Pediatric Inflammatory Bowel Disease

Pediatric Inflammatory Bowel Disease

Pediatric Inflammatory Bowel Disease Edited by

Petar Mamula, M.D. Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine, Attending Physician, Division of GI, Hepatology and Nutrition, Director, Endoscopy Suite, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

Jonathan E. Markowitz, M.D., M.S.C.E Associate Professor of Clinical Pediatrics, University of South Carolina School of Medicine, Attending Physician, Children’s Center for Digestive Health, Greenville Hospital System University Medical Center, Greenville, South Carolina

Robert N. Baldassano, M.D. Professor, University of Pennsylvania School of Medicine, Attending Physician and Director, Inflammatory Bowel Disease Center, Division of GI, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

Petar Mamula, M.D. Assistant Professor of Pediatrics University of Pennsylvania School of Medicine Attending Physician, Division of GI Hepatology and Nutrition Director, Endoscopy Suite The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Jonathan E. Markowitz., M.D., M.S.C.E. Associate Professor of Clinical Pediatrics University of South Carolina School of Medicine Attending Physician, Children’s Center for Digestive Health Greenville Hospital System University Medical Center Greenville, South Carolina

Robert N. Baldassano, M.D. Professor University of Pennsylvania School of Medicine Attending Physician and Director Inflammatory Bowel Disease Center Division of GI, Hepatology and Nutrition The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Library of Congress Control Number: 2007929784 ISBN-13: 978-0-387-73480-4

e-ISBN-13: 978-0-387-73481-1

Printed on acid-free paper. © 2008 Springer Science+Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. 9 8 7 6 5 4 3 2 1 springer.com

We dedicate this book... To our families. To Gordana-Dana, to Kay, and to Joanne. For their love, understanding and encouragement. To Niko, to Jack, Leo, and Benjamin, and to Chris, Steven, and Julie. For making us believe that the best is yet to come. To our colleagues everywhere, past and present. For working hard each day to make a difference. To our patients. For inspiring us. Petar, Jon, Robert

Foreword Pediatric Inflammatory Bowel Diseases (IBD) are the most common and most significant chronic disorders in Pediatric Gastroenterology. The onset of Crohn disease and ulcerative colitis in the first two decades of life presents a number of diagnostic and therapeutic challenges that are unique to pediatric patients. Although the studies available for pediatric diagnosis have improved dramatically in the past three decades, the improvement in technology alone cannot account for the increased frequency of IBD recognized in early childhood. While therapy for older patients has improved dramatically with the use of immunomodulators and the development of exciting biologic strategies, rarely if ever have comprehensive studies of the pharmacokinetics, safety and efficacy of any of the IBD medications been performed in pediatric patients. A number of excellent medications are not available in liquid preparations that can be swallowed by children, and others, such as timed-release formulations, are developed for delivery to an adult gastrointestinal tract. It is unfortunate that the care we provide to children is often an extrapolation of what is known about and available for adults with IBD. Pediatric patients with IBD face a number of unique challenges. The onset of disease before puberty can be devastating. Growth failure is a particularly difficult problem with potentially permanent consequences. Much of the pediatric specific research has focused on the role of nutritional therapy to treat growth failure and induce remission. Strategies such as nocturnal nasogastric administration of supplements are widespread in most pediatric centers, and are surprisingly well-tolerated even by the youngest patients, particularly when the value of nutritional therapy is presented in advance to both the family and the child. Nutrition must be strongly advocated for pediatric patients, as it has great therapeutic value, and it is the only therapy for which there are no serious potential complications. The long-term consequences of medical and surgical therapy are particularly troubling for pediatric patients. The complications of corticosteroids in childhood and adolescence can seem worse than the disease itself. While most of the cosmetic side effects are reversible, the psychological trauma to an adolescent can be overwhelming. We are only beginning to understand and address the long term consequences of therapy given at an early age. Bone mass accumulation and linear growth are critical processes that are age dependent, with peaks in early adolescence. Failure of therapy at this stage will have permanent, and possibly debilitating consequences. In order to spare cumulative steroid exposure there has been a marked shift in the last two decades to immunodulator therapies, often initiated in the first decade of life. More recently, biologic therapy has resulted in a dramatic shift in therapeutic armamentarium and the style of its administration. In adults, the “therapeutic pyramid” has been turned on all of its sides, with a resulting dramatic improvement in quality of life and a decrease in overall corticosteroid exposure, but with a new set of adverse events from therapy. While pediatric patients undoubtedly benefit from the adult data supporting these “bottom up” and “top down” strategies, the data in adults does not necessarily predict the optimal strategies for children. The effects of more “aggressive” therapy are being recognized for their positives and negatives, and the risks and benefits in pediatrics are undoubtedly different in children and adolescents. Whether it is the state of the immature immune

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system, the effect of rapid growth, or the background susceptibility to different malignancies at different ages, the incidence of profound problems such as hepatosplenic T cell lymphomas reminds all practitioners that we do not understand the unique aspects of the younger patient that confer such increased susceptibility. There is no better care than that given by a well educated and experienced practitioner who considers all aspects of a patient’s problems. This book is designed for those practitioners who care for children. IBD therapy must be customized for each individual patient. There is no more ultimate “individual” patient that a child or adolescent with IBD. The many challenges of growth, nutrition, psychology and adaptation weigh heavily upon the profound challenges of pediatric Crohn disease and ulcerative colitis. In addition to the need for induction and maintenance of remission, the pediatric gastroenterologist must be obsessed with the long term consequences of therapy, not just a decade away, but hopefully a half century or more hence. Although these patients will move on to adult gastroenterologists, the problems will only accumulate and multiply. “Above all else, do no harm” is a wise admonition for pediatric IBD, where therapies are rapidly improving and there is a great potential for a cure of these devastating illnesses. This therapies and ultimate cures for Crohn disease and ulcerative colitis will come from the extraordinary advances in immunology and immunogenetics that are well detailed in this book. Until that time, we must rely on the conventional approached developed in adults, but with the conviction to verify their efficacy for children with IBD. This book is a landmark step toward better understanding of pediatric IBD and the challenges of IBD therapy in children. The editors are highly respected clinical scientists who have each contributed substantially to the knowledge about pediatric IBD. In addition, their knowledge gained from their extensive clinical experience is reflected in this book. They have assembled a truly extraordinary group of authoritative leaders whose contributions to this volume will guarantee that this will be a reference for all who care for pediatric IBD. The book is a tribute to those authors, but is dedicated to the children and adolescents with Crohn disease and ulcerative colitis. It is a sign of the times that increased focus at every level is directed toward these children, and this book is one significant step along the road toward improving care for the hundreds of thousands of children with inflammatory bowel diseases. It should be required reading for all those who care for these children.

Preface As this first edition of Pediatric Inflammatory Bowel Disease goes to press, we find ourselves reflecting not only upon our hopes and expectations for the textbook, but also upon the discipline of caring for children with inflammatory bowel disease (IBD). We have been saying amongst ourselves for several years that the time has come for a textbook dedicated to the unique aspects of pediatric IBD. This does not imply that the existing textbooks on IBD and pediatric gastroenterology are not useful. Rather, it is a testament that the collective knowledge about children and adolescents with IBD has grown, and continues to grow, to a point that warrants its own volume. Despite its growth, the community of pediatric gastroenterologists remains a fairly intimate one. We were fortunate to have a highly talented and internationally renowned group of physicianscientists who shared our vision for this project and willingly contributed their time and effort to provide the chapters for the book. However, we also recognize that there remain many geographic regions where access to specialists trained to care for children with IBD is limited. To this end, we have tried to design this book as a resource for not just pediatric gastroenterologists, but also for general pediatricians, internists, family practitioners, and internist-gastroenterologists who will likely care for children or adolescents with IBD at some point in their practice. We also aimed to maintain the focus of this book on the pediatric aspects of IBD, rather than simply recapitulating the excellent general IBD textbooks already available. This was easier in some chapters than others, highlighting both the progress that has been made in studying IBD in children and also the need for further pediatric based studies. Also included is a unique section highlighting some topics such as advocacy, and transition of care from pediatric- to internist-gastroenterologists—areas where even experienced physicians may need guiding resources. Pediatric IBD continues to grow as a discipline, and certainly many changes have occurred over the past few years. Our understanding of the immune system and its interplay with the environment and genetic susceptibilities has vastly improved providing us with further insight into the etiology and pathogenesis of the constellation of disorders that are defined by the term IBD. New approaches to treatment have been discovered, and new drugs developed. This textbook discusses these new approaches to treatment and aims at improving one’s knowledge of the pathogenesis, epidemiology, diagnosis, and treatment of Pediatric IBD. We hope that our readers will profit by the collective experience, resulting in improved care for children afflicted by IBD.

