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 ...............................................................................................................
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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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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
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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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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 <5% for weight at the time of diagnosis, while only 15% of those without a genetic variant were <5% for weight at the time of diagnosis [63]. Although similar trends were seen for height, these results did not reach statistical significance. Another study of 93 Crohn patients, however, did not show any correlation between NOD2/CARD15 status and height or weight Z scores at disease onset or for the lowest Z score during childhood [67]. Rather disease severity was the strongest predictor for impaired growth and ileal involvement was associated with height retardation at disease onset and the lowest Z-score during follow-up. Finally, a German group did not find any statistically significant difference in mean body mass index (BMI) or mean height percentiles at diagnosis between patients with and without NOD2/CARD15 variants [69]. The authors did note a non-significant trend of greater numbers of patients possessing NOD2/CARD15 polymorphisms being below the 3% for BMI. Taken together, these data imply that while NOD2/CARD15 variants may be associated with poor growth, this effect may be more a reflection of malnutrition secondary to ileal location and disease severity as opposed to an inherent genetic effect.
Association with Risk of Surgery Results of pediatric studies correlating NOD2/CARD15 status with the need for small bowel surgical resection have consistently delineated a positive association. Russell et al estimated an odds ratio for risk of surgery among children with Crohn possessing any NOD2 mutation to be 4.45 [68]. Pediatric Crohn patients with the 1007fsInsC variant appeared to have a greater likelihood of requiring surgery with an odds ration of 4.8. Among US Caucasian Crohn patients, hazard ratios for surgery indicate that children possessing the 3020insC variant are at 6-fold greater risk of requiring surgical intervention [64]. Furthermore, these children also showed a trend toward a need for earlier surgery at median of 14 months versus 23 months after diagnosis. Finally, it has been suggested that there is a positive correlation between the number mutations possessed by an individual and increased risk of surgery [65].
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Summary That there is a genetic basis for IBD had been previously theorized through observations of racial/ethnic variations in disease, as well as family and twin studies. The recent advent of genome-wide association studies has markedly advanced the identification of well-replicated IBD association, and has substantiated this concept at a molecular level and catapulted the field of IBD genetics into a new realm of discovery.
References 1. Hugot JP, Laurent-Puig P, Gower-Rousseau C, et al. Mapping of a susceptibility locus for Crohn disease on chromosome 16. Nature 1996;379(6568):821–3. 2. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn disease. Nature 2001;411(6837):599–3. 3. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn disease. Nature 2001;411(6837):603–6. 4. Duerr RH. The genetics of inflammatory bowel disease. Gastroenterology clinics of North America 2002;31(1):63–76. 5. Basu D, Lopez I, Kulkarni A, Sellin JH. Impact of race and ethnicity on inflammatory bowel disease. The American Journal of Gastroenterology 2005;100(10):2254–1. 6. Weinstein TA, Levine M, Pettei MJ, Gold DM, Kessler BH, Levine JJ. Age and family history at presentation of pediatric inflammatory bowel disease. Journal of pediatric gastroenterology and nutrition 2003;37(5):609–3. 7. Laharie D, Debeugny S, Peeters M, et al. Inflammatory bowel disease in spouses and their offspring. Gastroenterology 2001;120(4):816–9. 8. Orholm M, Fonager K, Sorensen HT. Risk of ulcerative colitis and Crohn disease among offspring of patients with chronic inflammatory bowel disease. The American Journal of Gastroenterology 1999;94(11):3236–8. 9. Orholm M, Binder V, Sorensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scandinavian Journal of Gastroenterology 2000;35(10):1075–1. 10. Thompson NP, Driscoll R, Pounder RE, Wakefield AJ. Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ 1996;312(7023):95–6. 11. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B. Ulcerative colitis and Crohn disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 1988;29(7):990–6. 12. Russell RK, Satsangi J. IBD: a family affair. Best practice & research 2004;18(3):525–39. 13. Lesage S, Zouali H, Cezard JP, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. American Journal of Human Genetics 2002;70(4):845–57. 14. Pauleau AL, Murray PJ. Role of nod2 in the response of macrophages to toll-like receptor agonists. Molecular and Cellular Biology 2003;23(21):7531–9. 15. Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005;307(5710):731–4. 16. Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP. Differential effects of NOD2 variants on Crohn disease risk and phenotype in diverse populations: a metaanalysis. The American Journal of Gastroenterology 2004;99(12):2393–04. 17. Cummings JR, Jewell DP. Clinical implications of inflammatory bowel disease genetics on phenotype. Inflammatory Bowel Diseases 2005;11(1):56–1. 18. Kugathasan S, Loizides A, Babusukumar U, et al. Comparative phenotypic and CARD15 mutational analysis among African American, Hispanic, and White children with Crohn disease. Inflammatory Bowel Diseases 2005;11(7):631–8.
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19. Weiss B, Shamir R, Bujanover Y, et al. NOD2/CARD15 mutation analysis and genotype-phenotype correlation in Jewish pediatric patients compared with adults with Crohn disease. The Journal of Pediatrics 2004;145(2):208–2. 20. Latiano A, Palmieri O, Valvano RM, et al. Contribution of IBD5 locus to clinical features of IBD patients. The American Journal of Gastroenterology 2006;101(2):318–5. 21. Noble CL, Nimmo ER, Drummond H, et al. The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn disease. Gastroenterology 2005;129(6):1854–64. 22. Yamazaki K, Takazoe M, Tanaka T, et al. Association analysis of SLC22A4, SLC22A5 and DLG5 in Japanese patients with Crohn disease. Journal of human genetics 2004;49(12):664–8. 23. Newman B, Gu X, Wintle R, et al. A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn disease. Gastroenterology 2005;128(2):260–9. 24. Peltekova VD, Wintle RF, Rubin LA, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 2004;36(5):471–5. 25. Pierik M, Yang H, Barmada MM, et al. The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interaction. Inflamm Bowel Dis 2005;11(1):1–7. 26. Armuzzi A, Ahmad T, Ling KL, et al. Genotype-phenotype analysis of the Crohn disease susceptibility haplotype on chromosome 5q31. Gut 2003;52(8):1133–9. 27. Torok HP, Glas J, Tonenchi L, et al. Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn disease. Gut 2005;54(10):1421–7. 28. Palmieri O, Latiano A, Valvano R, et al. Variants of OCTN1–2 cation transporter genes are associated with both Crohn disease and ulcerative colitis. Alimentary Pharmacology & Therapeutics 2006;23(4):497–6. 29. Russell RK, Drummond HE, Nimmo ER, et al. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease. Gut 2006;55(8):1114–3. 30. Babusukumar U, Wang T, McGuire E, Broeckel U, Kugathasan S. Contribution of OCTN variants within the IBD5 locus to pediatric onset Crohn disease. The American Journal of Gastroenterology 2006;101(6):1354–1. 31. Silverberg MS, Duerr RH, Brant SR, et al. Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn disease. European Journal of Human Genetics 2007;15(3):328–5. 32. Stoll M, Corneliussen B, Costello CM, et al. Genetic variation in DLG5 is associated with inflammatory bowel disease. Nature genetics 2004;36(5):476–80. 33. Buning C, Geerdts L, Fiedler T, et al. DLG5 variants in inflammatory bowel disease. The American Journal of Gastroenterology 2006;101(4):786–92. 34. Ahmad T, Marshall S, Jewell D. Genotype-based phenotyping heralds a new taxonomy for inflammatory bowel disease. Current Opinion in Gastroenterology 2003;19(4):327–35. 35. Stokkers PC, Reitsma PH, Tytgat GN, van Deventer SJ. HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta- analysis. Gut 1999;45(3):395–1. 36. Silverberg MS, Mirea L, Bull SB, et al. A population- and family-based study of Canadian families reveals association of HLA DRB1*0103 with colonic involvement in inflammatory bowel disease. Inflammatory Bowel Diseases 2003;9(1):1–9. 37. Orchard TR, Chua CN, Ahmad T, Cheng H, Welsh KI, Jewell DP. Uveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes. Gastroenterology 2002;123(3):714–8. 38. Orchard TR, Thiyagaraja S, Welsh KI, Wordsworth BP, Hill Gaston JS, Jewell DP. Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology 2000;118(2):274–8. 39. Yap LM, Ahmad T, Jewell DP. The contribution of HLA genes to IBD susceptibility and phenotype. Best Practice & Research 2004;18(3):577–96. 40. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006;314(5804):1461–3. 41. Van Limbergen JE, Russell RK, Nimmo ER, et al. IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland. Gut 2007.
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42. Libioulle C, Louis E, Hansoul S, et al. A novel susceptibility locus for Crohn disease identified by whole genome association maps to a gene desert on chromosome 5p13.1 and modulates the level of expression of the prostaglandin receptor EP4. Plos Genetics 2007. 43. Parham C, Chirica M, Timans J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL12Rbeta1 and a novel cytokine receptor subunit, IL-23R. Journal of Immunology 2002;168(11):5699–8. 44. Hue S, Ahern P, Buonocore S, et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. The Journal of Experimental Medicine 2006;203(11):2473–83. 45. Kullberg MC, Jankovic D, Feng CG, et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. The Journal of Experimental Medicine 2006;203(11):2485–4. 46. Uhlig HH, McKenzie BS, Hue S, et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 2006;25(2):309–18. 47. Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. The Journal of Clinical Investigation 2006;116(5):1310–6. 48. Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003;421(6924):744–8. 49. Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. American Journal of Human Genetics 2007;80(2):273–90. 50. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn disease. The New England Journal of Medicine 2004;351(20):2069–79. 51. McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends in immunology 2006;27(1):17–3. 52. Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genetics 2007;39(2):207–11. 53. Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genetics 2007. 54. Kabashima K, Saji T, Murata T, et al. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. The Journal of Clinical Investigation 2002;109(7):883–93. 55. Carter MJ, Di Giovine FS, Cox A, et al. The interleukin 1 receptor antagonist gene allele 2 as a predictor of pouchitis following colectomy and IPAA in ulcerative colitis. Gastroenterology 2001;121(4):805–11. 56. Carter MJ, di Giovine FS, Jones S, et al. Association of the interleukin 1 receptor antagonist gene with ulcerative colitis in Northern European Caucasians. Gut 2001;48(4):461–7. 57. Craggs A, West S, Curtis A, et al. Absence of a genetic association between IL-1RN and IL-1B gene polymorphisms in ulcerative colitis and Crohn disease in multiple populations from northeast England. Scandinavian Journal of Gastroenterology 2001;36(11):1173–8. 58. Panwala CM, Jones JC, Viney JL. A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. Journal of Immunology 1998;161(10):5733–44. 59. Langmann T, Moehle C, Mauerer R, et al. Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes. Gastroenterology 2004;127(1):26–40. 60. Schwab M, Schaeffeler E, Marx C, et al. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology 2003;124(1):26–33. 61. Borm ME, van Bodegraven AA, Mulder CJ, Kraal G, Bouma G. A NFKB1 promoter polymorphism is involved in susceptibility to ulcerative colitis. International Journal of Immunogenetics 2005;32(6):401–5. 62. Achkar JP, Dassopoulos T, Silverberg MS, et al. Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus. The American Journal of Gastroenterology 2006;101(3):572–80. 63. Tomer G, Ceballos C, Concepcion E, Benkov KJ. NOD2/CARD15 variants are associated with lower weight at diagnosis in children with Crohn disease. The American Journal of Gastroenterology 2003;98(11):2479–84. 64. Kugathasan S, Collins N, Maresso K, et al. CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn disease. Clinical Gastroenterology and Hepatology 2004;2(11):1003–9. 65. Sun L, Roesler J, Rosen-Wolff A, et al. CARD15 genotype and phenotype analysis in 55 pediatric patients with Crohn disease from Saxony, Germany. Journal of Pediatric Gastroenterology and Nutrition 2003;37(4):492–7.
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66. Meinzer U, Idestrom M, Alberti C, et al. Ileal involvement is age dependent in pediatric Crohn disease. Inflammatory Bowel Diseases 2005;11(7):639–44. 67. Wine E, Reif SS, Leshinsky-Silver E, et al. Pediatric Crohn disease and growth retardation: the role of genotype, phenotype, and disease severity. Pediatrics 2004;114(5):1281–6. 68. Russell RK, Drummond HE, Nimmo EE, et al. Genotype-phenotype analysis in childhood-onset Crohn disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflammatory Bowel Diseases 2005;11(11):955–64. 69. Roesler J, Thurigen A, Sun L, et al. Influence of CARD15 mutations on disease activity and response to therapy in 65 pediatric Crohn patients from Saxony, Germany. Journal of Pediatric Gastroenterology and Nutrition 2005;41(1):27–32.
2 Gut Immunity and Inflammatory Bowel Disease William A. Faubion∗ and Claudio Fiocchi
Introduction Gut Immunity and Inflammatory Bowel Disease: A Pediatrician’s Perspective Inflammation is by far the single most common response that the body mounts in response to a variety of challenges. The vast majority of these challenges comes from the external environment and, in the specific case of the gastrointestinal tract, they include foods, the commensal flora, microbial pathogens and xenobiotics. What protects the intestine from such a large and permanent antigenic load is the mucosal immune system, explaining why this makes up the largest and most varied collection of immune cells of the body. Not only the antigenic challenge to the gut is massive and continuous, but it also occurs at the largest area of interface with the external milieu, as the total surface of the gastrointestinal tract is roughly equal to that of a tennis court (400 m2 ). Therefore, an effective immune response in the gut must adapt not only to the type and size of the challenge, but also the location where the challenge occurs. To be fully effective mucosal immunity sets in motion an assortment of cellular and molecular mechanisms, transforming a relatively quiescent immune system into an active one. The degree of such activation varies considerably, ranging from a perfectly controlled inflammatory response that eliminates potential dangers without even alerting the host, to an uncontrolled full-blown inflammation that results in structural tissue damage and overt clinical symptoms. Within this wide range of performance, mucosal immunity must transit from a physiological to a pathological response, but the boundaries between a protective and a deleterious response are not clearly delineated. A child with inflammatory bowel disease (IBD) has often already reached the pathological extreme end of the immune response, inflicting damage rather than affording protection. To understand what goes wrong in pediatric IBD it is necessary first to understand how the intestinal immune system works. Much is known about both its composition and function, including its anatomical basis [1], its cellular and secretory components [2], and its critical interaction with the enteric flora [3]. Unfortunately, most of this information derives from studies carried out in adult murine species and humans, and whether the derived knowledge also applies to children, and to what degree, is uncertain. As it will be discussed later on in this chapter, some information on neonatal mucosal
*Department of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, Phone: 507-284-2468, Fax: 507-266-0335
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immunity is also available, but this derives almost entirely from newborn mice, raising again the issue of relevance and reproducibility in younger humans. Thus, when a pediatrician aims at better comprehending the inflammatory events occurring in the gut of a patient affected by Crohn disease or ulcerative colitis, he or she will have to rely on a mix of information on mucosal immunity gathered primarily from human adults and animal models. Despite these limitations, most of the knowledge on the intestinal immunity is likely to apply to children, with the exclusion of the short neonatal period, when limited exposure to external antigens and a status of relative immune immaturity creates special conditions. This chapter will review currently accepted concepts of physiological intestinal immunity with selected references to dysfunctions found in IBD.
Innate Intestinal Immunity and IBD Epithelial Barrier The cellular barrier of the gastrointestinal tract is formed by a continuous single layer of epithelial cells sealed with tight junctions. The competency of these tight junctions depends upon the regulation of a meshwork of proteins such as occludin, claudin family members and the junctional adhesion molecule JAM [4]. On the luminal surface, a thick and resilient layer of mucus, rich in secreted IgA antibodies [5], proteins with antibacterial activity (i.e., - and -defensins) [6], and proteolytic and glycolytic enzymes [7], offers the first line of defense against invasion by a variety of potential pathogens. Despite this protective barrier, luminal antigens and gut bacteria do enter the subepithelial lamina propria, a large extracellular matrix compartment which contains a variety of immune and nonimmune cellular components. Although some entry occurs through unwanted breaks in the barrier, under physiological circumstances much of the entry occurs by design through specialized, follicle-associated epithelium (FAE) that overlies the organized lymphoid tissue of the gut (Gut-Associated Lymphoid Tissue - GALT). The FAE overlies large lymphoid aggregates called Peyer’s patches. When compared to the rest of the intestinal epithelium, the FAE is deficient in goblet cells and has a lower concentration of brush border enzymes. These conditions facilitate the controlled transport of selected luminal macromolecules into the underlying lymphoid follicle through unique M (microfold) cells. M cells are highly specialized epithelial cells that differ from enterocytes in regard to characteristics required to facilitate transepithelial transport of antigen. Such characteristics include fewer microvilli, decreased alkaline phosphatase activity, and no IgA secretory component [8]. Antigen transported through the M cells is then captured below by underlying dendritic cells, which then present antigenic peptides to interfollicular T cells or naïve T cells within the mesenteric lymph nodes (Figure 2.1).
