity and inflammation [23,24]. IL-1α or IL-1β initially binds to the first extracellular chain of the IL-1 receptor (IL-1RI). In turn, this leads to the recruitment of the IL-1 receptor accessory protein (IL-1RAcP), which serves as a coreceptor and is necessary for signal transduction via MyD88 adaptor. Both IL-1α or IL-1β have a natural antagonist IL-1Ra (IL-1 receptor antagonist). IL-1Ra counterbalances proinflammatory activity of both IL-1α and IL-1β by competing with them for binding sites of the receptor.

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So far, three IL-1-targeted agents have been approved for clinical use: the IL-1Ra anakinra, the soluble decoy receptor rilonacept, and the neutralizing monoclonal anti-IL-1β antibody canakinumab.

Anakinra Chemistry. Anakinra is a recombinant, nonglycosylated form of the human IL1Ra [25]. The main difference between anakinra and the native human IL-1Ra is the addition of a single methionine residue at its amino terminus. Anakinra blocks the biologic activity of IL-1 by competitively inhibiting IL-1 binding to the IL-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues. Anakinra blocks the biologic activity of both IL-1α and IL-1β. Its bioavailability after subcutaneous injection is 95% and its half-life ranges from 4 to 6 h. Approved Indications. Anakinra has been approved for the treatment of RA and cryopyrin-associated periodic fever syndromes (CAPS) including neonatal onset multisystem inflammatory disease (NOMID). The recommended dose of anakinra for the treatment of patients with RA is 100 mg/day administered daily by subcutaneous injection. Higher doses do not result in a higher response. For CAPS patients, the recommended starting dose of anakinra is 1
2 mg/kg. The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation. Clinical Efficacy in CAPS. The efficacy of anakinra in NOMID was evaluated in a prospective, long-term, open-label, and uncontrolled study that incorporated a withdrawal period in a subset of 11 patients [25]. This study included 43 NOMID patients 0.7 to 46 years of age treated for up to 60 months. Patients were given anakinra at the initial dose of 1
2.4 mg/kg body weight. During the study, the dose was adjusted by 0.5
1 mg/kg increments to a protocol-specified maximum of 10 mg/kg daily, titrated to control signs and symptoms of disease. The maximum dose actually studied was 7.6 mg/kg per day. The average maintenance dose was 3
4 mg/kg daily. In general, the dose was given once daily, but for some patients, the dose was split into twice daily administrations for better control of disease activity. NOMID symptoms were assessed with a disease-specific Diary Symptom Sum Score (DSSS), which included the prominent disease symptoms fever, rash, joint pain, vomiting, and headache. In addition, serum amyloid A, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) levels were monitored. Improvements occurred in all individual disease symptoms comprising the DSSS, as well as in the serum markers of inflammation. Anakinra treatment also appeared to be associated with improvement of, or stability in, assessments of other NOMID disease manifestations, such as central nervous system, audiogram, and visual acuity data, at month 60. Clinical Efficacy in RA. In clinical trials in RA, anakinra showed only moderate but statistically significant therapeutic efficacy. ACR20 response was achieved in 30
40% of the patients versus 20
30% in the placebo groups. In most studies, however, MTX was administered concomitantly [26].

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Clinical Efficacy in SJIA. Anakinra administered in daily subcutaneous injections at the doses of 1
2 mg/kg has been empirically used to treat SJIA based on small studies [27
30]. In one controlled trial [31], 24 children with SJIA were randomized to receive either anakinra (2 mg/kg daily, maximum 100 mg) or placebo. After 1 month, patients treated with placebo were switched to anakinra. The adapted pediatric ACR30 response was initially assessed at month 1. There were 8/12 responders in the anakinra group and 1/12 in the placebo group (p 5 0.003). Twenty-two patients entered the open-label extension study lasting 1 year. Although initially about two-thirds of the patients receiving anakinra showed improvement, a loss of response over time was observed in many patients in this cohort [31]. Clinical Efficacy in Polyarticular JIA. The clinical efficacy of anakinra in children with polyarticular JIA was assessed in a randomized, controlled trial with a duration of follow-up of 19 months [32]. Eighty-six patients entered a 12-week open-label lead-in phase (1 mg/kg anakinra daily, #100 mg/day). Fifty responders were randomized to anakinra or placebo in a 16-week blinded phase, followed by a 12-month open-label extension (N 5 44). In the blinded phase of the trial, anakinra produced a nonsignificant (p 5 0.11) reduction in disease flares compared with placebo [32]. Safety and Tolerability. The most common side effects of anakinra are injection site reactions such as redness, itching, rash, and pain. Bruising or bleeding also can occur, but it is rare. These effects are a common reason to discontinue the treatment. Infections, headaches, and low white blood cell counts also can occur, but these are very rare. In 43 NOMID patients followed for up to 60 months, 2 patients experienced neutropenia that resolved over time during continued anakinra treatment [25]. Although there were no serious adverse events in the randomized phase of the trial of children with SJIA [31], six patients developed a serious adverse event in the open-label phase. Four infections and one vertebral collapse had a favorable outcome and these five patients continued the trial; one patient was diagnosed with Crohn’s disease shortly after month 2 and was withdrawn from the trial. Other adverse events mainly consisted of nonsevere injection site reactions and common infections. One patient stopped anakinra owing to a sudden increase in serum transaminases at month 6 [31]. Overall, the rate of serious infections in this trial was rather high, but this may be related to the fact that most patients were concomitantly receiving high dose steroids. As a monotherapy, anakinra appears much safer.

Rilonacept Chemistry. Rilonacept is a dimeric fusion protein containing ligand-binding domains of the extracellular portions of the IL-1 receptor and IL-1 receptor accessory protein (IL-1RAcP) fused with the Fc portion of human IgG1 [33]. It binds both IL-1α and IL-1β with high affinity, but potentially can also bind to the IL-1Ra. In the United States, it has been approved for the treatment of CAPS [34].

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Pharmacodynamics and Pharmacokinetics. In adults, the terminal apparent elimination half-life is approximately 1 week (154
184 hours) irrespective of dose, route of administration, or disease status. In pediatrics, rilonacept is administered as subcutaneous injections (4.4 mg/kg loading dose followed by 2.2 mg/kg weekly). Clinical Efficacy in SJIA. Twenty-four SJIA patients between 4 and 20 years of age were enrolled in the first pilot, double-blind, placebo-controlled study of rilonacept in SJIA [35]. Although the primary efficacy end points were not met in this study, rilonacept was well tolerated and efficacious, allowing for corticosteroid reduction in the open-label long-term extension phase. Another recent Phase III trial included an initial 4-week double-blind, placebo-controlled phase followed by an open-label phase for 20 weeks [36]. Rilonacept was administered as subcutaneous injections (4.4 mg/kg loading dose followed by 2.2 mg/kg weekly). In the blinded phase at week 4, 20/35 (57%) of patients in the rilonacept arm showed adapted ACR30 response compared to 9/33 (27%) in the placebo arm (p 5 0.016). Safety and Tolerability. The most consistently reported adverse events associated with rilonacept were infusion site reactions [36]. These were generally mild to moderate in intensity, occurred more frequently at the higher dose, and rarely led to discontinuation from the studies. Four of 35 patients in the rilonacept arm developed elevations in liver transaminase levels of $ 2 times the upper limit of normal, and two patients developed elevations $ 5 times the upper limit of normal. One patient had two separate episodes of streptococcal pharyngitis during the long-term extension phase [36].

Canakinumab Chemistry. Canakinumab is a high-affinity, fully human monoclonal anti-IL-1β antibody of the IgG1/k isotype designed to bind and neutralize the activity of human IL-1β [37,38]. It does not bind IL-1α or IL-1Ra. It was generated in transgenic mice capable of producing human sequence IgGk antibodies in response to immunization with recombinant human IL-1β. Pharmacodynamics and Pharmacokinetics. As other IgGs, canakinumab is mainly eliminated through intracellular catabolism. In adults with CAPS, the mean terminal half-life of canakinumab was demonstrated to be 26 days [33,39]. In the Phase II trial of canakinumab in children with SJIA, after subcutaneous administration, the mean peak serum concentration was reached within 2 days in most patients [40]. The half-life of canakinumab in this study was 16.7 6 5.45 (mean 6 standard deviation). Canakinumab has been approved for the treatment of CAPS and active SJIA in the United States and European Union. In the European Union, it has also been approved for the treatment of gouty arthritis. Clinical Efficacy in SJIA. Clinical efficacy of canakinumab in SJIA has been assessed in one phase II open-label dosage escalation study [40] and

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two double-blind, placebo-controlled phase III clinical trials [41]. The phase II multicenter, open-label, dosage escalation study of canakinumab in active SJIA determined that a dosing regimen of canakinumab at 4 mg/kg given every 4 weeks should maintain patients in a flare-free condition. This regimen was used in the two subsequent phase III trials of canakinumab in SJIA. [41]. Eligible patients in both trials were 2
19 years of age with active SJIA with active systemic features. In Trial 1, 84 SJIA patients were randomly assigned in a double-blind fashion to a single subcutaneous dose of canakinumab or placebo and followed for 29 days. At Day 15 of Trial 1, 36 of 43 patients in the canakinumab group (84%) had an adapted ACR30 response, as compared to 4 of 41 (10%) in the placebo group (p , 0.0001). Furthermore, 60% of patients on canakinumab achieved an adapted ACR70 and 33% achieved an ACR100 response. Trial 2 consisted of three phases: corticosteroid tapering, canakinumab withdrawal, and open-label extension. About 62% of the patients successfully tapered and 46% discontinued corticosteroids. Significantly fewer flares occurred in the canakinumab group in the blinded withdrawal part of the study. Both systemic and arthritic components of the disease respond to the treatment with canakinumab, and the degree of improvement for both components is consistent with overall ACR response results [42]. Stratification of SJIA patients based on the duration of the disease revealed that patients with both early and established disease responded equally well [42]. Safety and Tolerability. Injection site reactions, infections, and abdominal pain were the most common adverse events observed in the Phase III clinical trials of canakinumab in SJIA [40,41]. Injection site reactions were mild or moderate, and none of these events led to discontinuation of canakinumab. Infections included nasopharyngitis, upper respiratory tract infection, pneumonia, rhinitis, pharyngitis, tonsillitis, sinusitis, urinary tract infection, gastroenteritis, and viral infections. Serious infections occurred in approximately 4
5% of patients treated with canakinumab. Generally, the observed infections in canakinumab clinical trials responded to standard therapy. There were no cases of tuberculosis or opportunistic infections in either of the trials. In the two SJIA trials, anticanakinumab antibodies were detected in 2% of the patients; none were neutralizing [40,41]. In Trial 1, thrombocytopenia was observed in 2 patients in the canakinumab group (5%) and 1 of 38 patients in the placebo group (3%). In addition, neutropenia developed in two patients in the canakinumab group (5%). In the withdrawal phase of Trial 2, three patients in the canakinumab group (6%) and one in the placebo group (2%) had thrombocytopenia, and six patients in the canakinumab group (12%) and one in the placebo group had neutropenia. In the open-label phase of Trial 2, 11 of 176 patients with assessment (6%) had thrombocytopenia and 10/176 (6%) had neutropenia. Laboratory abnormalities resolved within a mean of 33 days in all patients.

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Targeting IL-23/Th17/IL-17 Axis Convergence of evidence from genetic studies, animal models, and translational studies strongly implicate the IL-23/Th17/IL-17 axis in the pathogenies of psoriasis, psoriatic arthritis, and ankylosing spondyloarthritis [43
46]. Th17 cells are a subset of helper T cells that produce IL-17, IL-21, and IL-22 [44] and differ functionally from Th1 and Th2 cells. Of the six highly conserved IL17 family members (IL-17A-F), IL-17A and IL-17F are secreted by Th17 T cells and represent the principal players. IL-17A has a number of biological effects, including induction of IL-6, IL-8, TNF, chemokines, matrix metalloproteinases, and RANK ligand in a variety of target cells including fibroblasts, epithelial and endothelial cells, macrophages, dendritic cells, chondrocytes, and osteoblasts. The IL-17 receptor complex consisting of IL-17RA and IL-17RC recognizes IL-17 and mediates downstream signaling events. IL-23 is now recognized to be essential for the proliferation and differentiation of Th17 T cells, maintaining IL-17 production ultimately driving the pathogenicity of these cells [45]. IL-23 is a heterodimeric cytokine composed of an IL12p40 subunit that is shared with IL-12 and the IL-23p19 subunit. A functional receptor for IL-23 is composed of IL-12Rβ1 (shared with IL-12) and IL-23R. Several strategies have been developed to target the IL-23/Th17/IL-17 axis. The fully human mAbs ixekizumab and secukinumab bind to and neutralize IL-17A. Both antibodies have high affinity and specificity only for this form of IL-17. In contrast to anti-IL17A antibodies, the human mAb brodalumab binds to the IL-17 receptor A (IL-17RA), thus inhibiting the activity of IL-17A, IL-17F, IL-17A/F, and IL-17E. Ustekinumab is a fully human IgG1κ mAb directed against the p40 subunit shared by IL-12 and IL-23, preventing the cytokines from interacting with their respective receptors. All these strategies were found to be effective in several clinical trials of adult patients with moderate to severe plaque psoriasis significantly diminishing skin lesions compared with placebo [47
50]. More recent phase III clinical trials also showed that secukinumab [51], brodalumab [52], and ustekinumab [53] significantly reduced signs and symptoms of psoriatic arthritis compared with placebo. In these trials more than half of the patients showed positive response at least at the levels of ACR20. Secukinumab also rapidly reduced clinical and biological signs of active ankylosing spondylitis with Assessment of SpondyloArthritis international Society criteria for improvement (ASAS 20) response achieved in 59% of the patients compared with 24% in the placebo group [54]. In general these biologics were well tolerated. Infections were the most common side effect. In the brodalumab trial, however, several patients developed suicidal thoughts and behavior. Pediatric experience with the biologics targeting the IL-23/Th17/IL-17 axis is very limited.

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B-Lymphocyte Depleting Therapies Theoretically B-cell depleting therapies are likely to be beneficial in rheumatic conditions associated with emergence of self-reactive B cells producing pathogenic autoantibodies. B-cell depletion is usually achieved either through the use of depleting antibodies directed against surface molecules expressed on B cells or through mAbs neutralizing growth factors critical for B-cell development. Rituximab Chemistry. Rituximab is a chimeric anti-CD20 mAb, comprising a human IgG1 constant region and a murine variable region [55]. CD20 is a specific B-cell differentiation antigen that is expressed on the surface of pre-, naive, mature, and memory B cells, but not on plasma, early pro-B, or stem cells. Administration of rituximab leads to depletion of B cells mediated by the induction of antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis. Since B cells are not only precursors of antibodyproducing plasma cells, but also highly effective antigen-presenting, cytokineproducing, and regulatory cells, the effects of rituximab probably rely on interference with all these functions [56,57]. Although plasma cells are not depleted, a reduction in pathogenic autoantibodies is seen. One example is a decrease in rheumatoid factor titers in rheumatoid arthritis (RA) or antinuclear antibodies (ANAs) in systemic lupus erythematosus (SLE). This is presumably caused by interference with activation and differentiation of B cells toward the effector plasma cell. Since plasma cells are not depleted, in the majority of patients treated with rituximab total immunoglobulin levels usually remain within reference range. Lasting hypogammaglobinemia, however, may be seen is as many as 10
20% of these patients. The therapeutic effect obtained by rituximab is transient in most cases. In general B-cell repopulation occurred at a mean of 6
10 months, although some patients may have much more prolonged B-cell depletion. Ng et al. report that repeat treatment with rituximab is effective; their series included seven adult patients with refractory SLE who responded to as many as three separate cycles of rituximab. Approved Indications. Rituximab has been used for treatment of nonHodgkin’s lymphoma for over 30 years. More recently, rituximab has been shown to be an effective RA treatment in several randomized controlled trials [58]. In the United States, it has been approved for use in combination with MTX for reducing signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to one or more anti-TNF-α therapy. In Europe, it is licensed for use in combination with MTX in patients with severe active RA who have had an inadequate response to one or more anti-TNF therapy. Rituximab has also been

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approved for granulomatosis with polyangiitis (Wegener’s Granulomatosis) and microscopic polyangiitis with glucocorticoids. Administration. Rituximab has mainly been used to achieve B-cell depletion in two regimens, either as two doses of 1000 mg given 2 weeks apart (two-dose regime, commonly used in SLE and RA in adults) or as four doses of 375 mg/m2 (four-dose regime, most common regime used in pediatric autoimmune diseases) given 1 week apart. Clinical Efficacy in SLE. Although the efficacy of rituximab in SLE has been noted in many observational studies, two large randomized controlled trails evaluating rituximab for the treatment of SLE failed to meet their primary end points [59]. Possible reasons for this include inadequate trail size, variability in concomitant immunosuppressive DMARDs, and corticosteroids usage and choice of end points that were not able to discriminate between minor disease fluctuations and meaningful clinical response [59]. Despite the failure of the trials, many physicians believe in the value of rituximab in the treatment of both renal and nonrenal lupus [60
64]. One of the first large series of pediatric SLE patients treated with rituximab were reported by Podolskaja et al. [62]. 19 children (89% female) with SLE, aged 6
16 (median 14) years, treated with rituximab in a single center were retrospectively reviewed. The British Isles Lupus Assessment Group (BILAG) index and biochemical, hematological, and immunological parameters were evaluated before and after treatment, with the primary outcome assessed as normal results. Rituximab therapy was used for acute life- or organ-threatening symptoms, or for symptoms that had not responded to standard treatment. The range of symptoms included lupus nephritis, cerebral lupus, and severe general symptoms. Rituximab 750 mg/m2 was given intravenously twice, usually within a 2-week period. Patients were followed up for 6
38 (median 20) months. Rapid reduction of SLE disease activity was observed within the first month, represented by a reduction of BILAG scores (14
6, p , 0.005) and an improvement in renal function (estimated glomerular filtration rate increased from 54 to 68 mL/min per 1.73 m2, p 5 0.07), immunological (complement C3: from 0.46 to 0.83 g/L, p 5 0.02), and hematological (hemoglobin: from 9.7 to 10.3 g/dL, p 5 0.04) parameters. No serious side effects were observed, except for herpes zoster in five cases. Another retrospective, single center cohort study was focused on pediatric SLE patients with autoimmune thrombocytopenia and/or autoimmune hemolytic anemia and treated with rituximab [63]. Nine patients (five had autoimmune thrombocytopenia, three had autoimmune hemolytic anemia, and one had both) with median disease duration to time of rituximab treatment of 6 months (range: 2
30 months) were included in the study. Complete response was achieved in all six children with autoimmune thrombocytopenia (median time to complete response: 2 weeks (range: 1
12 weeks)). Two patients’ conditions flared at 48 and 68 weeks, respectively, and were retreated. The remaining four patients continued to be in remission

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at 24, 32, 36, and 88 weeks, respectively. All four children with autoimmune hemolytic anemia achieved complete response at a median time of 4 weeks (range: 4
32 weeks). All patients remained in complete response at 24, 44, 84, and 100 weeks of follow-up. Complete B-cell depletion was seen in all children after rituximab treatment. No serious infections occurred, but one patient had an infusion reaction. A more recent study assessed the long-term outcome of SLE treated systematically with cyclophosphamide and rituximab [64]. Twelve patients with childhood onset lupus nephritis or corticosteroid-resistant SLE received systematic treatment with a combination of rituximab (750 mg/m2 up to 1 g) and cyclophosphamide (750 mg/m2). Two infusions of rituximab and cyclophosphamide, 2 weeks apart, were administered at the start of the study, 6 months later, and 18 months later. There was sustained improvement in all clinical parameters with a dramatic reduction in both mean SLEDAI score and mean daily prednisone dosage (29.7 mg/day to 12.7 by 1 year and 7.0 mg/day at 5 years with sustained improvement in mean C3 (55.5 mg/mL to 113 at 1 year and 107.5 at 5 years)), which was maintained through 60 months of follow-up. Serum immunoglobulin levels were transiently depressed but mean values were within the normal range for both IgG and IgM at 1 and 5 years. Few complications were observed, with two episodes of febrile neutropenia during the first year of treatment as the only serious adverse events. Safety and Tolerability. The most frequently reported infusion-related reactions (IRR) to rituximab are flu-like symptoms (fever, chills, and rigors). Less common reactions include hypotension, bronchospasm, pruritus, and rash. A cytokine release may be partially responsible for the IRRs observed in some patients receiving rituximab. Although the abovementioned pediatric series described few serious side effects, numerous concerns remain. In general, after a single course of rituximab, peripheral blood remains depleted of B cells for 6
12 months. Since long-lived plasma cells (the major source of protective antibodies), presumably, are not depleted in most patients, serum IgG and IgM levels are generally maintained. Lasting hypogammaglobinemia, however, may be seen is as many as 10
20% of these patients (serum IgG levels drop in about 5
7% of patients, and serum IgM levels drop in up to 20%). Since these patients appear to be at a higher risk for infection, posttreatment laboratory monitoring of immunoglobulin levels has been recommended, and many physicians would proceed with IVIG replacement in these patients. In the pediatric population, there are also theoretic concerns about possible long-lasting effects of B-cell depletion on the developing immune system. Significantly impaired vaccination responses have been documented in patients treated with rituximab [65]. Furthermore, in a case report describing the use of rituximab during pregnancy [66], a complete B-cell depletion was noted in the newborn baby, with some B-cell repopulation starting at 4 months. B-cell numbers in this child reached the normal range only by 20 months.