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Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xxiii Section 1

Etiology and Pathogenesis

Chapter 1. Genetics of Inflammatory Bowel Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Nancy McGreal and Judy H. Cho Introduction........................................................................................................... 3 Crohn Disease and Ulcerative Colitis: Genetic Epidemiology ........................... 4 Identifiable Gene Variants in Crohn Disease ...................................................... 5 Genome-wide Association Studies in Crohn Disease ......................................... 7 Genetic Studies in Ulcerative Colitis................................................................... 8 Genotype-Phenotype Correlations in Pediatric IBD............................................ 9 Summary ............................................................................................................... 11 Chapter 2. Gut Immunity and Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . William A. Faubion and Claudio Fiocchi Introduction........................................................................................................... Innate Intestinal Immunity and IBD .................................................................... Development of the Epithelial Barrier and Innate Immune Cells....................... Adaptive Intestinal Immunity and IBD................................................................ Putting it all Together: Integrating Gut Microbes, Epithelial Cells, and Lymphocytes in the Pathogenesis of IBD .................................... Innate and Adaptive Immune Responses Unique to Pediatrics........................... Summary ...............................................................................................................

15

Chapter 3. Cytokines and Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Edwin F. de Zoeten and Ivan J. Fuss Introduction........................................................................................................... Pro-inflammatory Cytokines ................................................................................ Anti-inflammatory Cytokines............................................................................... Summary ...............................................................................................................

31

Section 2

15 16 19 19 23 24 25

31 32 37 39

Epidemiology and Clinical Features

Chapter 4. Epidemiology of Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . 45 Shehzad Saeed and Subra Kugathasan

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Introduction........................................................................................................... Descriptive Epidemiology .................................................................................... Hygiene Hypothesis and Other Epidemiological Observation in IBD ............................................................................................................. Environmental Risk Factors ................................................................................. Appendectomy ...................................................................................................... Breast Feeding ...................................................................................................... Dietary Factors ..................................................................................................... Drugs..................................................................................................................... Socio-Economical, Educational and Occupational Status ................................... Stress ..................................................................................................................... New Epidemiology ............................................................................................... Genetic Epidemiology & its Impact on the Pathogenesis of IBD ...................... Challenges in the Way Forward; Genes and Environmental Interactions...................................................................................................... IBD Among New Populations ............................................................................. New Approaches................................................................................................... Summary ............................................................................................................... Chapter 5. Early Onset Inflammatory Bowel Disease- Epidemiology and Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Melvin B. Heyman and Neera Gupta Introduction........................................................................................................... Epidemiology of Pediatric Inflammatory Bowel Disease ................................... Clinical Features of Pediatric Inflammatory Bowel Disease ..............................

45 46 49 51 53 53 53 54 54 55 55 55 55 56 56 57 61 61 61 63

Chapter 6. The Natural History of Pediatric Crohn Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . James Markowitz Introduction........................................................................................................... Disease Activity.................................................................................................... Evolution of Disease Phenotype .......................................................................... Growth .................................................................................................................. Corticosteroid Dependence................................................................................... Surgery.................................................................................................................. Postoperative Recurrence ..................................................................................... Cancer Risk........................................................................................................... Quality of Life ......................................................................................................

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Chapter 7. Natural History of Pediatric Ulcerative Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jeffrey S. Hyams Introduction........................................................................................................... Historical Perspective – Children......................................................................... Historical Perspective – Adults............................................................................ Clinical Characteristics Influencing Course......................................................... Drug Modification of Natural History ................................................................. Can We Predict the Course of Disease? .............................................................. Summary ...............................................................................................................

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67 67 68 69 69 69 70 70 72

75 75 76 77 77 79 79

Chapter 8. Natural History of Pediatric Indeterminate Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Michael D. Kappelman and Richard J. Grand Introduction........................................................................................................... 83 Factors Leading to a Diagnosis of Indeterminate Colitis.................................... 84

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Definitions............................................................................................................. Epidemiology........................................................................................................ Natural History ..................................................................................................... Recommendations................................................................................................. Summary ...............................................................................................................

85 85 86 89 89

Chapter 9. Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease . . . . . Shervin Rabizadeh and Maria Oliva-Hemker Introduction........................................................................................................... Growth Failure...................................................................................................... Joint Manifestations.............................................................................................. Bone Disease ........................................................................................................ Oral Lesions.......................................................................................................... Skin Lesions ......................................................................................................... Eye Lesions........................................................................................................... Liver Disease ........................................................................................................ Other Extraintestinal Manifestations.................................................................... Summary ...............................................................................................................

91 91 92 93 93 94 94 96 97 98 99

Chapter 10. Growth Impairment in Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . 103 Thomas D. Walters and Anne M. Griffiths Introduction........................................................................................................... 103 Normal Growth and Pubertal Development ........................................................ 103 Growth in Pediatric IBD ...................................................................................... 104 Pathophysiology of Growth Impairment in IBD ................................................. 107 Facilitation of Normal Growth in IBD ................................................................ 110 General Principles of Management ...................................................................... 110 Summary ............................................................................................................... 114 Chapter 11. Skeletal Health in Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . 119 Francisco Sylvester Introduction........................................................................................................... 119 Growth, Bone Modeling and Remodeling ........................................................... 119 Bone Cells and Inflammation............................................................................... 121 Effects of Intestinal Inflammation on Bone......................................................... 123 Conclusions........................................................................................................... 128 Chapter 12. Puberty and Pediatric-Onset Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . 133 Barbara S. Kirschner and Barry H. Rich Introduction........................................................................................................... 133 The Pubertal Process in Healthy Children and Adolescents ............................... 133 The Influence of Inflammatory Bowel Disease on Puberty................................ 135 Pubertal Arrest ...................................................................................................... 136 Potential Causes of Pubertal Delay in Patients with IBD ................................... 136 Psyschosocial Issues and Puberty ........................................................................ 139 Therapeutic Approach to Addressing Pubertal Issues in IBD............................. 139 Chapter 13. Classification of Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . 143 Athos Bousvaros Introduction........................................................................................................... 143 Diagnostic Evaluation of Inflammatory Bowel Disease ..................................... 143

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Distinguishing Acute Self-limited Colitis from Inflammatory Bowel Disease Involving the Colon ..........................................................................144 Distinguishing Ulcerative Colitis from Crohn Disease ....................................... 145 “Indeterminate Colitis” or “Colonic IBD Type Unclassified” ............................ 150 Subclassification of Ulcerative Colitis and Crohn Disease................................. 152 Summary ............................................................................................................... 153 Section 3

Diagnosis

Chapter 14. The History and Physical Exam in Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Cheryl Blank and David J. Keljo Introduction........................................................................................................... 159 History................................................................................................................... 159 Physical Exam ...................................................................................................... 161 Conclusion ............................................................................................................ 162 Chapter 15. Differential Diagnosis of Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Thierry Lamireau Introduction........................................................................................................... 165 Acute Onset Diarrhea ........................................................................................... 165 Chronic or Recurrent Intestinal Symptoms.......................................................... 167 Abdominal Mass................................................................................................... 172 Isolated Esophagogastroduodenal Involvement ................................................... 173 Isolated Perianal Disease...................................................................................... 173 Chapter 16. Laboratory Evaluation of Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Jennifer Strople and Benjamin D. Gold Introduction........................................................................................................... 179 Blood Tests ........................................................................................................... 179 Stool Evaluation ................................................................................................... 186 Summary ............................................................................................................... 187 Chapter 17. Radiologic Evaluation of Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Benedict C. Nwomeh and Wallace V. Crandall Introduction........................................................................................................... 193 Crohn Disease....................................................................................................... 193 Imaging Techniques ............................................................................................. 194 Ulcerative Colitis .................................................................................................. 198 Imaging Techniques ............................................................................................. 198 Indeterminate Colitis ............................................................................................ 200 Other Radiologic Modalities in IBD.................................................................... 200 Evaluation of Complications ................................................................................ 202 Extraintestinal Disease ......................................................................................... 205 Hepatobiliary Disease........................................................................................... 205 Bone and Joint Disease ........................................................................................ 205 Future Trends........................................................................................................ 206