Evidence for barrier dysfunction in the pathogenesis of IBD Several lines of investigation indicate that disruption of the epithelial barrier may either instigate or perpetuate chronic intestinal inflammation. Abnormal intestinal permeability has been established among patients with Crohn disease and their healthy first-degree relatives, and may represent a primary abnormality predisposing to excessive antigen uptake, continuous immune stimulation, and eventually mucosal inflammation. Potential etiologic factors for barrier dysfunction in Crohn disease may be environmental or genetic. Smoking and non-steroidal anti-inflammatory drugs both potentially affect gut permeability and are variably associated with IBD [9]. Mutations in two genes recently found to be potentially associated with Crohn disease (OCTN and DLG5) appear to affect epithelial permeability and may lead to inappropriate exposure of the mucosal immune system to luminal antigen [10, 11].
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Gut lumen FAE M cell
APC DC T cell T cell
B cell zone
Germinal center
Figure 2.1. Basic organizational structure of the follicular associated epithelium (FAE). The main functional component of the FAE is the M (microfold) cell, which is specialized in transepithelial antigen transport. Transported antigen is taken up and processed by dendritic cells (DCs) and antigen-presenting cells (APC) which present it to naïve T cells.
Innate Immune Cells The immune system can be divided into two main branches: innate and adaptive immunity, characterized by differences in regard to specificity and timing of response. In contrast to adaptive immune cells, typically represented by T cells, which require some time for priming and clonal expansion for full effectiveness, cells of the innate immune system rapidly seize upon potential threats to the host. The rapidity of response occurs because the receptors used to quickly detect invading microorganisms or toxic macromolecules are germ-line encoded, invariable, and predetermined to recognize a repertoire of bacterially/virally associated carbohydrate and lipid structures. These pathogen recognition receptors may be membrane-bound (i.e., Toll-Like Receptors–TLRs) or cytoplasmic (i.e., Nucleotide-binding Oligomerization Domain family members–NODs). Innate immune cells primarily responsible for immediate bactericidal activity include professional phagocytic cells (macrophages and neutrophils), eosinophils, and lymphoid cells that have evolved to fulfill innate rather than adaptive immune functions. As a prelude to the discussion of the relationship between luminal bacteria and lymphocytes, background information regarding the macrophage, dendritic cell, and the atypical lymphocytes (NKT and T cell) will be presented. Macrophages Macrophages are phagocytic cells present in large numbers throughout the gastrointestinal mucosa. In fact, the GALT contains the largest reservoir of macrophages within the body [12]. Macrophages mature continuously from peripheral blood monocytes that are recruited to sites of mucosal inflammation [13], while neutrophils are produced and lost in large numbers each day. In the non-inflamed intestine macrophages differ from peripheral monocytes in their hyporesponsiveness to TLR ligands, diminished ability to prime adaptive immune responses, yet preserved capacity for phagocytosis and intracellular killing [13]. However, in the setting of pathogen invasion and inflammation, intestinal macrophages freshly recruited from blood monocytes, instead of developing a primarily scavenger function, rapidly display a pro-inflammatory phenotype marked by abundant cytokine production and accessory cell function. The conversion to this pro-inflammatory phenotype is stimulated by ligation of their pathogen recognition receptors.
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Activated macrophages express membrane-bound receptors specific for opsonized particles and pathogens, complement, and common bacterial proteins (i.e., mannose receptor, TLR, NOD). The complement receptor for C5a is largely responsible for the movement of macrophages to sites of inflammation, and reduced expression as seen in patients with acquired immunodeficiency syndrome results in susceptibility to mycobacterial infection [14]. Recognition of pathogens through these receptors leads to phagocytosis and intracellular degradation. Activation of macrophages also results in the secretion of bioactive molecules called cytokines. Cytokines are proteins produced and secreted by one cell that affect the function of another cell, thus allowing cell-cell communication in the absence of cell contact. The cytokine TGF- produced by activated macrophages is also a potent chemoattractant leading to the further recruitment of macrophages and neutrophils to the area of inflammation [15]. Not only is cytokine secretion important for the augmentation of phagocytic intracellular killing, but it also represents a critical link between innate and adaptive immunity, a topic discussed more fully below. Dendritic cells are also phagocytic cells, but their most important role is that of antigen presentation and activation of T cells. Dendritic Cells The dendritic cell (DC) is the most potent inducer of adaptive immune responses. Current evidence supports the model that intestinal DCs continuously migrate in an immature or tolerogenic form scavenging apoptotic cells and acquiring antigen sampled either directly from the lumen [16] or shuttled from the lumen through M cells (Figure 2.1) [17]. T cells activated by Peyer’s patchderived DCs (intestinal DCs) produce IL-4, IL-10, and TGF-, three cytokines that promote the induction of T cells with regulatory function (discussed more fully below). This cytokine profile indicates that intestinal DCs may have a role in the induction of regulatory T cells and/or B cell responses. Upon activation through microbial products or pro-inflammatory molecules, mature DCs migrate to T cell areas of the GALT where they induce effector rather than tolerogenic T cell responses. Intestinal DCs can induce the mucosal homing receptor 47 on T cells, suggesting that they can instruct a T cell to home back to the original site of activation [18]. Upon acquisition of antigen, DCs process the antigen within the cell and load antigenic peptide onto MHC class II molecules displayed on the surface membrane. DCs fully loaded with antigen migrate to the draining mesenteric lymph nodes where the greatest opportunity exists for presentation of a particular MHC-peptide complex to T cells bearing the T cell receptor (TCR) specific for the antigen being presented. Under normal circumstances, these antigen-loaded DCs express low levels of co-stimulatory molecules and cytokines, stimulating preferentially the differentiation of regulatory T cells. As opposed to these tolerogenic DCs isolated from non-inflamed bowel, DCs stimulated with pathogenic bacteria or isolated from sites of inflammation are strongly immunogenic, expressing on the cell surface high levels of co-stimulatory molecules, adhesion molecules, and abundantly produce cytokines. The resultant T cell activation will be discussed further below. Atypical Lymphocytes The atypical lymphocytes NKT (Natural Killer T) cells and T cells also play a role in the innate immune response. NKT cells mature in the thymus and recognize lipid antigen (presumably bacterial) presented on the “MHC-like” complex Cd1d. NKT cells secrete large amounts of proinflammatory cytokines and readily kill infected cells or tumor cells. The potential importance of these cells to the pathogenesis of ulcerative colitis has been recently described. Pro-inflammatory cytokine-producing NKT cells isolated from patients with ulcerative colitis have cytotoxic activity against colonic epithelial cells in culture and produce large amounts of IL-13 [19]. T cells that express gamma and delta TCR chains (T cells), rather than the typical TCR chains, are atypical lymphocytes that only exist in significant quantity in epithelial tissues. In the
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intraepithelial space, T cells make up approximately 10% of the total number of T cells, the remaining majority being CD8+ T cells [20]. Unlike conventional T cells, T cells do not require the thymus for development [21], do not recognize antigen in association with MHC class I or II [22], and do not participate in adaptive immune responses [23]. While their precise function in humans remains enigmatic, experimental evidence suggests that T cells perform different functions depending upon tissue distribution and the local microenvironment [24].
Development of the Epithelial Barrier and Innate Immune Cells While the functional properties of the fetal intestinal epithelial barrier are unknown, progressive maturation of epithelial tight junctions has been identified histologically [25]. It is apparent that neonatal intestinal permeability is higher than that in adulthood [26]; yet, its relationship to the development of a an efficient mucosal immune system by facilitating exchange of dietary antigen, enteric colonizing bacteria, and maternal antibody or trophic factors is unknown. Interspersed within the intestinal epithelium, M cells sample the lumen and deliver antigen to DCs positioned below the FAE. M cells are present by week 17 of gestation following the appearance of lymphoid aggregates. Indeed, it appears that lamina propria lymphocytes and luminal bacteria promote M cell differentiation from enterocytes [27]. A second form of differentiated enterocyte is the Paneth cell, a specialized epithelial cell present within small intestinal crypts and dedicated to the production of various anti-bacterial peptides, like defensins. The Paneth cell is also present by 17 weeks of gestation [28]. Macrophages and CDs appear in the fetal intestine by 12 weeks, but little is known about their functional maturational state [29]. Data available on neonatal macrophages document defective production of pro-inflammatory cytokines such as IL-12 and TNF- [30]. Evidence for Innate Immune Cellular Dysfunction in the Pathogenesis of IBD At least three pieces of evidence exist indicating a major role for innate immune cells in the perpetuation of human chronic intestinal inflammation. First, the strongest genetic association to date with small bowel Crohn disease is the loss of function polymorphisms in the bacterial sensing gene CARD15/NOD2. Whether the ultimate pathogenic dysfunction rests in Paneth cells [31] or monocytes, [32] it appears certain that dysregulation in the detection of and/or responsiveness to enteric bacteria by innate immune cells promotes chronic inflammation in this subgroup of patients. The second piece of evidence rests in the efficacy of immune therapy targeted against pro-inflammatory cytokines produced by innate immune cells. Activated macrophages produce large amounts of TNF- and IL-12, two cytokines responsible for the recruitment and activation of pathogenic effector T cells. The efficacy of anti-TNF- therapy is established [33], and promising anti-IL-12 studies are currently ongoing [34]. The third piece of evidence is the presence of a defective acute inflammatory response to injury and bacterial products in Crohn disease patients, demonstrated by reduced neutrophilic infiltration, IL-8 production and vascular flow [35], and corroborated by the clinical improvement provided by the administration of GM-CSF, supposedly by improving macrophage and neutrophilic function [36].
Adaptive Intestinal Immunity and IBD T Cells Within the lamina propria of the intestine CD4+ and CD8+ T cells bearing the conventional TCR are roughly equally represented. The intraepithelial space contains unusual and enigmatic T cell populations bearing the TCR and CD8+ cells with homodimeric expression of TCR (discussed briefly above). As current understanding of both human and experimental IBD
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emphasizes the primary importance of activated CD4+ TCR T cells to disease pathogenesis, the discussion below will focus on activation of CD4+ T cells and the homing pattern that ensues. Upon maturation in the thymus, naïve T cells (cells which have yet to experience antigen exposure) circulate the lymphatic tissues in search of its cognate MHC-peptide complex. Constitutive expression of the selectin CD62L (L-selectin) and the chemokine receptor 7 (CCR7) ensures that naïve T cells bind to glycosylated CD34 and the chemokine ligand 21 expressed on endothelial cells of high endothelial venules [37]. The interaction of CD62L and CD34 (among other glycosylated endothelial molecules) promotes a rolling action of the T cell across the endothelial surface. The T cell surface adhesion molecule LFA-1 binds to ICAM-1 and ICAM-2 promoting firm adhesion and crossing of the endothelial lining into the lymphoid tissue. Within the underlying lymphatics await DCs loaded with antigen in variable states of activation. Naïve T cells search the DC selection for a recognizable MHC-peptide complex. If none is found the cells exit the lymph node, return to the circulation, and reenter other nodes to repeat this process. Eventually, a naïve T cell finds its specific antigenic mate and receives the appropriate activation signals upon ligation of its TCR (Figure 2.2). A full T cell activation requires two signals: signal 1 is delivered by TCR stimulation and signal 2 is a co-stimulatory signal provided by secondary accessory pathways. Among the latter, co-stimulation through CD28 by B7.1 or B7.2 results in T cell activation; in contrast, co-stimulation through CTLA-4 by B7.1 or B7.2 results in T cell inhibition. In addition, TCR signaling in the absence of co-stimulation results in anergy, defined as a lack of response upon re-exposure to the same antigen in the future. A key consequence resulting from activation of CD4+ T cells is cytokine secretion, and the particular pattern of cytokines secreted orchestrates the type of the ensuing immune response (i.e., directed against intracellular pathogens, parasites, etc). The phenotype of the mature effector T cell depends upon in large part the cytokine milieu available to the T cell while undergoing the activation and differentiation program. While insight into these complex events is in constant evolution, current understanding is as follows (Figure 2.3). Activation of CD4+ T cells in the presence of IL-12 and absence of IL-4 results in a T helper 1 (Th1) phenotype, resulting in IFN-producing cells effective in the control of intracellular pathogens. Cells activated in the presence of IL-4 acquire a T helper 2 (Th2) phenotype, generating IL4-, IL5-, and IL13-producing cells effective in allergic responses and clearance of parasitic infections. Finally, activation in the presence of IL6, TGF and IL-23 result in cells expressing the recently described Th17 phenotype, i.e., IL17 and IL6-producing T cells responsible for acute inflammation and recruitment of granulocytes [38, 39]. Full activation of T cells takes 4-5 days and is accompanied by clonal expansion and remarkable changes in the homing behavior of these cells.
CD28
B7.1/.2
T cell + signal 2
APC
MHC II
Ag
TCR
+ signal 1 - signal
B7.1/.2
CTLA-4
Figure 2.2. Major molecular receptor-ligand pairs and co-stimulatory / inhibitory signals involved in antigenspecific stimulation of a T cell. APC, antigen-presenting cell; MHC II, major histocompatibility complex class II; Ag, antigen; TCR, T cell receptor; CTLA-4, cytotoxic T lymphocyte antigen-4.
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Th1
IFN-γ
Th2
IL-4 IL-5 IL-13
Th17
IL-17
21
IL-12 IL-4 APC
TGF-β IL-6
Figure 2.3. Current understanding of the pathways mediating differentiation of naïve T cells into the three major types of effector Th cells (Th1, Th2 and Th17). The ultimate functional phenotype of mature effector T cells depends upon the type and amount of antigen, and the cytokine milieu present at the time of activation. APC, antigen-presenting cell.
Once activated, these effector T cells leave the lymph node returning to the circulation, thus allowing a locally generated immune response to promote defense at distance throughout the gastrointestinal tract [40]. Activated T cells express unique adhesion molecules that direct the cells to sites of inflammation, and indeed T cells primed by mucosal DCs are destined to return to the gut through the upregulation of two surface molecules, 47 integrin and the chemokine receptor CCR9 [18]. The integrin 4 binds to the vascular adhesion molecule VCAM-1, a molecule expressed on vascular endothelium only at sites of inflammation. The 47 integrin recognizes the more ubiquitous vascular endothelial molecule MAdCAM-1, directing migration to the intestinal lamina propria [41, 42], while E7 is uniquely expressed on T cells destined to the intestinal intraepithelial space. MAdCAM-1 has been shown to be upregulated during exacerbations of IBD, and thus represents a promising target for therapeutic intervention [42]. Effector T cells appear to enter nearly all tissues in limited numbers. Recognition of cognate antigen within the tissue results in T cell cytokine production. Pro-inflammatory cytokines, such as TNF-, stimulate endothelial cells to upregulate adhesion molecules such as E-selectin (that recruits monocytes and neutrophils), and VCAM-1 and ICAM-1 (both of which recruit activated T cells). TNF- and IFN- likewise act to alter the vascular permeability, endothelial cell shape, and blood flow, resulting in enhanced infiltration of inflammatory cells into the tissue. These inflammatory cascades set in motion by activated T cells and the significant structural alterations they cause in the inflamed tissue eventually trigger the signs and symptoms characteristic of active IBD. Thus, naïve T cells circulate nearly all tissues due to the expression of CD62L, CCR7, and LFA-1. Activation of T cells in the GALT leads to expression of 47 and CCR9 expression, two molecules that produce selective homing to the intestine through endothelial expression of MAdCAM-1 and CCL-25. Mucosal inflammation results in upregulation of MAdCAM-1, in addition to other endothelial ligands, and enhanced recruitment of pro-inflammatory T cells to the inflamed organ. T Regulatory Cells (TREG) It is now well established that subpopulations of CD4+ T cells with regulatory potential exist in both mice and humans. Current models describe three major and not necessarily mutually exclusive subtypes of Tregs: the “naturally occurring” CD4+CD25+ cell, the IL-10- and TGF-producing Tr1 cell, and the TGF--producing Th3 cell derived through oral tolerance [43]. While accurate description of this rapidly evolving field is a moving target, the more studied and
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better understood Treg cell type is the CD4+CD25+ T cell expressing the transcription factor FOXP3. The importance of this cell type to murine colitis and its capacity to suppress mucosal inflammation are well established [44, 45]. However, although this type of Treg has also been described in IBD [46], the function of these cells in the periphery and the gut of patients with IBD has yet to contribute to a better understanding of IBD pathogenesis.