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In adult trials, serious infections occurred in approximately 4
5% of patients treated with rituximab. In most of these cases, however, rituximab was administered in combination with other immunosuppressive drugs. Among infections, encapsulated organisms such as Pneumococcus, Meningococcus, or Haemophilus are of a particular concern. The immune response to the polysaccharide antigens associated with these infections depends on B cells rather than T cells. Therefore, B-cell depletion profoundly compromises the ability to mount an effective response against these antigens. Other common infections include varicella zoster virus, and perhaps hepatitis C virus. Recent reports of progressive multifocal leukoencephalopathy, a demyelinating disease caused by human polyoma virus, in SLE patients treated with rituximab raised concerns for possible association [67,68]. The prevalence of human antichimeric antibodies to rituximab in RA patients treated with this drug was higher than what was reported in patients treated for lymphomas (4.2% after 24 weeks of treatment compared to 0.6% in lymphomas) [69]. This number may be even higher in SLE. The presence of these antibodies has been associated with an increased risk for infusion reactions, enhanced clearance, and decrease in therapeutic efficacy.

Belimumab Chemistry. Belimumab is a fully humanized IgG1-λ mAb that binds to soluble B-lymphocyte stimulator (BLyS) and inhibits its binding to receptors and thus its activity [70,71]. BLyS is a prominent factor in B-cell differentiation, homeostasis, and selection. BLyS promotes survival and reduces apoptosis of autoantibody-producing B cells. Therefore, high levels of BLyS may promote expansion of B cells increasing the probability of autoreactive B cells to escape negative selection. By neutralizing BLyS, belimumab allows more B cells to undergo the normally occurring process of apoptosis. In turn, this leads to decreased survival of B cells, including autoreactive B cells and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. Approved Indications. The indication for use of belimumab is a lack of clinical improvement despite standard treatment for active disease in seropositive patients with SLE. Recommended dosage regimen is 10 mg/kg at 2-week intervals for the first three doses and at 4-week intervals thereafter. Belimumab is administered as a 1-hour IV infusion only and given every 4 weeks after the loading phase. Efficacy in SLE. The two large prospective, randomized, controlled phase III trials evaluated the efficacy of belimumab in mild to moderate SLE with mainly joint and skin manifestations. The trials were designated BLISS-52 and BLISS-76 according to their duration in weeks [70,72]. The BLISS-52 trial involved 865 patients, and the BLISS-76 trial involved 819 patients. In both studies, patients were randomly assigned to belimumab at a dose of 1 mg/kg body weight, belimumab at a dose of

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10 mg/kg, or placebo. The study drugs were administered by intravenous infusion on days 0, 14, and 28, then every 28 days. The primary outcome measure in both studies was the Systemic Lupus Erythematosus Responder Index at week 52. In the combined studies, response occurred in 50.6% of patients assigned to belimumab at a dose of 10 mg/kg versus 38.6% of patients assigned to placebo (p , 0.001). The efficacy of belimumab has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. Belimumab has not been studied in combination with other biologics or intravenous cyclophosphamide. Safety and Tolerability. Severe infections occurred in 7
8% of patients assigned to belimumab and in 6% of patients assigned to placebo [70
73]. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections resulting in death occurred in 0.3% (4/1458) of patients treated with belimumab. In the studies of belimumab that lasted 52 weeks to 4 years, deaths occurred in all groups, including the placebo groups; the death rate did not exceed that expected in the overall population of patients with SLE.

GENERAL SAFETY CONSIDERATIONS Active Infections The use of biologics targeting various components of the immune system has been associated with increased risk for infections. As a general rule, these biologics should not be administered during an active infection, including localized infections. If a serious infection develops, they should be interrupted until the infection is controlled.

Combination Therapy One clinical trial in adult RA assessed the potential for synergistic effects of combination therapy with two biologics, etanercept and anakinra [73]. This combination therapy provided no treatment benefit over etanercept alone, but was associated with highly increased risk for serious infections (0% for etanercept alone vs 7.4% for the combination therapy). Based on these observations, coadministration of two biologics targeting the immune system is not recommended because this may increase the risk of serious infections.

Vaccinations Live vaccines should not be given concurrently with biologics targeting various components of the immune system. Since some biologics may interfere with normal immune response to new antigens, patients being treated with

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biologics, particularly if in combination with MTX, may have a mild decrease in the prevalence of adequate protection after vaccination. Therefore, vaccinations should be given before starting treatment (eg, influenza, polysaccharide pneumovax, hepatitis B) and then during, as appropriate when indicated.

Surgical Procedures Increased risk of infection in RA patients continuing TNF-inhibiting agents during joint replacement has been reported. Although there is no consensus on how biologics should be managed during elective surgery, some physicians withhold treatment with etanercept for 2
4 weeks and adalimumab, certolizumab, golimumab, and infliximab 4
8 weeks prior to major surgical procedures. In these patients, treatment is restarted postoperatively if there is no evidence of infection and wound healing is satisfactory.

Pregnancy There are reports of women continuing biologics both until conception and during pregnancy without apparent adverse effects. Furthermore, the available registry data does not suggest increased teratogenicity. However, numbers are small and there is insufficient data available on long-term fetal safety. The recommendations have been to cease treatment 3
6 months (9 months for rituximab) before a pregnancy is planned or to discontinue if unexpected pregnancy occurs [74].

RARE ADVERSE EVENTS Conceptually, there are theoretic concerns that targeting various components of the immune system may result in increased frequency of serious opportunistic infections, malignancies, and autoimmune diseases. For most biologics discussed in this chapter, the available safety data is based mainly on the findings in the clinical trials. These trials were designed mainly to assess the efficacy and were often underpowered for analysis of the rare adverse events such as malignancies. Extension studies of the original clinical trials and national registries may address these deficiencies. As an example, the incidence of serious infections was low in most pediatric clinical trials, but the data from registries shows that serious infection rates are higher in patients receiving biologics.

Opportunistic Infections The registry data now clearly implicate TNF-inhibiting agents as a risk factor new tuberculosis as well as reactivation of latent tuberculosis. Although unusual infections including tuberculosis have not been seen frequently with

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other types of biologics, they do remain a concern, and until more data from long-term safety studies are available, screening for prior exposure to tuberculosis is recommended before starting therapy. Use with hepatitis C is probably safe but hepatitis B and HIV infection require consultation with the local relevant expert. Currently there does not appear to be an increase in incidents of serious infections with increasing repeat treatments.

Malignancies Although cases of malignancies, especially lymphomas, have been reported in JIA patients treated with biologics (most notably TNF inhibitors), the more recent data form registries look reassuring.

New Autoimmunity Cases of new autoimmune diseases such as lupus, demyelinating neurologic diseases, uveitis, or sarcoidosis in patients treated with biologics have been reported. Although a causal relationship cannot be excluded in these patients, unmasking of a misdiagnosed underlying disease initially presenting with arthritis may be an alternative explanation. These considerations underscore the importance of long-term large registries.

GENERAL SAFETY LABORATORY MONITORING Consider ESR and CRP, full blood count, renal and liver function tests every 3 months. PPD and/or QuantiFERON assay (prebiologic) and postbiologic if reexposure to tuberculosis is occurring. Hepatitis B and C serology should be considered prebiologic and annually if appropriate. HIV screening should be considered in at-risk patients. ANA, dsDNA, RF, anti-CCP should be considered initially prebiologic. These maybe repeated if appropriate (eg, ANA, dsDNA if there is development of clinical SLE symptoms).

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[24] Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012;11:633
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52. [27] Verbsky JW, White AJ. Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J Rheumatol 2004;31:2071
5. [28] Irigoyen PI, Olson J, Hom C, Ilowite NT. Treatment of systemic onset juvenile rheumatoid arthritis with anakinra. Arthritis Rheum 2004;50(Suppl.):S437. [29] Pascual V, Allantaz F, Arce E, et al. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 2005;201:1479
86. [30] Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum 2011;63:545
55. [31] Quartier P, Allantaz F, Cimaz R, et al. A multicentre, randomised, double-blind, placebocontrolled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis 2011;70:747
54. [32] Ilowite N, Porras O, Reiff A, Rudge S, Punaro M, Martin A, et al. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin Rheumatol 2009;28:129
37. [33] Kuemmerle-Deschner JB, Ramos E, Blank N, et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1beta mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther 2011;13:R34
5. [34] Arcalyst [rilonacept], prescribing information. Tarrytown Regeneron Pharamaceuticals; 2010. [35] Lovell DJ, Giannini EH, Reiff AO, et al. Long-term safety and efficacy of Rilonacept in patients with systemic juvenile idiopathic arthritis. Arthritis Rheum 2013;65:2486
96. [36] Ilowite NT, Prather K, Lokhnygina Y, et al. The randomized placebo phase study of Rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis Rheum 2014;66:2570
9. [37] Grom AA. Canakinumab for the treatment of systemic juvenile idiopathic arthritis. Expert Rev Clin Immunol 2014;10:1427
35. [38] ILARIS, prescribing information. East Hanover, NJ, USA: Novartis Pharmaceuticals Corp; 2013. [39] Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 2009;360:2416
25. [40] Ruperto N, et al. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum 2012;64:557
67. [41] Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2396
406. [42] Brunner HI, Quartier P, Constantin T, et al. Canakinumab in the treatment of systemic juvenile idiopathic arthritis: results from a 12-week pooled post-hoc analysis for efficacy. Arthritis Rheum 2013;65(S10):S112
13.

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[43] Colbert RA, Ward MM. 17 and 23: prime numbers for ankylosing spondylitis? Lancet 2013;382:1682
3. [44] Gaffen SL. Structure and signaling in the IL-17 receptor family. Nat Rev Immunol 2009;9:556
67. [45] Tang C, Chen S, Qian H, Huang W. Interleukin-23: as a drug target for autoimmune inflammatory diseases. Immunology 2012;135:112
24. [46] Benson JM, Peritt D, Scallon BJ, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs 2011;3:535
45. [47] Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, et al. Secukinumab in plaque psoriasis: results of two phase 3 trials. N Engl J Med 2014;371:326
38. [48] Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al. Antiinterleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012;366:1190
9. [49] Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 2012;366:1181
9. [50] Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008;371:1665
74. [51] McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-ofconcept trial. Ann Rheum Dis 2014;73:349
56. [52] Mease PJ, Genovese MC, Greenwald MW, Ritchlin CT, Beaulieu AD, Deodhar A, et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med 2014;370:2295
306. [53] Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 2009;373:633
40. [54] Baeten D, Baraliakos X, Braun J, Sieper J, Emery P, van der Heijde D, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 2013;382:1705
13. [55] Rituximab [rituxan], prescribing information. Genentech; 2010. [56] Anolik JH, Barnard J, Cappione A, Pugh-Bernard AE, Felgar RE, Looney RJ, et al. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 2004;50:3580
90. [57] Looney RJ, Srinivasan R, Calabrese LH. The effects of rituximab on immunocompetency in patients with autoimmune disease. Arthritis Rheum 2008;58:5
14. [58] Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793
806. [59] Thanou A, Merill JL. Treatment of systemic lupus erythematosus: new therapeutic apporaches and blind alleys. Nat Rev Rheumatol 2014;10:23
34. [60] Ng KP, Cambridge G, Leandro MJ, Edwards JC, Ehrenstein M, Isenberg DA. B cell depletion therapy in systemic lupus erythematosus: long-term follow-up and predictors of response. Ann Rheum Dis 2007;66:1259
62.

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[61] Beckwith H, Lightstone L. Rituximab in systemic lupus erythematosus and lupus nephritis. Nephron Clin Pract 2014;128:250
4. [62] Podolskaya A, Stadermann M, Pilkington C, Marks SD, Tullus K. B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus. Arch Dis Child 2008;93:401
6. [63] Kumar S, Benseler SM, Kirby-Allen M, Silverman ED. B-cell depletion for autoimmune thrombocytopenia and autoimmune hemolytic anemia in pediatric systemic lupus erythematosus. Pediatrics 2009;123:e159
63. [64] Lehman TJ, Singh C, Ramanathan A, Alperin R, Adams A, Barinstein L, et al. Prolonged improvement of childhood onset systemic lupus erythematosus following systematic administration of rituximab and cyclophosphamide. Pediatr Rheumatol Online J 2014;12:3. [65] Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005;31:456
73. [66] Friedrichs B, Tiemann M, Salwender H, Verpoort K, Wenger MK, Schmitz N. The effects of rituximab treatment during pregnancy on a neonate. Haematologica 2006;91:1426
7. [67] Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIVnegative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009;113:4834
40. [68] Fleischmann RM. Progressive multifocal leukoencephalopathy following rituximab treatment in a patient with rheumatoid arthritis. Arthritis Rheum 2009;60:3225
8. [69] Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, doubleblind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54:1390
400. [70] Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63:3918
30. [71] Wallace DJ, Navarra S, Petri MA, et al. Safety profile of belimumab: pooled data from placebo-controlled phase 2 and 3 studies in patients with systemic lupus erythematosus. Lupus 2013;22:144
54. [72] Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:721
31. [73] Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2004;50:1412
19. [74] Hyrich KL, Verstappen SMM. Biologic therapies and pregnancy. The story so far. Rheumatology 2014;53:1377
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Chapter 25

Physiotherapy Management of Pediatric Rheumatology Conditions S. Maillard Great Ormond Street Hospital, London, United Kingdom

INTRODUCTION Pediatric rheumatology is a relatively small specialty within physiotherapy; however, within its case load there are a complexity of challenging conditions that are either related to an inflammatory disease or a biomechanical malfunction. The commonality between them is that all the conditions have features of pain, fatigue, and loss of function within the musculoskeletal system, specifically the muscles and the joints. The skill for the therapist is to be able to assess and consider the inflammatory and noninflammatory components for the symptoms presented by the patient. The key symptoms of pain and altered function may be related to a flare of disease and require a medical management; however, they may also be due to abnormal biomechanics and therefore will only respond to physical therapy interventions. This chapter will focus upon the key assessment required to inform the therapist to be able to make a decision about whether the symptoms are related to inflammatory disease or abnormal biomechanics and therefore be able to provide the correct focus for any intervention (Fig. 25.1 and Tables 25.1 and 25.2).

PHILOSOPHY OF TREATMENT PRINCIPLES The physiotherapy approach for all the rheumatology conditions follow similar principles and are based around ensuring the muscle control for a specific joint are maximized in order to be able to progress to more functional

Pediatrics in Systemic Autoimmune Diseases. DOI: http://dx.doi.org/10.1016/B978-0-444-63596-9.00025-6 © 2016 Elsevier B.V. All rights reserved.

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Pain

Inflammatory disease

Joint stiffness

Swelling

Inflammatory cytokines

Loss of muscle function

Muscle atrophy

Muscle weakness

Loss of MM stamina

Pain

Loss of independence and function (B)

Biomechanical dysfunction

Pain

Loss of active range

Unstable joints

Muscle atrophy

Reduced stamina

Loss of strength

FIGURE 25.1 Pain cycling in inflammatory disease (A) and noninflammatory disease (B).

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TABLE 25.1 The Most Common Conditions Seen and Managed Within a Physiotherapy Department for Pediatric Rheumatology Inflammatory Disease

Noninflammatory Musculoskeletal Pain Symptoms

Juvenile idiopathic arthritis

Musculoskeletal pain related to hypermobility

Juvenile dermatomyositis

Ehlers Danlos syndrome

Scleroderma

Marfan syndrome

Systemic lupus erythematosus

Complex regional pain syndrome

Vasculitis

Chondromalacia patellae

Chronic Recurrent Multifocal Osteomyelitis/ Synovitis, acne, pustulosis, hyperostosis, and osteitis

Chronic pain syndromes

Chronic infantile neurologic cutaneous and articular syndrome

TABLE 25.2 Reasons for Muscle Weakness and Muscle Atrophy in Children With a Rheumatological Condition Symptom

Muscle Response

Pain in joint

Inhibits function of muscles that control that joint

Stiffness/loss of movement of specific joint

Muscles working with specific joints are unable to function through full range and therefore the muscles weaken within the range not used

Joint swelling

Inhibits function of muscles that control the joint

Systemic illness

Causes generalized loss of muscle strength and endurance

Deranged cytokines

The cytokines that promote active disease also affect muscle function and cause a nonspecific myositis and muscle weakness and loss of endurance

Decreased physical function due to pain and fatigue

Less physical activity causes global loss of strength and endurance

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activities providing accurate biomechanical functioning of the body. Regaining normal range of movement of the joint is also important and then increasing aerobic fitness levels will also need consideration. The goals for all treatments and all conditions will be to enable the young person to attend fulltime school and to participate in physical activity including sport.

ASSESSMENT All assessments include the subjective and objective aspects and the rheumatology assessment is no different. The following assessment is based on work done within an expert consensus in the management of rheumatological conditions and can be found in more detail through the British Society of Pediatric and Adolescent Rheumatology. In order to plan effective management of children with a rheumatological condition an assessment will need to encompass the physical, psychological, and social impact of the disease on the child and the family. In this section is included a comprehensive list of topics that could be covered in the assessment, both subjectively and objectively. It is important that the relevant age-appropriate milestones are considered at all times during the assessments to ensure that the correct inferences may be gained from all the information.

SUBJECTIVE ASSESSMENT History of Present Condition It is necessary to ask about the history of the symptoms and to ask about their progression and any important factors that precipitated them. This needs to include systemic features such as spiking fever, rash, mouth ulcers, headaches, sore throats, trauma, viral/bacterial infection, travel abroad, or vaccinations received. This is important to differentiate between diseases and gives an indication of severity and speed of onset of disease, length of time of symptoms, and possible precipitating factors. It is recommended that previous hospital admissions and investigations are recorded chronologically to ensure that a clear picture is gained as to the investigations and treatments already provided. It is useful to identify the pathway taken to come to a clear diagnosis and also to have more ideas as to the appropriateness of treatment and whether the disease is untreated for a significant period of time. Understanding the medical pathway that the family has traveled is also important to understand the challenges the young person may already have experienced. This is particularly relevant to children with noninflammatory musculoskeletal pain symptoms.

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Presenting Problems and Symptoms It is important to establish when the changes occurred during the progression of the disease because the longer the condition has been present the greater the clinical changes are. However the main current problems also need to be established within a relevant time scale, that is, in the last 1 2 weeks. First allow the family time to tell you what the young person is experiencing and then focus your questioning upon these main areas.

Pain Gain a good description of the areas affected, type, severity, and intensity of the pain. Also ask about the length of time and when the pain is experienced (periodic, etc.) as well as the relieving and exacerbating factors. This will give a clear picture of the biggest concern for most children and indicates what and where treatment is most appropriate. Using a pain scale is often very useful and provides a slightly more objective outcome measure (ie, pain visual analog scale 0 10). General Functioning (This needs to be in context of the appropriate developmental milestones.) Establish what activities they are able to do now compared to what they could do previously, and what activities they have difficulty with, particularly in functional tasks. Ask about walking distance, and stairs. Fatigue is an important issue to many children with these conditions. This is important in order to gain a clear picture of function and problems experienced now. Early Morning Stiffness Early morning stiffness (EMS) is particularly important for children with juvenile idiopathic arthritis (JIA) and it is useful to know how severe the stiffness is, for how long it lasts, and what areas of the body are affected. Also establish whether there is stiffness at any other time in the day. This is important as EMS is an indication of the severity and degree of activity of inflammatory disease. Also stiffness at other times of the day may indicate other issues; for example, in the evening stiffness is often an indication of muscle fatigue due to biomechanical abnormalities and hypermobility. These can also be experienced with inflammatory and noninflammatory conditions alike, but evening stiffness is due to fatigue and not inflammation. Child’s and Parent’s Main Concerns Ask what they are most worried about, and what they think can be done about it. Ask about their understanding of the diagnosis and treatment given.

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This ensures that everyone is aware of the issues and that the family’s main concerns are considered within the treatment program and that everyone is focused upon the same goals.

Past Medical History Taking a brief history about development is important to ensure there is not an underlying neurological condition alongside the rheumatological one. Often children with hypermobility will be slightly slower in reaching their milestones and will often not crawl at all. Ensure information about previous illness and medical interventions is also recorded. Other conditions will have a relevance to the provision of treatment and diagnosis of rheumatological/musculoskeletal condition. Inquire about any operations that the child has had before or has planned for the future and whether there have been any other injuries such as fractures, sprains, or dislocations. This will also give an indication about previous hospital and pain experiences. Ask about all the investigations that the child has received, for this condition, or other conditions.