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Chapter 18. Endoscopic Modalities in Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . 211 Krishnappa Venkatesh and Mike Thomson Introduction........................................................................................................... 211 Endoscopy – Background History ....................................................................... 211 Patient Preparation................................................................................................ 212 Bowel Preparation ................................................................................................ 213 Monitoring and Sedation ...................................................................................... 214 Endoscopic Techniques in Inflammatory Bowel Disease ................................... 215 Ileocolonoscopy .................................................................................................... 217 Ileocolonoscopy Basic Technique........................................................................ 218 Complications of Ileocolonoscopy ....................................................................... 226 Endoscopic Findings in Inflammatory Bowel Disease........................................ 227 Follow-up and Surveillance Ileocolonoscopy ...................................................... 228 Enteroscopy........................................................................................................... 229 Double Balloon Enteroscopy................................................................................ 231 Endosonography ................................................................................................... 233 New Endo-diagnostic Methods ............................................................................ 234 Summary ............................................................................................................... 235 Chapter 19. The Pathology of Chronic Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . 241 Pierre Russo Introduction........................................................................................................... 241 Major Histologic Features Noted in Mucosal Specimens ................................... 241 Pathologic Features of Ulcerative Colitis and Crohn Disease ............................ 243 Ulcerative Colitis .................................................................................................. 245 Crohn Disease....................................................................................................... 248 Backwash Ileitis.................................................................................................... 254 Upper GI Tract Involvement in UC..................................................................... 255 Chapter 20. Video Capsule Endoscopy in Pediatric Inflammatory Bowel Disease . . . . . . . . . 263 Marc Girardin and Ernest G. Seidman Introduction........................................................................................................... 263 Potential Uses of Capsule Endoscopy for Inflammatory Bowel Disease ........... 265 Detection of Post-operative Recurrence............................................................... 267 Indeterminate Colitis ............................................................................................ 267 Experience in Pediatric Inflammatory Bowel Disease ........................................ 267 Specificity of Capsule Findings ........................................................................... 267 Practical Issues in Pediatric Patients.................................................................... 268 Conclusions........................................................................................................... 271 Chapter 21. Bone Health Assessment in Pediatric Inflammatory Bowel Disease . . . . . . . . . . 275 Meena Thayu, Edisio Semeao and Mary B. Leonard Introduction........................................................................................................... 275 Skeletal Modeling and Bone Accrual During Childhood.................................... 276 Changes in Cortical and Trabecular Bone with Growth ..................................... 277 Potential Threats to Bone Health in Pediatric IBD ............................................. 278 Assessment of Bone Status in Children and Adolescents ................................... 280 Clinical Studies of Bone Health in Pediatric IBD............................................... 283 Potential Therapies for Bone Health in Pediatric IBD........................................ 285 Summary ............................................................................................................... 287

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Chapter 22. Assessment of Growth and Nutritional Status in Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 Babette Zemel Introduction........................................................................................................... 295 Medical History and Laboratory Evaluation........................................................ 295 Anthropometry...................................................................................................... 296 Skeletal Maturation............................................................................................... 302 Sexual Maturation................................................................................................. 303 Summary ............................................................................................................... 304 Section 4

Medical Therapy

Chapter 23. Pharmacogenetics in Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . 309 Marla C. Dubinsky Introduction........................................................................................................... 309 A Historical Perspective of TPMT Pharmacogenetics ........................................ 309 Pharmacology of Thiopurines .............................................................................. 311 The Clinical Application of TPMT Pharmacogenetics ....................................... 312 Pharmacokinetics: The Role of Metabolite Monitoring ...................................... 313 Conclusion ............................................................................................................ 314 Chapter 24. 5-Aminosalicylate Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 M. Susan Moyer Introduction........................................................................................................... 317 Pharmacokinetics .................................................................................................. 317 Mechanism of Action ........................................................................................... 320 Indications and Efficacy ....................................................................................... 320 Safety and Side Effects ........................................................................................ 323 Adherence ............................................................................................................. 324 Future Directions .................................................................................................. 324 Chapter 25. Antibiotic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Douglas Jacobstein and Howard Kader Introduction........................................................................................................... 329 Antibiotic Use in Crohn Disease.......................................................................... 330 Antibiotics in Ulcerative Colitis........................................................................... 332 Emerging Therapies.............................................................................................. 333 Summary ............................................................................................................... 334 Chapter 26. Nutritional Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 Wael El Matary and Mary Zachos Introduction........................................................................................................... 337 Nutritional Impairment in Pediatric Inflammatory Bowel Disease..................... 337 General Management of Nutrition in Inflammatory Bowel Disease .................. 339 Adverse Effects of Enteral Nutrition ................................................................... 345 Mechanisms of Enteral Nutrition ......................................................................... 346 Conclusions........................................................................................................... 347 Chapter 27. Probiotic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 David R. Mack Introduction........................................................................................................... 351 Ulcerative Colitis .................................................................................................. 352 Pouchitis................................................................................................................ 354

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Crohn’s Disease .................................................................................................... 355 Associated Conditions .......................................................................................... 357 Summary ............................................................................................................... 357 Chapter 28. Corticosteroid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Johanna C. Escher Introduction........................................................................................................... 363 The Working Mechanism of Corticosteroids....................................................... 363 Systemic Corticosteroids ...................................................................................... 364 Topical Corticosteroids......................................................................................... 364 Efficacy of Oral Budesonide Treatment in Crohn Disease ................................. 365 Side Effects of Budesonide in Children............................................................... 366 Maintenance Treatment in Crohn Disease........................................................... 368 Budesonide Enemas in Ulcerative Colitis............................................................ 368 Conclusion ............................................................................................................ 368 Chapter 29. 6-Mercaptopurine Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 Carmen Cuffari Introduction........................................................................................................... 371 Clinical Indication ................................................................................................ 371 Drug Monitoring................................................................................................... 373 6-MP Toxicity....................................................................................................... 376 Conclusions........................................................................................................... 376 Chapter 30. Methotrexate Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 Joel R. Rosh Introduction........................................................................................................... 379 Mechanism of Action ........................................................................................... 380 Dose and Administration...................................................................................... 381 Efficacy ................................................................................................................. 382 Toxicity and Monitoring ...................................................................................... 383 Summary ............................................................................................................... 384 Chapter 31. Infliximab Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Séverine Vermeire, Gert Van Assche and Paul Rutgeerts Introduction........................................................................................................... 387 Efficacy of Infliximab in Adult Crohn Disease................................................... 388 Efficacy of Infliximab in Paediatric Crohn Disease............................................ 389 Infliximab for Paediatric Ulcerative Colitis......................................................... 392 Side Effects and Safety Profile of Infliximab...................................................... 393 Summary ............................................................................................................... 397 Chapter 32. Biologic Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Jeanne Tung and William J. Sandborn Introduction........................................................................................................... 403 Anti-tumor Necrosis Factor.................................................................................. 403 Anti-adhesion........................................................................................................ 410 Anti-interleukin 12/23 .......................................................................................... 413 Anti-interleukin-2 Receptor (Anti-CD25)............................................................ 414 Miscellaneous Biotechnology Agents .................................................................. 414

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Chapter 33. Treatment of Perianal Crohn Disease Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Mark T. Osterman and Gary R. Lichtenstein Introduction........................................................................................................... 429 Background ........................................................................................................... 429 Medical Treatment................................................................................................ 431 Summary ............................................................................................................... 439 Chapter 34. Treatment of Fulminant Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 Harland Winter Case....................................................................................................................... 447 Discussion ............................................................................................................. 449 Section 5

Surgical Therapy

Chapter 35. Surgical Management of Crohn’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 Daniel von Allmen Introduction........................................................................................................... 455 History of Surgical Therapy................................................................................. 455 Operative Indications............................................................................................ 456 Surgical Emergencies ........................................................................................... 457 Elective Surgery ................................................................................................... 458 Surgical Therapy................................................................................................... 459 Stricturoplasty ....................................................................................................... 461 Laparoscopy.......................................................................................................... 462 Colonic Disease .................................................................................................... 462 Perineal Disease.................................................................................................... 463 Rectal Strictures.................................................................................................... 463 Impact of Medical Therapy .................................................................................. 464 Post-operative Recurrence .................................................................................... 464 Adjuvant Procedures............................................................................................. 464 Chapter 36. Surgical Treatment of Ulcerative Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469 Peter Mattei and John L. Rombeau Introduction........................................................................................................... 469 Indications for Surgery ......................................................................................... 469 Surgical Procedures .............................................................................................. 471 Preparation for Surgery ........................................................................................ 475 Outcomes of Surgery............................................................................................ 476 Complications ....................................................................................................... 477 Current Trends and Future Considerations .......................................................... 479 Summary ............................................................................................................... 480 Chapter 37. Pouchitis After Ileal Pouch-Anal Anastomosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485 Christine Carter-Kent and Robert Wyllie Introduction........................................................................................................... 485 Definition and Incidence ...................................................................................... 486 Etiology and Pathogenesis.................................................................................... 486 Diagnosis............................................................................................................... 488 Classification......................................................................................................... 489 Treatment .............................................................................................................. 490 Outcome................................................................................................................ 491 Summary ............................................................................................................... 493