B Cells B cells of the GALT work in close collaboration with the epithelium to export secretory IgA (sIgA) and to some extent secretory IgM (sIgM) to enhance mucosal defense from intestinal pathogens. Mucosal B cells exhibit a predominant IgA class switch and, upon differentiation to mature plasma cells, produce approximately 3 grams of sIgA per day [47]. Over 80% of all human plasma cells are found in the gut, and nearly all these plasma cells produce IgA [48]. Mucosal plasma cells produce primarily dimeric or polymeric forms of IgA. The joining or “J” chain of polymeric IgA spontaneously interacts with the polymeric Ig receptor expressed on the basolateral surface of epithelial cells facilitating exportation of the sIgA to the gastrointestinal lumen [49]. Once in the lumen, sIgA coats commensal and potentially pathogenic bacteria. This coating may promote M cell-mediated bacterial uptake and target presentation to intestinal DCs and macrophages, providing a barrier to bacterial penetration as well as a positive feedback loop to enhance secretory immunity [50].
Development of Adaptive Immune Cells Lymphocytes begin to populate the lamina propria by 12 weeks of gestation (after the thymus matures) and are primarily CD4+ cells [51]. Organized lymphoid tissue of the small bowel (Peyer’s patches) consisting of B cell follicles, and interfollicular CD4+ and CD8+ T cells are detected by 16–18 weeks of gestation [51]. Dendritic cells are detected at 19 weeks, representing the last of the required cellular components of an adaptive immune response [52]. Neither the T cells nor the B cells of the Peyer’s patch exist in an activated state within the fetal intestine. Indeed, the number of Peyer’s patches increases from 80–120 at birth to 250 by adolescence [53]. Without antigenic stimulation, there are no IgA secreting cells; yet, within 2 weeks of birth IgA and IgM secreting plasma cells are present within the lamina propria [54].
Evidence for Adaptive Immune Cellular Dysfunction in the Pathogenesis of IBD There are multiple lines of evidence strongly supporting the notion that activated CD4+ T cells are a central feature of human IBD. First, T cell-driven animal models of colitis mimic human IBD in both histologic features and susceptibility to similar treatment regimens [19, 55–57]. In human IBD, Crohn disease displays all the major features of a well defined Th1 response pattern [58], while ulcerative colitis represents an atypical Th2 response [19]. As mentioned previously, established and emerging therapy for human IBD is directed towards the destruction or deterrence of activated effector T cells, or blockade of Th1-driving cytokines [59] Third, clonal populations of T cells have been described in patients with Crohn disease [60]. A similar development of T cell clones has been described in an animal model of IBD. Importantly, these T cell clones specifically recognize endogenous gut bacteria and are proven pathogenic in their ability to mediate colitis when transferred into non-colitic recipient mice [61]. Finally, the presence of antibodies unique to patients with IBD directed against microbial antigen signifies a potentially pathogenic adaptive immune responses against the intestinal flora [62].
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Putting it all Together: Integrating Gut Microbes, Epithelial Cells, and Lymphocytes in the Pathogenesis of IBD With rare exception, murine models of IBD require the presence of intestinal bacteria for the development of colitis. The presence of antibodies to bacterial antigen in most patients with IBD and the beneficial effects of antibiotics and probiotics suggest an important role of bacteria in the instigation or perpetuation of human IBD. Thus, understanding the interaction between gut flora, epithelial cells, and adaptive immune cells is important. Intestinal epithelial cells encounter commensal and pathogenic bacteria routinely, and constitutively express membrane-bound and intracellular receptors to sense gut microbes. The membrane bound TLR2 and 4 have been described in mouse and human intestinal epithelial cells lines [63]. Experimental evidence suggests that interaction between commensal gut flora and TLRs protects against colitis and enhances the mucosal barrier [64, 65]. An additional set of intracellular bacterial sensing receptors, NOD1 and NOD2, exists to detect intracellular pathogens. Experimental evidence indicates an anti-bacterial effect of the NOD2 protein in infected intestinal epithelial cell lines [66]. The importance of NOD2 in epithelial cell defense systems (particularly Paneth cells of the terminal ileum) underscores the relevance of polymorphisms in the NOD2/CARD15 gene in the pathogenesis of Crohn disease [67, 68]. It is established that the downstream signaling pathways of TLRs and NODs lead to activation of NF-B responsive genes mediating inflammatory responses, but the precise details of these important cascades are beyond the scope of this chapter. Thus, intestinal epithelial cells directly sense enteric bacteria, and this interaction is essential to normal barrier function. Potential pathogenic and probably commensal bacteria may contact immune cells of the GALT in at least three ways (Figure 2.4). First, infected epithelial cells may undergo apoptosis (either spontaneously or killed by effector immune cells), and apoptotic fragments containing bacteria may be ingested by resident phagocytic cells (macrophages and DCs) and subsequently presented to host T cells. In this fashion, bacterial antigen may be presented to CD4+ T cells through MHC class II-TCR interaction and/or CD8+ cytotoxic T cells, as antigen from apoptotic fragments may be presented as “self” on MHC class I molecules [69]. Second, DCs and macrophages may acquire bacteria directly from the environment. DCs have been shown to directly sample intestinal antigen from the lumen, and both cell types engulf and kill whole bacteria, presenting bacterial antigen Gut lumen
Bacteria
DC
Apoptotic infected cell
TLR
Macrophage T cell
T cell T cell
1
2
3
Figure 2.4. Potential pathways through which bacterial antigens can activate mucosal T cells. 1) Apoptosis of infected epithelial cells; 2) Luminal sampling and acquisition of bacteria by mucosal dendritic cells (DC); 3) Direct contact of translocated bacteria with T cells mediated by Toll-like receptor (TLR) recognition.
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on MHC class II to CD4+ T cells. Third, lymphocytes may contact bacterial antigen directly in the absence of antigen presenting cells. T lymphocytes have been shown to express TLRs and in certain model systems, respond by proliferation and cytokine secretion [70]. Thus, multiple pathways exist with the potential of presenting enteric bacterial products to CD4+ T lymphocytes. As previously pointed out, the T cell response to recognition of bacterial antigen on MHC class II molecules through the TCR depends upon the expression of co-stimulatory molecules on the antigen-presenting cell (Figure 2.2). Activation of the CD4+ T cell results in cytokine secretion and the pattern of cytokines secreted determines the type of the ensuing immune response (i.e., directed against intracellular pathogens, parasites, etc). These pro-inflammatory cytokines incite and amplify a vigorous immune response through many factors including increased blood flow, increased vascular permeability, and recruitment of effector immune cells. Activated CD4+ T cells also stimulate B cells through expression of the cell surface molecule CD40 ligand. CD40-CD40 ligand interaction results in B cell proliferation, variation in the class of antibody secretion (i.e., IgG, IgA, etc), and initiation of antibody secretion. Following this multifactorial antigen-driven immune response, a series of secondary events also unfolds, including the production of proteolytic enzymes, like matrix metalloproteinases that digest the extracellular matrix [71], and oxygen reactive metabolites which are directly toxic to the cells in the surrounding microenvironment [72], ultimately leading to necrosis and structural tissue damage.
Innate and Adaptive Immune Responses Unique to Pediatrics Maturation of the mucosal immune system is a continuum with no definitive markers defining a “mature” and “immature” status. The only evidence available from which to draw conclusions unique to the pediatric mucosal immune system is from studies of human neonates or animal studied at the time of weaning. The most noticeable difference between developing (neonatal) and established immune responses would appear to be in adaptive immunity. The rationale for this assumption is that adaptive immune responses are antigen-specific and thus require post-natal exposure to dietary and microbial antigen to develop immunologic memory. On the contrary, as pointed out above, innate immune responses are for the most part germline-encoded through recognition of microbial ligands by pathogen recognition receptors. Indeed, fetal intestinal epithelial cell lines exhibit responsiveness to inflammatory stimuli and bacterial products [73]. Thus, this section will briefly address three established differences in adaptive immune responses between pediatric and adult populations. Neonates are capable of humoral and cellular immune responses at the time of birth. Immediately upon leaving the birth canal the gastrointestinal tract encounters microbes resident in the birth canal and the surrounding environment. Within hours the gastrointestinal tract is colonized with facultative and strict anaerobic bacteria. Specific secretory IgA responses to organisms such as Escherichia coli are produced within the first week of life [74, 75]. Infants and young children are capable of generating the full spectrum of functional T cells (Th1, Th2, etc.) and T celldependent B cell responses [76]; yet, T cell-independent B cell immune responses do not reach full maturity for several years. It is possible that this impaired B cell response to T cell-independent antigens (i.e., polysaccharides) that leaves young children susceptible to encapsulated bacteria (i.e., Haemophilus influenzae type b) [77]. The second major difference is the tendency of the young mucosal immune system to generate systemic immune responses to oral antigen. The evidence for this exists in epidemiologic studies of neonatal protein intolerance [78] as well as animal data demonstrating antigen-feeding and the induction of systemic antibody responses [79]. The third point commonly highlighted is the propensity of neonatal effector T cell responses to be preferentially Th2 polarized [80]. The significance of this observation is unclear, but it has been suggested that this may represent a “default” pathway aimed at keeping inflammatory reactions controlled at an early stage of life when vigorous Th1 polarization could lead to damaging
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inflammatory responses [81]. How any of the three aforementioned neonatal adaptive immune features relate to human IBD remains to be explored.
Summary As discussed in other chapters of this book dealing with treatment of pediatric IBD, it is obvious that all recent advances in the field of novel therapeutic approaches, notably biological therapies, are directly derived from knowledge harnessed by studies of mucosal immunity in the normal and inflamed intestine [82]. In spite of these striking advances, some aspects of gut immunity remain unclear. Perhaps the most critical one is how the mucosal immune system interacts with the endogenous commensal flora under physiological and pathological conditions, a fundamental issue considering the widely accepted notion that IBD is an abnormal immune response to the autologous enteric bacteria in genetically susceptible individuals [83]. The problem in understanding the mutual relationship between the gut and its luminal flora resides more in the latter than the former. In fact, the immune cells and the molecular tools the gut uses to communicate with intestinal microorganisms are reasonably understood, but far less knowledge exists on the composition and the function of the commensal flora. This is due in part to the limited attention paid to classical enteric microbiology for several decades, but in even greater part to the unrecognized complexity of the gut flora and the practical observation that most of it cannot be identified by traditional culture techniques. New perceptions of the gut microbiota are needed as well as new tools to dissect and classify it, and some of these are being now implemented, such as fluorescence in situ hybridization (FISH), terminal restriction length polymorphism (T-RFLP), polymerase chain reaction combined with denaturing gradient or temperature gradient gel electrophoresis (PCR/DGGE and PCR/TGEE), and 16S rRNA gene libraries [84]. These new methodologies do not necessarily allow the isolation of the actual microbes, but provide a far more detailed molecular classification of the hundreds of bacterial strains that populate the gut, and permit to get closer to the identification of bacteria against which the gut mucosal immune system reacts and induces inflammation. Another critical aspect of gut immunity is the nature of the mucosal immune response mediating inflammation during the course of a chronic disease, as typically found in IBD. It is plausible, if not probable, that long lasting intestinal inflammatory processes like Crohn disease and ulcerative colitis undergo substantial changes of the underlying biological response regardless of the initial triggering events. This point is fundamentally important for pediatric IBD, when the disease is at its earliest possible stages of detection and there is perhaps an opportunity to change the natural history of the disease, a far more difficult goal to attain in adult IBD patients with a long clinical history. Studying early events of IBD pathogenesis and follow them up during disease evolution into chronicity is obviously difficult in humans and more so in children, but this can be accomplished in animal models, which are starting to generate concrete evidence of substantial changes in the gut immune response from the early to the chronic stages of inflammation. Switches from a Th1 to a Th2 pattern occur in at least two models of experimental IBD. In the colitis of IL-10-deficient mice and the ileitis of SAMP1/YitFc mice, both of which are Th1-mediated initially, there is a marked increase in disease-mediating Th2 cytokines in late disease, e.g., IL-4 and IL-13 in the colitis model, and IL-5 and IL-13 in the ileitis model [85, 86]. The lesson here is that, even though the clinical manifestations of IBD remain constant, the underlying pathogenic immunopathology changes rather dramatically over time. Therefore, immunomodulators that are effective in early disease may no longer be effective in chronic disease, as again exemplified by the above animal models where blockade of Th1 cytokines is therapeutically effective in early but not late inflammation, a period when blockade of Th2 cytokines ameliorates disease. When these observations and concepts are translated into the human situation it is reasonable to assume that different immunomodulatory approaches should be used at different stages of IBD. Preliminary
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evidence for the existence of a differential susceptibility to immune modulation in children with IBD comes from both clinical and in vitro studies. Children with early onset Crohn disease have a significantly longer remission in response to TNF- blockade than children with late disease [87], and the cytokine secretory pattern of mucosal T cell clones derived from children with IBD can be modulated only in patients with early but not late disease (Kugathasan et al., submitted). In summary, investigation of gut immunity in IBD has been and still is extremely rewarding, as it has provided not only new information on the biology of its components and overall function, but also practical new ways to exploit this new information for current and future therapeutic applications. References 1. Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 2003;3:331–41. 2. Johansen FE, Brandtzaeg P. Transcriptional regulation of the mucosal IgA system. Trends Immunol 2004;25:150–7. 3. Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 2004;4:478–85. 4. Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2005;2:416–22. 5. Fagarasan S, Honjo T. Intestinal IgA synthesis: regulation of front-line body defences. Nat Rev Immunol 2003;3:63–72. 6. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 2003;3:710–20. 7. Harwig SS, Tan L, Qu XD, Cho Y, Eisenhauer PB, Lehrer RI. Bactericidal properties of murine intestinal phospholipase A2. J Clin Invest 1995;95:603–10. 8. Newberry RD, Lorenz RG. Organizing a mucosal defense. Immunol Rev 2005;206:6–21. 9. Cobrin GM, Abreu MT. Defects in mucosal immunity leading to Crohn disease. Immunol Rev 2005;206:277–95. 10. Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, Newman B, Van Oene M, Cescon D, Greenberg G, Griffiths AM, St George-Hyslop PH, Siminovitch KA. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 2004;36:471–5. 11. Stoll M, Corneliussen B, Costello CM, Waetzig GH, Mellgard B, Koch WA, Rosenstiel P, Albrecht M, Croucher PJ, Seegert D, Nikolaus S, Hampe J, Lengauer T, Pierrou S, Foelsch UR, Mathew CG, Lagerstrom-Fermer M, Schreiber S. Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet 2004;36:476–80. 12. Lee SH, Starkey PM, Gordon S. Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80. J Exp Med 1985;161:475–89. 13. Smith PD, Ochsenbauer-Jambor C, Smythies LE. Intestinal macrophages: unique effector cells of the innate immune system. Immunol Rev 2005;206:149–59. 14. Smith PD, Ohura K, Masur H, Lane HC, Fauci AS, Wahl SM. Monocyte function in the acquired immune deficiency syndrome. Defective chemotaxis. J Clin Invest 1984;74:2121–8. 15. Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A 1987;84:5788–92. 16. Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR, Reinecker HC. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 2005;307:254–8. 17. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol 2003;21:685–711. 18. Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 2003;424:88–93. 19. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 2004;113:1490–7.
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20. Hayday A, Theodoridis E, Ramsburg E, Shires J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat Immunol 2001;2:997–1003. 21. Kanamori Y, Ishimaru K, Nanno M, Maki K, Ikuta K, Nariuchi H, Ishikawa H. Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lymphohemopoietic progenitors develop. J Exp Med 1996;184:1449–59. 22. Groh V, Steinle A, Bauer S, Spies T. Recognition of stress-induced MHC molecules by intestinal epithelial gamma delta T cells. Science 1998;279:1737–40. 23. Boismenu R, Havran WL. An innate view of gamma delta T cells. Curr Opin Immunol 1997;9:57–63. 24. Carding SR, Egan PJ. Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2002;2:336–45. 25. Polak-Charcon S, Shoham J, Ben-Shaul Y. Tight junctions in epithelial cells of human fetal hindgut, normal colon, and colon adenocarcinoma. J Natl Cancer Inst 1980;65:53–62. 26. Udall JN, Pang K, Fritze L, Kleinman R, Walker WA. Development of gastrointestinal mucosal barrier. I. The effect of age on intestinal permeability to macromolecules. Pediatr Res 1981;15:241–4. 27. Kerneis S, Bogdanova A, Kraehenbuhl JP, Pringault E. Conversion by Peyer’s patch lymphocytes of human enterocytes into M cells that transport bacteria. Science 1997;277:949–52. 28. Trier JS. The Paneth cells: an enigma. Gastroenterology 1966;51:560–2. 29. Teitelbaum JE, Allan Walker W. The development of mucosal immunity. Eur J Gastroenterol Hepatol 2005;17:1273–8. 30. Marodi L. Innate cellular immune responses in newborns. Clin Immunol 2006;118:137–44. 31. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA. Nod2dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005;307:731–4. 32. Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, Eckmann L, Karin M. Nod2 mutation in Crohn disease potentiates NF-kappaB activity and IL-1beta processing. Science 2005;307:734–8. 33. Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn disease. Crohn Disease cA2 Study Group. N Engl J Med 1997;337:1029–35. 34. Orenstein R. Anti-interleukin-12 antibody for active Crohn disease. N Engl J Med 2005;352:627–8. 35. Marks DJ, Harbord MW, MacAllister R, Rahman FZ, Young J, Al-Lazikani B, Lees W, Novelli M, Bloom S, Segal AW. Defective acute inflammation in Crohn disease: a clinical investigation. Lancet 2006;367:668–78. 36. Korzenik JR, Dieckgraefe BK, Valentine JF, Hausman DF, Gilbert MJ. Sargramostim for active Crohn disease. N Engl J Med 2005;352:2193–201. 37. Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci U S A 1998;95:258–63. 38. Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest 2006;116:1218–22. 39. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006;24:677–88. 40. Johansson-Lindbom B, Svensson M, Pabst O, Palmqvist C, Marquez G, Forster R, Agace WW. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J Exp Med 2005;202:1063–73. 41. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, Weissman IL, Hamann A, Butcher EC. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993;74:185–95. 42. Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, McEvoy LM, Butcher EC, Kassam N, Mackay CR, Newman W, Ringler DJ. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 1997;151:97–110. 43. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006;25:195–201. 44. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–64. 45. Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 2003;170:3939–43.