Medication Ask about all medication taken previously, including dosage, dates started, and dates finished so that it is clear about the drugs taken, their effect on the disease, and any potential side effects (eg, steroids). A complete list of current medication and doses prescribed, including homeopathic medicines, is required in order to be aware of all drugs taken and potential affect of them on treatment (eg, steroids). Social History and Family History Draw a tree of the relationships in the immediate family, including ages of other children. It is also necessary to ask who actually lives at home as this may well be different from the family tree. Ask about the occupation of the parents as this will give some indications about the pressures on the family both with time and financially. Also ask about who is the primary caregiver of the child as this may not be the mother, and therefore they will need to be included in the teaching of a home treatment plan. There may also be a friend or relative who they spend regular time with who may need to be involved with their care. Ask about any diseases or illness within the family such as diabetes, rheumatoid arthritis, thyroid disease, psoriasis, gastrointestinal tract problems, chronic pain, or other conditions. It is important to know the family’s experience of illness, etc. this may have an impact upon the child’s coping mechanisms and perception of their condition.

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Accommodation Ask about type of accommodation, ownership, stairs, general access, accessibility of bathroom, and so on. This may have an impact if mobility is an issue and if adaptations are needed to the house. State Benefits Ask about which benefits they are already receiving and if there are any that they are in the process of claiming. This is to ensure whether the appropriate support has been provided, and to highlight any shortfalls.

Activities of Daily Living/Function At Home In this area of the assessment the focus should be on the young person’s ability to function in the following areas: G

G G G

Hygiene: 2 Washing 2 Toileting Dressing and grooming Walking distance and mobility Eating and food preparation.

School The goal for all interventions should be to enable the young person to be able to fully participate in school; however, there may be many factors that have an influence over the success of this goal and these should be explored in some detail. The following areas would be important to consider: G G G G G G G G G

Attendance Transport Support provided by the school Writing ability Physical education/sport Rest facilities Play/break time Other school subjects that provide some difficulties Support or modifications the family consider to be important but have not been provided.

Hobbies, Interests, and Socialization These can also be used as treatment goals or strategies to make interventions more relevant and fun.

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Family Hobbies Inquire about hobbies that the family enjoy doing together, including any that they are unable to do now due to this illness. Individual Hobbies Hobbies that the child likes to do, including any that had to be stopped due to this illness. Swimming/Sports Details as to whether they are able to and enjoy swimming, and whether they play any other sports regularly. It is also important to find out about any that they are now unable to play. Socialization Inquire about peer interaction, and whether they have stable friendships or not. Drugs/Alcohol/Sexual Activity This needs to be age appropriate, and will often not be asked on the first visit.

Future Career Planning and Development Discussion of this area is important from a relatively early age (ie, 10 11) just to establish some of their ideas, and to also ensure that it is an ongoing concern to ensure a holistic approach. Inquire as to whether they have had any contact with a career advisor. This will help establish whether their career goals are realistic in the light of the arthritis and to provide goals for treatment.

OBJECTIVE ASSESSMENT It is important to observe the family during the assessment as it will help gain an impression of family dynamics. The visual analog scale (VAS) for pain completed by the child is a useful tool for the ongoing assessment of the level of pain they are experiencing. The VAS global assessment of disease and function completed by the parents is also important and one of the core-outcome variables in the assessment of JIA. A physician’s VAS should also be completed, especially in the management of JIA.

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Assessment of Each Joint, Including Spinal Movements Active range of movement is important; however, often children will not tolerate a very long assessment and therefore it is recommended to assess the passive range of movement as a priority. (It is also important to note the time of assessment, as the findings will often differ depending on time day as children with arthritis are stiffer in the morning than the afternoon.) As a physiotherapist it is vital to assess specific ranges and not just to know that the joint is restricted as many of the interventions will be to increase range. Therefore it is an important outcome measure. It is vital to know whether the joint is restricted due to pain, stiffness, muscle shortening, or true joint contracture. This will then determine the treatment plan. When treatment is based around improving restricted range then an accurate recording of joint angles is recommended using either a goniometer or eyeballing. Fluidity of movement is important to notice as this will also give information as to the causes of the loss of movement and whether there is any muscle spasm protecting the joint. Hypermobility is as important a finding as a restricted joint. It is also important to assess all joints as the parents or the child will often miss important changes. Deformities are important to assess accurately as these may affect the program that is prescribed. Always look for the color and temperature around the joint and any pain associated with the movement or palpation. Always observe any bony overgrowth affecting a joint.

Palpation It is important to observe the end-feel of a joint as well as the stability of a joint including evidence of subluxation or dislocation, any swelling either of joint (effusion), soft tissues, or of tendons. Feel for muscle spasm, which is often evident around the neck and spine. Muscle Strength and Function This should include specific outcome measures for the assessment of juvenile dermatomyositis (JDM). The accurate assessment of muscle strength is vital in both the assessment of disease activity and to be able to prescribe a specific and targeted treatment program. As previously mentioned the key symptoms experienced by young people with inflammatory and noninflammatory conditions are directly linked to the strength of the muscles in that area of the body. The weaker the muscles the greater the reported symptoms; therefore it is important through accurate assessment that it is clear where the specific muscle weakness occurs. Many scales are used in assessment of muscle strength. They all have a slightly different focus and give different information. The most common testing system used is the Medical Research Council (MRC) scale of 0 5,

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which is widely accepted despite its limitations. Muscle testing is an extremely important outcome measure for effectiveness of treatment and can be measured before and after intervention. It is also vital to assess muscle function to ensure that the physiotherapy program is prescribed specifically to address the muscle weakness experienced by each child. Specific measures of muscle strength and function have been developed for the assessment of JDM. These include a modification of the MRC scale to a 0 10 scale called the Kendal scale, which is then applied to eight muscle groups (MMT8) to give a score of 80 (or 150 if used bilaterally). The other important measure is that of the Childhood Myositis Assessment Scale, which is a validated assessment tool of muscle function and an accepted core-outcome assessment tool for the management of JDM. This score is out of 52, with 52 indicating full function. Muscle strength can also be assessed in a more objective manner such as using a handheld myometer. A myometer will give measurements of force that can then be followed over time more accurately that the 0 5 scale; however, this does have some limitations as it only measures antigravity strength, but is useful for research purposes [1 11].

Posture Observe posture in standing and sitting, looking at position of neck, shoulders, elbows wrists, hand, spine, hips, knees, and ankles. It would also be prudent to observe familial posture in order to assess the potential variations to be expected. Gait This is very important in the assessment of any child with a physical difficulty as it provides a great deal of information about the function, independence, limitations, and level of pain of the child; for example, loss of big toe extension limits the push-off phase. Fixed flexion deformities of hips and knees often causes continual loss of strength in hip abductors and extensors and inner range quadriceps, often resulting in the development of a positive Trendelenburg gait pattern. Valgus knees and ankles alter the correct muscle function and observing the heel/toe action highlights difficulties in the feet and ankles [12,13]. Video may be a useful record of gait.

Observation of General Movement and Function Look for any compensatory movements that may be performed both during the assessment and in the movement to get from the waiting area to the examination room.

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Functional Questionnaires (or Some Form of Validated Disease Function Measure) G G

Childhood Health Assessment Questionnaire (CHAQ) Childhood Health Questionnaire (CHQ)

These have all been validated in the assessment of inflammatory disease in children. The ones that are used most commonly are the CHAQ and the CHQ. In fact the CHAQ is one of the core set outcome measures in both JIA and JDM [14 19].

Stamina This is an important feature for all children with rheumatological conditions. However, there are no routinely used objective assessments. The 6 minute walk test is a validated tool but is time consuming and so is not usually used in a clinic setting. Therefore the most common assessment is just a subjective questioning of fatigue [20]. Leg Length This is important to measure as children with both inflammatory and noninflammatory disease develop transient differences, which if left unmanaged, can cause permanent deformities to the spine. All leg length differences of greater than 1 cm should be treated with a complete shoe raise. Muscle Bulk This is often a useful measure particularly when the condition only affects one side as it can give an objective measure for change in muscle size. Often measures are taken 10 cm above knee joint line, the knee joint line, and 10 cm below the knee joint line. Ensure that this is consistent for each child. Skin Condition Assess the condition of the skin and note any abnormalities or broken/vulnerable areas. In JDM you would expect to see a purple/red rash around their eyelids, across the knuckles, and across the extensor surfaces of the knees and elbows. In lupus you would expect to see a red rash in a butterfly distribution under the eyes and across the cheeks. Also look for signs of scleroderma as in mixed connective tissue disease several skin rashes can be present.

PHYSIOTHERAPY MANAGEMENT After a thorough assessment it will be possible to prioritize the specific problems for each child; that is, what joints are restricted, which muscles are

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weak, how the balance is affected, and so on. From this the specific treatment program can be designed. The treatment program has to be prescribed for each child individually and will need to be reviewed and monitored regularly.

Specific Information for Individual Conditions In the management of JIA it is vital to exercise even when the joint is active. The goals of all treatment are to maintain range of movement and maximize the specific muscle strength as much as possible in order to maintain full function. Physiotherapy management of JDM has changed over the last few years and it has been shown that exercise during active disease is no longer contraindicated. Therefore physiotherapy should be started at diagnosis and progressed as the child is able. The ultimate goal will still be full strength and stamina. Many children have hypermobile joints; however, only a percentage of those will suffer from symptoms, and if they follow a chronic pattern these children may be diagnosed as having Benign Joint Hypermobility Syndrome or Ehlers Danlos Syndrome. However, care should be taken when labeling young people and children with genetic syndromes to be mindful of the potential harm this may cause if the child and the family do not realize that the symptoms can actually be very well managed. It may be more helpful to consider describing the presentation using terms such as musculoskeletal pain with hypermobile joints. The symptoms and the severity may vary from child to child, and can occur at any age. Symptoms generally include muscle and joint pain particularly after activity, toward the end of the day and at nighttime (growing pains). Occasionally a joint can become swollen but this lasts for hours to days, and not weeks as in JIA. On examination either all or some of the joints can be hypermobile, and there is an associated loss of muscle strength particularly in the lower limbs. The knee is often the main area of pain followed by the ankle. The most influential factor over pain and fatigue and loss of function is in fact loss of muscle strength and stamina, both specifically and globally. The muscle weakness also follows a specific pattern, usually involving inner range quadriceps, hip abductors, and extensors as well as plantar flexors. The ideal management for this presentation is physical therapy to improve the strength and function of these specific muscles in order to control the hypermobile joints. In the management of chronic pain conditions, exercise has been shown to be one of the most effective modalities in order to regain function and reduce pain. It is vital that the young person and his or her family understand that the pain will not resolve until the function (both specific and global) has returned completely. Cognitive behavior therapy is also very effective in conjunction with an exercise program (Fig. 25.2).

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Assessment

Provide intervention

Identify problems

Set goals

FIGURE 25.2 The basic cycle of physiotherapy assessment and treatment.

Main Treatment Goals for All Conditions 1. Full range of movement at each joint 2. Full muscle strength throughout the whole range, including hypermobile range 3. Stable joints 4. Excellent stamina a. specific muscles b. general 5. Full physical function independent of pain 6. Good balance and proprioception 7. Age-appropriate neuromuscular coordination 8. No pain 9. Independent function 10. Minimize loss of bone density 11. Educate family and child. The program may need to include many different techniques depending upon the specific problems, and the main principles of each intervention will be described. These may include muscle strengthening, stretching, pain relief, pacing, balance, and proprioception reeducation, gait reeducation, splinting, and hydrotherapy.

MUSCLE STRENGTHENING AND ENDURANCE EXERCISES There are many reasons for children to have loss of muscle strength and stamina and these are listed next. This explains why a muscle strengthening program is the backbone to any physical management program.

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Pain Inhibits Muscle Function Pain in a muscle of the joint it is linked with will reduce the strength and function of that muscle and very quickly atrophy of the muscle will occur.

Inflammation Inflammation or swelling in a joint will inhibit the functioning of the muscles around it and within days of reduced function, atrophy will occur.

Biomechanical Joint function can change biomechanically for many reasons. If there is swelling then the position and movement of the joint will alter and this in turn will alter the muscle function around that joint. Equally when the swelling has reduced, the ligaments and capsule may remain overstretched and therefore render the joint unstable, also affecting muscle function. In the case of the noninflammatory conditions poor muscle control is not gained throughout the full range of the joint especially into the hypermobile range, which in turn causes instability of the joint resulting in pain, and then the pain inhibition cycle begins (Fig. 25.3).

Swelling

Reduced movement

Hypermobility

Pain

Biomechanically altered joint

Altered muscle function/ strength/fitness/ atrophy

Strength not through range

Muscle function inhibited

Affect of cytokines

Myositis

FIGURE 25.3 Cycle of muscle weakness in inflammatory disease.

Muscle imbalance

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Loss of Mobility When a joint does not move fully, such as when there are contractures or a joint effusion, then the muscle is not able to move through full range and loses its function within the range not moved. This then has a knock-on effect to the rest of the muscle, and the whole muscle will gradually lose strength and function. In the case of hypermobility the muscles are generally not functioning into the hypermobile range, and therefore, there is poor control into inner range causing overstretching of the joints and pain.

Disease Activity In inflammatory disease the whole body is affected and causes a systemic response to varying degrees, depending on the nature and severity of the disease. This in turn affects the muscles as the child is not eating effectively or because of feeling unwell, is not exercising and playing normally, which causes loss of muscle function. There are also small molecules called cytokines that are important in the continuation of the inflammatory diseases but that also have very significant roles in muscle function. This will be explained later.

Muscle Imbalance The body tries to compensate for difficulties and this also happens in the way the muscles function. For example, in the case of a child with a swollen knee, the knee flexes due to the swelling and therefore the inner range quadriceps stop functioning. As the knee is flexed the hip flexes in compensation and the hip abductors and extensors—gluteus medius, minimus, and maximus—are unable to function. However, other muscles start to compensate, such as Psoas and mid-range quadriceps, which now do too much work but keep the body mobile. If this situation continues then the stronger muscles (Psoas and mid-range quads) keep being used and get stronger and the other muscles just keep getting weaker! This results in significant muscle weakness and a muscle imbalance.

TRAINING CHILDREN’S MUSCLES In order to improve muscle strength and stamina in children the research shows that they do this best with a progressive resisted exercise program using the principles of high repetitions and low weights for specific muscles. It is recommended to increase repetitions to a minimum of 15 before weights are added; however, to regain full fitness of the muscles 30 repetitions are recommended. Low weights are also recommended with increases of 0.5 kg to a maximum of 2.5 kg in most children though increasing to 5 kg is also safe.

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The exercise program needs to be regular and it has been shown that twice a week is more effective than once a week, but that 4 5 times a week is the most effective. The other important aspect is that the exercise program should be started slowly but should be constantly progressed until full strength and fitness are regained. It has also been shown that progressions on a daily or weekly basis are more effective than monthly progressions. Therefore it is really important to remember that children can increase their strength and fitness beyond normal growth and maturation and this is a vital principal in the management of children with rheumatological conditions [21 28].

Specific Exercise Program In developing a program for any child with a rheumatological condition the most important aspect will be regaining joint range of movement and regaining muscle strength and fitness. Children with these conditions often develop similar and specific muscle weakness patterns. These are usually involving hip abductors and extensors, inner range quadriceps, and plantar flexors. Therefore a home management program should include a strengthening and stamina program for these muscles. It is important to isolate the muscles that are weak and provide a specific strengthening program so that they can then function fully in normal activities. It is extremely important that the child and the family also realize that for any physiotherapy program to be effective it has to be completed regularly at home and that the role of the physiotherapist is to monitor the home program and to facilitate the progression of the program as necessary. If the exercises are not completed regularly at home then no progress can be made and more importantly it is vital that the child and the family learn how to manage these conditions themselves [19,29 35]. For any specific prescribed exercise program to be effective in the management of these conditions these principles need to be followed: 1. Muscle strengthening and stamina of muscles is the most vital aspect of the program. This program should target the specific muscles that are weak and unfit and the program should be regularly progressed until 30 repetitions and 2.5 kg weights can be used for each exercise. (These guides should be modified for the smaller or larger child.) 2. If inflammatory disease is causing loss of joint movement then a daily stretching program should be included. 3. Balance and proprioception are also very important and can easily be included into a program.

Stretching Stretching is an important part of the treatment program both for reducing contractures or preventing them and also for lengthening shortened muscles.

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In inflammatory disease the joints become swollen and the synovial fluid becomes thinner but full of inflammatory cells. These cells alter the effectiveness of the synovial fluid in its role as a lubricant and also change the structure of the capsule and other soft tissues. These soft tissues lose elasticity and become stiffer and in children this then causes contractures very quickly. Often children with inflammatory disease such as arthritis (but this also may occur in any of the other inflammatory diseases) experience stiffness in the joints first thing in the morning and after periods of immobilization, such as sitting in a class room or after a car journey. This is because with no movement of the joint, the circulation around the joint is reduced and the fluid just builds up in the joint, the capsule gets tighter, and the joint is then limited in range at both ends (ie, full flexion and full extension). Pain is also produced by this process both in and around the joint, but also in the muscles around the joint (Tables 25.3 and 25.4). Therefore it is vital to stretch the joints out first thing in the morning to regain full range of movement as soon as possible in order to prevent the development of contractures (permanent loss of joint movement) and to reduce the pain and the stiffness. If the child has particularly active disease with many swollen joints then initially you will need to discuss with the medical team as to whether the child has adequate medical control of their disease and secondly the stretches may be more effectively completed in a warm bath or hydrotherapy pool. Role of Stretching The role of stretching is to: 1. Reduce pain 2. Reduce stiffness 3. Maintain or increase joint range of movement in order to prevent contractures or to resolve them if necessary 4. Increase muscle length. TABLE 25.3 How to Develop a Successful Home Exercise Program for Children With a Rheumatological Condition? The exercises need to be easy to do at home Minimal equipment should be used Use progressive and resisted exercises that can be done on the floor Ensure the program is not too long Make the program specific to the muscle weakness found on assessment

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TABLE 25.4 Example of a Home Exercise Program for a Child With a Rheumatological Condition Muscle Involved

Starting Position

Inner range quadriceps

Lying supine Static quadriceps contraction Straight leg raise

Hip abductors

Straight side lying Lift straight leg up, keeping body still and slightly tilted forward

Hip extensors

Prone lying

Plantar flexors and balance

Standing

Lift straight leg up, keeping hips still

On one leg, go up and down slowly on to tiptoes

Stretching stiff joints is one of the few techniques that is used in the management of these conditions that should be completed by someone else for the young person as it is extremely difficult to complete effective joint stretches by oneself. However, muscle length stretches can be completed by themselves. Important Rules for Stretching Joints 1. Stretch only one joint at a time. 2. Initially apply a slight traction in order to reduce any muscle spasm and to ensure the joint is in a good alignment. 3. The stretch needs to be completed gently but also firmly to ensure that it is effective. 4. The stretch should be uncomfortable (not painful) and into a new range that the child is not able to do actively. 5. Most stretches are into extension as that is the end of range that is most often lost, and muscles also get weaker and find it difficult to maintain the range against gravity. However there are some exceptions as it is also important that range into flexion is not lost in the fingers and elbows and that plantar and dorsiflexion are maintained. Some joints will also need rotational stretches completed too, and these will use a similar technique. 6. Stretches must be completed when the joint is inflamed. It is vital that stretches are done when the joint is swollen as this is the time when the most movement is lost. However, if a joint is swollen then it will probably also require an alteration in the medical management in order to reduce the swelling effectively and limit the damage.

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Stretching Shortened Muscles Muscles are very likely to shorten in conditions such as JDM due to the inflammatory nature of the muscle disease. The muscles most commonly affected are gastrocnemius, causing loss of dorsiflexion, hamstrings and the long flexors of the arm preventing full extension of all joints in the upper limbs. However, muscle tightening can also occur as well as joint contractures, and these will need to be assessed for. In children with hypermobility and pain syndromes muscle shortening can also occur, especially of the hamstrings. The rules for stretching muscles are slightly different but it is important to remember to stretch the whole muscle, so this may include several joints at a time. It is important to remember the anatomy of the joints and ensure that the stretch is maintaining normal movement [36]. Stretch and Cast In some cases the contracture may be very severe and will not be able to be stretched on a daily basis and progress maintained. These types of contractures are often associated with active disease and are most common in the knees. It would then be recommended to take the child to the operating theater, and under general anesthetic, the joint would be injected by the medical team and then the therapist can stretch very slowly into full extension and a full cast then applied. This cast should remain on for a few days only, and then it should be removed and intensive physiotherapy provided. It is important that the cast is not kept on for too long—5 days maximum—in order to prevent stiffness into extension instead of flexion. It is vital that while the cast is on, the child performs many static quadricep contractions in order to start the process of gaining adequate inner-range quadriceps strength in order to maintain full range and to prevent the contracture returning. When the cast is removed then intensive physiotherapy is vital—twice a day minimum. The main focus of the program should be to regain full strength, particularly in inner-range quadriceps but also hip abductors and extensors and plantar flexors, which also become very weak. Splinting Splinting in the management of juvenile arthritis was one of the main treatments in years past. However, with new and more effective medical management, splints are rarely required now. The main splints now required are active wrist support splints that support the wrist into extension but allow full function of the fingers. These are used mainly during activities such as writing to prevent fatiguing and pain and to maintain a good functional position. Very rarely leg splints are now made to keep the knee into extension and the ankle into dorsiflexion; this would be when the disease was refractory to the medical management.