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Chapter 38. Enteral Feeding Devices and Ostomies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495 Susan N. Peck Gastrostomy .......................................................................................................... 495 Complications of Gastrostomy/Gastrojejenunostomy Tubes............................... 496 Ostomy Education and Management ................................................................... 501 Section 6

Research

Chapter 39. Clinical Indices for Pediatric Inflammatory Bowel Disease Research . . . . . . . . . 507 Angela Noble and Dan Turner Introduction........................................................................................................... 507 Assessment of Instruments Used in Clinical Research ....................................... 507 Outcomes for Clinical Research in Paediatric Inflammatory Bowel Disease .... 509 Gastrointestinal Endoscopy Indices ..................................................................... 515 Quality of Life Instruments.................................................................................. 516 Summary ............................................................................................................... 516 Appendix A........................................................................................................... 521 Appendix B........................................................................................................... 525 Appendix C........................................................................................................... 526 Appendix D........................................................................................................... 530 Chapter 40. Clinical Trials (Clinical Perspective) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 Salvatore Cucchiara and Osvaldo Borrelli Introduction........................................................................................................... 531 Markers and Indexes of Disease Activity............................................................ 531 Quality of Life ...................................................................................................... 536 Summary ............................................................................................................... 537 Chapter 41. Clinical Trials (Industry Perspective) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541 Allan David Olson Introduction........................................................................................................... 541 Key Players in the Drug Development Process................................................... 541 Drug Development Process .................................................................................. 543 Key Clinical Trial Design Features...................................................................... 545 The Regulatory Agencies and the Regulatory Process........................................ 545 Good Clinical Practice.......................................................................................... 545 Practicing Physicians and Conduct of Clinical Trials ......................................... 547 Economics of Drug Development ........................................................................ 548 Unique Issues in Pediatric Research: Dosing and Consent/Assent..................... 549 Impact of the Pediatric Rule(s) ............................................................................ 549 Summary ............................................................................................................... 549 Glossary of acronyms ........................................................................................... 550 Websites................................................................................................................ 551 Section 7

Special Considerations

Chapter 42. Psychological Aspects of Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . 555 Laura M. Mackner and Wallace V. Crandall Introduction........................................................................................................... 555 Behavioral/Emotional Functioning....................................................................... 555 Social Functioning ................................................................................................ 558 Family Functioning............................................................................................... 559

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Contents

Body Image and Self-esteem ............................................................................... 559 Stress and Coping ................................................................................................. 560 Eating Problems.................................................................................................... 560 Education .............................................................................................................. 560 Psychotherapy and Other Resources .................................................................... 561 Summary ............................................................................................................... 561 Chapter 43. Measurement of Quality of Life in Pediatric Inflammatory Bowel Disease . . . 565 Anthony Otley Introduction........................................................................................................... 565 Quality of Life: Concepts/Definitions.................................................................. 565 Health-related Quality of Life Assessment in Pediatrics .................................... 568 Health-related Quality of Life Assessment in Inflammatory Bowel Disease: Adult IBD Perspective .....................................................................569 Health-related Quality of Life Assessment in Pediatric Inflammatory Bowel Disease.................................................................................................571 IMPACT ............................................................................................................... 572 Deficiencies in Current Knowledge and Areas for Future Research .................. 576 Chapter 44. Irritable Bowel Syndrome and Functional Gastrointestinal Disorders in Pediatric Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 Manu R. Sood Introduction........................................................................................................... 581 Epidemiology........................................................................................................ 581 Clinical Features ................................................................................................... 582 Pathophysiology.................................................................................................... 583 Diagnosis............................................................................................................... 586 Treatment .............................................................................................................. 587 “Irritable” Pouch Syndrome ................................................................................. 589 Summary ............................................................................................................... 589 Chapter 45. Inflammatory Bowel Disease in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593 Sunanda Kane Introduction........................................................................................................... 593 Onset and Diagnosis During Pregnancy .............................................................. 593 Contraception........................................................................................................ 593 Fertility.................................................................................................................. 594 Effect of IBD on Pregnancy................................................................................. 595 Effect of Pregnancy on IBD................................................................................. 595 Management of IBD During Pregnancy .............................................................. 596 Medical Therapies ................................................................................................ 596 Immunomodulators ............................................................................................... 599 Breastfeeding ........................................................................................................ 602 Mode of Delivery ................................................................................................. 603 Surgery and Pregnancy......................................................................................... 604 Transition of Care................................................................................................. 604 Summary Points.................................................................................................... 605 Chapter 46. Malignant Tumors Arising in Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . 611 Thomas A. Ullman Introduction........................................................................................................... 611 Pathogenesis and Molecular Basis of Cancer in IBD ......................................... 611

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Colorectal Cancer in Ulcerative Colitis: Epidemiology and Clinical Practice ... 613 Colorectal Cancer in Crohn Disease .................................................................... 622 Crohn Disease and Adenocarcinoma of the Small Intestine ............................... 624 Other Malignancies............................................................................................... 624 Summary ............................................................................................................... 625 Chapter 47. Quality Improvement in Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . 631 Richard B. Colletti and Peter A. Margolis Introduction........................................................................................................... 631 Variation in Care .................................................................................................. 632 The Chronic Illness Care Model .......................................................................... 633 The Need for Quality Improvement in IBD ........................................................ 634 The Improvement Model...................................................................................... 635 The Improvement Collaborative .......................................................................... 636 Collaborative Networks ........................................................................................ 638 Chapter 48A. Advocacy for Pediatric Patients with Inflammatory Bowel Disease . . . . . . . . . . 641 Janis Arnold, Athos Bousvaros, and Jennifer C. Jaff Introduction........................................................................................................... 641 Advocacy Directed at Schools ............................................................................. 641 Advocacy Directed at Insurance Companies ....................................................... 644 Social Security Disability ..................................................................................... 648 Family and Medical Leave for Caregivers .......................................................... 649 Summary ............................................................................................................... 650 Appendix 1. Sample Letter for Patient’s Student File Regarding Educational Accommodations Needed for an IBD Diagnosis ......................650 Appendix 2. Preparing an Effective Insurance Company Letter of Medical Necessity ......................................................................................651 Appendix 3. Sample Letter for Appeal of Denial of Mental Health Benefits ..............................................................................652 Appendix 4. Social Security Listing of Impairments for Children with IBD .... 652 Appendix 5. Preparing an Effective Letter for Family Medical Leave Act Provisions.................................................................................................653 Chapter 48B. Legislative Advocacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655 Suzanne Rosenthal Introduction........................................................................................................... 655 Legislative Initiatives ........................................................................................... 656 Looking Back One Could Ask............................................................................. 658 Chapter 49. Transition from Pediatric to Adult Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661 George D. Ferry and M. Susan Moyer Introduction........................................................................................................... 661 Background ........................................................................................................... 662 Who is the Target ................................................................................................. 662 Goals/objectives.................................................................................................... 662 Transition Steps .................................................................................................... 663 Monitoring the Process......................................................................................... 664

Contributors

Janis Arnold, LICSW Pediatric Clinical Social Worker Inflammatory Bowel Disease Center Division of Gastroenterology and Nutrition Boston Children’s Hospital Boston, Massachusetts Robert N. Baldassano, MD Professor University of Pennsylvania School of Medicine Attending Physician and Director, Inflammatory Bowel Disease Center The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Cheryl Blank, DO Assistant Professor of Pediatrics University of Pittsburgh School of Medicine Department of Gastroenterology Children’s Hospital of Pittsburgh of UMPC Pittsburgh, Pennsylvania Osvaldo Borrelli, MD Pediatric Gastroenterology and Liver Unit Pediatric Inflammatory Bowel Disease Center University of Rome “La Sapienza” Rome, Italy Athos Bousvaros, MD, MPH Associate Director, Inflammatory Bowel Disease Center Boston Children’s Hospital Boston, Massachusetts Christine Carter-Kent, MD Pediatric Gastroenterology Cleveland Clinic Foundation Cleveland, Ohio