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46. Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A, Zeitz M, Duchmann R. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology 2005;128:1868–78. 47. Conley ME, Delacroix DL. Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann Intern Med 1987;106:892–9. 48. Brandtzaeg P, Farstad IN, Johansen FE, Morton HC, Norderhaug IN, Yamanaka T. The B-cell system of human mucosae and exocrine glands. Immunol Rev 1999;171:45–87. 49. Brandtzaeg P, Prydz H. Direct evidence for an integrated function of J chain and secretory component in epithelial transport of immunoglobulins. Nature 1984;311:71–3. 50. Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004;303:1662–5. 51. Spencer J, Dillon SB, Isaacson PG, MacDonald TT. T cell subclasses in fetal human ileum. Clin Exp Immunol 1986;65:553–8. 52. Spencer J, MacDonald TT, Isaacson PG. Heterogeneity of non-lymphoid cells expressing HLA-D region antigens in human fetal gut. Clin Exp Immunol 1987;67:415–24. 53. Cornes JS. Peyer’s patches in the human gut. Proc R Soc Med 1965;58:716. 54. Perkkio M, Savilahti E. Time of appearance of immunoglobulin-containing cells in the mucosa of the neonatal intestine. Pediatr Res 1980;14:953–5. 55. Powrie F, Leach MW, Mauze S, Menon S, Caddle LB, Coffman RL. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1994;1:553–62. 56. Totsuka T, Kanai T, Uraushihara K, Iiyama R, Yamazaki M, Akiba H, Yagita H, Okumura K, Watanabe M. Therapeutic effect of anti-OX40L and anti-TNF-alpha MAbs in a murine model of chronic colitis. Am J Physiol Gastrointest Liver Physiol 2003;284:10. 57. Sugawara K, Olson TS, Moskaluk CA, Stevens BK, Hoang S, Kozaiwa K, Cominelli F, Ley KF, McDuffie M. Linkage to peroxisome proliferator-activated receptor-gamma in SAMP1/YitFc mice and in human Crohn disease. Gastroenterology 2005;128:351–60. 58. Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F, Pallone F. Interleukin 12 is expressed and actively released by Crohn disease intestinal lamina propria mononuclear cells. Gastroenterology 1997;112:1169–78. 59. Van Assche G, Vermeire S, Rutgeerts P. Emerging biological treatments in inflammatory bowel diseases. Dig Dis 2006;24:131–6. 60. Probert CS, Chott A, Turner JR, Saubermann LJ, Stevens AC, Bodinaku K, Elson CO, Balk SP, Blumberg RS. Persistent clonal expansions of peripheral blood CD4+ lymphocytes in chronic inflammatory bowel disease. J Immunol 1996;157:3183–91. 61. Cong Y, Brandwein SL, McCabe RP, Lazenby A, Birkenmeier EH, Sundberg JP, Elson CO. CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease. J Exp Med 1998;187:855–64. 62. Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR, Fort M, Hershberg RM. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 2004;113:1296–306. 63. Sansonetti PJ. War and peace at mucosal surfaces. Nat Rev Immunol 2004;4:953–64. 64. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004;118:229–41. 65. Cario E, Gerken G, Podolsky DK. Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 2004;127:224–38. 66. Hisamatsu T, Suzuki M, Reinecker HC, Nadeau WJ, McCormick BA, Podolsky DK. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 2003;124: 993–1000. 67. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M, Herrlinger KR, Stallmach A, Noack F, Fritz P, Schroder JM, Bevins CL, Fellermann K, Stange EF. NOD2 (CARD15) mutations in Crohn disease are associated with diminished mucosal alpha-defensin expression. Gut 2004;53:1658–64. 68. Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, Ogunbiyi O, Nunez G, Keshav S. Crohn disease and the NOD2 gene: a role for paneth cells. Gastroenterology 2003;125:47–57. 69. Bevan MJ. Cross-priming. Nat Immunol 2006;7:363–5.
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70. Sutmuller RP, Morgan ME, Netea MG, Grauer O, Adema GJ. Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol 2006;27:387–93. 71. Heuschkel RB, MacDonald TT, Monteleone G, Bajaj-Elliott M, Smith JA, Pender SL. Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease. Gut 2000;47:57–62. 72. Pavlick KP, Laroux FS, Fuseler J, Wolf RE, Gray L, Hoffman J, Grisham MB. Role of reactive metabolites of oxygen and nitrogen in inflammatory bowel disease. Free Radic Biol Med 2002;33:311–22. 73. Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA. Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci U S A 2000;97:6043–8. 74. Mackie RI, Sghir A, Gaskins HR. Developmental microbial ecology of the neonatal gastrointestinal tract. Am J Clin Nutr 1999;69:1035S–1045S. 75. Mellander L, Carlsson B, Jalil F, Soderstrom T, Hanson LA. Secretory IgA antibody response against Escherichia coli antigens in infants in relation to exposure. J Pediatr 1985;107:430–3. 76. Fadel S, Sarzotti M. Cellular immune responses in neonates. Int Rev Immunol 2000;19:173–93. 77. Rijkers GT, Dollekamp EG, Zegers BJ. The in vitro B-cell response to pneumococcal polysaccharides in adults and neonates. Scand J Immunol 1987;25:447–52. 78. Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow’s milk allergy. J Exp Med 2004;199:1679–88. 79. Hanson DG. Ontogeny of orally induced tolerance to soluble proteins in mice. I. Priming and tolerance in newborns. J Immunol 1981;127:1518–24. 80. Rowe J, Macaubas C, Monger TM, Holt BJ, Harvey J, Poolman JT, Sly PD, Holt PG. Antigen-specific responses to diphtheria-tetanus-acellular pertussis vaccine in human infants are initially Th2 polarized. Infect Immun 2000;68:3873–7. 81. Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity comes of age. Nat Rev Immunol 2004;4:553–64. 82. Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science 2005;307:1920–5. 83. Oliva-Hemker M, Fiocchi C. Etiopathogenesis of inflammatory bowel disease: the importance of the pediatric perspective. Inflamm Bowel Dis 2002;8:112–28. 84. Tannock GW. New perceptions of the gut microbiota: implications for future research. Gastroenterol Clin North Am;2005 Sep;34:361–82. 85. Spencer DM, Veldman GM, Banerjee S, Willis J, Levine AD. Distinct inflammatory mechanisms mediate early versus late colitis in mice. Gastroenterology 2002;122:94–105. 86. Bamias G, Martin C, Mishina M, Ross WG, Rivera-Nieves J, Marini M, Cominelli F. Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation. Gastroenterology 2005;128:654–66. 87. Kugathasan S, Werlin SL, Martinez A, Rivera MT, Heikenen JB, Binion DG. Prolonged duration of response to infliximab in early but not late pediatric Crohn disease. Am J Gastroenterol 2000;95:3189–94.
3 Cytokines and Inflammatory Bowel Disease Edwin F. de Zoeten∗ and Ivan J. Fuss
Introduction The etiology of inflammatory bowel diseases (IBD) is generally described as multifactorial including genetic predisposition, environmental insult and a dysregulated immune response. The immune response is the only one of these that is currently amenable to therapy. Understanding the factors that go into the activation of inflammation, and those that perpetuate this effect is improving greatly. With this mastery we are able to define the cytokines that are important in the etiology of IBD. Over the past 15 years many of the newest and arguably the most successful therapies for Crohn disease (CD) and ulcerative colitis (UC) have been developed due to an increased understanding of the immune response and specifically the cytokines essential to this response. As stated above, IBD is in part due to a dysregulated or an inappropriate immune reaction, which has been thought in part to be against the microflora of the gut. Upon activation of the immune system, cytokines and chemokines, which are proteins produced by the cells involved in the immune response, are produced, and trigger a cascade of downstream reactions. These cytokines are increasingly being defined as important molecules in the pathogenesis of IBD as well as putative and known targets for the therapy of IBD. With the advent of murine models of mucosal inflammation a great deal of knowledge has been acquired which has advanced our understanding of inflammation in IBD. In these models it has been initially noted that the inflammation is due either to an excessive Th1 T cell response or an excessive Th2 T cell responses, with the former characterized by increased interleukin 1 (IL-1), IL-2, IL-6, IL-12, IL-18, interferon gamma (IFN-) and tumor necrosis factor alpha (TNF-) production and the latter by increased IL-4, IL-5, IL-10, and/or IL-13 production. An example of a murine Th1 colitis is that induced by the haptenating agent trinitrobenzesulfonic acid (TNBS) [1], a colitis in which the predominant immune response is dominated by IL-12, IFN- and TNF-. This correlates with human studies, which have shown increased levels of TNF-, IFN-, IL-1 and IL-6 in the intestinal tissues and the peripheral blood of patients with CD [2]. Similar to what has been observed in patients with UC [3, 4] the oxazolone model of colitis in mice, which has similar histologic features as those seen in UC is associated with a Th2 response that is dominated by IL-13. These murine models have given important insights into the
*Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, 34th Street and Civic Ctr. Blvd., Philadelphia, PA 19104, Phone: 215-590-9146, Fax: 215-590-3606, E-mail:
[email protected]
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IBD entities; however, questions of whether CD and UC are “true” Th1 or Th2 mediated disease processes remain. This will be discussed later. In the immune cascade, cytokines help to determine the nature of the immune response, and they can act in a dual nature as either pro- (IL-1, IL-6, TNF-) or anti-inflammatory (IL-4, IL-5, IL-10, transforming growth factor beta (TGF-)) molecules. They can affect the synthesis or secretion of reactive oxygen species, nitric oxide, leukotrienes, platelet-activating factor, and prostaglandins. In addition, they can have differing qualities depending on when they are present in the inflammatory cascade. Finally, it is important to understand that pro- and anti- inflammatory responses are required to maintain the integrity of the intestinal mucosa due to the environment in which it exists. The intestinal mucosa is constantly bombarded with antigen from food, comensal and pathogenic bacteria and therefore it is important to be able to mount an inflammatory response to rid itself of harmful bacteria. At the same time, the mucosal immune system must be able to regulate itself either by the action of specific regulatory cells or by the action of cytokines such as IL-4, IL-5, IL-10, TGF-, IL-1ra, and TNF-.
Pro-inflammatory Cytokines Tumor Necrosis Factor Alpha For most gastroenterologists TNF- is the most recognized cytokine due to the increasing use of the chimeric monoclonal anti-TNF- antibody, infliximab, for the treatment of CD and UC. TNF- is secreted by macrophages, monocytes, neutrophils, T cells, and NK cells following their stimulation by bacterial lipopolysaccharides. CD4+ T lymphocytes secrete TNF- while CD8+ T cells do not. The synthesis of TNF- is induced by many different stimuli including interferons, IL-2, and granulocyte macrophage colony stimulating factor (GM-CSF). The production of TNF- is inhibited by IL-6, and TGF-. TNF- is an agonist of the p38 and c-jun N terminal kinase cascades, two important signaling pathways of the mitogen activated protein (MAP) kinase family involved in the generation of the inflammatory responses [5]. It is a potent proinflammatory cytokine that exerts its stimulatory effect on cells which produce IFN-. Indeed, in synergy with factors from non-lymphocyte lamina propria mononuclear cells it can act with prostaglandin E2 to stimulate IL-12- mediated T cell production of IFN-. ˜In resting macrophages, TNF- induces the synthesis of IL-1 and prostaglandin E2 which can act in concert to potentiate the inflammatory cascade. TNF- can also enhance the proliferation of T cells induced by various stimuli in the absence of IL-2, in fact some subpopulations of T cells only respond to IL-2 in the presence of TNF-. Beyond its effect on the immune response, TNF- activates osteoclasts and thus induces bone resorption and this effect is associated to one of the theories of why patients with CD may have decreased bone mineral density. Although TNF- is required for normal host immune responses the overexpression can have severe pathologic consequences as exemplified by mice in which the overexpression of TNF by a transgene is associated with a severe colitis [6]. In animal models TNF- knockout mice do not develop significant colitis [7] and as proof of principle that TNF- is important for the pathogenesis of IBD TNF- neutralizing antibodies have been shown to be effective in ameliorating intestinal inflammation. Associated human studies have reported elevated levels of TNF- in serum, stool and mucosal tissue [8, 9] correlating with clinical and laboratory indices of intestinal activity. Furthermore, dramatic effects have been noted in clinical studies in patients with Crohn disease treated with infliximab [10, 11]. These effects have been observed in both disease amelioration and induction of clinical remission. Important for the understanding of some of the critical side effects of infliximab, TNF- mediates a part of the cell-mediated immunity against obligate and facultative bacteria and parasites by stimulating
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phagocytosis and the synthesis of superoxide dismutase in macrophages. It confers protection against Listeria monocytogenes infections and tuberculosis. Anti-TNF- antibodies have been shown to weaken the ability of mice to cope with these infections. Infection with these organisms is a possible risk of using anti-TNF monoclonal antibody therapy in the treatment of IBD and a reason that patients are screened for tuberculosis prior to initiation of therapy with infliximab. Interferon-gamma Interferon gamma is produced mainly by CD4+ , CD8+ T-lymphocytes and natural killer cells activated by antigens, and mitogens. IFN- synergises with TNF- in inhibiting the proliferation of various cell types, however, the main biological activity of IFN- appears to be immunomodulatory in contrast to the other interferons (IFN- or ) which are mainly antiviral. IL-2 and IFN- appear to be intricately interwoven in their functions. In T-helper cells IL-2 induces the synthesis of IFN- and other cytokines. IFN- acts synergistically with IL-1 and IL-2 and appears to be required for the expression of IL-2 receptors (CD25) on the cell surface of T-lymphocytes. Blocking of the IL-2 receptor by specific antibodies inhibits the synthesis of IFN-. IFN- is a modulator of T-cell growth and functional differentiation, it is a growth-promoting factor for T-lymphocytes and it potentiates the response of these cells to growth factors. Most importantly, IFN- can increase the expression of MHC class molecules allowing greater antigenic recognition. Furthermore, it can increase permeability at epithelial tight junction barriers, thereby allowing further antigenic exposure [12]. Finally, in concert with TNF-, IFN- can cause direct tissue destruction as it increases local inflammation. [13] IFN- is one of the few cytokines that correlates with severity of disease in patients with Crohn disease. As a known proinflammatory cytokine it would appear to be an obvious choice to target for treatment of IBD. IFN- has been targeted in Crohn disease using, fontolizumab, a humanized monoclonal antibody against IFN- [14, 15]. In studies using these antibodies positive results were found in patients with moderate to severe Crohn disease when compared to placebo. Although the studies did not reach statistical significance the results did indicate a trend toward effect. This suggests a potential benefit of blocking IFN- in patients with Crohn disease. Interleukin -1 This cytokine consists of IL-1 and IL-1 subunits which are both produced by monocytes, macrophages and endothelial cells. In addition to these pro-inflammatory cytokines there is an IL-1 receptor antagonist (IL-1ra) produced by intestinal epithelial cells which is capable of inhibiting the proinflammatory actions of IL-1 by binding the IL-1 receptor and competitively blocking the interaction with IL-1. IL-1ra is considered to be one intestinal mechanism for down regulation of the immune response and has been shown to be elevated in the serum of patients with CD. Stimulation of IL-1ra secretion has been shown to be activated by IL-1 itself, therefore forming a negative feedback loop. IL-1- and – are essential biologically equivalent pleiotropic factors that act locally and systemically. IL-1 has a multitude of effector functions, some of which are mediated indirectly by the induction of the synthesis of other mediators including adrenocorticotropic hormone (ACTH), prostaglandin E2 , IL-6 and IL-8 (a chemotactic cytokine in the chemokine family). The main biological activity of IL-1 is the stimulation of T-helper cells, which are induced to secrete IL-2 and to express IL-2 receptors. IL-1 can also act on B-cells, promoting their proliferation and the synthesis of immunoglobulins. IL-1 stimulates the proliferation and activation of other immune cells such as NK-cells, fibroblasts, and thymocytes. The IL-1 mediated proliferative effects can be inhibited by the suppressive cytokine, TGF-. The synthesis of IL-1 can be induced by other cytokines including TNF-, IFN-, , or and also by bacterial endotoxins, and viruses. Furthermore IL-1 activity is not limited to stimulation