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However, this type of splinting is mainly used in inflammatory disease and should not be encouraged in the biomechanical problems such as hypermobility as they encourage muscle weakness, which then increases pain. Splinting is completely contraindicated in pain syndromes such as reflex sympathetic dystrophy as immobilization always makes these conditions worse. Pain Relief Techniques such as ice and heat are useful in the management of the pain in all these conditions. There is no reason why either can’t be used, and the best judge as to which one is most effective is the child under treatment. However when reflex sympathetic dystrophy is present then cold is contraindicated as it makes the condition worse. Other techniques such as wax can be useful in all these conditions and will not only help with pain but can also be used as exercise. Massage is also a useful technique to use. The young person can be taught some self-massage techniques and the family can also be taught as well. Massage is very useful as a desensitization technique for the management of the pain syndromes, but it is also useful for the reduction of muscle spasm and to help improve the circulation around an inflamed joint. However, the main technique for reducing pain in all these conditions is to actually regain normal movement and full muscle strength and for the joint, limb, and body to be used normally. This applies to all the conditions, but especially the pain syndromes. Waiting for the pain to go before physiotherapy is started will mean that physio is never started; however, exercising and stretching are the most effective methods of reducing pain and keeping it away [37 39]. Pacing Activities Children and young people naturally have lots of energy and want to keep going all day and then still keep going. However, with these types of inflammatory and noninflammatory conditions often the pain and symptoms are made worse by doing too much on one day, which results in pain and stiffness at night or the next day. It is therefore important to teach the child and their family about pacing and energy conservation, like simple techniques such as proper planning for a task to ensure that they have everything they need before they start to avoid many individual trips to get the items needed during the task. Also it is useful to advise planning activities throughout a week, so that each day has similar challenges in it, and how to avoid doing more on one day than another, which often results in less activity for the next few days. After a flare in the condition it is important to start gradually with a return to activity to ensure that energy is conserved and that there is a paced approach back into full function. This may include reducing some activities

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initially so that the young person can manage school first, and as that becomes easier, add in more activities around that gradually. However it is important that when progressing back to full function, when the tasks are set, that they are achieved whether it is a good day or a bad day, and that if it is a good day they don’t do more than the program requires. This is important to avoid activity cycling and the “roller-coaster” effect developing. Balance and Proprioception Balance and proprioception are altered by joint swelling, joint pain, muscle weakness, and inactivity. However without adequate balance/proprioception than it is very difficult to complete some tasks safely and the risk of injury is increased. The most simple and effective exercise to improve lower limb proprioception is to practice standing on one leg without wobbling, progressing to doing this with eyes closed and then progressing to adding in plantar flexion on one leg (ie, going up and down on toes). Other methods using equipment, such as a wobble board, are also very useful in this aspect of the treatment program and can be purchased for use at home [40]. Gait Reeducation In children it is not uncommon for the gait to be altered due to altered biomechanics, inflammation, and muscle weakness; however, for some children correcting these issues is not adequate as they have learned a new gait pattern and that has become their normal walk. Therefore, it is important to spend some time practicing walking and the use of mirrors is very useful for this. Often marching can help with this process as it overcorrects most abnormal gaits and encourages good use of range and muscle strength. The use of supportive footware is also vital to ensure that normal gait is achieved. Shoes should be high and supportive around the heel, with a strap, laces, or Velcro to hold it firmly in place. However for children with unstable feet and ankles (hypermobile or inflamed joints), ankle boots are really useful as they support both the feet and the ankles and should have really effective shock-absorbing soles [41]. Advice About Sporting Activities For all these conditions the aim of all the management is to give every child the chance for a normal and full life. In inflammatory disease medication and therapy is required and in the noninflammatory only therapy is required. The principles for both are the same. Providing each muscle group is doing its job properly and the young person is fit and strong, they are encouraged to join in any sporting activity they want. However, there are some sports that they will need to be really strong for, including distance running, rugby, and football. A trampoline should

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also be used with care as sometimes the lands and jumps can be unpredictable. It is important to encourage sport and physical activity as many studies have shown that children with these conditions are often less fit than their peers and it is vital that this is changed for the future [42 50].

Hydrotherapy Hydrotherapy has been an accepted technique for the management of pediatric rheumatology conditions for many years. However research into its effectiveness has shown that it is not as effective as “dry land” treatment in regaining range of movement, increasing muscle strength, or returning to full function; but when asked the children preferred it as a treatment. Hydrotherapy, however, is extremely effective when used in close conjunction with a land-based program and when the hydrotherapy treatments are employed effectively. Unfortunately it is sometimes too easy to put a child into hydrotherapy each week and not use the specific effects of buoyancy to target the specific problems and make effective progress. Therefore hydrotherapy should be provided with specific goals in mind and a land-based home treatment program also prescribed. When hydrotherapy is being provided the effect of buoyancy needs to be remembered at all times as this dramatically affected the muscle function used. It is also important to remember that for young children it is often difficult for them to initially understand what is required and unless closely supervised may in fact not complete the exercises correctly. It is also important for the therapist and the child to remember that moving through the water is much easier that walking on land, due to buoyancy, and that this technique will not make up for the work they do on land [51,52].

Effects of Hydrotherapy These are gained with the combined effect of the warmth from the water and the buoyancy supporting the body. G G

G

G

G

G

To reduce pain and muscle spasm To increase joint range of movement and muscle strength by using buoyancy to stretch To reduce joint stiffness by allowing more comfortable movement, especially first thing in the morning, encouraging joints to move through range and therefore improving circulation and reducing swelling Increase muscle strength, when movement is completed against buoyancy and turbulence Increase aerobic capacity by encouraging swimming and fast-action games Increase a fun element to the treatment program.

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Osteoporosis Immobilization causes increased bone reabsorption and decreased bone formation and it is believed that bone density loss due to immobilization may be as high as 5% per month for the first 6 months; the rate of loss then slows but does continue. The evidence shows that children who exercise regularly have stronger bones and that it is vital that children exercise regularly especially during puberty in order to maximize bone density for adulthood. It is estimated that 90% of bone mineral density is accumulated by the end of adolescence. However, differences in bone mineral density are 75% genetic with the other variations due to level of calcium uptake, disease activity, and up to 17% of the variation due to the amount of weight-bearing activity being performed. Therefore for children with inflammatory disease who have medication that often causes bone loss (such as steroids) combined with the actual disease process and the immobility and loss of function as a result of the disease, osteoporosis is a very real concern. Impact exercise is the most effective for laying down bone and should be encouraged at all times [53 57]. The Role of Cytokines in Muscle Function Cytokines are small molecules produced by the body to send messages from one cell to another. Cytokines have become extremely important in the understanding of the nature of inflammatory disease and this knowledge has been used to produce a new group of medical therapies called the biologics. Medicines such as etanercept and infliximab have been developed and these are anti-TNFα drugs. Other important anticytokine drugs are also being developed such as anti-interleukin (IL)-6 and anti-IL-1. However these cytokines also have an important normal role in the function of muscle and may explain why children with inflammatory disease become so weak so quickly. Cytokine function is extremely complex and each cytokine will have a different function depending upon what cell it is communicating with and what other cytokines and how much of them there are around. Two of the most important cytokines in rheumatological conditions at the present time are TNFα and IL-6. IL-1 is also an important cytokine and is important in the control of IL-6 and in pain sensation as some of its functions. TNFα and IL-6 are homeostatic in their relationship. If the level of TNFα reduces, then the level of IL-6 also reduced, and because IL-6 has reduced TNFα production is then increased. TNFα Function and Muscles TNFα has a very important role in the normal function of muscle, which is to initially increase the proliferation of new muscle cells and then to facilitate the apoptosis of old muscle cells, therefore keeping the regeneration cycle active. However, when the normal level of TNFα is changed then abnormal functioning of muscle occurs.

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TNFα inhibits muscle contractile function, within hours of a raised TNFα level. It does this by reducing the contractile force and by blunting the muscles response to calcium activation. It also causes muscle atrophy by increasing proteolysis, inhibiting the insulin affect upon muscles, and by blocking the glycogen uptake by the muscles. A prolonged increase in TNFα causes inhibition of skeletal muscle synthesis and skeletal muscle myopathy. IL-6 Function and Muscles This cytokine is vital for the normal function of healthy muscle but it is also understood to be a proinflammatory cytokine in the inflammatory diseases in childhood. IL-6 is vital for the homeostasis of muscle function and the provision of its food source, glycogen. The more IL-6 is produced the more glycogen is made available for the muscles either from using the available store in the blood or by lipolysis to create more supplies. IL-6 is therefore produced naturally by functioning muscles, not only to regulate the glycogen requirement but also within its role as a proinflammatory cytokine. In order to increase the strength and size of muscle a small local inflammatory process is established causing local damage, which can therefore be repaired by the function of the satellite cells. The amount of IL-6 produced naturally by the muscles is dependent upon the type of exercise and the intensity of it. Eccentric muscle work produced more IL-6 than concentric, as does endurance work versus resisted work, and the longer and harder the exercise the more IL-6 is produced. Therefore running a long distance downhill will produce the most IL-6! However in inflammatory disease there are increased levels of IL-6, therefore promoting muscle inflammation beyond normal, resulting in loss of muscle function. It has been shown, however, that the body’s natural response to cytokine production can be altered by exercise and that muscles can become more efficient in their production of TNFα and IL-6 by following a moderate progressive resisted exercise program. Good nutrition is also important in ensuring exercise is effective and efficient and at the maximum [58 65].

Muscle Repair and Growth Satellite cells are extremely important in the process of muscle cell repair and growth. These cells are undifferentiated cells stored within the muscles, which can then be stimulated to either replace damaged muscle cells or to add new muscle cells. These cells are stimulated by exercise and therefore muscles cannot gain strength, stamina, or function without exercise. Daily exercise after damage also encourages repair and is important in the healing process. There are, however, a finite number of satellite cells and the body has its maximum amount at birth and the number starts to decrease after about 9 years of age.

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As muscles have such varied functions it is important to consider all of these in a training program to regain full muscle function. However using concentric and eccentric muscle work is often the most effective and easier for the children to manage.

KEY POINTS In the management of children with rheumatological conditions there are several principles to always consider. 1. At the assessment there is often underestimation as to the strength of children and so weakness is missed. 2. With all the conditions involved the children usually have less muscle strength than normal. 3. Loss of strength and stamina is very quick, especially in inflammatory disease and this is then exacerbated by a. lack of activity b. pain c. loss of range of movement. 4. Strength and stamina of muscles can only be regained by exercise. 5. Exercise should be progressed and resisted should be used to ensure maximum benefit. 6. Muscles are the only dynamic control of joints and therefore need to be as strong and as fit as possible in order to protect the joints. 7. Children with rheumatological conditions can regain full strength and function and then can be encouraged to join in with all activities, including sport, in the same way as their peers would do. So there are many reasons as to why children with rheumatological conditions are weak but with a regular progressive and resisted exercise program these children can be strong and fit and have an active and pain-managed life.

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[4] Rider LG, Werth VP, Huber AM, Alexanderson H, Rao AP, Ruperto N, et al. Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res 2011;63(Suppl. 11): S118 57. [5] Huber AM. Juvenile dermatomyositis: advances in pathogenesis, evaluation, and treatment. Paediatric Drugs 2009;11(6):361 74. [6] Huber AM, Lovell DJ, Pilkington CA, Rennebohm RM, Rider LG. Confusion concerning multiple versions of the childhood myositis assessment scale. Arthritis Care Res 2014;66 (4):648. [7] Lazarevic D, Pistorio A, Palmisani E, Miettunen P, Ravelli A, Pilkington C, et al. The PRINTO criteria for clinically inactive disease in juvenile dermatomyositis. Ann Rheum Dis 2013;72(5):686 93. [8] Quinones R, Morgan GA, Amoruso M, Field R, Huang CC, Pachman LM. Lack of achievement of a full score on the childhood myositis assessment scale by healthy fouryear-olds and those recovering from juvenile dermatomyositis. Arthritis Care Res 2013;65 (10):1697 701. [9] van der Net J, Kamphuis SS, Helders PJ. The childhood myositis assessment scale to assess muscle function in a patient with juvenile dermatomyositis. Arthritis Rheum 2002;47(6):694 5. [10] Wind AE, Takken T, Helders PJ, Engelbert RH. Is grip strength a predictor for total muscle strength in healthy children, adolescents, and young adults? Eur J Pediatrics 2010;169(3):281 7. [11] Molenaar HM, Selles RW, Schreuders TA, Hovius SE, Stam HJ. Reliability of hand strength measurements using the Rotterdam Intrinsic Hand Myometer in children. J Hand Surg 2008;33(10):1796 801. [12] Celletti C, Galli M, Cimolin V, Castori M, Tenore N, Albertini G, et al. Use of the gait profile score for the evaluation of patients with joint hypermobility syndrome/ Ehlers Danlos syndrome hypermobility type. Res Dev Disabil 2013;34(11):4280 5. [13] Fatoye FA, Palmer S, van der Linden ML, Rowe PJ, Macmillan F. Gait kinematics and passive knee joint range of motion in children with hypermobility syndrome. Gait Posture 2011;33(3):447 51. [14] Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S, Filocamo G, et al. Development and validation of a composite disease activity score for juvenile idiopathic arthritis. Arthritis Rheum 2009;61(5):658 66. [15] Nugent J, Ruperto N, Grainger J, Machado C, Sawhney S, Baildam E, et al. The British version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ). Clin Exp Rheumatol 2001;19(4 Suppl. 23):S163 7.

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[16] Pouchot J, Ecosse E, Coste J, Guillemin F. Validity of the childhood health assessment questionnaire is independent of age in juvenile idiopathic arthritis. Arthritis Rheum 2004; 51(4):519 26. [17] Norgaard M, Thastum M, Herlin T. The relevance of using the Childhood Health Assessment Questionnaire (CHAQ) in revised versions for the assessment of juvenile idiopathic arthritis. Scand J Rheumatol 2013;42(6):457 64. [18] Bekkering WP, ten Cate R, van Rossum MA, Vliet Vlieland TP. A comparison of the measurement properties of the Juvenile Arthritis Functional Assessment Scale with the childhood health assessment questionnaire in daily practice. Clin Rheumatol 2007;26(11): 1903 7. [19] Gueddari S, Amine B, Rostom S, Badri D, Mawani N, Ezzahri M, et al. Physical activity, functional ability, and disease activity in children and adolescents with juvenile idiopathic arthritis. Clin Rheumatol 2014;33(9):1289 94. [20] Engelbert RH, van Bergen M, Henneken T, Helders PJ, Takken T. Exercise tolerance in children and adolescents with musculoskeletal pain in joint hypermobility and joint hypomobility syndrome. Pediatrics 2006;118(3):e690 6. [21] Faigenbaum AD, Kraemer WJ, Blimkie CJ, Jeffreys I, Micheli LJ, Nitka M, et al. Youth resistance training: updated position statement paper from the national strength and conditioning association. J Strength Cond Res/Natl Strength Cond Assoc 2009;23(5 Suppl.):S60 79. [22] Faigenbaum AD, Lloyd RS, Myer GD. Youth resistance training: past practices, new perspectives, and future directions. Pediatr Exerc Sci 2013;25(4):591 604. [23] Faigenbaum AD, Farrell AC, Fabiano M, Radler TA, Naclerio F, Ratamess NA, et al. Effects of detraining on fitness performance in 7-year-old children. J Strength Cond Res/Natl Strength Cond Assoc 2013;27(2):323 30. [24] Naclerio F, Faigenbaum AD, Larumbe-Zabala E, Perez-Bibao T, Kang J, Ratamess NA, et al. Effects of different resistance training volumes on strength and power in team sport athletes. J Strength Cond Res/Natl Strength Cond Assoc 2013;27(7):1832 40. [25] Behm DG, Faigenbaum AD, Falk B, Klentrou P. Canadian society for exercise physiology position paper: resistance training in children and adolescents. Appl Physiol Nutr Metabol 2008;33(3):547 61. [26] Habers GE, Takken T. Safety and efficacy of exercise training in patients with an idiopathic inflammatory myopathy—a systematic review. Rheumatology (Oxford) 2011;50 (11):2113 24. [27] Maillard SM, Jones R, Owens CM, Pilkington C, Woo PM, Wedderburn LR, et al. Quantitative assessments of the effects of a single exercise session on muscles in juvenile dermatomyositis. Arthritis Rheum 2005;53(4):558 64. [28] Maillard SM, Jones R, Owens C, Pilkington C, Woo P, Wedderburn LR, et al. Quantitative assessment of MRI T2 relaxation time of thigh muscles in juvenile dermatomyositis. Rheumatology (Oxford) 2004;43(5):603 8. [29] Faigenbaum AD, Myer GD. Pediatric resistance training: benefits, concerns, and program design considerations. Curr Sports Med Rep 2010;9(3):161 8. [30] Faigenbaum AD, Myer GD. Resistance training among young athletes: safety, efficacy and injury prevention effects. Br J Sports Med 2010;44(1):56 63. [31] Lloyd RS, Faigenbaum AD, Stone MH, Oliver JL, Jeffreys I, Moody JA, et al. Position statement on youth resistance training: the 2014 International Consensus. Br J Sports Med 2014;48(7):498 505.

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[32] Ganley KJ, Paterno MV, Miles C, Stout J, Brawner L, Girolami G, et al. Health-related fitness in children and adolescents. Pediatr Phys Ther Off Publ Sect Pediatr Am Phys Ther Assoc 2011;23(3):208 20. [33] Dahab KS, McCambridge TM. Strength training in children and adolescents: raising the bar for young athletes? Sports Health 2009;1(3):223 6. [34] Dogru Apti M, Kasapcopur O, Mengi M, Ozturk G, Metin G. Regular aerobic training combined with range of motion exercises in juvenile idiopathic arthritis. BioMed Res Int 2014;2014:748972. [35] Mendonca TM, Terreri MT, Silva CH, Neto MB, Pinto RM, Natour J, et al. Effects of Pilates exercises on health-related quality of life in individuals with juvenile idiopathic arthritis. Arch Phys Med Rehab 2013;94(11):2093 102. [36] Apostolopoulos N, Metsios GS, Flouris AD, Koutedakis Y, Wyon MA. The relevance of stretch intensity and position—a systematic review. Front Psychol 2015;6:1128. [37] Katholi BR, Daghstani SS, Banez GA, Brady KK. Noninvasive treatments for pediatric complex regional pain syndrome: a focused review. PM & R: J Injury, Funct Rehab 2014;6(10):926 33. [38] Nieto R, Raichle KA, Jensen MP, Miro J. Changes in pain-related beliefs, coping, and catastrophizing predict changes in pain intensity, pain interference, and psychological functioning in individuals with myotonic muscular dystrophy and facioscapulohumeral dystrophy. Clin J Pain 2012;28(1):47 54. [39] Harris EJ, Schimka KE, Carlson RM. Complex regional pain syndrome of the pediatric lower extremity: a retrospective review. J Am Podiatr Med Assoc 2012;102(2):99 104. [40] Behm DG, Muehlbauer T, Kibele A, Granacher U. Effects of strength training using unstable surfaces on strength, power and balance performance across the lifespan: a systematic review and meta-analysis. Sports Med (Auckland, NZ). 2015. [41] Sil S, Thomas S, DiCesare C, Strotman D, Ting TV, Myer G, et al. Preliminary evidence of altered biomechanics in adolescents with juvenile fibromyalgia. Arthritis Care Res 2015;67(1):102 11. [42] Hebert JJ, Moller NC, Andersen LB, Wedderkopp N. Organized sport participation is associated with higher levels of overall health-related physical activity in children (CHAMPS Study-DK). PLoS One 2015;10(8):e0134621. [43] Myer GD, Faigenbaum AD, Edwards NM, Clark JF, Best TM, Sallis RE. Sixty minutes of what? A developing brain perspective for activating children with an integrative exercise approach. Br J Sports Med 2015. [44] Pate RR, O’Neill JR, Brown WH, Pfeiffer KA, Dowda M, Addy CL. Prevalence of compliance with a new physical activity guideline for preschool-age children. Child Obes (Print) 2015. [45] Jakubowski TL, Faigenbaum AD, Lindberg C. Increasing physical activity in children: from evidence to action. MCN Am J Maternal Child Nursing 2015. [46] Kalman M, Inchley J, Sigmundova D, Iannotti RJ, Tynjala JA, Hamrik Z, et al. Secular trends in moderate-to-vigorous physical activity in 32 countries from 2002 to 2010: a cross-national perspective. Eur J Public Health 2015;25(Suppl. 2):37 40. [47] Janssen I, Leblanc AG. Systematic review of the health benefits of physical activity and fitness in school-aged children and youth. Int J Behav Nutr Phys Activity 2010;7:40. [48] Slining MM, Neelon SE, Duffey KJ. A review of state regulations to promote infant physical activity in child care. Int J Behav Nutr Phys Activity 2014;11:139.