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Contributors

Judy H. Cho, MD Associate Professor of Medicine and Pediatrics Director, Inflammatory Bowel Disease Center Yale University New Haven, Connecticut Richard B. Colletti, MD Professor and Vice-Chair Department of Pediatrics Associate Chief, Vermont Children’s Hospital University of Vermont Burlington, Vermont Wallace V. Crandall, MD, FAAP Associate Professor of Clinical Pediatrics The Ohio State University Director, The Center for Pediatric and Adolescent IBD Columbus Children’s Hospital GI & Nutrition Columbus, Ohio Salvatore Cucchiara, MD, PhD Division of Pediatric and Liver Unit, Head Pediatric Inflammatory Bowel Disease Center, Director University Hospital Umberto 1 University of Rome “La Sapienza” Rome, Italy Carmen Cuffari, MD The Johns Hopkins Hospital Department of Pediatrics, Division of Gastroenterology Baltimore, Maryland Edwin F. de Zoeten, MD, PhD Division of Gastroenteroloyg, Hepatology and Nutrition The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Marla C. Dubinsky, MD Assistant Professor of Pediatrics David Geffen School of Medicine University of California at Los Angeles Director Pediatric IBD Center Cedars-Sinai Medical Center Los Angeles, California Wael El Matary, MBBCH, MD, MRCP Assistant Professor of Pediatrics University of Alberta

Contributors

Division of Gastroenterology – Department of Pediatrics Stollery Children’s Hospital Edmonton, Alberta Canada Johanna C. Escher, MD, PhD Erasmus MC-Sophia Children’s Hospital University Medical Center Department of Pediatric Gastroenterology Rotterdam, The Netherlands William A. Faubion, Jr, MD Department of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota George D. Ferry, MD Professor of Pediatrics Baylor College of Medicine Director, IBD Center Texas Children’s Hospital Houston, Texas Claudio Fiocchi, MD The Cleveland Clinic Foundation Department of Gastroenterology and Hepatology Department of Pathobiology, Lerner Research Institute Cleveland, Ohio Ivan J. Fuss, MD National Institute of Allergy Immunology and Infectious Disease Mucosal Immunity Section National Institutes of Health Bethesda, Maryland Marc Girardin, MD Research Fellow McGill Center for IBD Division of Gastroenterology Faculty of Medicine McGill University Montreal, Quebec Canada Benjamin D. Gold, MD Professor of Pediatrics and Microbiology Marcus Professor and Director Division of Pediatric Gastroenterology, Hepatology and Nutrition Emory University School of Medicine Atlanta, Georgia

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Contributors

Richard J. Grand, MD Center for Inflammatory Bowel Disease Treatment and Research Division of Gastroenterology and Nutrition Children’s Hospital Boston and Department of Pediatrics Harvard Medical School Boston, Massachusetts Anne M. Griffiths, MD, FRCP (C) Professor of Paediatrics Division of Gastroenterology/Nutrition The Hospital for Sick Children Toronto, Ontario Canada Neera Gupta, MD, MAS Department of Pediatrics Pediatric Gastroenterology, Hepatology and Nutrition University of California, San Francisco San Francisco, California Melvin B. Heyman, MD, MPH Department of Pediatrics Pediatric Gastroenterology, Hepatology and Nutrition University of California, San Francisco San Francisco, California Jeffrey S. Hyams, MD Professor of Pediatrics University of Connecticut School of Medicine Head, Division of Digestive Diseases and Nutrition Connecticut Children’s Medical Center Hartford, Connecticut Douglas Jacobstein, MD Division of Pediatric Gastroenterology Sinai Hospital of Baltimore Baltimore, Maryland Jennifer C. Jaff, Esq. Executive Director Advocacy for Patients with Chronic Illness, Inc. Farmington, Connecticut Howard Kader, MD Division of Pediatric Gastroenterology Sinai Hospital of Baltimore Baltimore, Maryland

Contributors

Sunanda Kane, MD Department of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota Michael D. Kappelman, MD, MPH Assistant Professor of Pediatrics University of North Carolina Chapel Hill 5143 Bioinformatics Bldg; CB#7229 Chapel Hill, NC 27599 E-mail: [email protected] David J. Keljo, MD, PhD Professor of Pediatrics University of Pittsburgh School of Medicine Director, Inflammary Bowel Disease Center Department of Gastroenterology Children’s Hospital of Pittsburch of UMPC Pittsburgh, Pennsylvania Barbara S. Kirschner, MD Professor of Pediatrics Section of Pediatric Gastroenterology, Hepatology & Nutrition Department of Pediatrics The University of Chicago The University of Chicago Corner Children’s Hospital Chicago, Illinois Email: [email protected] Subra Kugathasan, MD Associate Professor of Pediatrics Department of Pediatrics Medical College of Wisconsin Milwaukee, Wisconsin Thierry Lamireau, MD, PhD Division of Pediatric Gastroenterology Children’s Hospital Victor Segalen University of Badeaux2 Bordeaux, France Mary B. Leonard, MD, MSCE Department of Pediatrics The Children’s Hospital of Philadelphia Department of Biostatistics and Epidemiology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

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Contributors

Gary R. Lichtenstein, MD Hospital of the University of Pennsylvania University of Pennsylvania School of Medicine Division of Gastroenterology Philadelphia, Pennsylvania David R. Mack, MD, FAAP, FRCPC Professor, Department of Pediatrics University of Ottawa Head, Pediatric Gastroenterology, Hepatology & Nutrition Children’s Hospital of Eastern Ontario Ottawa, Ontario Canada Laura M. Mackner, PhD Division of Psychology Department of Pediatrics Columbus Children’s Hospital and The Ohio State University Petar Mamula, MD Assistant Professor of Pediatrics University of Pennsylvania School of Medicine Attending Physician, Division of G.I. and Nutrition The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Peter A. Margolis, MD, PhD Professor and Co-Director, Center for Health Care Quality Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio James Markowitz, MD Professor of Pediatrics New York University School of Medicine Attending Pediatrician North Shore – LIJ Health System Division of Pediatric Gastroenterology Schneider Children’s Hospital New Hyde Park, New York Jonathan E. Markowitz, M.D., M.S.C.E Associate Professor of Clinical Pediatrics University of South Carolina School of Medicine Attending Physician, Children’s Center for Digestive Health Greenville Hospital System University Medical Center Greenville, South Carolina

Contributors

Peter Mattei, MD Department of General, Thoracic and Fetal Surgery The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Nancy McGreal, MD Fellow, Medicine and Pediatrics University of Chicago Chicago, Illinois M. Susan Moyer, MD Cincinnati Children’s Hospital Medical Center Division of GI, Hepatology & Nutrition Cincinnati, Ohio Angela Noble, MD Clinical Instructor in Pediatrics Department of Gastroenterology, Hepatology and Nutrition St. Justine Hospital University of Montreal Montreal, Canada Benedict C. Nwomeh, MD, FACS, FAAP Assistant Professor of Surgery The Ohio State University Surgical Director, The Center for Pediatric and Adolescent IBD Columbus Children’s Hospital Columbus, Ohio Maria Oliva-Hemker, MD Division of Pediatric Gastroenterology and Nutrition The Johns Hopkins University School of Medicine Baltimore, Maryland Allan David Olson, MD, MS, MBA Director Immunology Centocor, Inc. Horsham, Pennsylvania Mark T. Osterman, MD Division of Gastroenterology Department of Medicine Pennsylvania Presbyterian Medical Center University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Anthony Otley, MD, MSc, FRCPC Division of Gastroenterology, Department of Pediatrics Associate Professor, Dalhousie University Halifax, Nova Scotia Canada

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Contributors

Susan N. Peck, MSN, CRNP Division of GI, Hepatology and Nutrition The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Shervin Rabizadeh, MD, MBA Division of Pediatric Gastroenterology and Nutrition The Johns Hopkins University School of Medicine Baltimore, Maryland Barry H. Rich, MD Associate Professor Section of Pediatric Endocrinology Department of Pediatrics The University of Chicago Chicago, Illinois John L. Rombeau, MD University of Pennsylvania School of Medicine Department of Surgery Division of Colon and Rectal Surgery Philadelphia, Pennsylvania Suzanne Rosenthal Crohn’s & Colitis Foundation of America, Inc. Co-Founder, Chairman of the Board Emerita Joel R. Rosh, MD Director, Pediatric Gastroenterology Atlantic Health/Goryeb Children’s Hospital Associate Professor of Pediatrics UMD – New Jersey Medical School Morristown, New Jersey Pierre Russo, MD Chief, Anatomic Pathology Department of Pathology The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Paul Rutgeerts, MD, PhD, FRCP Division of Gastroenterology University Hospital Leuven Leuven, Belgium Shehzad A. Saeed, MD Associate Professor of Pediatrics Department of Pediatrics and Nutrition Sciences Division of Gastroenterology and Nutrition