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of T cells but it also promotes the adhesion of neutrophils, monocytes, T-cells, and B-cells by enhancing the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule (ELAM) all of which can contribute to the pathogenesis of CD. IL-1 is also a strong chemoattractant for leukocytes as demonstrated by the local accumulation of neutrophils at the site of injection of tissue with IL-1. Finally, in combination with TNF- IL-1 appears to be involved in the generation of lytic bone lesions. IL-1 activates osteoclasts thereby suppressing the formation of new bone. Low concentrations of IL-1, however, promote new bone growth. IL-1 was one of the first cytokines targeted for therapy in animal colitis models. In these studies, administration of IL-1ra led to amelioration of colitis, in a rabbit model. Thus, it was also one of the first demonstrations that blockade of a single cytokine could be effective in therapy of colitis [16]. In patients with IBD, increased serum levels of IL-1 are seldom detected. However, in intestinal lesions in patients with both CD and UC, IL-1 levels are elevated [17]. IL-1ra is a possible intestinal mechanism for down regulation of the immune response and is elevated in the serum of patients with CD. IL-1 receptor antagonist determines the biological effects of IL-1, as increased concentrations of this mediator will decrease IL-1 activity. In the inflammatory lesions of patients with IBD, levels of this mediator are increased, although not as much as IL-1, leading to a disproportionate increase in IL-1 activity. Interleukin-2 IL-2 is a major T cell growth factor, secreted by activated T cells acting via the high-affinity IL-2 receptor (CD25) on T cells. This binding to CD25 promotes cell proliferation. Under physiologic conditions IL-2 is produced mainly by CD4+ T lymphocytes following cell activation. Resting cells do not produce IL-2. In T-helper cells IL-2 induces the synthesis of IFN- and other cytokines. IFN- acts synergistically with IL-1 and IL-2 and appears to be required for the expression of IL-2 receptors on the cell surface of T-lymphocytes. Blocking of the IL-2 receptor by specific antibodies also inhibits the synthesis of IFN-. IFN- in return is a modulator of T-cell growth and functional differentiation. It is a growth-promoting factor for T-lymphocytes and potentiates the response of these cells to growth factors IL-2 is a growth factor for all subpopulations of T-lymphocytes including importantly suppressive T regulatory cells. It is an antigen-unspecific proliferation factor for T-cells that induces cell cycle progression in resting cells and thus allows clonal expansion of activated T-lymphocytes. In patients with CD it has been demonstrated in many studies that IL-2 secretion from lamina propria cells is decreased as compared to normal patient samples. Daclizumab, a humanized monoclonal antibody to CD25, produced in an effort to block the binding of IL-2 to the IL-2R was tested in patients with UC and initially appeared promising in a small open label study [18], but upon testing in a placebo controlled study the therapy did not show efficacy [19]. This effect could be related to the fact that IL-2R (CD25) is also present on T regulatory cells. The inhibition of binding of IL-2 to its receptor present on T regulatory (T reg) cells, thereby inhibits the proliferation of these cells which are important in down regulation of the immune response. This highlights a common problem in the targeting of the cytokine pathway for treatment of inflammatory diseases, in that, cytokines frequently have multiple effects and can function in both a pro-inflammatory as well as an anti-inflammatory capacity. Interleukin-6 IL-6 is a pleiotropic cytokine considered to be a major cytokine in inflammation, regulation of T cell responses and apoptosis. IL-6 is produced by many different cell types. The main sources in vivo are stimulated monocytes, fibroblasts, endothelial cells, macrophages, T-cells, and
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B-lymphocytes. IL-6 is a B-cell differentiation factor in vivo and in vitro and an activation factor for T-cells. In the presence of IL-2, IL-6 induces the differentiation of mature and immature T-cells into cytotoxic T-cells. IL-6 also induces the proliferation of thymocytes and likely plays a role in the development of thymic T-cells. Most significantly IL-6 and TGF- together can induce the development of the inflammatory Th17 cell lineage. Finally, in opposition, if IL-6 is present, there is decreased propensity to development of FOXP3 positive T reg cells. Interestingly IL-6 levels are increased in the serum of patients with active CD and UC compared to normal controls. A study looking at a known functional polymorphism of the IL-6 gene and the site of disease in CD patients did not demonstrate an association of IL-6 functional polymorphisms with CD or protection from CD. It did demonstrate that patients with the high producer genotype were more likely to have ileocolonic disease, while those with the low producer genotype had primarily colonic type disease, whereas those with intermediate producer genotype were more likely to have isolated ileal disease. These studies indicated an association of IL-6 production and site of disease [20]. The activity of IL-6 has made it an obvious target for clinical trials not only due to its proinflammatory effects but due to its involvement in T cell apoptosis cell death [21]. A pilot study was performed [22] to investigate safety and efficacy of a humanized anti-IL-6R monoclonal antibody in patients with Crohn disease. This target appeared to be promising with 80% of the patients treated for 12 weeks demonstrating clinical improvement as compared to 31% treated with placebo. Interleukin-12 IL-12 is a heterodimeric molecule composed of IL-12 p40 and IL-12 p35 subunits. IL-12 is secreted by antigen presenting cells such as monocytes, macrophages, dendritic cells, and to a lesser extent by NK cells. The most powerful inducers of IL-12 are bacteria, bacterial products, and parasites. IL-12 is a proinflammatory cytokine that is important in the differentiation of naïve T cells into IFN- producing pathogenic CD4+ Th1 cells [13, 23]. In peripheral lymphocytes of the Th1 T-helper cell type, IL-12 induces the synthesis of IFN-, IL-2, and TNF-. TNF- also appears to be involved in mediating the effects of IL-12 on natural killer cells since the effects of IL-12 are inhibited by an antibody directed against TNF-. IL-12 and TNF- are co-stimulators for IFN- production with IL-12 maximizing the IFN-g response; the production of IL-12, TNF-, and IFN- is inhibited by IL-10. In Th2 T-helper cells IL-12 reduces the synthesis of IL-4 IL-5, and IL-10. This cytokine is considered a driving force behind chronic intestinal inflammation. Evidence for this is derived from murine models of colitis demonstrating that disease development could be inhibited by treatment with anti IL-12p40 monoclonal antibodies [23]. In human studies, this master T cell differentiating cytokine has been shown to be produced in large amounts in the intestines of patients with CD [24]. In addition, this cytokine has been targeted in human CD using an anti-IL-12p40 monoclonal antibody and found to be effective in early studies [25]. The long lasting clinical effect observed may be due in part to the induction of apoptosis of the inflammatory effector cells. These studies suggest that in addition to IL-2, IL-12 is a necessary growth and survival factor for T cells [26]. It also brings about the point that the mechanism of action of the various anti-biologic therapies lies not only in their capability to neutralize their respective cytokines but due to their ability to induce cell death of the inciting inflammatory effector cells. Interestingly, the p40 subunit is also found to be a portion of another significant proinflammatory master cytokine, IL-23. The positive effects observed of the anti IL-12 p40 antibody may indeed have been due to both the effect on IL-12 and IL-23 [24]. Further studies in models of colitis indicate that IL-23 is important in the inflammatory response in IBD in that it plays a significant role in the maintenance of Th-17 effective inflammatory cells [27].
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Interleukin-23 IL-23 is a proinflammatory cytokine that has become a recent focus of attention. IL-23 is secreted by activated dendritic cells and macrophages. It is a proinflammatory cytokine that shares structural homology with IL-12, specifically it is composed of the p40 subunit and a unique p19 chain. Initial studies indicating an ameliorating effect of an anti-p40 antibody in murine models of inflammation was felt to be due to its effect on IL-12. However, recently this effect has been reevaluated and studies indicate that this ameliorating effect may be due to a decrease in IL-23 mediating effect. In these studies, mice deficient in the p19 subunit of IL-23 displayed attenuated inflammation in colitis models, whereas mice deficient in the p35 chain of IL-12 (therefore deficient in IL-12, but not IL-23) had no effect on colitis. These studies together suggest that the initial effects observed with anti-p40 in a variety of animal models may have been due to a decrease in IL-23. IL-23 promotes a novel subset of CD4+ T cells (Th17 cells) that is characterized by the production of IL-17, IL-6, and TNF- and has been associated with autoimmune tissue inflammation [28]. The exact mechanism by which IL-23 promotes the Th17 response has not been defined but it appears TGF- and IL-6 are important for the commitment into a Th17 cell and IL-23 is important for the proliferation of this cell type [29, 30]. IL-23 effect is not limited to Th17 cells but appears to have an effect of the innate immune system inducing monocytes and macrophages to produce proinflammatory cytokines such as IL-1, IL-6 and TNF- as well. In addition, in a genome wide association study in adults [31] as well as in a pediatric population (Baldassano, personal communication) the IL-23 receptor (IL-23R) gene on chromosome 1p31 has been shown to have a highly significant association with CD specifically, and an uncommon coding variant of the IL-23R gene was shown to confer protection. These data indicate that the IL-23 pathway may have a causal link to CD. Interleukin-17 IL-17 has been associated with multiple immune regulatory functions. Most notably, IL-17 is involved in inducing and mediating proinflammatory responses. IL-17 induces the production of many other cytokines, such as IL-6, granulocyte colony stimulating factor (G-CSF), GM-CSF, IL-1, TGF-, TNF-, chemokines including IL-8, growth regulated oncogene alpha (GRO-) and monocyte chemotractic protein 1 (MCP-1) and prostaglandins (e.g. PGE2 ) from many cell types (fibroblasts, endothelial cells, epithelial cells, and macrophages). IL-17 expression is currently believed to be stimulated by IL-23 expression. IL-23 appears to activate expression of IL-17 by subset of CD4+ T-cells called T-Helper-17 (Th17) cells, monocytes, and neutrophils [32]. Increased expression of IL-17 has been reported in the intestinal mucosa of patients with IBD [33]. Some reports suggest that IL-17 alone is capable of inducing autoimmune tissue reactivity whereas other groups suggest that IL-17 and IFN- synergize to stimulate this autoimmune reactivity [28, 34]. In these studies it was indicated that IL-17 was produced by T cells and monocytes in the intestinal mucosa. IL-17 binds to the IL-17 receptor on endothelial cells and epithelial cells to promote secretion of proinflammatory substances that recruit inflamatory cells to the site [35]. As a result of these roles, the IL-17 family has been linked to many immune/autoimmune related diseases including rheumatoid arthritis, asthma, and lupus. IL-17 expression is increased in patients with a variety of allergic and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, IBD, and asthma, suggesting the contribution of IL-17 to the induction and/or development of such diseases. This work identifies IL-17 as another possible target for IBD therapy. Interleukin-18 This cytokine initially identified as interferon- inducing factor (IGIF) is similar to the IL-1 family in structure, processing, receptor, and proinflammatory properties. It has been found to be
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produced by intestinal epithelial cells and appears to induce other proinflammatory cytokines and Th1 polarization. IL-12 and IL-18 have a synergistic relationship. Their production by activated macrophages appears to drive the development of Th1 CD4+ T cell predominance in the intestinal mucosa. Recombinant IL-18 alone is able to induce a proliferative response in vitro in freshly isolated mucosal lymphocytes from patients with CD. The synergistic effect is likely due to the upregulation of the IL-18 receptor by IL-12. Intestinal mucosa from patients with CD have been evaluated and found to have increased expression of IL-18 [36] and this was also noted in experimental murine colitis [37]. Tissues from patients with CD have been shown in vitro to have decreased suppressive cytokine IL-10 expression after treatment with IL-18 indicating one possible effector mechanism. IL-12 and IL-18 together appear to synergize to drive the lamina propria lymphocytes into a Th1 type response. IL-12 appears to induce increased IL-18 expression thus the synergistic effect [38, 39]. Using models of colitis multiple laboratories have tried to block IL-18 and the results indicate that IL-18 may have a role in the initiation of intestinal inflammation, while others have shown that IL-18 acts to reduce inflammation. Interleukin-13 IL-13 can have a dual functional role in that it can down-modulate macrophage activity, reducing the production of pro-inflammatory cytokines (IL-1, IL-6, IL-8, IL-10, IL-12) and chemokines (macrophage inflammatory protein 1 (MIP-1), MCP) in response to IFN- or bacterial lipopolysaccharides. IL-13 can also enhance the production of the IL-1 receptor antagonist and decrease the production of nitric oxide by activated macrophages, leading to a decrease in parasiticidal activity. Yet interestingly it appears that IL-13 is important in the development of Th2 type colitis such as the murine model of colitis oxazolone and its human counterpart, UC. In these studies it was found that IL-13 produced by natural killer T cells, when neutralized led to decreased inflammation in the oxazolone model of colitis. Furthermore, most importantly, in human studies, these IL-13 secreting NK T cells exhibited an increased cytolytic function against epithelial cell lines. Finally, IL-13 itself has been shown to be directly toxic to epithelial cells as well as to cause increased permeability barrier functional defects [40, 41]. Thus, in the oxazolone model of colitis and its human counterpart ulcerative colitis it is believed that IL-13 secreting NK T cells plays an important role in the etiology of this disease entity. This is in contrast to the Th1/Th17 disease process discussed in the pathogenesis of Crohn disease. Finally, although IL-13 can function as a pro inflammatory molecule in UC it stills retains anti-inflammatory effects as mentioned above, its role in Th1 disease entities remains uncertain.
Anti-inflammatory Cytokines As the host requires a pro-inflammatory response in the presence of a stimulating antigen, so too, the host requires an anti-inflammatory response once the antigen has been dealt with or the offending infection has been cleared. Without the ability to turn off or down-regulate the immune response the inflammation becomes overwhelming and can be detrimental to the host. This issue is exemplified in patients with the disease known as IPEX (immune dysregulation, polyendocrinopathy, and enteropathy, X-linked). This syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life. It is associated with mutations identified in the FoxP3 gene. FoxP3 is a member of the forkhead/winged-helix family of transcriptional regulators known to be specific to regulatory T cells and important for their function. Without functional T reg cells the activated immune system has little or no halt to the inflammatory process. Tolerance, in normal hosts, is mediated by these regulatory T cells, as well as, B lymphocytes, natural killer T cells and dendritic cells that secrete TGF-, IL-10, IFN-/
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and prostaglandin J2. Another mechanism for regulation is the secretion of anti-inflammatory cytokines. As these cytokines are defined they are being evaluated for methods to increase their secretion or for systemic therapy with the cytokine itself to treat IBD. Transforming Growth Factor Beta TGF- belongs to a family of multi-functional polypeptides produced by a wide variety of lymphoid and non-lymphoid cells. They exist in five different isoforms, three of which are expressed in mammals and designated as TGF-1, TGF-2 and TGF-3 [1]. TGF- can act in both autocrine and paracrine modes to control the differentiation, proliferation and state of activation of immune cells. TGF- can inhibit the production of and response to cytokines associated with CD4+ Th1 T cells and CD4+ Th2 T cells. TGF- inhibits the proliferation of T-lymphocytes by down-regulating predominantly IL-2 mediated proliferative signals. It also inhibits the growth of natural killer cells in vivo and deactivates macrophages. Of significance, TGF- has been shown to be important in stimulating the development of Foxp3+ T regulatory cells. These activities have been verified in animal models of IBD [42]. These studies indicate that TGF- production is relevant in the pathogenesis of experimental colitis. In two different models of Th1-mediated murine experimental colitis, it has been shown that protection from colitis development is strictly associated with the presence of increased numbers and/or up-regulation of TGF-1 producing cells [1, 43]. In humans, the data pertaining to regulatory cells remains sparse. In a single study, Maul et al. [44] have shown that there exists a decrease in FoxP 3 expressing cells in the periphery of patients with IBD. However, examination of mucosal tissue reveals that as compared to controls, patients with IBD had a relative increase in these cells albeit this increase was less than that seen in other inflammatory disorders such as diverticulitis. The authors postulated that there is a relative lack of counter-regulation at the mucosal level in IBD and therefore, an ability to increase the number of local resident regulatory cells in the face of inflammation. The theory that IBD may be due to a defect in regulatory cells number or suppressive function still requires further investigation. Interleukin-4 IL-4 is produced mainly by a subpopulation of activated T-cells (Th2) which are the biologically most active helper cells for B-cells and which also secrete IL-5 and IL-6. Another subpopulation, Th1 also produces IL-4 albeit to a lesser extent. IL-4 is a stimulatory molecule for both B and T cells that has known immunosuppressive effects in the intestine where it promotes the proliferation and differentiation of activated B-cells, and the expression of major histocompatibility complex (MHC) class 2 antigens. IL-4 enhances expression of MHC class 2 antigens on B-cells. It can promote their capacity to respond to other B-cell stimuli and to present antigens for T-cells. While IL-4 is frequently described as an anti-inflammatory cytokine, recent studies have shown its capacity to perpetuate inflammatory diseases. Specifically, in a murine model of ileitis a monoclonal antibody against IL-4 was shown to suppress disease severity [45]. Interestingly, IL-4 mediated disease in certain animals models appears to be most important in inflammation limited to the ileum and small intestine [46]. In the aforementioned oxazolone model of colitis, IL-4 is the predominant initial cytokine to appear in the mucosal lesions, however this is subsequently superceded by an IL-13 response. This coincided with what one sees in the IBD entities as no significant measurable secreted levels of IL-4 have been found in either UC or CD patients to suggest a pathogenic role. Thus, IL-4 as IL-13 displays both anti-inflammatory and inflammatory cytokine properties. Its targeting for therapy in animal studies has had some beneficial effects. Targeting in human disease is not as clear.