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[49] Hills AP, Dengel DR, Lubans DR. Supporting public health priorities: recommendations for physical education and physical activity promotion in schools. Prog Cardiovasc Dis 2015;57(4):368 74. [50] Konstabel K, Veidebaum T, Verbestel V, Moreno LA, Bammann K, Tornaritis M, et al. Objectively measured physical activity in European children: the IDEFICS study (2005) Int J Obesity 2014;38(Suppl. 2):S135 43. [51] Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis. Health Technol Assess (Winchester, England), 9. 2005. p. iii iv, ix x, 1 59. [52] Takken T, Van Der Net J, Kuis W, Helders PJ. Aquatic fitness training for children with juvenile idiopathic arthritis. Rheumatology (Oxford) 2003;42(11):1408 14. [53] Bachrach LK. Diagnosis and treatment of pediatric osteoporosis. Curr Opin Endocrinol Diabetes Obesity 2014;21(6):454 60. [54] Bachrach LK. Consensus and controversy regarding osteoporosis in the pediatric population. Endocr Pract Off J Am College Endocrinol Am Assoc Clin Endocr 2007;13(5): 513 20. [55] Bachrach LK. Osteoporosis in children: still a diagnostic challenge. J Clin Endocrinol Metabol 2007;92(6):2030 2. [56] Bachrach LK. Measuring bone mass in children: can we really do it? Hormone Res 2006;65(Suppl. 2):11 16. [57] Baxter-Jones AD, Burrows M, Bachrach LK, Lloyd T, Petit M, Macdonald H, et al. International longitudinal pediatric reference standards for bone mineral content. Bone 2010;46(1):208 16. [58] Febbraio MA, Steensberg A, Fischer CP, Keller C, Hiscock N, Pedersen BK. IL-6 activates HSP72 gene expression in human skeletal muscle. Biochem Biophys Res Commun 2002;296(5):1264 6. [59] Toft AD, Jensen LB, Bruunsgaard H, Ibfelt T, Halkjaer-Kristensen J, Febbraio M, et al. Cytokine response to eccentric exercise in young and elderly humans. Am J Physiol Cell Physiol 2002;283(1):C289 95. [60] Pedersen BK, Toft AD. Effects of exercise on lymphocytes and cytokines. Br J Sports Med 2000;34(4):246 51. [61] Pedersen BK, Bruunsgaard H, Ostrowski K, Krabbe K, Hansen H, Krzywkowski K, et al. Cytokines in aging and exercise. Int J Sports Med 2000;21(Suppl. 1):S4 9. [62] Steensberg A, Toft AD, Schjerling P, Halkjaer-Kristensen J, Pedersen BK. Plasma interleukin-6 during strenuous exercise: role of epinephrine. Am J Physiol Cell Physiol 2001; 281(3):C1001 4. [63] Benatti FB, Pedersen BK. Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation. Nat Rev Rheumatol 2015;11(2):86 97. [64] Laye MJ, Nielsen MB, Hansen LS, Knudsen T, Pedersen BK. Physical activity enhances metabolic fitness independently of cardiorespiratory fitness in marathon runners. Dis Markers 2015;2015:806418. [65] Ostrowski K, Schjerling P, Pedersen BK. Physical activity and plasma interleukin-6 in humans—effect of intensity of exercise. Eur J Appl Physiol 2000;83(6):512 15.

Index

Note: Page numbers followed by “f ” and “t” refer to figures and tables, respectively.

A AA amyloidosis, 281, 290 risk, 284 285 Abatacept, 16, 18, 139, 505 506 Absolute neutrophil count (ANC), 508 Accommodation, 533 ACE. See Angiotensin converting enzyme (ACE) Acetyl salicylic acid (ASA), 349 350, 459 ACLA. See Anticardiolipin antibodies (ACLA) Acquired HLH, 90 91 ACR. See American College of Rheumatology (ACR) ACR Pediatric 30 criteria, 107 109 ACR-Pedi-30. See American College of Rheumatology Pediatric 30 (ACR-Pedi-30) Activated partial thromboplastin time (aPTT), 385 386 Active (poly)arthritis, 11 Active disease, 109 Active infections, 519 Activity index for hereditary recurrent fever syndrome (AIDAI), 274 Acupuncture, 160 Acute pulmonary hemorrhage, 180 181 Acute rheumatic fever (ARF), 14 Acute-recurrent uveitis, 130 Adalimumab, 135, 138 139, 476 ADH. See Antidiuretic hormone (ADH) Adult-type childhood sarcoid arthritis, 440 Adverse effects (AEs), 474 Adverse events (AEs), 478, 520 521 TNF blockade, 483 484 TNFα blockade, 479 autoantibody-mediated diseases, 484 485 chronic AU reactivation as AE, 485 486 cutaneous manifestations, 480 481

German Etanercept registry, 479 hyperergic reactions, 480 IBD, 485 infections, 482 483 MAS, 483 484 neuropsychiatric manifestations, 481 482 vaccines, 483 Aerobic training, 159 AEs. See Adverse effects (AEs)Adverse events (AEs) AGS. See Aicardi Goutieres syndrome (AGS) AHA. See American Heart Association (AHA) Aicardi Goutieres syndrome (AGS), 292 AIDAI. See Activity index for hereditary recurrent fever syndrome (AIDAI) AIFEC. See Autoinflammation with infantile enterocolitis (AIFEC) ALPL, 326 327 American College of Rheumatology (ACR), 107 109, 146, 249 250, 362, 506 American College of Rheumatology Pediatric 30 (ACR-Pedi-30), 475 American Heart Association (AHA), 350 351 Amitriptyline, 160 Amplified musculoskeletal pain syndromes, 145 acupuncture, 160 age, sex, and race, 149 amputation, 163 antiepileptics, 161 bisphosphonates, 161 clinical presentation, 151 153 common patterns, 151t course and outcomes, 163 164 criteria, 146, 147t differential diagnosis, 154, 155t epidural infusions, 162 etiology and pathogenesis, 149 151

557

558

Index

Amplified musculoskeletal pain syndromes (Continued) history, 146 imaging examinations, 154 155 incidence and prevalence, 146 149 invasive procedures, 162 ketamine, 161 laboratory examination, 154 medical treatment, 160 miscellaneous therapies, 163 nomenclature, 145 146 opioids, 161 other antidepressants, 160 pain, dysfunction, and stress measurement, 153 154 pathology, 156 peripheral nerve blocks, 162 philosophy of therapy, 163 physical and occupational therapy, 158 159 psychotherapy, 157 158 sleep, 153 spinal cord stimulators, 162 steroids, 161 sympathetic blocks and sympathectomy, 162 TENS, 159 160 treatment, 156 157 tricyclic antidepressants, 160 Amputation, 163 Anakinra, 55, 64 66, 71, 73, 290, 510 511 ANAs. See Antinuclear antibodies (ANAs) ANC. See Absolute neutrophil count (ANC) ANCAs. See Antineutrophil cytoplasmic antibodies (ANCAs) Anemia, 203, 372 373 Angiotensin converting enzyme (ACE), 441 Ankylosing spondylitis (AS), 31 32 Ankylosing tarsitis, 43 composite images, 33f Anterior uveitis (AU), 129, 477 Anti-Borrelia IgM antibodies, 13 Anti-C1q vasculitis, 377 anti-ENA. See Antibodies to extractable nuclear antigens (anti-ENA) Anti-Interleukin-1 treatments, 140 Anti-p200, 196 Anti-RO/SSA antibodies anti-RO/SSA-negative congenital heart block, 209 other pregnancy outcomes in women with, 209

Anti-SSA/Ro SSB/La-exposed fetuses, 191 Anti-TNFα agents, 471 therapies, 135 therapy in JIA, 473 adalimumab, 476 biological agents, 475 etanercept, 475 308G genotype, 474 infliximab, 475 476 JIA patients, 474 Anti-β2 glycoprotein I antibodies (antiβ2GPI), 385 anti-β2GPI. See Anti-β2 glycoprotein I antibodies (anti-β2GPI) Antibodies to extractable nuclear antigens (anti-ENA), 11 Anticardiolipin antibodies (ACLA), 181 182, 242, 257, 385 Anticyclic citrullinated peptide (CCP), 7 Antidiuretic hormone (ADH), 61 Antiepileptics, 161 Antineutrophil cytoplasmic antibodies (ANCAs), 365 Antinuclear antibodies (ANAs), 1, 11, 131 132, 257, 441, 484, 506, 515 tests, 66 Antiphospholipid antibodies (aPL antibodies), 385, 397 Antiphospholipid syndrome (APS), 181 182, 385 aPL antibodies prevalence, 385 healthy children, 385 386 infections, 387 388 JIA, 387 SLE, 386 vaccinations, 387 388 clinical manifestations, 390 391 arterial thrombosis manifestations, 392t catastrophic APS, 391 393 chronic leg ulcers, 395f dermatological manifestations, 395 echocardiographic studies, 396 hematological manifestations, 393 394 Livedo reticularis, 395f neonatal APS, 396 397 neurological manifestations, 394 thromboses, 391 venous thrombosis manifestations, 392t diagnostic investigations, 397 398 differential diagnosis, 398 epidemiology, 388 389

Index etiology and pathogenesis, 389 390 preliminary criteria for classification, 388t treatment, 398 399 catastrophic APS treatment, 400 neonatal APS treatment, 400 401 primary thrombosis prophylaxis, 399 secondary thrombosis prophylaxis, 399 400 Antithymocyte globulin (ATG), 99 100 Antitopoisomerase I antibodies, 242 APAF-1. See Apoptotic protease activating factor-1 (APAF-1) Aphthosis, 419 420 aPL antibodies. See Antiphospholipid antibodies (aPL antibodies) APLAID. See Autoinflammation and PLCγ 2associated antibody deficiency and immune dysregulation (APLAID) ApoER2. See Apolipoprotein E receptor 2 (ApoER2) Apolipoprotein E receptor 2 (ApoER2), 390 Apoptosis, 193 194 Apoptotic protease activating factor-1 (APAF1), 429 430 Apoptotic speck protein (ASC), 274 APS. See Antiphospholipid syndrome (APS) aPTT. See Activated partial thromboplastin time (aPTT) Area under the ROC curve (AUC-ROC), 96 97 ARF. See Acute rheumatic fever (ARF) Arrhythmogenesis, 192 193 Arterial thrombosis, 391 Arthralgia, 14 15, 364 Arthritis, 13, 59 60, 182 183, 364, 421, 440, 442 444, 454, 465 466 “Arthritogenic bacteria” hypothesis, 32 Articular features, 416 Articular involvement, 241, 435 437 AS. See Ankylosing spondylitis (AS) ASA. See Acetyl salicylic acid (ASA) ASC. See Apoptotic speck protein (ASC) ASCT. See Autologous stem cell transplantation (ASCT) Aseptic meningitis, 75 76 Aspartate aminotransferase (AST), 97 98 Associated inflammatory disorders, 322 323 AST. See Aspartate aminotransferase (AST) ATG. See Antithymocyte globulin (ATG) Atrioventricular block, 198 Atrioventricular node (AV node), 191 block, 197 Atrophoderma of Pasini and Pierini, 240

559

AU. See Anterior uveitis (AU) AUC-ROC. See Area under the ROC curve (AUC-ROC) Autoantibodies, 175, 242 autoantibody-mediated diseases, 484 485 binding site, 193 Autoimmune connective tissue diseases, 69 70 endocardial fibroelastosis, 201 Autoimmunity, 467, 521 Autoinflammation and PLCγ 2-associated antibody deficiency and immune dysregulation (APLAID), 293 Autoinflammation with immunodeficiency ADA2 Deficiency, 293 294 HOIL-1 Deficiency, 292 293 PLCG2-associated antibody deficiency and immune dysregulation, 293 PLCγ2 Mutations, 293 SIFD, 294 Autoinflammation with infantile enterocolitis (AIFEC), 279 Autoinflammatory diseases, 14, 70, 268. See also Juvenile localized scleroderma (JLS); Juvenile systemic sclerosis (jSSc) autoinflammation with immunodeficiency ADA2 Deficiency, 293 294 HOIL-1 Deficiency, 292 293 PLCG2-associated antibody deficiency and immune dysregulation, 293 PLCγ2 Mutations, 293 SIFD, 294 clinical characteristics, 272t differential diagnosis, 271 273 disorders indirectly affecting IL-1 family cytokine regulation autosomal recessive sJIA, 288 FMF, 280 HIDS, 280 282 Majeed syndrome, 288 PAPA syndrome, 286 288 disorders primarily affecting IL-1 family cytokine regulation cryopyrin-associated periodic syndromes, 274 277 DIRA, 277 278 DITRA, 278 familial cold autoinflammatory syndrome 2, 279 280 NLRC4-associated autoinflammatory syndromes, 279

560

Index

Autoinflammatory diseases (Continued) NLRP12-associated periodic syndrome, 279 280 interferonopathies, 291 292 AGS, 292 STING-associated vasculopathy with onset in infancy, 292 molecular classification of monogenic, 269t protein folding disorders PRAAS, 290 291 TRAPS, 288 290 treatment in general, 274 Autoinflammatory disorders. See Autoinflammatory diseases Autoinflammatory syndromes. See Autoinflammatory diseases Autologous stem cell transplantation (ASCT), 182 Autosomal recessive sJIA, 288 AV node. See Atrioventricular node (AV node) Avascular necrosis, 182 183 Azathioprine (AZA), 135, 137, 179

B B lymphocyte stimulator (BLyS), 183 184, 518 B-cell-depleting anti-CD20 antibody rituximab, 99 100 B-lymphocyte depleting therapies, 515 Bacterial arthritis, 12 13 BAFF. See B lymphocyte stimulator (BLyS) Balance, 547 Bartonella infections, 68 Behc¸et’s disease (BD), 133, 377, 409 410 articular features, 416 cardiac involvement, 418 clinical manifestations, 412 fever, 412 mucocutaneous lesions, 412 414 neurological lesions, 415 416 ocular lesions, 414 415 clinical symptoms in pediatric and adult, 413t diagnostic investigation, 419 differential diagnosis aphthosis, 419 420 arthritis, 421 neurological involvement, 420 periodic fever syndromes, 420 uveitis, 420 421 epidemiology, 411 412 etiology/pathogenesis, 410 411

EULAR recommendations for management, 422t gastrointestinal involvement, 417 genetics, 411 international classifications criteria, 410t outcome and prognosis, 418 419 perianal ulceration, 414f pulmonary involvement, 418 treatment, 421 arthritis, 421 mucocutaneous lesions, 421 severe manifestations, 422 423 urinary and nephrological involvement, 418 vascular involvement, 417 418 Belimumab, 183 184, 518 519 Benign Joint Hypermobility Syndrome, 538 Betaagonists, 208 Bethametasone, 206 Bier block, 162 BILAG. See British Isles Lupus Assessment Group (BILAG) Biologic(s), 135, 503 504, 549 agents, 475 drugs, 479 in pediatric rheumatic diseases, 505 cytokine inhibitors, 507 508 IL-1 inhibiting biologics, 509 519 laboratory abnormalities management, 509 proteins, 505 506 properties, 504 response modifiers non anti-TNF-alpha biologic activity modifiers, 139 140 tumor necrosis factor alpha inhibitors, 137 139 therapies, 89 90, 100 Biomarkers, 92 Biomechanical, 540 Biosimilars, 503 504 Bisphosphonates, 161 Blau syndrome (BS), 427 Blood chemistry, 10 BLyS. See B lymphocyte stimulator (BLyS) Body mass index (BMI), 175 176 Body weight (BW), 508 Bone biopsy with histologic assessment, 325 Bone islets, 33 Bone marrow aspirate, 87, 87f Bone marrow suppression, 486 Borrelia burgdorferi, 241, 466 British Isles Lupus Assessment Group (BILAG), 516

Index Bronchoalveolar lavage, 259 BS. See Blau syndrome (BS) Bullous morphea, 240 BW. See Body weight (BW)

C C-reactive protein (CRP), 10, 54, 242, 342 343, 369, 456, 510 CAAs. See Coronary artery aneurysms (CAAs) Calcinosis, 222, 223f, 486 487 Calcium channels, 193 Calcium-binding proteins S100A8, 56 Canakinumab, 64, 71 72, 290, 512 513 CANDLE syndrome. See Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE syndrome) CAPFUN, 117 CAPS. See Cryopyrin-associated periodic syndromes (CAPS) CARD15 gene, 429 Cardiac arrhythmia, 255 Cardiac involvement, 254, 418 Cardiac manifestations, 181 atrioventricular block, 198 autoimmune endocardial fibroelastosis, 201 cardiomyopathy, 201 electrocardiographic abnormalities, 198 201 immunomediated valvular damage, 201 outcome of infants, 199t Cardinal symptoms, 305 306 Cardiomyopathy, 201 Cardiopulmonary involvement, 254, 258 259 Carditis, 454, 459 CARDs. See Caspase recruitment domains (CARDs) CARRA. See Childhood Arthritis and Rheumatology Research Alliance (CARRA) Caspase recruitment domains (CARDs), 283, 429 Catastrophic APS treatment, 400 CAU. See Chronic anterior uveitis (CAU) CBT. See Cognitive behavioral therapy (CBT) 174CC genotype, 55 CCHB. See Congenital complete heart block (CCHB) CCP. See Anticyclic citrullinated peptide (CCP)

561

CD. See Crohn’s disease (CD) CD2 antigen-binding protein 1 (CD2BP1). See Proline/serine/threonine phosphatase-interacting protein 1 (PSTPIP1) gene CD20, 178 CD4 1 T lymphocytes, 6 CD45RA EMRA CD 4 T lymphocytes, 251 CD8 1 T lymphocytes, 6 CDA. See Congenital dyserythropoietic anemias (CDA) CECR1 gene, 293 294 Central nervous system (CNS), 85 86, 179, 224, 276, 365, 481 vasculitis, 241 Cerebrospinal fluid (CSF), 275, 377, 415 416 analysis, 63 64 CHAQ. See Childhood Health Assessment Questionnaire (CHAQ) CHB. See Congenital heart block (CHB) Chemical synthesis, 504 Chest films, 442 Child Health Questionnaire (CHQ), 117 119, 537 Childhood Arthritis and Rheumatology Research Alliance (CARRA), 177 178 Childhood Health Assessment Questionnaire (CHAQ), 116, 153 154, 223, 537 Childhood Myositis Assessment Scale, 259, 536 Childhood Myositis Assessment Score (CMAS), 223 Childhood primary central nervous system vasculitis (cPACNS), 445 446 Childhood sarcoidosis, 427 clinical manifestations, 434 adult-type childhood sarcoid arthritis, 440 articular involvement, 435 437 cutaneous manifestations, 437 438 cyst-like synovitis and ichtyosiform rash, 436f internal organ disease, 439 late disease, 439 ocular manifestations, 438 439 onset, 434 435 pediatric granulomatous inflammatory disease variants, 439 440 vascular involvement, 439 wrist synovitis, 437f diagnostic investigations genetic testing, 441 442

562

Index

Childhood sarcoidosis (Continued) imaging, 442 pathology, 441 routine laboratory investigations, 440 441 differential diagnosis, 442 arthritis, 442 444 chronic pediatric arthritis with uveitis, 444t cutaneous manifestations, 445 uveitis, 445 vasculitis, 445 446 epidemiology, 429 etiology/pathogenesis, 429 CARD domain, 431 cytoplasmic localization of CARD15, 434 NOD proteins, 430f NOD variants, 433f NOD1 and NOD2 proteins, 432f NOD2 protein, 429 431 pathologic hallmark of BS, 431 434 history, 428 nomenclature, 427 428 treatment and prognosis, 446 Childhood SLE (cSLE), 173 174 Childhood uveitis, 129 causes of, 130, 130t complications, 133 134 Children, 129 132, 145 146 KD in, 341 342 Children’s muscles, training, 541 specific exercise program, 542 hydrotherapy, 548 muscle repair and growth, 550 551 osteoporosis, 549 550 stretching, 542 548 Chorea, 394 CHQ. See Child Health Questionnaire (CHQ) Chromosome 18q21. 3 18q22, 318 Chronic anterior uveitis (CAU), 8 9 Chronic arthritis, 10, 12 Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE syndrome), 290 291 Chronic AU reactivation as AE, 485 486 Chronic iridocyclitis (CIC), 485 Chronic monoarthritis, 11 12 chronic multifocal osteomyelitis (cmo), 315 Chronic nonbacterial osteomyelitis (CNO), 315 316