Contributors

The University of Alabama at Birmingham and The Children’s Hospital of Alabama Birmingham, Alabama William J. Sandborn, MD Professor of Medicine Mayo College of Medicine Vice Chairman, Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota Ernest G. Seidman, MD, FRCPC, FACG Bruce Kaufman Chair in IBD at McGill Professor of Medicine & Pediatrics McGill University Health Center Montreal Children’s Hospital Montreal, Quebec Canada Edisio Semeao, MD Department of Pediatrics The Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Manu R. Sood, MD Associate Professor of Pediatrics Department of Pediatrics Medical College of Wisconsin Milwaukee, Wisconsin Jennifer Strople, MD Division of Pediatric Gastroenterology, Hepatology and Nutrition Children’s Memorial Hospital Chicago, Illinois Francisco Sylvester, MD Associate Professor of Pediatrics University of Connecticut School of Medicine Connecticut Children’s Medical Center Hartford, Connecticut Meena Thayu, MD Department of Pediatrics The Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

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Contributors

Dr. Mike Thomson Centre for Pediatric Gastroenterology Sheffield Children’s NHS Foundation Trust Sheffield, United Kingdom Jeanne Tung, MD Division of Gastroenterology and Hepatology Department of Pediatrics Mayo Clinic Rochester, Minnesota Dan Turner, MD Department of Gastroenterology, Hepatology and Nutrition St. Justine Hospital University of Montreal Montreal, Canada Thomas A. Ullman, MD Assistant Professor of Medicine The Dr. Henry D. Janowitz Division of Gastroenterology The Mount Sinai School of Medicine New York, New York Gert Van Assche, MD, PhD Division of Gastroenterology University Hospital Leuven Leuven, Belgium Dr. Krishnappa Venkatesh Centre for Pediatric Gastroenterology Sheffield Children’s NHS Foundation Trust Sheffield, United Kingdom Séverine Vermeire, MD, PhD Division of Gastroenterology University Hospital Leuven Leuven, Belgium Daniel von Allmen, MD Division of Pediatric Surgery The University of North Carolina Chapel Hill Chapel Hill, North Carolina Thomas D. Walters, MBBS, FRACP The Hospital for Sick Children University of Toronto Toronto, Canada

Contributors

Harland Winter, MD Pediatric GI Unit-MGH 175 Cambridge Street-CPZS-560 Boston, MA 02114 Robert Wyllie, MD Cleveland Clinic Foundation Chair, Department of Pediatric GI and Nutrition Cleveland, Ohio Mary Zachos, MD, FRCPC Assistant Professor Department of Pediatrics University of Toronto Clinical Director – Inflammatory Bowel Disease Program Staff Gastroenterologist, Hospital for Sick Children The Hospital for Sick Children Toronto, Ontario Canada Babette Zemel, PhD Director, Nutrition and Growth Laboratory Division of Gastroenterology, Hepatology and Nutrition The Children’s Hospital of Philadelphia Associate Professor of Pediatrics University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

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Section 1 Etiology and Pathogenesis

1 Genetics of Inflammatory Bowel Diseases Nancy McGreal and Judy H. Cho∗

Introduction The inflammatory bowel diseases (IBD), Crohn disease and ulcerative colitis, are immune-mediated disorders resulting in chronic, relapsing inflammation of the gastrointestinal tract. While no specific etiology has been defined, the complex nature of IBD supports the notion that its origin is likely multi-factorial. Current theory suggests that in genetically predisposed individuals, environmental factors and maladaptive immune responses to gastrointestinal flora generate a dysregulated inflammatory cascade creating mucosal injury. Over the last decade, considerable interest and research has focused on the genetic aspect of IBD. The identification of linkage between Crohn disease and the pericentromeric region of chromosome 16 (IBD1) by Hugot in 1996, spawned a series of genome scans and linkage analyses in search of susceptibility and phenotypic modifier genes [1]. In 2001, the discovery that specific polymorphisms in the CARD15/NOD2 gene at the IBD1 locus were associated with Crohn disease engendered a new era of genotype-phenotype investigations [2, 3]. The advent of genome-wide association studies has resulted in the successful identification of new, well-replicated disease associations. The heterogeneity of IBD phenotypes suggests that it is a polygenic disorder in which susceptibility loci act in epistasis with other disease-modifying genes and the environment to produce disease. The field of IBD genetics is of special interest to pediatric gastroenterologists for both practical and investigational reasons. From a clinical practice standpoint, pediatric gastroenterologists are often faced with questions from concerned parents regarding the risk of IBD among current or future siblings, as well as the eventual offspring of the affected child. Understanding genetic associations of IBD can provide patients and their families with useful information that may help them cope with the disease. Furthermore, as our knowledge of genotype-phenotype associations grows, it is anticipated that genotyping at the onset of disease may enable physicians to predict disease course and tailor medical therapies specific for each patient. In terms of advancing the field of gastroenterology through research, studies of pediatric IBD genetics are of significance because children have been exposed to fewer environmental confounders of disease than their adult counterparts. Examining the disease of young individuals could provide us with keys to unlock intrinsic genetic mechanisms in IBD that may not otherwise be detected in adult studies. This may be of special importance in individuals with very early

*Associate Professor of Medicine and Pediatrics, Director, Inflammatory Bowel Disease Center, Yale University, Phone: 203-785-4138

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Nancy McGreal and Judy H. Cho

onset IBD (< 5 years), whose disease course and phenotypes are the most discordant with those of adult-onset IBD.

Crohn Disease and Ulcerative Colitis: Genetic Epidemiology Ethnic and Racial Variations of Disease That IBD has a genetic component is supported by ethnic and racial variations in disease prevalence. The highest rates of IBD are found in Caucasian individuals, especially those of Jewish heritage. Among Jewish sub-groups, Ashkenazi Jews have a 2 to 9 fold greater prevalence of IBD over non-Jewish counterparts [4]. This increased occurrence has been noted to be stable over time and geographic distribution, substantiating the important role of genetics in IBD. African Americans and Asians are believed to have a lower risk of IBD; although there appears to be a trend towards growing prevalence in these populations. In a study of the impact of race and ethnicity on IBD, Basu et al. found that African Americans and whites were more likely to have Crohn disease, whereas ulcerative colitis predominated among Mexican Americans [5]. While intestinal manifestations did not appear to vary based upon race or ethnicity, there were differences in extraintestinal manifestation between groups. Among Crohn patients, African Americans were more likely to evidence arthritis and uveitis than whites, whereas, joint symptoms and osteoporosis were more common among whites with UC than Mexican Americans. Family Studies The concept that IBD may, in part, be hereditary has been well-established through observations of familial disease aggregation. Family studies have demonstrated that 5–30% of probands with Crohn disease and ulcerative colitis identify the presence of IBD in a family member [4]. This association appears to be stronger for Crohn disease than ulcerative colitis. Phenotypically, relatives of probands with IBD are more likely to develop the same form of disease as the affected family member. Furthermore, there is literature to suggest that within families with IBD, there is a concordance between family members in terms of localization of disease, but not disease severity. With regard to age of disease onset, patients with a family history of IBD are thought to be more likely to develop disease at an earlier age than affected individuals lacking a family history [6]. Among family members, the risk of developing IBD is greatest among first degree relatives, especially siblings. The relative risk (RR) for a sibling of a Crohn patient developing disease is 13–26 and 7–17 for siblings of ulcerative colitis patients [7]. Parents of children with IBD are at a lower risk of developing disease than siblings [7]. With regard to the offspring of affected individuals, Orholm et al. found that 6.2% of children born to a parent with ulcerative colitis developed IBD and 9.2% of children born to a parent with Crohn disease developed IBD [8]. In the rare instance that both parents have IBD, studies estimate that their children have a 33% chance of developing IBD by age 28 [7]. Although, second and third degree relatives of IBD probands have a lower likelihood of disease, their risk is still elevated compared to the background population. Twin Studies Investigations of monozygotic and dizygotic twins have provided strong evidence that genetics play an integral role in the etiology of IBD. Twin studies are based upon the premise that in the setting of a similar environmental milieu, rates of disease concordance between twins correlate with the influence of genetic factors. To date, three large studies of twin pairs with IBD from Scandinavia and the United Kingdom have consistently identified higher concordance rates among monozygotic twins with Crohn disease and ulcerative colitis than dizygotic twins [9–11]. The

Chapter 1 Genetics of Inflammatory Bowel Diseases

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influence of genetics appears to be greater in Crohn disease than ulcerative colitis with reported cumulative monozygotic concordance rates of 36% and 16%, respectively [12]. Concordance rates for dizygotic twins are approximately 4% in both Crohn disease and ulcerative colitis. Similar to data from family studies, co-twins with IBD are likely to develop the same disease type, however, mixed pairs of dizygotic twins with ulcerative colitis and Crohn disease have been reported. With regard to disease-specific characteristics, Scandinavian twin registries demonstrated concordance of 40–77% for disease location, however, there appeared to be no association of disease behavior or extent among co-twins [9, 11]. Furthermore, a trend towards concordance for age at diagnosis was identified with 40–67% receiving a diagnosis of IBD within 2 years of one another. Taken together, the data from twin studies regarding concordance between monozygoytes provides evidence that genetic influences are important in the development of IBD. However, the fact that monozygotic concordance is not 100%, and the low concordance between dizygotes suggests that genotype alone is not sufficient for disease evolution.