Chapter 3 Cytokines and Inflammatory Bowel Disease
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Interleukin-10 IL-10 is produced by activated CD8+ peripheral blood T-cells, by T-helper CD4+ T-cell clones after both antigen-specific and polyclonal activation. IL-10 has been defined as having multiple biologic effects all acting to down regulate the inflammatory response. IL-10 inhibits the synthesis of a number of cytokines such as IFN-, IL-2 and TNF- in Th1 T-helper subpopulations of T-cells but not of Th2 T-helper cells. This activity is antagonized by IL-4. The inhibitory effect on IFN- production is indirect and appears to be the result of a suppression of IL-12 synthesis by accessory cells. In the human system, IL-10 is produced by, and down-regulates the function of, Th1 and Th2 cells. In macrophages stimulated by bacterial lipopolysaccharides IL-10 inhibits the synthesis of IL-1, IL-6 and TNF- by promoting, among other things, the degradation of cytokine mRNA. It also leads to an inhibition of antigen presentation. The activation of macrophages can be prevented by IL-10. In human monocytes, IFN- and IL-10 antagonize each other’s production and function. IL-10 has been shown also to be a physiologic antagonist of IL-12. In macrophages stimulated with bacterial lipopolysaccharides IFN- increases the synthesis of IL-6 by inhibiting the production of IL-10. In B-cells activated via their antigen receptors or via CD40 IL-10 induces the secretion of IgG, IgA, and IgM. This effect is synergised by IL-4 while the synthesis of immunoglobulins induced by IL-10 is antagonized by TGF-. It has been shown that human IL-10 is a potent and specific chemoattractant for human T-lymphocytes. Finally, IL-10 also inhibits the chemotactic response of CD4(+) cells, but not of CD8(+) cells, towards IL-8. In support of its role in IBD, mice deficient in IL-10 (IL-10-/-) gene spontaneously develop chronic colitis. Using this information recombinant IL-10 has been used as therapy in patients with CD. While initial studies appeared red positive, upon further evaluation in larger clinical trials results were not noted to be significant. Due to the concern that IL-10 was not delivered in significant quantitites at the local mucosal level, another approach was attempted using “Turbo Probiotics”. This was done by engineering Lactobacillus Lactis to secrete IL-10 specifically at the intestinal level. A similar construct has been tried in patients with IBD. This novel approach has shown some promising results.
Summary As is evidenced above, there are many cytokines that are involved in the inflammatory response of the mucosa in inflammatory bowel disease. These cytokines can have either pro-, anti- or both pro and anti-inflammatory effects and are important in the pathogenesis of this and other autoimmune diseases. The above-described cytokines are those that were deemed most significant to inflammatory bowel disease but there are multiple other cytokines that are currently being evaluated (IL-22, IL-32, IL-33, IL-35, TL1A, IL-15) or are as yet unknown, that may be targets for IBD therapy in the future. References 1. Neurath, M.F., et al., Experimental granulomatous colitis in mice is abrogated by induction of TGFbeta-mediated oral tolerance. J Exp Med, 1996. 183(6): pp. 2605–16. 2. Reinecker, H.C., et al., Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn disease. Clin Exp Immunol, 1993. 94(1): pp. 174–81. 3. Camoglio, L., et al., Altered expression of interferon-gamma and interleukin-4 in inflammatory bowel disease. Inflamm Bowel Dis, 1998. 4(4): pp. 285–90. 4. Boirivant, M., et al., Oxazolone colitis: A murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med, 1998. 188(10): pp. 1929–39.
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5. Shetty, A. and A. Forbes, Pharmacogenomics of response to anti-tumor necrosis factor therapy in patients with Crohn disease. Am J Pharmacogenomics, 2002. 2(4): pp. 215–21. 6. Strober, W., et al., Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. Immunol Today, 1997. 18(2): pp. 61–4. 7. Neurath, M.F., et al., Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice. Eur J Immunol, 1997. 27(7): pp. 1743–50. 8. Murch, S.H., et al., Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease. Gut, 1991. 32(8): pp. 913–7. 9. Reimund, J.M., et al., Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn disease. J Clin Immunol, 1996. 16(3): pp. 144–50. 10. Targan, S.R., et al., A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn disease. Crohn Disease cA2 Study Group. N Engl J Med, 1997. 337(15): pp. 1029–35. 11. Hanauer, S.B., et al., Maintenance infliximab for Crohn disease: the ACCENT I randomised trial. Lancet, 2002. 359(9317): pp. 1541–9. 12. Bruewer, M., et al., Proinflammatory cytokines disrupt epithelial barrier function by apoptosisindependent mechanisms. J Immunol, 2003. 171(11): pp. 6164–72. 13. Strober, W., I.J. Fuss, and R.S. Blumberg, The immunology of mucosal models of inflammation. Annu Rev Immunol, 2002. 20: pp. 495–549. 14. Reinisch, W., et al., A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn disease. Gut, 2006. 55(8): pp. 1138–44. 15. Hommes, D.W., et al., Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn disease. Gut, 2006. 55(8): pp. 1131–7. 16. Cominelli, F. and T.T. Pizarro, Interleukin-1 and interleukin-1 receptor antagonist in inflammatory bowel disease. Aliment Pharmacol Ther, 1996. 10 Suppl 2: p. 49–53; discussion 54. 17. Mahida, Y.R., K. Wu, and D.P. Jewell, Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn disease. Gut, 1989. 30(6): pp. 835–8. 18. Van Assche, G., et al., A pilot study on the use of the humanized anti-interleukin-2 receptor antibody daclizumab in active ulcerative colitis. Am J Gastroenterol, 2003. 98(2): pp. 369–76. 19. Van Assche, G., et al., Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial. Gut, 2006. 55(11): pp. 1568–74. 20. Cantor, M.J., P. Nickerson, and C.N. Bernstein, The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease. Am J Gastroenterol, 2005. 100(5): pp. 1134–42. 21. Atreya, R. and M.F. Neurath, Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Clin Rev Allergy Immunol, 2005. 28(3): pp. 187–96. 22. Ito, H., et al., A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn disease. Gastroenterology, 2004. 126(4): pp. 989–96; discussion 947. 23. Bouma, G. and W. Strober, The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol, 2003. 3(7): pp. 521–33. 24. Fuss, I.J., et al., Both IL-12p70 and IL-23 are synthesized during active Crohn disease and are downregulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis, 2006. 12(1): pp. 9–15. 25. Mannon, P.J., et al., Anti-interleukin-12 antibody for active Crohn disease. N Engl J Med, 2004. 351(20): pp. 2069–79. 26. Fuss, I.J., et al., Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice. Gastroenterology, 1999. 117(5): pp. 1078–88. 27. Harrington, L.E., et al., Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol, 2005. 6(11): pp. 1123–32. 28. Langrish, C.L., et al., IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med, 2005. 201(2): pp. 233–40. 29. Mangan, P.R., et al., Transforming growth factor-beta induces development of the T(H)17 lineage. Nature, 2006. 441(7090): pp. 231–4.
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30. Bettelli, E., et al., Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 2006. 441(7090): pp. 235–8. 31. Duerr, R.H., et al., A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science, 2006. 314(5804): pp. 1461–3. 32. Hue, S., et al., Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med, 2006. 203(11): pp. 2473–83. 33. Fujino, S., et al., Increased expression of interleukin 17 in inflammatory bowel disease. Gut, 2003. 52(1): pp. 65–70. 34. Kullberg, M.C., et al., IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med, 2006. 203(11): pp. 2485–94. 35. Kolls, J.K. and A. Linden, Interleukin-17 family members and inflammation. Immunity, 2004. 21(4): pp. 467–76. 36. Pizarro, T.T., et al., IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn disease: expression and localization in intestinal mucosal cells. J Immunol, 1999. 162(11): pp. 6829–35. 37. Reuter, B.K. and T.T. Pizarro, Commentary: the role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe? Eur J Immunol, 2004. 34(9): pp. 2347–55. 38. Okamura, H., et al., Regulation of interferon-gamma production by IL-12 and IL-18. Curr Opin Immunol, 1998. 10(3): pp. 259–64. 39. Nakanishi, K., et al., Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev, 2001. 12(1): pp. 53–72. 40. Fuss, I.J., et al., Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest, 2004. 113(10): pp. 1490–7. 41. Heller, F., et al., Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology, 2005. 129(2): pp. 550–64. 42. Powrie, F., et al., A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med, 1996. 183(6): pp. 2669–74. 43. Duchmann, R. and M. Zeitz, T regulatory cell suppression of colitis: the role of TGF-beta. Gut, 2006. 55(5): pp. 604–6. 44. Maul, J., et al., Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology, 2005. 128(7): pp. 1868–78. 45. Bamias, G., et al., Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation. Gastroenterology, 2005. 128(3): pp. 654–66. 46. Dohi, T., et al., T helper type-2 cells induce ileal villus atrophy, goblet cell metaplasia, and wasting disease in T cell-deficient mice. Gastroenterology, 2003. 124(3): pp. 672–82.
Section 2 Epidemiology and Clinical Features
4 Epidemiology of Pediatric Inflammatory Bowel Disease Shehzad Saeed and Subra Kugathasan∗
Introduction Inflammatory bowel disease (IBD), one of the most serious chronic gastrointestinal conditions affecting growth, social well-being, education, and employment, is increasing in incidence among children. It is increasing comprised of two distinct entities – Crohn disease (CD) and Ulcerative colitis (UC). Although the exact details of disease pathogenesis remain unknown, the general accepted hypothesis is that IBD occurs as the result of an inappropriate and exaggerated mucosal immune response to ubiquitous environmental factors including commensal microflora in a genetically susceptible host. Although only about 25% of all IBD occurs in the pediatric age group, continued assessment of epidemiology among children is important since it may facilitate better understanding of the disease etiology since in childhood the disease is “Pure” and not complicated by long standing environmental exposures. Studies of epidemiology in children may therefore provide better clues as to the progression, predictors and outcomes of IBD. Various and seemingly unrelated environmental factors such as diet, breastfeeding, drugs, socioeconomic status, and stress have been implicated in the rapid worldwide spreading of IBD. In principle, epidemiology holds that each factor deserves credit, but the strength of the supporting data varies considerably for each factor with only a few factors emerging as clinically associated with disease. The first is smoking. Despite an obscure mechanism of action, the epidemiological evidence that smoking is related to disease is too strong and reproducible to be dismissed. The second factor is the gut commensal flora. Backed by an impressive amount of experimental evidence from animal models, reasonable patient clinical data, and the recently established link between CD and abnormal NOD2-mediated bacterial sensing, gut commensal flora appears to be clearly associated with IBD. In fact, currently efforts are devoted to better understanding which enteric bacteria may have a pathogenic potential, and why their recognition by the mucosal immune system leads to inflammation in IBD subjects but not the general population. The third factor to consider is appendectomy which has been demonstrated to reduce risk of UC by 69%. This inverse relationship between UC and appendectomy is particularly strong in pediatric population. In this chapter, we will discuss not only the descriptive epidemiology of childhood IBD, but also the emerging and exciting areas of growth (“new epidemiology”) including as-yet-unidentified environmental risk factors, clinical epidemiology (outcome of IBD), IBD in emerging populations
*Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee WI 53226, Phone: 414 266 3690, Fax: 414 266 3676, E-mail:
[email protected]
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and the need for studies to understand the complex interplay between environmental and genetic risk factors.
Descriptive Epidemiology Descriptive epidemiology refers to the study of disease incidence, prevalence, temporal and geographical trends, and demographic factors, such as age, gender and race/ethnicity which may influence disease. Although emerging data from Asia, Pacific regions and South America suggest the incidence of IBD in children is increasing worldwide, most of the data regarding the descriptive epidemiology of IBD (including childhood onset) is derived from European and North American cohorts. The United States prevalence of CD and UC combined is estimated to be 400 cases per 100,000 persons, or 0.4%. Based on the current US population of 320 million, there are approximately 1.4 million Americans with IBD [1]. Accordingly, the age-specific incidence rates of IBD in North America for children aged 1 to 17 years old is approximately 2/100,000 for UC and 4.5/100,000 for CD [2]. About 30% of all patients with CD present before the age of 20 years. In addition, only 4% of pediatric IBD cases occur before the age of 5 years, and 20% before the age of 10 years with a peak age of onset in the adolescent years [3]. Although there are no prevalence data of IBD among children available from North America, extrapolations of available data suggest that anywhere between 45,000–100,000 children and adolescents in North America are suffering from IBD and about 10,000 new cases are diagnosed annually [4]. In fact, IBD is one of the most common chronic gastrointestinal conditions being managed by gastroenterologists in the US. The incidence and prevalence data from available pediatric studies from around the world is summarized in Table 4.1. Time Trends in Pediatric IBD Several studies from Europe have reported an increasing incidence of CD and UC. For instance, a Scottish cohort of hospitalized pediatric IBD patients noted a 3 fold increase in incidence of CD from 1968 to 1983, with essentially no change in incidence of UC [5]. A follow up study aimed at documenting the incidence of pediatric-onset IBD between 1981 and 1995 examined the temporal trends of IBD in scotland between 1968 and 1995 [6]. The incidence of pediatric-onset CD was noted to rise with the prevalence increased by 30% since 1983. The authors further concluded that unlike the previous reports, the incidence of childhood-onset UC was also increasing. Whether this represents a real rise in incidence, or merely the inclusion of milder cases remains uncertain. Additional evidence of the increasing incidence of CD comes from Sweden where the incidence of CD increased from 2.4/100,000 in 1990–92 to 5.4 between 1996–98. In contrast, the incidence of UC remained stable over the same time period [7]. Furthermore, the incidence of pediatric IBD almost doubled in Finland from 1987 to 2003 [8], and data from Eastern Europe is similar with a Czech cohort [9], reporting an increased incidence from 0.25/100,000 to 1.25/100,000 in CD patients aged less than 15 years between 1990 and 2001. This increasing incidence of IBD has been contradicted by other studies such as a cohort from Northern France, which documented no significant change in the incidence of CD over a 10 year period [10]. Geographic Trends of Pediatric IBD Several studies have noted higher predisposition of IBD in northern latitudes than southern regions [11, 12]. This gradient difference is even seen within countries. The study populations with the highest incidence and prevalence rates are reported from the northern latitudes. Few pediatric studies have assessed this trend, a Scottish report noted a higher incidence of CD in northern
Table 4.1. Available world-wide epidemiological data from pediatric studies. Authors and reference
Country
Year
IBD incidence IBD 7.1 CD 4.5 UC 2.2 IBD 3.9 CD 2.3 UC 1.6 IBD 3.81 CD 3.1 UC 0.71 IBD 6.9 CD 3.8 UC 2.1 IC 1.1 1.25 CD IBD 3.1 CD 2.3 UC 0.8 CD 8.5 IBD 2.6 CD 2.1 UC 0.5 IBD 4.7 CD 2.7 UC 2.0
Kugathasan et al. [2]
USA
2003
Barton et al. [5]
UK
1989
Cosgrove et al. [67]
UK
1996
Askling et al. [7]
Sweden
1999
Pozler et al. [9] Auvin et al. [10]
Czech Republic France
2006 2005
Bjornsson et al. [68] Gottrand et al. [69]
Iceland France
2000 1991
Størdal et al. [70]
Norway
2004
IBD prevalence
Other comments
N/A
Prospective Population based
N/A
Retrospective Population based
CD-16.6 UC3.4
Retrospective
N/A
Retrospective
N/A
Partly retrospective and partly prospective
N/A N/A
Prospective Population based Published in French
N/A
Prospective
(Continued)
Table 4.2. (Continued) Authors and reference
Country
Year
IBD incidence IBD 6.8 CD 2.5 UC 4.3 IBD 4.5 CD1.3 UC3.2 IBD 7.4 CD 4.9 UC 2.2 IBD 2.6 CD 1.36 UC 0.75 UC 6.02 IBD 3.8 CD 2.5 UC 1.3 CD 2.0
Olafsdottir et al. [71]
Norway
1989
Lindberg et al. [72]
Sweden
2000
Hildebrand et al. [73]
Sweden
2003
Hassan et al. [74]
UK / Wales
2000
Sood et al. [75] Armitage et al. [6]
India / Punjab UK / Scotland
2003 2001
Phavichitr et al. [76]
Australia
2003
N/A – not available, IC indeterminate colitis
IBD prevalence
Other comments
N/A
Prospective
N/A
Prospective
N/A
Prospective
N/A
Prospective
UC 44.3 N/A
Prospective Retrospective
N/A
Retrospective
Chapter 4 Epidemiology of Pediatric Inflammatory Bowel Disease
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Scotland than in the southern regions of the country; this trend was not replicated for UC [13]. Data is lacking from North America with no prospective multicenter assessment of this observation. A retrospective review of all hospitalized patients in the US (including adults) over a two year period (1986–87) noted higher frequencies of both CD and UC in northern regions and in urban areas [11]. Racial/Ethnicity Trends Traditionally, IBD is thought to be less prevalent in non-Caucasian populations. This is most probably related to under-representations of non-Caucasians in the study populations/centers. An assessment of the epidemiology of these disorders in non-Caucasians is complicated by a wide range of factors including the absence of population based registries in ethnically diverse regions, the use of retrospective data, and highly variable clinical presentations which may delay or obscure the diagnosis [14, 15]. In addition, two pediatric studies have also shown comparable incidence and disease characteristics in African American compared with Caucasian populations in two different geographical locations of the US – Wisconsin [2] and Georgia [16]. These studies demonstrate differing proportions of African Americans afflicted with IBD and therefore, suggest IBD among African-Americans is not rare among pediatric populations. Jewish ancestry is thought to confer increased susceptibility to IBD. One study showed life time risk of developing IBD in offspring of an affected non-Jewish parent to be 5 and 2% for CD and UC, respectively [17]. The risk increased to 8 and 5% if the affected parent happened to be Jewish. In addition, if both parents are affected, life-time risk of developing IBD increases to 33% by age 28. Gender and Pediatric IBD Although previous studies have not found gender to be a significant variable in the incidence, prevalence or outcome of IBD, recent epidemiological data suggest overall incidence and prevalence of CD among adult females slightly exceeds that of adult males [18]. In sharp contrast, however, population based studies of pediatric onset CD in the US [2], Canada [19] and the United Kingdom [20] demonstrate a nearly 1.5:1 male-to-female incidence of pediatric onset CD. This “male excess” in incidence among childhood onset CD remains unexplained, but genetic predisposition and other intrinsic factors are suspected to play a role. Furthermore, no gender differences in the epidemiology is seen for UC.