Chronic pain, 149 150, 154 Chronic recurrent multifocal osteomyelitis (CRMO), 315 clavicular involvement, 324f clinical manifestations of nonsyndromic, 322 associated inflammatory disorders, 322 323 pathologic fracture, 323f diagnostic testing, 323 326 differential diagnosis, 326 327 etiology and pathogenesis genetics, 318 immune dysregulation and possible triggers, 316 318 Mendelian autoinflammatory bone disorders DIRA, 321 322 Majeed syndrome, 318 321 nomenclature, 315 316 prevalence and epidemiology, 316 prognosis, 328 treatment, 327 328 vertebral body damage, 325f Chronic uveitis, 445 Churg Strauss syndrome. See Eosinophilic granulomatous polyangiitis CIC. See Chronic iridocyclitis (CIC) CICs. See Circulating immune complexes (CICs) CID. See Clinically inactive disease (CID) Cimetidine, 310 CINCA/NOMID, 274, 276 Circulating immune complexes (CICs), 5 Circumscribed morphea (CM), 235, 236t, 237f cJADAS. See Clinical JADAS (cJADAS) Class V LN with heavy proteinuria, 179 Classical Reynaud’s attack, 252 Clinical efficacy, 506 Clinical JADAS (cJADAS), 114 Clinical remission (CR), 474 Clinical remission on medication (CRM), 474 Clinically inactive disease (CID), 15 CM. See Circumscribed morphea (CM) CMAS. See Childhood Myositis Assessment Score (CMAS) cmo. See chronic multifocal osteomyelitis (cmo) CNO. See Chronic nonbacterial osteomyelitis (CNO) CNS. See Central nervous system (CNS) Cogan syndrome, 377 Cognitive behavioral therapy (CBT), 157 158, 538 Colchicine, 282, 286, 421

Index Combination therapy, 519 Complex regional pain syndrome (CRPS), 145 Composite disease activity scores, 110 111 Computerized skin score (CSS), 243 Congenital complete atrioventricular block, 196 197 Congenital complete heart block (CCHB), 192 obstetric management of pregnancy at risk, 204 205 risk of delivering child with, 197 198 Congenital dyserythropoietic anemias (CDA), 318 319 Congenital heart block (CHB), 192 Congenital sideroblastic anemia (CSA), 294 Conjunctival biopsy, 441 Consensus treatment plan (CTP), 177 178 Coronary arteritis, 345 Coronary artery aneurysms (CAAs), 341, 350 352 Corrected QT interval (QTc), 193 Corticosteroids (CSs), 135 136, 198, 282, 375 376 corticosteroid-sparing effect, 134 135 effects, 176 Costimulatory signals for T-cell activation, 505 506 Counterimmunoelectrophoresis, 197 cPACNS. See Childhood primary central nervous system vasculitis (cPACNS) CR. See Clinical remission (CR) Creative arts therapy, 158 CREST syndrome, 253 254 CRM. See Clinical remission on medication (CRM) CRMO. See Chronic recurrent multifocal osteomyelitis (CRMO) Crohn’s disease (CD), 42 43, 428 CRP. See C-reactive protein (CRP) CRPS. See Complex regional pain syndrome (CRPS) Crying, 152 Cryopyrin, 274 Cryopyrin-associated periodic syndromes (CAPS), 271, 510 CINCA/NOMID, 276, 277f clinical manifestations, 275 diagnostic investigations, 276 277 etiology/pathogenesis, 274 familial cold autoinflammatory disease, 275 Muckle Wells syndrome, 276 prevalence/epidemiology, 274 treatment, 277

563

CSA. See Congenital sideroblastic anemia (CSA) CsA. See Cyclosporine (CyA) CSF. See Cerebrospinal fluid (CSF) cSLE. See Childhood SLE (cSLE) CSS. See Computerized skin score (CSS) CSs. See Corticosteroids (CSs) CTLA-4. See Cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) CTLA4-Ig. See Abatacept CTP. See Consensus treatment plan (CTP) Cutaneous leukocytoclastic angiitis, 377 Cutaneous manifestations, 366, 445, 480 481 erythema nodosum, 438 ichthyosiform skin eruption, 438f tan-colored rash, 437 438 Cutaneous PAN, 70 CyA. See Cyclosporine (CyA) CYC. See Cyclophosphamide (CYC) Cyclic neutropenia, 307 308 Cyclophosphamide (CYC), 176 178, 366 Cyclosporine (CyA), 73, 135, 137, 179 Cytokine inhibitors interleukin-6 inhibiting biologics, 507 tocilizumab, 507 508 Cytokines, 4, 541 in muscle function, 549 550 Cytomegalovirus, 68 Cytotoxic T-cell lymphocyte antigen-4 (CTLA-4), 505

D Dactylitis, 37 Daily living/function activities, 533 534 Damage measures, 122 123 DCs. See Dendritic cells (DCs) Deficiency of IL-1 receptor antagonist (DIRA), 277 278, 318, 321 322 Deficiency of IL-36 receptor antagonist (DITRA), 268, 278 Delphi process, 249 250 Delphi survey technique, 96 Dendritic cells (DCs), 7 Dermatomyositis (DM), 219. See also Juvenile dermatomyositis (JDM) Dexamethasone, 206 Diagnostic criteria, 227, 227t, 457 458 Diagnostic imaging, 67 68 Diagnostic investigation, 419 Diagnostic problems, 227 228 Diary Symptom Sum Score (DSSS), 510 Differential diagnosis, 228, 458

564

Index

Differential diagnosis (Continued) aphthosis, 419 420 arthritis, 421 GPA, 373 374 neurological involvement, 420 PAN, 370 periodic fever syndromes, 420 uveitis, 420 421 vasculitides in children, 365 Diffusion factor (DLCO), 226 DIL. See Drug-induced lupus (DIL) DIRA. See Deficiency of IL-1 receptor antagonist (DIRA) Discoid lupus (DL), 183, 185. See also Neonatal lupus (NL) Disease activity, 541 Disease Activity Criteria, 260 Disease course, 224 225 Disease-modifying antirheumatic drugs (DMARDs), 13, 62, 229, 472 DITRA. See Deficiency of IL-36 receptor antagonist (DITRA) DL. See Discoid lupus (DL) DLCO. See Diffusion factor (DLCO) DM. See Dermatomyositis (DM) DMARDs. See Disease-modifying antirheumatic drugs (DMARDs) Doppler echocardiography, 456 Drug treatment, evidence base for, 228 229 Drug-induced lupus (DIL), 185 Drugs/alcohol/sexual activity, 534 DSSS. See Diary Symptom Sum Score (DSSS)

E Early morning stiffness (EMS), 531 Early onset sarcoidosis (EOS), 427 EBV. See Epstein-Barr virus (EBV) ECDS. See En coup de sabre (ECDS) ECG. See Electrocardiogram (ECG) Echocardiographic studies, 396 Echocardiography, 351, 456 EFE. See Endocardial fibroelastosis (EFE) Ehlers Danlos Syndrome, 538 Electrocardiogram (ECG), 351 abnormalities, 198 201 Electromyogram (EMG), 225 226 Electrophysiological effects, 192 193 EMG. See Electromyogram (EMG) EMRA. See Expressing effector memory (EMRA) EMS. See Early morning stiffness (EMS)

En coup de sabre (ECDS), 237 239, 239f Endocardial fibroelastosis (EFE), 191 Endothelial cell activation, 389 390 Endothelial dysfunction, 417 418 Enthesitis, 442 features, 36 37 Enthesitis-related arthritis (ERA), 31, 478 HLA B27-positive, 132 EOS. See Early onset sarcoidosis (EOS) Eosinophilic fasciitis, 240 Eosinophilic granulomatous polyangiitis, 373 374, 376, 445 446 Epidemiology, BD, 411 412 Epidural infusions, 162 Epstein-Barr virus (EBV), 64, 68 ERA. See Enthesitis-related arthritis (ERA) Erysipelas-like erythema, 284f Erysipelas-like rash, 284 Erythema marginatum, 455 Erythema nodosum, 412 414, 438, 445 Erythrocyte sedimentation rate (ESR), 38, 55, 86, 109, 241 242, 342 343, 369, 456, 510 ESPN. See European Society of Pediatric Nephrology (ESPN) ESR. See Erythrocyte sedimentation rate (ESR) Etanercept, 44 45, 138, 475, 488 Ethnicity, 174 Etiology/pathogenesis, BD, 410 411 EULAR. See European League Against Rheumatism (EULAR) European League Against Rheumatism (EULAR), 249 250, 347 348, 362 guidelines, 261 European Society of Pediatric Nephrology (ESPN), 362 Expressing effector memory (EMRA), 251

F Facial dysmorphia, 281f Familial cold autoinflammatory disease, 275 Familial cold autoinflammatory syndrome 2, 279 280 Familial HLH (FHLH), 90 92 Familial Mediterranean Fever (FMF), 283, 306 307, 420. See also Hyper IgD syndrome (HIDS); Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome AA amyloidosis risk, 284 285 clinical manifestations, 284

Index Diagnosis, 285 286 erysipelas-like erythema, 284f etiology/pathogenesis, 283 laboratory Investigations, 284 prevalence/epidemiology, 283 Tel Hashomer criteria, 285 286, 285t treatment, 286 Family hobbies, 534 Fatigue, 531 FDI. See Functional Disability Inventory (FDI) Febrile illness, 63 64 Ferritin, 64 Fetal EFE, 201 Fever, 305, 412 FHLH. See Familial HLH (FHLH) Fibromyalgia, 145 150, 153, 159 First-degree atrioventricular block in utero assessment, 205 Fluorinated corticosteroids, 206 207 neurological problems and possible role, 202 203 Fluorinated steroids, 205 FMF. See Familial Mediterranean Fever (FMF) Focal lesions, 361 Food and Drug Administration Adverse Event Reporting System, 485 FOXP3 gene, 6 French retrospective study, 485 Frequency of ocular examination, 133 Functional Disability Inventory (FDI), 153 154 Functional questionnaires, 537 leg length, 537 muscle bulk, 537 skin condition, 537 stamina, 537 Functional tests, 226

G 308G genotype, 474 Gabapentin, 161 GABHS. See Group A beta-hemolytic Streptococci (GABHS) Gait, 536 Gait reeducation, 547 GAs. See Giant aneurysms (GAs) GAS. See Group A β-hemolytic Streptococcus (GAS) Gastrointestinal involvement, 256f, 258, 417 Gastrointestinal system, 255 256

565

Gene expression profiling, 7 8, 55 56 Generalized morphea, 235 236, 237f, 260 261 Genetic predisposition, 3 CD4 1 and CD8 1 T lymphocytes, 6 CICs, 5 complement activation, 4 cytokines, 4 disease status and JADAS cut-off values, 6t FOXP3 gene, 6 HSPs, 4 impaired thymic function, 6 JIA, 4 natural and adaptive Tregs, 6 non-HLA immune regulatory genes, 4 partial C4 deficiency, 5 recommended frequency of ophthalmological investigation in children, 5t T-lymphocyte-mediated immune response, 5 Th17 cells, 6 7 Tregs, 6 7 Genetic(s), 151, 174 175, 194 195, 318 BD, 411 confirmation, 419 420 diseases, 14 factors, 132 HLH, 90 91 testing, 441 442 Genome-wide association (GWA) studies, 174 175 Gevokizumab, 422 423 174GG genotype, 55 GH. See Growth hormone (GH) Giant aneurysms (GAs), 351 352 Glucocorticoids, 8, 16 therapy, 370 β(2)-Glycoprotein I (β(2)GPI), 194, 242 Glycoprotein Ib α (GPIbα), 390 GO-KIDS trial of golimumab, 17 GPA. See Granulomatous polyangiitis (GPA) β(2)GPI. See β(2)-Glycoprotein I (β(2)GPI) GPIbα. See Glycoprotein Ib α (GPIbα) Graft versus host disease (GVHD), 240 Gram-negative bacterium, 12 13 Granulomatous angiitis, 445 446 Granulomatous polyangiitis (GPA), 371 clinical manifestations, 372 diagnostic investigations, 372 373 differential diagnosis, 373 374 epidemiology, 371 etiology and pathogenesis, 371 372 treatment, 374

566

Index

Group A beta-hemolytic Streptococci (GABHS), 14 Group A β-hemolytic Streptococcus (GAS), 451 Growth delay, 67 68 Growth hormone (GH), 60 GVHD. See Graft versus host disease (GVHD) GWA studies. See Genome-wide association (GWA) studies

H HACAs. See Human antichimeric antibodies (HACAs) HAQ. See Health Assessment Questionnaire (HAQ) HCQ. See Hydroxychloroquine (HCQ) Health Assessment Questionnaire (HAQ), 39 Health-related quality of life (HRQoL), 36 37, 39, 107, 117 120, 118t Heart failure, 418 Heat shock proteins (HSPs), 4 HSP-60, 4 Heliotrope rash, 222f Hemophagocytic lymphohistiocytosis (HLH), 63, 90, 91t Hemophagocytic syndrome, 86, 90 Hemophilia, 14 Hemorrhagic cystitis, 177 178 Henoch Scho¨nlein purpura (HSP), 361 362 Hepatitis B and C serology, 521 Hereditary factors, 132 HFTC. See Hyperphosphatemic familial tumoral calcinosis (HFTC) HIDS. See Hyper IgD syndrome (HIDS) Hip arthroplasty, 73 HLA. See Human leukocyte antigen (HLA) HLA-B27, 32 HLA-Cw 05 variants, 195 HLA-Cw 06 variants, 195 HLA-DRB1 04 variants, 195 HLA-DRB1 13 variants, 195 HLH. See Hemophagocytic lymphohistiocytosis (HLH) HOIL-1-deficient human fibroblasts, 292 293 Homozygosity for M694V, 284 285 HRQoL. See Health-related quality of life (HRQoL) HSP. See Henoch Scho¨nlein purpura (HSP) HSPs. See Heat shock proteins (HSPs) 5-HT4. See 5-Hydroxytryptamine (5-HT4) Human antichimeric antibodies (HACAs), 178 179

Human leukocyte antigen (HLA), 132, 174 175, 194 195 Hydrocephalus, 202 Hydrotherapy, 548 Hydroxychloroquine (HCQ), 208, 399 5-Hydroxytryptamine (5-HT4), 193 Hyper IgD syndrome (HIDS), 280 281, 419 420. See also Familial Mediterranean Fever (FMF); Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome clinical manifestations, 281 diagnostic investigations, 282 etiology/pathogenesis, 280 281 prevalence/epidemiology, 280 treatment, 282 Hyperergic reactions, 480 Hyperferritinemia, 86 Hypermobility, 150, 535 Hyperphosphatemic familial tumoral calcinosis (HFTC), 326 Hypertrophic osteodystrophy, 318 Hypocomplementemic urticarial vasculitis, 377 Hypophosphatasia, 326 327

I IBD. See Inflammatory bowel disease (IBD) IBP. See Inflammatory back pain (IBP) ICs. See Immune complexes (ICs) Idiopathic inflammatory myopathies (IIM), 486 487 IFN. See Interferon (IFN) IgA vasculitis (IgAV), 361 362 IgA vasculitis/Henoch Scho¨nlein purpura (IgAV (HSP)), 362 clinical manifestations, 364 365 diagnostic investigations, 365 differential diagnosis, 365 epidemiology, 362 363 etiology and pathogenesis, 363 364 EULAR/PRINTO/PRES HSP, 364t treatment, 366 367 IgAV. See IgA vasculitis (IgAV) IgAV (HSP). See IgA vasculitis/ Henoch Scho¨nlein purpura (IgAV (HSP)) IGF binding protein-3 (IGFBP-3), 60 IGF-1. See Insulin-like growth factor 1 (IGF-1) IGFBP-3. See IGF binding protein-3 (IGFBP-3) IgM. See Immunoglobulin M (IgM)

Index IgM RF negative polyarticular JIA, 2 positive polyarticular JIA, 2 IIM. See Idiopathic inflammatory myopathies (IIM) IKK. See Inhibitor of NF-κB kinase (IKK) IL. See Interleukin (IL) IL-1 family cytokine regulation. See also Protein folding disorders disorders indirectly affecting autosomal recessive sJIA, 288 FMF, 280 HIDS, 280 282 Majeed syndrome, 288 PAPA syndrome, 286 288 disorders primarily affecting cryopyrin-associated periodic syndromes, 274 277 DIRA, 277 278 DITRA, 278 familial cold autoinflammatory syndrome 2, 279 280 NLRC4-associated autoinflammatory syndromes, 279 NLRP12-associated periodic syndrome, 279 280 IL-1 inhibiting biologics, 509 anakinra, 510 511 B-lymphocyte depleting therapies, 515 belimumab, 518 519 canakinumab, 512 513 rilonacept, 511 512 rituximab, 515 518 targeting IL-23/Th17/IL-17 axis, 514 IL-1 receptor (IL-1RI), 509 510 IL-1 receptor accessory protein (IL-1RAcP), 509, 511 IL-1 receptor antagonist (IL-1RA), 55, 277 278, 321 322 IL-1RA. See IL-1 receptor antagonist (IL-1RA) IL-1RAcP. See IL-1 receptor accessory protein (IL-1RAcP) IL-1RI. See IL-1 receptor (IL-1RI) IL-23/Th17/IL-17 axis, targeting, 514 IL-23R genes. See Interleukin-23 receptor (IL-23R) genes IL-36 receptor antagonist (IL-36Ra), 278 IL-36Ra. See IL-36 receptor antagonist (IL-36Ra) IL-6 receptor (IL-6R), 54, 507 IL-6R. See IL-6 receptor (IL-6R)

567

ILAR. See International League of Associations for Rheumatology (ILAR) ILD. See Interstitial lung disease (ILD) Illness, 150 IMACS. See International Myositis and Clinical Studies Group (IMACS) Imaging, 442 Immobilization, 549 Immune complexes (ICs), 4 Immune dysregulation and possible triggers, 316 318 Immune system activation, 344 Immunoblotting, 242 Immunodeficiency, autoinflammation with ADA2 Deficiency, 293 294 HOIL-1 Deficiency, 292 293 PLCG2-associated antibody deficiency and immune dysregulation, 293 PLCγ2 Mutations, 293 SIFD, 294 Immunoglobulin M (IgM), 1 Immunomediated valvular damage, 201 Immunopathological reactions, 466 Immunosuppressive agents, 135 immunosuppressant therapies, 137 MTX, 136 137 Impaired linear growth in sJIA, 60 Impaired thymic function, 6 In utero therapy, 206 betaagonists, 208 fluorinated corticosteroids, 206 207 HCQ, 208 IVIG, 207 208 Inactive disease, 109 110, 110t Incomplete AV blocks, 198 200 Individual hobbies, 534 Infections, 482 483 Infectious arthritis, 12 13 Infectious nonsuppurative arthritis, 42 Inflammation, 271, 361, 540 Inflammatory back pain (IBP), 37 38 Inflammatory bowel disease (IBD), 42 43, 485 Inflammatory process, 137 138 Infliximab, 135, 138, 471, 475 476, 487 488 Infrared thermography (IT), 243 Infusion reactions (IRs), 476 Infusion reactions, 178 179 Inhibitor of NF-κB kinase (IKK), 431 Injury, 150

568

Index

Innate immunity, 268 Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC 8), 343 Insulin-like growth factor 1 (IGF-1), 60 Interferon (IFN), 174 175, 291, 431 434, 452 453 IFN-γ, 93 Interferon regulatory factor 5 gene polymorphisms, 92 Interferon-regulatory factor 5 (IRF5), 174 175 Interferonopathies, 291 292 AGS, 292 STING-associated vasculopathy with onset in infancy, 292 Interleukin (IL), 53, 390, 410 411, 431 434, 471, 503, 549 IL-1, 132, 315, 344 IL-1β, 54 IL-6, 54, 93, 132 function and muscles, 550 IL-10, 93 IL-18, 93 Interleukin-23 receptor (IL-23R) genes, 32 Internal organ disease, 439 International Consensus Conference on MAS Classification Criteria, 97 International League of Associations for Rheumatology (ILAR), 53, 131 132, 477 International Myositis and Clinical Studies Group (IMACS), 230 231 International Registry of Blau Syndrome, 434 435 International Uveitis Study Group (IUSG), 129 Interstitial lung disease (ILD), 223 224, 226 Intraarticular triamcinolone hexacetonide, 73 Intravenous immunoglobulin (IVIG), 180, 207 208, 341, 350 Invasive procedures, 162 IRF5. See Interferon-regulatory factor 5 (IRF5) IRs. See Infusion reactions (IRs) Ischemia, 150 IT. See Infrared thermography (IT) ITPKC 8. See Inositol 1,4,5-trisphosphate 3kinase C (ITPKC 8) IUSG. See International Uveitis Study Group (IUSG) IVIG. See Intravenous immunoglobulin (IVIG)