Identifiable Gene Variants in Crohn Disease NOD2/CARD15 Gene and Crohn Disease The NOD2/CARD15 gene located on the IBD1 locus of chromosome 16 is associated with an increased susceptibility to Crohn disease but not ulcerative colitis. Among the more than 30 known amino acid polymorphisms identified in the NOD2/CARD15 gene [13], the most common variants are two missense mutations, R702W and G908R, and one frameshift mutation L1007fsinsC. From a disease pathogenesis perspective, NOD proteins (NOD1 and NOD2) are mammalian pattern recognition receptors which serve the innate immune system as bacterial sensing molecules. NOD2 is a cytosolic protein found in a variety of cells including monocytes, macrophages, B and T lymphocytes, dendritic cells, and intestinal epithelial cells. Stimulation of NOD2 by its ligand, muramyl dipeptide (MDP), propagates signal transduction pathways leading to nuclear factor B (NF-B) and mitogen activated protein kinase (MAPK) activation. Functional Effects of NOD2 Mutations How mutations in NOD2/CARD15 contribute to the pathogenesis of IBD remains an active area of research. In mice which lacked NOD2 [14, 15], no spontaneous intestinal inflammation was identified and bone marrow macrophage response to MDP was impaired. Further investigation into the impact of bacterial infection on NOD2 mutations showed that knockouts had increased susceptibility to infection with administration of oral Listeria monocytogenes compared to control mice. When Listeria was administered systemically, however, there was no difference in bacterial clearance between controls and NOD2 deficient mice. These findings substantiated the importance of NOD2 in bacterial recognition and activation of inflammatory pathways. They also served to identify a key antibacterial role for NOD2 in the intestinal epithelial layer which has been linked to -defensin deficiency in human Crohn disease [15]. Epidemiology of NOD2 Mutations Possession of one NOD2/CARD15 allele confers a two-three fold relative risk of developing Crohn disease; this risk is increased to 17-fold if two alleles are present [16]. Ten to thirty percent of patients with Crohn disease are heterozygous for one of the three mutations, while 3–15% are homozygous or compound heterozygotes [17]. Although these variants are associated with an increased risk of Crohn disease, 8–15% of the healthy population possesses at least one of these mutations and 1% of healthy individuals are homozygous or compound heterozygotes. That genotypic variants are found in individuals without known Crohn suggests phenotypic expression of disease is subject to polygenic factors, variable penetrance, and other environmental mediators.

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Studies of patients with Crohn disease world-wide have revealed that the association of NOD2/CARD15 polymorphisms with Crohn varies between different ethnic populations. North American adult Caucasian cohorts report carriage rates of 10–30% for the three common NOD2/CARD1 variants, while minority groups were found to have lower allele frequencies. A North American, multi-center study of pediatric patients with Crohn disease identified NOD2/CARD15 polymorphisms among 25% White, 1.6% African American, and 1.6% Hispanic participants [18]. Significant diversity in allele carriage has been described among Crohn patients in European countries and background control populations. NOD2/CARD15 variants are virtually absent in Japanese, Korean, Chinese, and sub-Saharan African individuals. High rates of NOD2/CARD15 mutations have been seen in the Jewish Ashkenazim with one Israeli group reporting the presence of variants in 51% of pediatric and 37.5% of adult Crohn patients studied [19]. SLC22A4/A5 Variants at the IBD5 Locus The IBD5 locus on chromosome 5 contains genes SLC22A4 and SLC22A5, also known as OCTN1 and OCTN2 (organic cation transporter proteins), respectively. While variants of these genes have been associated with both ulcerative colitis and Crohn disease, the linkage with Crohn appears stronger [20, 21]. Similar to the differential distribution of NOD2/CARD15 polymorphisms among various ethnic backgrounds, the OCTN variants also appear more prevalent in the Caucasian population than Asian populations [22]. Studies of Caucasian individuals demonstrate that possession of one OCTN allele increases the risk of Crohn disease by 2.5 fold and two copies raises the risk by 4 fold [23, 24]. Some studies have demonstrated an interactive effect between NOD2/CARD15 polymorphisms, however, these findings have not been consistently observed. Phenotypic correlates have been reported for perianal disease [25, 26], colonic location [27], disease complications and progression [21, 28], extensive disease in UC [20], as well as for decreased height and weight at diagnosis in pediatric cohorts [29]. In contrast, some studies have not observed clear genotype-phenotype correlations [30, 31]. DLG5 Gene Variants and IBD Polymorphisms of the DLG5 (Drosophila Discs Large Homolog 5) gene on chromosome 10q22–23 were reported to have an association with IBD by Stoll et al. [32] DLG5 is a member in the MAGUK (membrane-associated guanylate kinase) family which mediates protein-protein interactions and adhesion of epithelial cell junctions. DLG5 has been postulated to play a role in maintenance of the intestinal epithelial barrier and permeability. Given the known increase in intestinal permeability of Crohn patients and their family members, mutations in the DLG5 gene have been conceptualized to result in impaired barrier function predisposing to a disease state. In a case control cohort it was demonstrated that variants, G113A and C4136A, resulted in amino acid substitutions that conferred a relative modest risk of disease, 1.6 and 1.5, respectively [32]. A different DLG5 variant was found to be weakly associated with Crohn disease in the Japanese population [22]. German and Hungarian investigators, however, were unable to replicate disease susceptibility with any DLG5 polymorphisms [33], nor did they find evidence to suggest that DLG5 variants were associated with increased intestinal permeability in patients with Crohn disease. Thus, further investigation is needed to understand what role DLG5 mutations may play in the pathogenesis of IBD. HLA Type and IBD Susceptibility The IBD3 locus on chromosome 6p encodes genes in the HLA region which serve an immunoregulatory role and contribute to lymphocyte function. Associated polymorphisms between HLA types and IBD have included: HLA-B, HLA-DRB1, HLADQB1, HLA-DP, tumor necrosis factor

Chapter 1 Genetics of Inflammatory Bowel Diseases

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(TNF), heat shock protein (HSP)-70, and MICA [34]. The polymorphic nature of the HLA region as well as its complex linkage disequilibrium has resulted in heterogeneous findings among investigators. Of the greater than 100 association studies of IBD and HLA performed to date, stronger evidence exists for an association with class II alleles than class I alleles. Class II alleles DRB1*0103, DRB*1502, and DRB*401 have been consistently associated with ulcerative colitis [35]. Phenotypic analyses have identified DRB1*0103 to be predictive of a more aggressive form of ulcerative colitis with shorter time to colectomy than those without the allele. Polymorphisms of a TNF promoter resulting in a low TNF- producing haplotype have also been associated with limited ulcerative colitis that remains distal over the disease course [34]. In Crohn patients, a particular link between DRB1*0103 and isolated colonic disease has been reported [36]. The correlation of DRB1*0103 with both colonic Crohn disease and ulcerative colitis has been postulated to provide a unifying molecular mechanism for colonic involvement in IBD. The relatively low frequency of this allele, however, makes it less likely to be a true susceptibility gene. Rather, it probably functions as a disease modifying gene in epistasis with other genetic and environmental factors. HLA associations with extraintestinal manifestations have also been evaluated. One small study of both ulcerative colitis and Crohn disease identified a connection between TNF promoter variants and erythema nodosum [37]. HLA-B27, HLA-B35 and HLA-DRB*103 have been associated with type I peripheral arthropathy, whereas, HLA-B*44 is associated with type II peripheral arthropathy [38, 39]. Symptoms of uveitis have been linked with HLA-B27 and DRB*0103.