Hygiene Hypothesis and Other Epidemiological Observation in IBD A remarkable change in the types of diseases affecting humans has occurred in the developed world over the last century [21] The most common illnesses responsible for the majority of morbidity and mortality have shifted from infectious diseases to chronic inflammatory diseases and cancer. This was initially noted in Northern Europe and North America (Figure 4.1), but since the end of World War II this phenomenon has been observed in other parts of the world, such as, Japan, Eastern Europe, and some South American countries. The emergence of chronic autoimmune disorders and chronic inflammatory diseases (including IBD) throughout the world has been closely linked to social and economical progress. Keeping with this trend, the emergence of IBD has most recently be observed in the Asian Pacific Region (Figure 4.1). The “hygiene hypothesis” has been proposed as the probable underlying reason for the switch from infectious to chronic inflammatory diseases such as IBD, and postulates that there has been a fundamental lifestyle change from one associated with high microbial exposure to one with low microbial exposure [23]. The lack of microbial antigens in infancy and childhood, therefore, leads
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1990-present
Legend: Light grey indicates low incidence of Inflammatory Bowel Disease isease Medium grey indicates moderate incidence of Inflammatory Bowel Disease Black indicates high incidence of Inflammatory Bowel Disease
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Figure 4.1. Changing distribution of IBD is shown here with World-wide distribution. Black area indicate high prevalence, light grey indicate low prevalence and medium grey indicate moderate prevalence of IBD.
World-wide distribution of IBD since its description
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Figure 4.2. Environmental risk factors and proposed etiology of IBD.
to a less educated and weaker immune system unequipped to properly handle new challenges later on in life. This leads then to generating an ineffective immune response that is prolonged and inappropriate because it is powerless to eliminate the offending agent. Many environmental modifications have been ascribed to the hygiene hypothesis, including better and bigger housing, safe food and water, improved hygiene and sanitation, vaccines, widespread use of antibiotics leading to lack of parasites, fewer infections, and better nutrition [24]. While contributing to the progressive decline of infectious diseases these changes may have simultaneously contributed to a surge in allergic and autoimmune diseases [25].
Environmental Risk Factors Smoking The most indisputable example of the influence of the environment on IBD is tobacco use, specifically, cigarette smoking. Smoking has a strikingly opposite effect on CD as compared to UC, supporting the notion that distinct mechanisms underlie the pathogenesis of these two forms of chronic inflammatory disease [26]. Notably, UC patients are frequently non-smokers, and furthermore, cessation of smoking is noted to increase the risk of developing UC. In fact, nicotine patches are currently being studies to treat UC, supporting its protective role in this disease. In sharp contrast, however, cigarette use is an important risk factor for CD, increasing the frequency of disease relapse and need for surgery, while discontinuation improves disease course [27]. The role of passive smoking, particularly in children, as either a risk factor or protective factor for CD and/or UC is still a matter of controversy with none of the studies having quantitatively assessed the passive smoke exposure. The mechanisms underlying the differential effect of smoking in CD or UC remain obscure. However, smoking has been demonstrated to affect both systemic and mucosal immunity, as well as alter a wide range of both innate and adaptive immune functions [28]. For instance, smoking alters the ratio of T-helper to T-suppressor cells, reduces T cell proliferation, modulates apoptosis, and significantly decreases serum and mucosal immunoglobulin levels. In animal models, smoking reduces mucosal cytokine production and promotes adhesion of leukocytes to endothelial cells. Furthermore, it enhances small bowel permeability and colonic
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mucus production. Interestingly, transdermal nicotine shows some beneficial effect in patients with mild to moderate UC. On the other hand, nicotine may be detrimental in CD by contributing to the hypercoagulability state present in this condition. Taken together, these divergent effects of smoking in human IBD indicate a complex interaction between smoking and IBD [29]. In childhood IBD, a concerted effort should be made to study smoking exposure and the risks of IBD development, progression, as well as its interaction with an individual’s genes in determining the eventual outcome. Microbial Factors; Specific Infectious Agents Search for specific infectious organisms as a cause of IBD has remained very attractive. The history of IBD is dotted by cyclic reports on the isolation of specific infectious agents thought to be responsible for CD or UC. Unfortunately, none of these initial reports have ever been reproduced. Several microorganisms have been proposed as having a potential etiologic role, such as Listeria monocytogenes, Chlamydia trachomatis, Escherichia coli, Cytomegalovirus, Saccharomyces cerevisiae, and others. Among those, the role of Mycobacterium Avium paratuberculosis (MAP) in CD has been the center of major controversy. This bacterium is the causative agent of Johne’s disease, a chronic granulomatous ileitis in ruminants that closely resembles CD. MAP was initially isolated from a few CD tissues[30], but follow-up studies that tried to culture Mycobacterium paratuberculosis, looked for specific DNA sequences in intestinal samples, or measured serum antibodies against M. paratuberculosis yielded conflicting or inconclusive results. In addition, controlled trials have repeatedly failed to show a therapeutic effect of antituberculous therapy in CD patients [31]. Recently, however, there has been a renewed interest in MAP as a cause of CD following the isolation of MAP by PCR in milk sold in supermarkets of California and Wisconsin [32]. In addition to bacteria, a few have proposed a viral etiology as the cause of IBD and specifically for CD. The finding of paramixovirus-like particles in CD endothelial granulomas has led to the suggestion that CD is a chronic vasculitis caused by the persistence of the measles virus in the mucosa [33]. In support of this hypothesis, an association between perinatal measles and predisposition to CD was also advanced based on some epidemiological and serologic data [34]. Despite these preliminary findings none were confirmed by later investigations [35]. Importantly, the progressive decline of measles virus infection in the last decades with the concomitant rise of CD during the same period of time speaks largely against an etiologic role of measles in CD. The hypothesis that measles vaccination, rather than measles infection, might be a risk factor for CD has also been raised, but again subsequent studies failed to confirm any association [36]. Microbial Factors; Intestinal Commensal Flora Over the past decade, there has been an exponential increase in interest about commensal bacteria as etiological agents of IBD (Figure 4.2). Based on fairly solid data, a substantial body of evidence has accumulated suggesting that the normal enteric flora plays a key role in the development of IBD [37]. Additionally, the following clinical observations support this hypothesis: 1) that the beneficial effect of antibiotics in the treatment of CD, and to a lesser extent UC, has been appreciated for years, 2) diversion of the fecal stream from inflamed bowel loops has been known to induce symptomatic improvement in CD patients, while relapse often occurs upon restoration of intestinal continuity, and 3) pouchitis, a chronic inflammation of a surgically constructed ileoanal pouch, develops in a considerable proportion of UC patients after proctocolectomy, and is associated with a dysbiosis caused by the contact of the once near sterile small bowel mucosa with a rich colon-like flora repopulating the pouch after surgery [38]. Furthermore, more recent data demonstrating that probiotics (primarily lactic acid bacteria), defined as live microbial feeds,
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beneficially affect the host by modulating gut microbial balance, and improve both human IBD and experimental colitis, adds an important dimension to the role of gut flora in IBD. In addition, it has been observed that much larger numbers and concentrations of bacteria make up the biofilm covering the intestinal epithelium of IBD patients compared to the epithelium of healthy subjects [39], and loss of immune tolerance against the autologous enteric aerobic and anaerobic flora has been reported [40]. Finally, and probably most convincingly, the majority of animal models of IBD fail to develop intestinal inflammation when kept in a germ-free environment [41]. Why there is an abnormal response to normal endogenous gut bacteria in IBD is not clear, but the recent discovery that CD is genetically associated with mutations of the NOD2 gene, whose products are bacteria-recognizing proteins, points to a link between gut inflammation and abnormal bacterial sensing [42].
Appendectomy Protective effects of appendectomy upon UC have been well established in a number of adult and pediatric studies. A meta-analysis of seventeen case control studies showed a 69% reduction in risk of subsequent development of UC in cases with appendectomy [43, 44]. This negative association is more pronounced in pediatric onset UC. Duggan et al. [45] also noted a protective effect of appendectomy on development of UC, especially if performed during childhood. On the other hand, risk for CD is reported to be increased after appendectomy [46]. The reasons for these observed differences remain ill defined with altered mucosal immunity in response to appendectomy as one of the proposed hypothesis.
Breast Feeding Breast feeding is thought to provide protection against infections and minimizes allergic triggers to a developing gut. It has also been suggested to provide long term beneficial effects like improved cognitive functioning, prevention of chronic disease like type I diabetes, celiac disease, lowering of blood pressure and improved cholesterol profile [47]. The role of breast feeding (or lack thereof) has been reported to be associated with development of Crohn disease in a few pediatric studies. A metanalysis by Klement et al. suggested a protective effects of breast feeding on later development of IBD [48]. This has been contradicted by a population based case control study which reported an increased risk of CD among breast fed infants [49]. They also reported increased risk of CD with eczema and BCG vaccines, but a protective effect of drinking tap water. Meanwhile, the risk of developing UC increased with family history of IBD, disease during pregnancy, and bedroom sharing, but appendectomy conferred a protective effect.
Dietary Factors The gastrointestinal tract is constantly being exposed to dietary antigens, and hence, this exposure has generated a number of observations relating to the potential role of different dietary components in the pathogenesis of IBD. Given the location of IBD, this relationship between components of the diet and disease has been long considered, and immunologic mechanisms have been postulated to link food antigens and the development of intestinal inflammation. However, this logical and appealing explanation is far from proven. In addition, only a few unpersuasive studies provide only indirect evidence of a possible cause-and-effect relationship between specific dietary factors and IBD. Most of these case control studies are limited by methodological problems including diet recall, role of pre-illness diet versus diet selection post diagnosis. Contrary to
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these case control studies, a population based study by Baron et al. [49] failed to identify any specific dietary factors as potential risk factors for development of IBD. However, a questionnaire based, population case control study [50] from Manitoba, Canada reported reduced ingestion of pork, and un- pasteurized milk as significantly associated with IBD compared to controls, while no difference was seen with beef or chicken meat ingestion, although the frequency of chicken intake was noted to be higher in patients with CD as compared to patients with UC. Ingestion of refined sugars has also been reported to be associated with CD [51, 52]. Gilat, et al. showed higher consumption of whole wheat bread and lower consumption of oat meal cereals in CD patients [53]. Lastly, there is some evidence supporting the benefits of elemental and polymeric liquid diets as primary or adjuvant therapy for CD, although in some studies this nutritional approach was less effective than conventional therapies, such as corticosteroids [54].
Drugs Oral contraceptives (OCP) and non-steroidal anti-inflammatory drugs (NSAIDs) are the two main classes of drugs that have been intensively studied for a possible epidemiological or causal relationship with IBD. Although there is no direct evidence for a causative relationship, the relative risk of CD in women taking oral contraceptives is about twice that of controls [55], In contrast, prevalence of usage of OCP in females in a case control study from Canada [50] did not differ in patients with IBD compared with controls; however, CD patients were more likely to use OCP than controls and patients with IBD tended to start OCPs at an earlier age than the controls. Inverse causality has also been implicated in OCP use in patients with abdominal symptoms since they are routinely used to treat menstrual associated complaints. The situation is less ambiguous in the case of NSAIDs, because their use is clearly associated with a higher risk of IBD. Primarily, IBD patients in clinical remission can relapse upon NSAIDs administration. In fact, interleukin-10 knockout mice spontaneously develop colitis when given NSAIDs and exhibit a far more rapid and severe form of colonic inflammation associated with blockade of protective prostaglandins and altered mucosal immune reactivity [56], suggesting a potential mechanisms by which NSAIDs may worsen IBD. However, NSAIDs and OCPs are less likely to be an important contributing factor in childhood onset IBD.
Socio-Economical, Educational and Occupational Status This group of interrelated factors is large and difficult to analyze, but is postulated to reflect the “westernization” process that is so intimately linked to the emergence of IBD in the last one-half century. Role of hygiene in pathogenesis of allergies, asthma and other chronic conditions has been well studied in both adults and children [57, 58]. Although much of the data comes from adult studies, emerging data from pediatrics also supports the role of “cleaner environment” as a risk factor for IBD, hypothesizing that the more sanitary environment prevents the host from developing tolerance to the microbial agents that may present later in life [59]. Both Baron, et al. [49] and Amre, et al. [60] reported increased risk of IBD with bedroom sharing and overcrowding. In a case control study, Gent, et al. [61] reported access to hot water, separate bathrooms and main drainage as increased risk factors for CD but not UC. Bernstein, et al. however, noted having larger families as a protective factor against CD [50]. Duggan, et al. [45] also reported no availability of hot water before 11 years of age as a protective factor. Traditionally, IBD has been more prevalent among higher socioeconomic groups, affecting more white-collar than blue-collar workers. Interestingly, outdoor workers have less risk of developing IBD, while individuals with indoor occupations are more susceptible. In addition, sedentary
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workers are at higher risk for IBD. A number of theories have been advanced to explain these intriguing disparities. One of them points to the delay in abdominal transit associated with being sedentary and the more prolonged time of contact of food antigens with the gut wall, resulting in inappropriate stimulation and inflammatory reaction. It is obvious that theories such as these are pure speculations, and the reality is that the relationship of social, economical, educational and occupational status with IBD is currently obscure.
Stress Investigations performed with the cotton top tamarin, a non-human primate native to tropical South American jungle, has shown that these animals develop an UC-type colitis only when kept in captivity in colder climates, and that the colitis goes into remission if returned to their natural habitat [62]. This observation supports the belief that stress may trigger IBD. In reality stress is more likely to modulate disease manifestations rather than being an initiating factor. Evidence that stress can modulate the course of IBD is provided by clinical observations, and studies of neuroimmune interactions in laboratory animals. Stress also augments intestinal permeability, and therefore, the entry of excessive amounts of luminal antigens could activate pre-sensitized mucosal T cells resulting in inflammation.
New Epidemiology We refer to “new epidemiology” as extensions and growth of descriptive epidemiology that advances our knowledge toward the pathogenesis of IBD. This will include genetic epidemiology, clinical epidemiology (outcome studies), some of the as-yet-to-be-identified environmental risk factors, studies of complex gene-environmental interactions as well as new approaches to analyze disease risk such as geo-coding and small area geographical mapping of disease incidence.