J JACAI. See Juvenile Arthritis Child Assessment Index (JACAI) JADAS. See Juvenile Arthritis Disease Activity Score (JADAS) JADI. See Juvenile Arthritis Damage Index (JADI) JADI-A. See Juvenile Arthritis Damage Index articular damage (JADI-A) JADI-E. See Juvenile Arthritis Damage Index extra-articular damage (JADI-E) JAFAR. See Juvenile Arthritis Functional Assessment Report (JAFAR) JAFAR-C. See Juvenile Arthritis Functional Assessment Report for children (JAFAR-C) JAFAR-P. See Juvenile Arthritis Functional Assessment Report for parents (JAFAR-P) JAFAS. See Juvenile Arthritis Functional Assessment Scale (JAFAS) JAFS. See Juvenile Arthritis Functionality Scale (JAFS) JAK inhibitors. See Janus kinase (JAK) inhibitors JAMAR. See Juvenile Arthritis Multidimensional Assessment Report (JAMAR) Janus kinase (JAK) inhibitors, 291 JAPAI. See Juvenile Arthritis Parent Assessment Index (JAPAI) Japanese Circulation Society (JCS), 352 353 JAQQ. See Juvenile Arthritis Quality of Life Questionnaire (JAQQ) JASI. See Juvenile Arthritis Self-Report Index (JASI) JCS. See Japanese Circulation Society (JCS) JDM. See Juvenile dermatomyositis (JDM) JIA. See Juvenile idiopathic arthritis (JIA) JIA-associated chronic anterior uveitis treatment, TNFα blockade in, 477 478 JLS. See Juvenile localized scleroderma (JLS) JMP syndrome. See Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome (JMP syndrome) Joint, spinal movements assessment, 535 gait, 536 hypermobility, 535 muscle strength and function, 535 536 palpation, 535 posture, 536

Index Joint ankylosis, 67 Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome (JMP syndrome), 290 291 Joint function, 540 JoSpA. See Juvenile-onset spondyloarthritis (JoSpA) JRA. See Juvenile rheumatoid arthritis (JRA) JSpA. See Juvenile spondyloarthropathies (JSpA) jSSc. See Juvenile systemic sclerosis (jSSc) Juvenile Arthritis Child Assessment Index (JACAI), 122 Juvenile Arthritis Damage Index (JADI), 122 123 Juvenile Arthritis Damage Index articular damage (JADI-A), 122 123 Juvenile Arthritis Damage Index extraarticular damage (JADI-E), 122 123 Juvenile Arthritis Disease Activity Score (JADAS), 15, 111, 112t disease activity states based on, 114 116 JADAS10, 111 113 JADAS27, 111 113 JADAS71, 111 113 Juvenile arthritis disease activity score, 110 114 Juvenile Arthritis Functional Assessment Report (JAFAR), 116 117 Juvenile Arthritis Functional Assessment Report for children (JAFAR-C), 116 117 Juvenile Arthritis Functional Assessment Report for parents (JAFAR-P), 116 117 Juvenile Arthritis Functional Assessment Scale (JAFAS), 116 117 Juvenile Arthritis Functionality Scale (JAFS), 116 Juvenile Arthritis Multidimensional Assessment Report (JAMAR), 120 121 Juvenile Arthritis Parent Assessment Index (JAPAI), 122 Juvenile Arthritis Quality of Life Questionnaire (JAQQ), 119 Juvenile Arthritis Self-Report Index (JASI), 116 117 Juvenile dermatomyositis (JDM), 69 70, 219, 486 487, 535 clinical manifestations

569

calcinosis, 222, 223f disease course, 224 225 general assessment at onset, 223 224 heliotrope rash, 222f muscle weakness, 222 223 poor prognostic factors, 225t rash, 221 222 symptoms at diagnosis, 220 221 diagnosis diagnostic criteria, 227, 227t diagnostic problems, 227 228 differential diagnosis, 228 diagnostic investigations functional tests, 226 laboratory tests, 225 muscle biopsy, 226 radiological, 225 226 epidemiology, 220 pathogenesis, 220 TNFα-inhibitors in, 486 487 treatment evidence base for drug treatment, 228 229 nonmedical treatment, 230 recent developments, 230 231 in United Kingdom, 219 220 Juvenile idiopathic arthritis (JIA), 1, 31, 53, 107, 130, 387, 442, 505, 531. See also systemic juvenile idiopathic arthritis (sJIA) categories, 2t core set of outcome measures and improvement in, 107 109, 108t damage measures, 122 123 diagnostic investigations, 10 12 differential diagnosis, 12 15 disease activity states, 109 110 etiology and pathogenesis, 3 clinical manifestations, 8 10 DC, 7 gene expression profiling, 7 8 genetic predisposition, 3 7 myeloid-related protein 8/14, 8 future, 17 concerns of development of other autoimmune diseases, 17 concerns on malignancies during biological treatment, 18 infectious complications concerns during treatment, 17 opportunistic infections concerns during treatment, 17

570

Index

Juvenile idiopathic arthritis (JIA) (Continued) health-related quality of life measures, 117 120 JADAS, 110 114 JIA-associated uveitis, 131 132 age and gender, 132 arthritis type, 131 132 genetic factors, 132 laboratory markers, 132 multidimensional questionnaire for, 120 122 oligoarticular, 2 parent and patient-centered disease activity measures, 122 parent/patient acceptable symptom state, 120 physical function measures, 116 117 prevalence/epidemiology, 3 prognosis, 18 19 TNF in pathogenesis, 472 473 anti-TNFα therapy in JIA, 473 476 TNFα blockade in JIA-associated chronic anterior uveitis treatment, 477 478 TNFα blockade in juvenile spondyloarthropathies treatment, 478 TNFα blockade in treatment of systemic onset JIA, 477 treatment, 15 drugs used in children with JIA, 15 17 outcome measures, 15 Juvenile localized scleroderma (JLS), 235, 240. See also Autoinflammatory diseases associated conditions, 239 240 clinical classification, 235 239, 236t course of disease and prognosis, 244 disease monitoring, 242 243 etiology, 240 241 Extracutaneous manifestations, 241 242 laboratory findings, 242 pathogenesis, 240 241 treatment, 243 244 Juvenile rheumatoid arthritis (JRA), 485 Juvenile spondyloarthropathies (JSpA), 442, 478 TNFα blockade in treatment, 478 Juvenile systemic sclerosis (jSSc), 249. See also Autoinflammatory diseases classification, 249 250, 250t clinical manifestations, 251 258 diagnostic investigations, 258 biochemistry/serology/immunology, 259 260 evaluation of severity of disease, 260

functional, 258 259 radiological, 258 differential diagnosis, 260 261 etiology/pathogenesis, 250 251 high-resolution computer tomography of lung, 255f incidence and prevalence, 249 key points, 261 odematous phase of skin, 253f pattern of organ involvement jSSc patients, 252t treatment, 261 Juvenile-onset AS, 41 42 Juvenile-onset psoriatic arthritis, 42 Juvenile-onset spondyloarthritis (JoSpA), 31 clinical features at onset, 36b clinical findings, 34 grade 3 bilateral sacroiliitis, 38f HRQoL and functioning, 39 initial symptoms and JoSpA differential diagnosis, 34 35 peripheral arthritis and enthesitis features, 36 37 sacroiliac and spinal features, 37 38 clinical presentation, 41 ankylosing tarsitis, 43 Crohn’s disease and ulcerative colitis, 42 43 juvenile-onset AS, 42 juvenile-onset psoriatic arthritis, 42 ReA, 42 undifferentiated SpA, 41 42 composite images of ankylosing tarsitis, 33f epidemiology, 31 32 histopathology, 32 33 imaging studies, 39 40 STIR and T1 MR image sequences, 40f Whole-body short tau inversion recovery MRI, 41f involvement of feet in patients with, 37f pathogenesis, 32 therapeutic recommendations, 43 46

K Kawasaki disease (KD), 70, 341, 488 atypical and incomplete, 348 clinical manifestations, 345 348 diagnostic criteria, 348t epidemiology, 341 342 etiology, 342 344 exfoliative desquamation of foot, 346f follow-up, 351 353

Index cardiac imaging, 352 353 outcome, 353 354 laboratory findings, 349 morbilliform macular trunk rash in infant, 346f pathogenesis, 344 345 reddening and cracking of lips, 347f strawberry-like tongue in infant, 347f treatment, 349 351 vaccinations, 351 Kawasaki syndrome. See Kawasaki disease (KD) KD. See Kawasaki disease (KD) Kendal scale, 536 Ketamine, 161 Kingella kingae, 12 13

L LA. See Lupus anticoagulant (LA)Lyme arthritis (LA) La antigen, 193 194 la belle indifference, 152 Laboratory abnormalities management, 509 Laboratory tests, 225, 456 LAC. See Lupus anticoagulant (LAC) Laser Doppler flowmetry (LDF), 243 Late disease, 439 LB. See Lyme borreliosis (LB) LDF. See Laser Doppler flowmetry (LDF) Leflunomide, 16 Leg length, 537 Leucine-rich repeat (LRR), 274, 428 domain, 280 Leukocyte count, 10 Leuprolide, 177 178 Libman Sacks endocarditis, 181 Lichen sclerosus et atrophicus, 239 240 Linear scleroderma, 236 237, 236t, 238f Linear ubiquitination chain assembly complex (LUBAC), 292 293 Lipoatrophy, 223 224, 224f Lipoid pneumonia, 62 Lipopolysaccharide (LPS), 431 Liver enzyme abnormalities, 509 Liver function tests, 10, 57 58 LN. See Lupus nephritis (LN) Local discoloration, 9 Localized scleroderma (LS), 235 epidemiology, 240 Localized Scleroderma Severity Index (LoSSI), 242 243 Loefgren’s syndrome, 443

571

Long-term fatal outcome, 249 Long-term sequelae, 328 Loss of mobility, 541 LoSSI. See Localized Scleroderma Severity Index (LoSSI) Low-dose glucocorticoids, 181 LPS. See Lipopolysaccharide (LPS) LRR. See Leucine-rich repeat (LRR) LS. See Localized scleroderma (LS) LUBAC. See Linear ubiquitination chain assembly complex (LUBAC) Luminal myofibroblastic proliferation, 345 Lung function tests, 226 Lupus anticoagulant (LA), 385 test, 397 398 Lupus anticoagulant (LAC), 242 Lupus nephritis (LN), 173 174, 176 179 Lupus-related cytopenias, 182 Lyme arthritis (LA), 13, 465 466 Lyme borreliosis (LB), 465. See also Rheumatic fever (RF) autoimmunity, 467 clinical manifestations, 465 immunopathological reactions, 466 persistent infection, 466 Lyme disease. See Lyme borreliosis (LB) Lymphomatoid granulomatosus, 445 446 Lymphoreticular malignancies, 68

M mAbs. See monoclonal antibodies (mAbs) Macrocephaly, 202 Macrophage activation syndrome (MAS), 53, 63, 85, 279, 483 484 classification criteria for, 65t clinical, laboratory, and histopathological features, 85 87 clinical features, 63 comparison of clinical and laboratory features of, 89t diagnostic guidelines, 94 95, 95t epidemiology, 87 88 ferritin, 64 HLH and, 63 initial treatment of, 65 66 laboratory features, 63 64 main features of, 88t management, 98 100 multiorgan involvement, 66 nomenclature and classification, 90 91 novel classification criteria for MAS complicating SJIA, 95 98, 97t

572

Index

Macrophage activation syndrome (MAS) (Continued) pathogenesis, 91 94 performance of new classification criteria in MAS, 98 preliminary diagnostic guidelines, 64 65 in sJIA patients, 64 triggering factors, 88 90 Macrophage migration inhibitory factor (MIF), 56 Macrophages, 486 487 Magnetic resonance imaging (MRI), 39, 154, 241 MAID. See Monogenic autoinflammatory disease (MAID) Majeed syndrome, 288, 318 321 clinical features, 320t Majeed syndrome associated mutations (S734L), 319 Major histocompatibility antigens, 452 Major histocompatibility complex (MHC), 466 Malignancies, 486, 521 Mannose-binding lectin (MBL), 4 Manual muscle testing (MMT), 222 223 MAP kinases. See Mitogen-activated protein (MAP) kinases MAS. See Macrophage activation syndrome (MAS) Masquerade syndrome, 131 Massage, 546 MBL. See Mannose-binding lectin (MBL) MCP-1. See Monocyte chemoattractant protein-1 (MCP-1) MCTD. See Mixed connective tissue disease (MCTD) MDP. See Muramyl dipeptide (MDP) Medical history, past, 532 accommodation, 533 family history, 532 medication, 532 social history, 532 state benefits, 533 Medical Research Council (MRC), 535 536 Medical treatment, 160 Medication, 532 Medsger Disease Severity Scale, 260 MEFV gene, 283 Mendelian autoinflammatory bone disorders DIRA, 321 322 Majeed syndrome, 318 321 Metatarsophalangeal (MTP) joint, 36

Methotrexate (MTX), 7 8, 43, 135 137, 244, 374, 472, 506 Mevalonate kinase deficiency (MKD). See Mevalonate kinase deficiency (MVK deficiency) Mevalonate kinase deficiency (MVK deficiency), 280 281, 307 308, 419 420 facial dysmorphia, 281f monoarthritis, 282f Mevalonic aciduria. See Mevalonate kinase deficiency (MVK deficiency) MHC. See Major histocompatibility complex (MHC) Microbiome, 317 Microscopic polyangiitis, 376 MIF. See Macrophage migration inhibitory factor (MIF) Mild anterior uveitis, 135 136 Minimal disease activity state, 109 110, 111t MIP-1α. See Monocyte inflammatory protein1α (MIP-1α) Mitogen-activated protein (MAP) kinases, 278 Mitral stenosis, 454 Mixed connective tissue disease (MCTD), 11, 69 70, 228 Mixed M1/M2 phenotype of monocyte activation, 56 Mixed morphea, 236t, 239 MMF. See Mycophenolate mofetil (MMF) MMT. See Manual muscle testing (MMT) MMT of eight muscles (MMT8), 222 223 MMT8. See MMT of eight muscles (MMT8) Modified Rodnan Skin Score, 259 Monoarthritis, 11, 282f monoclonal antibodies (mAbs), 472, 504 Monocyte chemoattractant protein-1 (MCP-1), 431 434 Monocyte inflammatory protein-1α (MIP-1α), 431 434 Monogenetic autoinflammatory diseases, 268 Monogenic autoinflammatory disease (MAID), 305 306 Morphea. See Localized scleroderma (LS) Mortality, 257 258 MPO-ANCA. See Myeloperoxidase-ANCA (MPO-ANCA) MRC. See Medical Research Council (MRC) MRI. See Magnetic resonance imaging (MRI) MSA. See Myositis-associated antibodies (MSA) MTP joint. See Metatarsophalangeal (MTP) joint

Index MTX. See Methotrexate (MTX) Muckle Wells syndrome, 276 Mucocutaneous lesions, 412 414, 421 Munc13 4 protein, 63 Muramyl dipeptide (MDP), 431 Muscle biopsy, 226 bulk, 537 imbalance, 541 repair and growth, 550 551 strength and function, 535 536 strengthening and endurance exercises, 539 biomechanical, 540 disease activity, 541 inflammation, 540 loss of mobility, 541 muscle imbalance, 541 muscle weakness in inflammatory disease, 540f pain inhibits muscle function, 540 testing, 535 536 Muscle weakness, 221 223 in inflammatory disease, 540f Musculoskeletal involvement, 254, 259 MVK deficiency. See Mevalonate kinase deficiency (MVK deficiency) Myalgia, 14, 62 Mycophenolate mofetil (MMF), 135, 137, 177 178 Mycoplasma pneumonia, 13, 68 MyD88. See Myeloid differentiation factor 88 (MyD88) Myeloid differentiation factor 88 (MyD88), 389 390 Myeloid-related protein 8/14, 8 Myeloperoxidase-ANCA (MPO-ANCA), 376 Myocardial dysfunction, 255 infarction, 150 Myocarditis, 62, 192 Myopathy, 254 Myositis, 182 183, 228 Myositis-associated antibodies (MSA), 225

N NACHT domain, 431 Nailfolds capillaroscopy, 258 Nakajo Nishimura syndrome (NNS), 290 291 Nasal septal perforation, 62 Natural killer (NK) cells, 55 56, 91 92, 410 411

573

NBD. See NeuroBD (NBD)Nucleotide binding domain (NBD) NBS domain. See NACHT domainNucleotide binding site (NBS) domain Neisseria meningococci infection, 14 Neonatal APS treatment, 400 401 Neonatal lupus (NL), 185, 191. See also Discoid lupus (DL) anatomical and pathological findings, 191 192 anti-RO/SSA-negative congenital heart block, 209 clinical features cardiac manifestations, 198 201 laboratory abnormalities, 203 neurological problems and possible role of fluorinated corticosteroids, 202 203 risk of delivering child with congenital complete heart block, 197 198 skin rash, 201 202 epidemiology and definition of congenital complete atrioventricular block, 196 197 evaluation of fine specificities of maternal autoantibody profile, 196 other pregnancy outcomes in women with anti-RO/SSA antibodies, 209 pathogenesis, 192 196 prognosis infants, 203 204 maternal, 204 risk of recurrence, 204 first-degree atrioventricular block in utero assessment, 205 fluorinated steroids and regression of second-degree atrioventricular block, 205 obstetric management of pregnancy, 204 205 treatment postnatal treatment, 208 209 in utero therapy, 206 208 Neonatal onset multisystem inflammatory disease (NOMID), 510 syndrome, 70 NeuroBD (NBD), 415 416 Neuroblastoma, 68 Neurological involvement, 420 lesions, 415 416 Neuromuscular diseases, 228

574

Index

Neuropsychiatric lupus, 179 180 manifestations, 481 482 Neuropsychiatric (NP) dermatologic manifestations, 173 174 Neutropenia, 203, 509 NF-κB. See Nuclear factor κB (NF-κB) NK cells. See Natural killer (NK) cells NL. See Neonatal lupus (NL) NLR. See Nod-like receptor (NLR) NLRC4 NLRC4-associated autoinflammatory syndromes, 279 maculopapular rash in toddler, 279f proteins, 279 NLRP NLRP12-associated periodic syndrome, 279 280 proteins, 280 NLRP3. See Cryopyrin NNS. See Nakajo Nishimura syndrome (NNS) NOD domain. See NACHT domainNucleotide-binding oligomerization domain (NOD domain) Nod-like receptor (NLR), 280 NOMID. See Neonatal onset multisystem inflammatory disease (NOMID) Nominal Group Technique, 97 Non-HLA immune regulatory genes, 4 Non anti-TNF-alpha biologic activity modifiers, 135, 139 Abatacept, 139 Anti-Interleukin-1 treatments, 140 Rituximab, 139 140 Tocilizumab, 140 Noncardiac manifestations, 209 Noninfectious chronic uveitis, 135, 136f Nonmedical treatment, 230 Nonrestorative sleep, 153 Nonsteroidal anti-inflammatory drug (NSAID), 10, 43, 57 58, 181, 277, 282, 321, 327, 366 Nortriptyline, 160 NP dermatologic manifestations. See Neuropsychiatric (NP) dermatologic manifestations NSAID. See Nonsteroidal anti-inflammatory drug (NSAID) Nuclear factor κB (NF-κB), 274, 278, 389 390

Nucleotide binding domain (NBD), 428 Nucleotide binding site (NBS) domain, 429 Nucleotide-binding oligomerization domain (NOD domain), 280, 427 NOD2, 428 430

O OA. See Oral aphthosis (OA) Objective assessment, 534. See also Subjective assessment assessment of joint, spinal movements, 535 536 functional questionnaires, 537 observation of movement and function, 536 Observation of movement and function, 536 Obstetric management of pregnancy, 204 205 Occupational therapy, 158 159 OCN. See Osteocalcin (OCN) Ocular disease, 276 involvement, 241 242 lesions, 414 415 manifestations, 438 439 Odd Ratio (OR), 411 Oligoarthritis, 435 Oligoarticular JIA, 2, 4, 6, 8 11 Opioids, 161 OPN. See Osteopontin (OPN) Opportunistic infections, 520 521 Optic atrophy, 276 OR. See Odd Ratio (OR) Oral aphthosis (OA), 412 414 Oral medications, 458 459 OspA. See Outer surface protein A (OspA) Osteocalcin (OCN), 35f Osteopenia, 9, 184 Osteopontin (OPN), 35f Osteoporosis, 67 68, 184, 549 550 Outer surface protein A (OspA), 467