Genome-wide Association Studies in Crohn Disease A major new development in the field of complex human genetics has been the capacity to perform dense genotyping across the genome. This technological development has made possible the performance of genome-wide association studies. These genome-wide association studies have the capacity to assay a large fraction of the common human genetic variation throughout the genome and have the potential to markedly increase understanding of the genetic basis for complex, multigenic disorders. Thus far, a number of novel gene associations have been reported in Crohn disease which have demonstrated promising results in early studies. Association of IL23R (Interleukin 23 Receptor) Polymorphisms to Crohn Disease and Ulcerative Colitis A genome-wide association study in a North American ileal Crohn disease cohort identified multiple new gene associations, notably to multiple polymorphisms within the IL23R gene on chromosome 1p31 [40]. In particular, an amino acid polymorphism, Arg381Gln, located in the cytoplasmic domain of the IL23R protein, demonstrated highly significant evidence for association. The less common glutamine allele conferred significant protection against developing IBD in non-Jewish and Jewish Crohn disease cohorts, a well as in non-Jewish ulcerative colitis cohorts. Additional independent association signals were observed indicating the presence of multiple associations within the IL23R gene [40]. Since the initial report, the IL23R associations have been replicated in a childhood onset IBD cohort from Scotland [41], as well as in a Belgian CD cohort [42]. The functional IL-23 heterodimeric receptor is comprised of the IL23R (chromosome 1p31) and IL12RB2 (chromosome 19p13) [43] subunits, with the latter subunit shared with the functional IL-12 receptor (Figure 1.1). Similarly, the IL-23 cytokine is comprised of a unique subunit, p19 (chromosome 12q13), as well as the p40 subunit which is common to the IL-12 functional cytokine. Significant recent progress has been reported in understanding the role of the IL-23 pathway in mediating end-organ inflammation. Prior work with mouse models has demonstrated a requirement for IL-23 in murine colitis [44–47], experimental autoimmune encephalitis [48], and

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Nancy McGreal and Judy H. Cho IL-23 signaling p40 p19 chr12q13 chr5q33

IL-12 signaling p40 p35 chr5q33 chr3q25

Cytokine

Receptor

IL23R chr1p31

IL12RB1 chr19p13

IL12RB1 IL12RB2 chr19p13 chr1p31

Figure 1.1. Interleukin 23 and interleukin 12 signaling. Both pathways are comprised of heterodimeric cytokines and receptors and share common subunits of both the cytokine (p40) and receptor (IL12RB1).

collagen-induced arthritis. Similar IL23R gene associations have been reported in human psoriasis [49]. Taken together, these findings would suggest that blocking the IL-23 pathway may be efficacious in the treatment of IBD. In support of this, anti-p40 antibodies (which would block both IL-12 and IL-23 pathways) [50] have been effective in the treatment of Crohn disease. Whether specific targeting of the p19 pathway to achieve IL-23 specific effects [51] will be more efficacious will be the focus of future studies. Association of the ATG16L1 Autophagy Gene to Crohn Disease A genome-wide association study focusing on coding region polymorphisms identified association of the amino acid polymorphism, Thr197Ala. The ATG16L1 gene is part of the autophagosome pathway and has been implicated in the processing of intracellular bacteria [52]. ATG16L1 is expressed in intestinal epithelial cells, as well as in CD4+ , CD8+ and CD19+ primary human lymphocytes [53]. Since the initial report in a German cohort, this association has been confirmed in independent Belgian [42] and North American cohorts [53]. Of interest is that no association was observed to ulcerative colitis, suggesting that ATG16L1, like the NOD2/CARD15 associations, represent CD-specific risk alleles. Taken together, the ATG16L1 association suggests that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of CD. Association of a Gene Desert on Chromosome 5p13 to Crohn Disease A genome-wide association study in a Belgian CD cohort demonstrated association to a broad genomic region on chromosome 5p13 not containing any genes [42]. The closest flanking gene is the prostaglandin receptor, EP4 (PTGER4). Of great interest is that some of the genetic variants in this region were demonstrated to regulate PTGER4 mRNA expression. PTGER4 represents a very strong candidate gene to account for the statistical association because PTGER4-deficient mice demonstrating increased susceptibility to dextran sodium sulfate-induced colitis [54]. These promising findings will need to be replicated in independent IBD association cohorts.

Genetic Studies in Ulcerative Colitis The search for genetic variants associated with ulcerative colitis has yielded fewer candidate genes than Crohn disease. One potential candidate, the interleukin-1 receptor antagonist (IL1RA) gene, was first identified in 1994 and remains controversial. Data from the primary investigators reported

Chapter 1 Genetics of Inflammatory Bowel Diseases

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an association between IL1RA and increased susceptibility to ulcerative colitis with an odds ratio (OR) of 1.3. Subgroup analysis showed that this relationship was strongest for individuals with extensive disease (OR 1.5), those undergoing colectomy (OR 1.5), and patients who developed pouchitis [55, 56]. Other researchers studying cohorts from the same region, however, failed to replicate an association between IL1RA and Crohn disease or ulcerative colitis suggesting the connection may be weak [57]. The multi-drug resistance gene, MDR1, which resides in a region of linkage on chromosome 7 has also been postulated to play a role in colitis. Encoding a set of membrane transporters, variants of the MDR1 gene modulate epithelial transport and barrier function. Animal studies have shown that murine MDR1 knockouts develop spontaneous colitis reminiscent of inflammatory bowel disease [58]. In humans, diminished mRNA expression of MDR1 from intestinal tissue of patients with IBD implies this pathway may be involved in disease pathogenesis [59]. Genetic analyses in humans, however, have exhibited contradictory results regarding susceptibility to UC and SNP C3435T. Taken together, this data suggests that variants of the MDR1 gene may warrant further study in relation to ulcerative colitis [60]. Recent studies have also identified associations between ulcerative colitis and polymorphisms of the NFB1 promoter and IBD2 susceptibility locus. Genes in the NFB pathway merit special interest based upon the integral role the signal transduction pathway plays in inflammatory processes. Murine models of colitis have demonstrated strong linkage between a locus on chromosome 3 that contains the NFB1 gene. Translated to humans, a Dutch study found allele frequency for the 94ins/delATTG variant was significantly higher in UC patients as compared to controls or those with Crohn. Individuals homozygous for the deletion also appeared to have younger age at onset of disease [61]. The IBD2 locus located on chromosome 12 has also been implicated in the pathogenesis of ulcerative colitis. In a linkage study of 904 affected relative pairs, the IBD2 locus was associated with a subset of patients manifesting extensive ulcerative colitis [62].

Genotype-Phenotype Correlations in Pediatric IBD Disease Type and Location The discovery of genetic polymorphisms in IBD has afforded investigators with the opportunity to identify predictive correlations between specific variants and phenotypic disease characteristics. Analyses of adult populations have demonstrated that carriage of NOD2/CARD15 risk alleles predicts disease onset at an earlier age and ileal disease location in a dose-dependent manner. Subsequently, a meta-analysis of 16 case-control studies confirmed the association of NOD2/CARD15 carriage with ileal disease location, and also identified a correlation with fibrostenosing behavior and family history of IBD [16]. The majority of pediatric studies have concurred with findings from adult counterparts that carriage of NOD2/CARD15 variants is associated with ileal disease. Estimates suggest that 20–65% of children with ileal Crohn disease possess at least one NOD2/CARD15 mutation; consistent phenotypic associations have not been seen for other regions of the gastrointestinal tract [63–68]. In contradistinction to the adult literature, correlates of NOD2/CARD15 variants with fibrostenosing disease have demonstrated conflicting results [19, 63, 64, 67, 68]. Two large studies from the US and Scotland found that 34–45% of Crohn patients possessing NOD2/CARD15 polymorphisms had evidence of fibrostenosing disease, especially the 1007fs and R720W variants [64, 68]. Three other pediatric studies, however, found no correlation of NOD2/CARD15 with fibrostenosing disease [19, 63, 67].

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Nancy McGreal and Judy H. Cho

Disease Age at Onset Previous literature has suggested that individuals with a family history of IBD are more likely to have early onset disease. This would imply a greater influence of genetic factors in those diagnosed with IBD at an earlier age. Analysis of age of disease onset with respect to NOD2 carriage, however, has not shown a clear association between age and these allelic variants [19, 64, 68]. Russell et al. reported a median age at diagnosis of 11 years for carriers of NOD2 variants and 11.3 years for non-carriers [68]. Similar results were published by Kugathasan et al. who found no difference in the mean age of disease onset among Caucasian children with Crohn disease possessing NOD2 mutations versus those who did not (11.98 years vs. 12.76 years, respectively) [64]. Only one study of 55 German pediatric Crohn patients showed a higher frequency of two NOD2 mutations among children than adults (35% vs. 17%) [65]. Thus, while genetic factors may predispose individuals to developing IBD at a young age, there is insufficient evidence at this time to conclude that NOD2 variants are associated with earlier onset disease in pediatric IBD.

Growth Parameters As growth failure is an important feature of pediatric IBD, several groups have investigated the relationship between anthropometric parameters and NOD2/CARD15 status. A study of 101 Crohn patients demonstrated that 44% of participants possessing a NOD2/CARD15 polymorphism were