P p-ANCA. See Positive perinuclear-ANCA (pANCA) p38 mitogen-activated protein kinase (p38MAPK), 389 390 Pacing activities, 546 547 Pain, 322, 531 relief, 546 Palmoplantar pustulosis, 278f Palpation, 535

Index PAN. See Polyarteritis nodosa (PAN) Panclerotic morphea, 236t, 239 Pansclerotic morphea, 260 261 Panuveitis, 129 PAP. See Phosphatidate phosphatase (PAP) PAPA syndrome. See Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome Parenchymal lung disease, 9 Parent and patient-centered disease activity measures, 122 Parent form 50 (PF50), 117 119 Parent/patient acceptable symptom state, 120 Parry Romberg syndrome (PRS), 238 239 Partial C4 deficiency, 5 Pathogenic mechanisms, 389 Pathology, 441 PBMC. See Peripheral blood mononuclear cell (PBMC) PCR. See Polymerase chain reaction (PCR) Peau d’orange, 240 Ped-APS Registry. See Pediatric APS registry (Ped-APS Registry) PEDBD. See Pediatric BD patients (PEDBD) Pediatric APS registry (Ped-APS Registry), 390 391. See also Antiphospholipid syndrome (APS) Pediatric BD patients (PEDBD), 409 410 Pediatric granulomatous inflammatory disease variants, 439 440 Pediatric Quality of Life Inventory (PedsQL), 119 Pediatric rheumatic diseases, biological therapies for biologics, 503 519 properties, 504 biosimilars, 503 504 inflammation in, 503 nomenclature, 505 rare adverse events, 520 521 safety considerations active infections, 519 combination therapy, 519 pregnancy, 520 surgical procedures, 520 vaccinations, 519 520 safety laboratory monitoring, 521 Pediatric rheumatologist, 1 Pediatric rheumatology, 527 assessment, 530 muscle strengthening and endurance exercises, 539

575

biomechanical, 540 disease activity, 541 inflammation, 540 loss of mobility, 541 muscle imbalance, 541 muscle weakness in inflammatory disease, 540f pain inhibits muscle function, 540 muscle weakness and muscle atrophy in children, 529t objective assessment, 534 assessment of joint, spinal movements, 535 536 functional questionnaires, 537 observation of movement and function, 536 pain cycling in inflammatory and noninflammatory disease, 528f philosophy of treatment principles, 527 530 physiotherapy department, 529t physiotherapy management, 537 538 information for individual conditions, 538 physiotherapy assessment and treatment, 539f treatment goals for conditions, 539 subjective assessment daily living/function activities, 533 534 past medical history, 532 533 present condition, 530 presenting problems and symptoms, 531 532 training children’s muscles, 541 551 Pediatric Rheumatology Collaborative Study Group (PRCSG), 231 Pediatric Rheumatology European Society (PRES), 249 250, 347 348, 362 Pediatric Rheumatology International Trials Organization (PRINTO), 231 Pediatric Rheumatology Quality of Life (PRQL), 119 Pediatric scoring systems for MRI, 12 PedsQL. See Pediatric Quality of Life Inventory (PedsQL) Penicillin allergy, 459 460 Pericardiocentesis, 181 Pericarditis, 181, 418 Periodic fever syndromes, 420 Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA), 305. See also TNF receptorassociated periodic syndrome (TRAPS)

576

Index

Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) (Continued) clinical presentation, 305 306 diagnosis, 306t, 307 308, 307t epidemiology, 306 307 pathogenesis, 308 309 syndrome, 412 treatment, 309 311, 310t Periorbital edema, 222 Peripheral arthritis, 36 37 Peripheral blood mononuclear cell (PBMC), 55 Peripheral nerve blocks, 162 PF50. See Parent form 50 (PF50) PFAPA. See Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) Pharmacodynamics, 506 rilonacept, 512 Pharmacokinetics, 506 rilonacept, 512 Philosophy of therapy, 163 Phosphate metabolism disorders, 326 Phosphatidate phosphatase (PAP), 319 Physical function measures, 116 117 Physical therapy, 158 159 Physiotherapy approach, 527 530 management, 537 538 information for individual conditions, 538 physiotherapy assessment and treatment, 539f treatment goals for conditions, 539 PIP. See Proximal interphalangeal (PIP) Placebo-controlled trial, 160 PLAID, 293 Plasmapheresis, 207 Platelets, 10 Pleuritis, 62, 180 181 Pneumonitis, 180 181 Polyarteritis nodosa (PAN), 70, 228, 362, 367 diagnostic investigations, 369 370 differential diagnosis, 370 epidemiology, 368 etiology and pathogenesis, 368 clinical manifestations, 368 369 EULAR/PRINTO/PRES, 368t treatment, 370 371 Polyarthritis, 14 Polyarticular JIA, 4, 6 9, 11

Polymerase chain reaction (PCR), 11, 466 Positive ANA titer, 132 Positive perinuclear-ANCA (p-ANCA), 376 Posterior uveitis, 129 Postnatal treatment, 208 209 Posture, 536 Poznanski score, 67 PRAAS. See Proteasome-associated autoinflammatory syndrome (PRAAS) PRCSG. See Pediatric Rheumatology Collaborative Study Group (PRCSG) Pregabalin, 161 Pregnancy, 520 PRES. See Pediatric Rheumatology European Society (PRES) Primary central nervous system vasculitis, 377 378 Primary thrombosis prophylaxis, 399 PRINTO. See Pediatric Rheumatology International Trials Organization (PRINTO) Prognosis, 418 419 Progressive cognitive impairment, 276 Proinflammatory cytokines, 56, 85, 89 92, 98, 137 138, 503 IL-1β, 316 317 Proline/serine/threonine phosphataseinteracting protein 1 (PSTPIP1) gene, 287, 318 disease related to mutations in, 287 288 Prophylaxis, 399, 459 460 Propionibacterium acnes, 317 Proprioception, 547 Proteasome subunit-type 8 (PSMB8), 290 Proteasome-associated autoinflammatory syndrome (PRAAS), 290. See also TNF receptor-associated periodic syndrome (TRAPS) Proteasomes, 291 Protein folding disorders. See also IL-1 family cytokine regulation PRAAS, 290 291 TRAPS, 288 290 Proximal interphalangeal (PIP), 435 PRQL. See Pediatric Rheumatology Quality of Life (PRQL) PRS. See Parry Romberg syndrome (PRS) Prudence, 157 PsA. See Psoriatic arthritis (PsA) PSMB8 gene, 291 PSMB8. See Proteasome subunit-type 8 (PSMB8)

Index Psoriatic arthritis (PsA), 31 Psoriatiform squamous eruption, 278f PSTPIP1 gene. See Proline/serine/threonine phosphatase-interacting protein 1 (PSTPIP1) gene Psychological stress, 150 Pulmonary function tests, 259 hypertension, 254 255 involvement, 254, 418 manifestations, 180 181 Pulse methylprednisolone, 181 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, 286. See also Familial Mediterranean Fever (FMF); Hyper IgD syndrome (HIDS) clinical manifestations, 287 diagnostic investigations, 287 disease related to mutations in PSTPIP1 gene, 287 288 etiology/pathogenesis, 287 prevalence/epidemiology, 286 treatment, 287 Pyrin, 283

Q Qigong training, 159 QoMLQ. See Quality of My Life Questionnaire (QoMLQ) QT interval, 193 QTc. See Corrected QT interval (QTc) Quality of My Life Questionnaire (QoMLQ), 119

R R92Q, TNFRSF1A variant, 289 RA. See Rheumatoid arthritis (RA) Radiographic findings, 39 Radiographic sacroiliitis, 38 RAS. See Recurrent aphthous stomatitis (RAS) Rash/Rashes, 183, 221 222 “Rat bite” necrosis, 252, 253f Reactive arthritis (ReA), 14, 32, 42, 68 69 Receptor I (RI), 316 317 Receptor-interacting protein 2 (RIP2), 431 Recurrent aphthous stomatitis (RAS), 419 420 Recurrent fever, 308 309 attacks, 281, 284

577

Recurrent oral aphthosis (ROA), 409 410, 412 414 “Red man syndrome”, 480 Regulatory T cells (Tregs), 6 Reiter’s syndrome, 14, 41 Renal amyloidosis, 420 Renal involvement, 173 174, 258 259 Renin angiotensin aldosterone system inhibitors, 177 Reynaud’s phenomenon, 251, 253 254, 258 RF. See Rheumatic fever (RF)Rheumatoid factor (RF) RHD. See Rheumatic heart disease (RHD) Rheumatic carditis, 456 457 Rheumatic disease-associated hemophagocytic syndrome, 91 Rheumatic fever (RF), 241 242, 451. See also Lyme borreliosis (LB) clinical manifestations, 453 arthritis, 454 carditis, 454 erythema marginatum, 455 other manifestations, 455 subcutaneous nodules, 455 Sydenham’s chorea, 454 455 diagnosis diagnostic criteria, 457 458 differential diagnosis, 458 guidelines for, 457t laboratory tests, 456 rheumatic carditis, 456 457 epidemiology, 452 etiology/pathogenesis, 452 453 prevalence, 451 treatment, 458 460 Rheumatic heart disease (RHD), 451 Rheumatoid arthritis (RA), 1, 467, 471, 505, 515 Rheumatoid factor (RF), 1, 131 132, 441 RI. See Receptor I (RI) Rilonacept, 72, 511 512 RIP2. See Receptor-interacting protein 2 (RIP2) Rituximab (RTX), 139 140, 176, 178, 515 518 Ro antigen, 193 194 ROA. See Recurrent oral aphthosis (ROA) Road to scar, 193 194 “Roller-coaster” effect developing, 546 547 RTX. See Rituximab (RTX)

578

Index

S S100A12. See Calcium-binding proteins S100A8 S100A9 (MRP-14). See Calcium-binding proteins S100A8 S734L. See Majeed syndrome associated mutations (S734L) SA nodal scarring. See Sinoatrial (SA) nodal scarring Sacroiliac features, 37 38 Sacroiliitis, 37 38 SAPHO syndrome. See Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome Satellite cells, 550 Scarlet fever, 342 343 SCID. See Severe combined immunodeficiency disease (SCID) Scleredema, 260 261 Sclermyxedema, 260 261 Scleroderma pattern, 252 Screaming, 152 Second-degree atrioventricular block regression, 205 Second-line treatment agents, 327 328 Secondary thrombosis prophylaxis, 399 400 vasculitides, 378 Septic arthritis. See Bacterial arthritisInfectious arthritis Serositis, 59 Severe combined immunodeficiency disease (SCID), 293 294 Short T1 (tau) inversion recovery (STIR) sequences, 39, 40f SIADH. See Syndrome of antidiuretic hormone secretion (SIADH) Sickle cell disease, 14 Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD), 294 SIFD. See Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) “Silk-road”, 377 Single organ vasculitides, 377 378 Sinoatrial (SA) nodal scarring, 191 Sinus bradycardia, 198 200 sJIA. See systemic juvenile idiopathic arthritis (sJIA) Sjo¨gren’s syndrome, 257

Skin, 259 condition, 537 rash, 201 202 SLE. See Systemic lupus erythematosus (SLE) Sleep, 153 disorders, 150 Social history, 532 Socialization, 534 Soluble CD163, 86 87 Soluble CD25. See Soluble interleukin-2 receptor α chain Soluble interleukin-2 receptor α chain, 86 87 Sore throat, 68 SpA. See Spondyloarthritis (SpA) Spinal cord stimulators, 162 Spinal features, 37 38 Splinting, 545 546 Spondylitis, 37 38 Spondyloarthritis (SpA), 471 Sporting activities, advice about, 547 548 SSA/Ro, 196 SSc. See Systemic sclerosis (SSc) ssRNA, 194 SSZ. See Sulfasalazine (SSZ) Stamina, 537 Standardized assessment, 251 Standardized Uveitis Nomenclature Working Group, 129 Staphylococcus aureus, 371 372 State benefits, 533 Steroid(s), 161 therapy, 135 136, 206 Stimulator of interferon genes (STING), 292 STING-associated vasculopathy with onset in infancy, 292 STING. See Stimulator of interferon genes (STING) STIR sequences. See Short T1 (tau) inversion recovery (STIR) sequences “Streaking leucocyte factor” disease. See Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome Streptococci species, 14 Streptococcus, 458 459 Stretch and cast, 545 Stretching, 542 543 Home Exercise Program, 543t, 544t role of, 543 544 rules for, 544 shortened muscles, 545

Index advice about sporting activities, 547 548 balance and proprioception, 547 gait reeducation, 547 pacing activities, 546 547 pain relief, 546 splinting, 545 546 stretch and cast, 545 stiff joints, 544 Subacute chronic vasculitis, 345 Subcutaneous nodules, 455 Subjective assessment. See also Objective assessment daily living/function activities, 533 534 past medical history, 532 533 present condition, 530 presenting problems and symptoms, 531 532 Sulfasalazine (SSZ), 16, 43 Surgical procedures, 520 Susceptibility genes, 194 195 Swimming/sports, 534 Sydenham’s chorea, 454 455, 459 Sympathectomy, 162 Sympathetic blocks, 162 Syndrome of antidiuretic hormone secretion (SIADH), 177 178 Synovial fluid analysis, 11, 67 Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, 315 316 Systemic corticosteroids, 71 glucocorticoids, 18 systemic juvenile idiopathic arthritis (sJIA), 53, 85, 288, 506. See also Juvenile idiopathic arthritis (JIA) causes of death in, 76t common clinical manifestations, 56 60 comparison of clinical and laboratory features of, 89t differential diagnosis, 68 70, 69t disease course, outcome, and prognosis, 74 75 growth, 60 61 laboratory investigations, 66 67 less common clinical manifestations, 61 62, 61t MAS, 63 66 mortality, 75 76 pathogenesis, 54 56 patient with sJIA with extensive urticarial, pruritic rash, 58f

579

prevalence and epidemiology, 53 54 radiologic investigations, 67 68 rapid progression of joint space loss, erosions, and ankylosis, 59f treatment, 70 73 typical once or twice daily fever patterns in child with, 57f typical salmon-pink macular rash on trunk and proximal upper limbs, 58f Systemic lupus erythematosus (SLE), 10, 69 70, 173, 221 222, 228, 361, 385, 484, 515 alternate forms of lupus, 185 clinical manifestations and treatment cardiac manifestations, 181 general principles, 175 176 hematologic manifestations, 181 182 LN, 176 179 neuropsychiatric lupus, 179 180 pulmonary manifestations, 180 181 systemic lupus erythematosus-related musculoskeletal disease, 182 183 course and prognosis, 184 definition/classification, 174 epidemiology, 174 etiology/pathogenesis, 175 general aspects of management, 184 genetics, 174 175 immune dysregulation, 173 new developments, 183 184 renal involvement, 173 174 SLE-related musculoskeletal disease, 182 183 cutaneous involvement, 183 Systemic sclerosis (SSc), 239 240, 251

T T-cell activation, proteins inhibits costimulatory signals for abatacept, 505 506 lymphocytes, 452 T-helper cells (Th cells), 410 411 Th17 cells, 6 7 T-lymphocyte-mediated immune response, 5 TA. See Takayasu arteritis (TA) Takayasu arteritis (TA), 362, 374 clinical and laboratory features, 375 epidemiology, 375 EULAR/PRINTO/PRES childhood, 375t treatment, 375 376

580

Index

Takayasu-like disease, 445 446 Tan-colored rash, 437 438 Tarsitis, 37 TB. See Tuberculosis (TB) Technetium scan, 154 Tel Hashomer criteria, 285 286, 285t Temporomandibular involvement, 9 Tenosynovitis, 37 TENS. See Transcutaneous nerve stimulation (TENS) TGF-β. See Transforming growth factor-β (TGF-β) Th cells. See T-helper cells (Th cells) Thermography, 258 Thrombocytopenia, 182, 203, 393 394, 509, 513 Thrombocytosis, 372 373 Thrombosis, 398 TINU syndrome, 445 TLR. See Toll-like receptor (TLR) TMEM171 gene, 292 TMEM173 gene, 292 TNF. See Tumor necrosis factor (TNF) TNF receptor (TNFR), 503 TNF receptor-associated periodic syndrome (TRAPS), 288, 307 308, 488. See also Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA); Proteasomeassociated autoinflammatory syndrome (PRAAS) clinical manifestations, 289 290 diagnostic investigations, 290 etiology/pathogenesis, 289 migratory rash in TRAPS patient, 289f prevalence/epidemiology, 288 treatment, 290 TNF-α. See Tumor necrosis factor-alpha (TNF-α) TNFR. See TNF receptor (TNFR) TNFRSF1A gene, 289 TNSALP. See ALPL Tocilizumab, 17, 72, 140 Toll-like receptor (TLR), 193 194, 410 411, 431 TLR-4, 389 390 TLR-9, 92, 317 Topical glucocorticoids, 18 Toxoplasmosis, 420 421 Traditional drug, 504 Transaminases, 66 67 Transcriptomics. See Gene expression profiling

Transcutaneous nerve stimulation (TENS), 159 160 Transforming growth factor-β (TGF-β), 193 194 TRAPS. See TNF receptor-associated periodic syndrome (TRAPS) Tregs. See Regulatory T cells (Tregs) Tricyclic antidepressants, 160 Tuberculosis (TB), 479 Tumor necrosis factor (TNF), 4, 32, 54, 93, 132, 471, 503 inhibitors, 328 in pathogenesis of JIA, 472 473 anti-TNFα therapy in JIA, 473 476 TNFα blockade in JIA-associated chronic anterior uveitis treatment, 477 478 TNFα blockade in juvenile spondyloarthropathies treatment, 478 TNFα blockade in treatment of systemic onset JIA, 477 Tumor necrosis factor alpha inhibitors, 137 138. See also Non anti-TNFalpha biologic activity modifiers adalimumab, 138 139 etanercept, 138 infliximab, 138 in juvenile dermatomyositis, 486 487 in other pediatric rheumatic diseases, 487 488 Tumor necrosis factor-alpha (TNF-α), 193 194, 316, 344, 410 411, 431 434, 452 453, 471 AEs of blockade, 479 autoantibody-mediated diseases, 484 485 chronic AU reactivation as AE, 485 486 cutaneous manifestations, 480 481 German Etanercept registry, 479 hyperergic reactions, 480 IBD, 485 infections, 482 483 MAS, 483 484 neuropsychiatric manifestations, 481 482 TNF blockade, 483 484 TNF blockade and vaccines, 483 anti-TNFα agents, 471 blockade in in JIA-associated chronic anterior uveitis treatment, 477 478 treatment of systemic onset JIA, 477 blockers, 44 45 function and muscles, 549 550 therapeutic approach to JIA, 472

Index

U Ulcerative colitis, 42 43 ULN. See Upper limit of normal (ULN) Ultrasound, 12, 40 Ultraviolet (UV), 243 244 Undifferentiated SpA, 41 42 uPA. See Urokinase plasminogen activator (uPA) uPAR. See Urokinase plasminogen activator receptor (uPAR) Upper limit of normal (ULN), 508 Urinalysis, 369 Urinary and nephrological involvement, 418 Urokinase plasminogen activator (uPA), 194 Urokinase plasminogen activator receptor (uPAR), 194 Ustekinumab, 514 UV. See Ultraviolet (UV) Uveitis, 62, 129, 420 421, 445 acute-recurrent, 130 biologic response modifiers, 137 140 corticosteroids, 135 136 diagnosis, 133 immunosuppressant agents, 136 137 IUSG, 129 juvenile idiopathic arthritis-associated uveitis, 131 132 screening intervals for, 134t Standardized Uveitis Nomenclature Working Group, 129 treatment, 18, 134 135

V Vaccinations, 519 520 Vaccines, 460 TNF blockade and, 483 Valvular disease, 201 heart disease, 181 Variable vessel vasculitides, 377

581

VAS. See Visual analog scale (VAS) Vascular disease, 418 419 imaging, 442 involvement, 417 418, 439 Vasculitic lesions, 183 syndromes classification, 362 Vasculitides in children eosinophilic granulomatous polyangiitis, 376 GPA, 371 374 IgA Vasculitis/HSP, 362 microscopic polyangiitis, 376 PAN, 367 371 secondary vasculitides, 378 single organ vasculitides, 377 378 TA, 374 376 2012 Revised Chapel Hill Consensus Conference, 363t variable vessel vasculitides, 377 Vasculitis, 361, 445 446 Vaso-occlusive episodes, 14 Venous thrombosis, 417 418 Visual analog scale (VAS), 119, 534

W WBC. See White blood cell (WBC) Weber Christian syndrome, 439 440 Wegener granulomatosis (WG), 70, 362 White blood cell (WBC), 349 WHO. See World Health Organization (WHO) Whole-body MRI, 39 World Health Organization (WHO), 176 Wrist synovitis, 437f

X X-ray studies, 154