Genetic Epidemiology & its Impact on the Pathogenesis of IBD Great advances have been made over the last decade to identify some of the candidate genes associated with IBD and this topic will be discussed in greater depth in another chapter of this book. Although, significant strides have occurred and candidate genes with biological significance have been discovered, it is very clear from twin studies that genetic determinants account for at most 50% of IBD susceptibility in CD, and even significantly lower contributions in UC, stresses the importance of environmental factors in the etiology of IBD. However, the best use of genetic knowledge in the context of epidemiology will likely yield more useful information and breakthroughs in the pathogenesis of IBD [63].
Challenges in the Way Forward; Genes and Environmental Interactions There is little argument that a complex disease like IBD is the result of life-long interactions between genetic and environmental susceptibilities. However, there is a paucity of research incorporating genotype-by-environment interaction into human genetic studies. Despite the importance of gene-environmental interactions, most genetic studies make an early and prominent assumption that no genotype-by-environment interactions exist. In fact, one explanation for the research falling short of earlier expectations in IBD is the inability to incorporate gene-environmental interactions in study designs and statistical analysis. There are many underlying reasons for the
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shortage of gene-environmental interaction studies. The greatest difficulty is the ability to measure an individual’s exposure to their environment. Although we have seen revolutionary advances in measuring genetic variation over the last decade, measurement of environmental factors are still largely based on questionnaires and indirect measurements. The second reason is the fear of further exponential explosions in the number of variables with which we have to contend with. There is clearly a lack of appreciation for good study design for estimating gene-environmental interactions. Arguably, however, the best study designs are those based on environmental modifications, such as cigarette smoking. The challenge is that such studies are expensive and difficult to execute in larger cohorts. Lastly, our inability to directly incorporate environmental factors into genetic studies is cultural. Most investigators who have the capability to perform state of the art genotyping technologies are likely to consider the results of diet habits and recall questionnaires to be soft and uninformative, and therefore, not worthy of serious considerations.
IBD Among New Populations The most exciting and intriguing aspect of IBD is the apparent exponential increase in the incidence of IBD. IBD continues to become more common in formerly low-incidence areas such as Southern Europe, the middle-East, East Asia, Indian subcontinent, Latin America and Eastern Europe. Although one can argue that improved methods of diagnosis and increased awareness among medical professionals is cause of this increase, the impact of IBD on same “low – incidence” immigrant population living in the Western world is undisputable. It has been suggested, therefore, that studies of these “new populations” will likely yield more clues about the etiology of IBD than studying the stable IBD populations.
New Approaches Geographical disease pattern analysis would be useful in epidemiological research of IBD to potentially identify locations of elevated disease incidence or “clusters”. These areas could be later examined for associations with specific geographic variables, such as the type of water supply. It is essential to perform this type of analysis with close collaboration between IBD epidemiologists and geographic information systems experts. To date however, studies of IBD clusters have remained outside the domain of medical geographers. Traditional disease mapping strategies have used geo-political boundaries such as countries, states or provinces, counties, or Zip-code areas to define incidence rates, but these arbitrary boundaries are unlikely to represent true distributions of disease. IBD cluster studies have been mostly limited to anecdotes of a few close individuals who develop IBD, but these have been without demographic or geo-spatial context. A few reports of IBD clusters have been reported in small towns or villages [64], but these too have used political boundaries. Furthermore, these clusters were often identified prior to specific geographic boundary definition, having the effect of erroneously minimizing the at-risk denominator populations, and thus increasing the apparent sizes of disease clusters. In many instances of cluster reporting, the terminology of cluster analysis has been applied loosely, with poor definitions of spatial boundaries. Modern Geographic Information Systems (GIS) spatial analytic technology, offers a new, high technology approach to disease cluster analysis [65] which could be applied to determining the pediatric IBD distribution within a defined location. Recently, Green et al. [66] reported another new approach to IBD epidemiology such as small area geographical mapping of disease incidence in the province of Manitoba, Canada to look for etiological clues.
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Summary Inflammatory bowel disease is a complex disease with an unknown etiology. Strong environmental influences have been implicated as the reason for the observed exponential increased incidence of IBD over the last five decades since the genetic determinants do not change within this short period of time. However, most of the environmental risks and associations are reported from retrospective data collection or questionnaire-based adult studies, and have not been systematically studied in a prospective and longitudinal format in a large population based cohort. With the association and identification of potential genetic loci for IBD, complex interaction between the environmental and genetic influences may well be within our reach. Continued assessment of pediatric epidemiology is necessary as the clinical presentation, progression of disease, risk factors for surgery and malignancy may drastically be altered in the next decade. It should be obvious to most people that if new discoveries are to be attained concerning the cause of IBD, the barriers to relaxing the assumptions of gene-environment interactions need immediate attention. The first design issue in studying a complex disorder like IBD is to identify and characterize the right population. Investigators should recognize this problem rather than simply work with convenient samples. For a variety of reasons, children with newly diagnosed IBD (incident cases) are ideally suited to carry out such investigations. It is imperative that pediatric focused, multicenter consortia efforts be established and tasked to develop well designed benchmarks for studying influences of environmental factors along with genetic determinants on early onset IBD. References 1. Loftus EV. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and enviromental influences. Gastroenterology 2004;126:1504–1517. 2. Kugathasan S, Judd RH, Hoffmann RG, Heikenen J, Telega G, Khan F, Weisdorf-Schindele S, San Pablo W, Jr, Perrault J, Park R, Yaffe M, Brown C, Rivera-Bennett MT, Halabi I, Martinez A, Blank E, Werlin SL, Rudolph CD, Binion DG. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: A statewide population-based study. J Pediatr 2003;143:525–31. 3. Baldassano RN, Piccoli DA. Inflammatory bowel disease in pediatric and adolescent patients. Gastroenterol Clin North Am 1999;28:445–58. 4. Markowitz JE, Mamula P, delRosario JF, Baldassano RN, Lewis JD, Jawad AF, Culton K, Strom BL. Patterns of complementary and alternative medicine use in a population of pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2004;10:599–605. 5. Barton JR, Gillon S, Ferguson A. Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983; marginal fall in ulcerative colitis, three-fold rise in Crohn disease. Gut 1989;30:618–22. 6. Armitage E, Drummond HE, Wilson DC, Ghosh S. Increasing incidence of both juvenile-onset Crohn disease and ulcerative colitis in Scotland. Eur J Gastroenterol Hepatol 2001;13:1439–47. 7. Askling J, Grahnquist L, Ekbom A, Finkel Y. Incidence of paediatric Crohn disease in Stockholm, Sweden. Lancet 1999;354:1179. 8. Turunen P, Kolho KL, Auvinen A, Iltanen S, Huhtala H, Ashorn M. Incidence of inflammatory bowel disease in Finnish children, 1987–2003. Inflamm Bowel Dis 2006;12:677–83. 9. Pozler O, Maly J, Bonova O, Dedek P, Fruhauf P, Havlickova A, Janatova T, Jimramovsky F, Klimova L, Klusacek D, Kocourkova D, Kolek A, Kotalova R, Marx D, Nevoral J, Petro R, Petru O, Plasilova I, Seidl Z, Sekyrova I, Semendak N, Schreierova I, Stanek J, Sykora J, Sulakova A, Toukalkova L, Travnickova R, Volf V, Zahradnicek L, Zeniskova I. Incidence of Crohn disease in the Czech Republic in the years 1990 to 2001 and assessment of pediatric population with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2006;42:186–9. 10. Auvin S, Molinie F, Gower-Rousseau C, Brazier F, Merle V, Grandbastien B, Marti R, Lerebours E, Dupas JL, Colombel JF, Salomez JL, Cortot A, Turck D. Incidence, clinical presentation and location at diagnosis of pediatric inflammatory bowel disease: a prospective population-based study in northern France (1988–1999). J Pediatr Gastroenterol Nutr 2005;41:49–55.
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11. Sonnenberg A, McCarty DJ, Jacobsen SJ. Geographic variation of inflammatory bowel disease within the United States. Gastroenterology 1991;100:143–9. 12. Shivananda S, Lennard-Jones J, Logan R, Fear N, Price A, Carpenter L, van Blankenstein M. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 1996;39:690–7. 13. Armitage EL, Aldhous MC, Anderson N, Drummond HE, Riemersma RA, Ghosh S, Satsangi J. Incidence of juvenile-onset Crohn disease in Scotland: association with northern latitude and affluence. Gastroenterology 2004;127:1051–7. 14. Reddy SI, Burakoff R. Inflammatory bowel disease in African Americans. Inflamm Bowel Dis 2003;9:380–5. 15. Straus WL, Eisen GM, Sandler RS, Murray SC, Sessions JT. Crohn disease: does race matter? The Mid-Atlantic Crohn Disease Study Group. Am J Gastroenterol 2000;95:479–83. 16. Ogunbi SO, Ransom JA, Sullivan K, Schoen BT, Gold BD. Inflammatory bowel disease in AfricanAmerican children living in Georgia. J Pediatr 1998;133:103–7. 17. Fielding JF. The relative risk of inflammatory bowel disease among parents and siblings of Crohn disease patients. J Clin Gastroenterol 1986;8:655–7. 18. Logan RF. Inflammatory bowel disease incidence: up, down or unchanged? Gut 1998;42:309–11. 19. Bernstein CN, Blanchard JF, Rawsthorne P, Wajda A. Epidemiology of Crohn disease and ulcerative colitis in a central Canadian province: a population-based study. Am J Epidemiol 1999;149:916–24. 20. Sawczenko A, Sandhu BK, Logan RF, Jenkins H, Taylor CJ, Mian S, Lynn R. Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet 2001;357:1093–4. 21. Cohen ML. Changing patterns of infectious disease. Nature 2000;406:762–7. 22. Ouyang Q, Tandon R, Goh KL, Ooi CJ, Ogata H, Fiocchi C. The emergence of inflammatory bowel disease in the Asian Pacific region. Curr Opin Gastroenterol 2005;21:408–13. 23. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911–20. 24. Danese S, Fiocchi C. Etiopathogenesis of inflammatory bowel diseases. World J Gastroenterol 2006;12: 4807–12. 25. Borchers AT, Keen CL, Gershwin ME. Hope for the hygiene hypothesis: When the dirt hits the fan. J Asthma 2005;42:225–47. 26. Thomas GA, Rhodes J, Green JT. Inflammatory bowel disease and smoking–a review. Am J Gastroenterol 1998;93:144–9. 27. Rubin DT, Hanauer SB. Smoking and inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000;12: 855–62. 28. Sopori ML, Kozak W, Savage SM, Geng Y, Kluger MJ. Nicotine-induced modulation of T Cell function. Implications for inflammation and infection. Adv Exp Med Biol 1998;437:279–89. 29. Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: The role of environmental factors. Autoimmun Rev 2004;3:394–400. 30. Chiodini RJ, Van Kruiningen HJ, Thayer WR, Merkal RS, Coutu JA. Possible role of mycobacteria in inflammatory bowel disease. I. An unclassified Mycobacterium species isolated from patients with Crohn disease. Dig Dis Sci 1984;29:1073–9. 31. Thomas GA, Swift GL, Green JT, Newcombe RG, Braniff-Mathews C, Rhodes J, Wilkinson S, Strohmeyer G, Kreuzpainter G. Controlled trial of antituberculous chemotherapy in Crohn disease: A five year follow up study. Gut 1998;42:497–500. 32. Ellingson JL, Anderson JL, Koziczkowski JJ, Radcliff RP, Sloan SJ, Allen SE, Sullivan NM. Detection of viable Mycobacterium avium subsp. paratuberculosis in retail pasteurized whole milk by two culture methods and PCR. J Food Prot 2005;68:966–72. 33. Wakefield AJ, Pittilo RM, Sim R, Cosby SL, Stephenson JR, Dhillon AP, Pounder RE. Evidence of persistent measles virus infection in Crohn disease. J Med Virol 1993;39:345–53. 34. Ekbom A, Daszak P, Kraaz W, Wakefield AJ. Crohn disease after in-utero measles virus exposure. Lancet 1996;348:515–7. 35. Fisher NC, Yee L, Nightingale P, McEwan R, Gibson JA. Measles virus serology in Crohn disease. Gut 1997;41:66–9. 36. Ghosh S, Armitage E, Wilson D, Minor PD, Afzal MA. Detection of persistent measles virus infection in Crohn disease: current status of experimental work. Gut 2001;48:748–52.
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37. Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003;361:512–9. 38. Katz JA. Prevention is the best defense: Probiotic prophylaxis of pouchitis. Gastroenterology 2003;124: 1535–8. 39. Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, Weber J, Hoffmann U, Schreiber S, Dietel M, Lochs H. Mucosal flora in inflammatory bowel disease. Gastroenterology 2002;122:44–54. 40. Duchmann R, Kaiser I, Hermann E, Mayet W, Ewe K, Meyer zum Buschenfelde KH. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol 1995;102:448–55. 41. Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernandez-Sueiro JL, Balish E, Hammer RE. The germfree state prevents development of gut and joint inflammatory disease in HLAB27 transgenic rats. J Exp Med 1994;180:2359–64. 42. Girardin SE, Hugot JP, Sansonetti PJ. Lessons from Nod2 studies: Towards a link between Crohn disease and bacterial sensing. Trends Immunol 2003;24:652–8. 43. Koutroubakis IE, Vlachonikolis IG, Kouroumalis EA. Role of appendicitis and appendectomy in the pathogenesis of ulcerative colitis: a critical review. Inflamm Bowel Dis 2002;8:277–86. 44. Koutroubakis IE, Vlachonikolis IG. Appendectomy and the development of ulcerative colitis: results of a metaanalysis of published case-control studies. Am J Gastroenterol 2000;95:171–6. 45. Duggan AE, Usmani I, Neal KR, Logan RF. Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: a case control study. Gut 1998;43:494–8. 46. Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy is followed by increased risk of Crohn disease. Gastroenterology 2003;124:40–6. 47. Schack-Nielsen L, Michaelsen KF. Breast feeding and future health. Curr Opin Clin Nutr Metab Care 2006;9:289–96. 48. Klement E, Cohen RV, Boxman J, Joseph A, Reif S. Breastfeeding and risk of inflammatory bowel disease: a systematic review with meta-analysis. Am J Clin Nutr 2004;80:1342–52. 49. Baron S, Turck D, Leplat C, Merle V, Gower-Rousseau C, Marti R, Yzet T, Lerebours E, Dupas JL, Debeugny S, Salomez JL, Cortot A, Colombel JF. Environmental risk factors in paediatric inflammatory bowel diseases: a population based case control study. Gut 2005;54:357–63. 50. Bernstein CN, Rawsthorne P, Cheang M, Blanchard JF. A population-based case control study of potential risk factors for IBD. Am J Gastroenterol 2006;101:993–1002. 51. Martini GA, Brandes JW. Increased consumption of refined carbohydrates in patients with Crohn disease. Klin Wochenschr 1976;54:367–71. 52. Cashman KD, Shanahan F. Is nutrition an aetiological factor for inflammatory bowel disease? Eur J Gastroenterol Hepatol 2003;15:607–13. 53. Gilat T, Hacohen D, Lilos P, Langman MJ. Childhood factors in ulcerative colitis and Crohn disease. An international cooperative study. Scand J Gastroenterol 1987;22:1009–24. 54. Griffiths AM. Enteral nutrition in the management of Crohn disease. JPEN J Parenter Enteral Nutr 2005;29:S108–12; discussion S112–7, S184–8. 55. Godet PG, May GR, Sutherland LR. Meta-analysis of the role of oral contraceptive agents in inflammatory bowel disease. Gut 1995;37:668–73. 56. Berg DJ, Zhang J, Weinstock JV, Ismail HF, Earle KA, Alila H, Pamukcu R, Moore S, Lynch RG. Rapid development of colitis in NSAID-treated IL-10-deficient mice. Gastroenterology 2002;123:1527–42. 57. Wiedermann U. Prophylaxis and therapy of allergy by mucosal tolerance induction with recombinant allergens or allergen constructs. Curr Drug Targets Inflamm Allergy 2005;4:577–83. 58. Umetsu DT, McIntire JJ, Akbari O, Macaubas C, DeKruyff RH. Asthma: an epidemic of dysregulated immunity. Nat Immunol 2002;3:715–20. 59. Ekbom A, Montgomery SM. Environmental risk factors (excluding tobacco and microorganisms): critical analysis of old and new hypotheses. Best Pract Res Clin Gastroenterol 2004;18:497–508. 60. Amre DK, Lambrette P, Law L, Krupoves A, Chotard V, Costea F, Grimard G, Israel D, Mack D, Seidman EG. Investigating the hygiene hypothesis as a risk factor in pediatric onset Crohn disease: a case-control study. Am J Gastroenterol 2006;101:1005–11. 61. Gent AE, Hellier MD, Grace RH, Swarbrick ET, Coggon D. Inflammatory bowel disease and domestic hygiene in infancy. Lancet 1994;343:766–7.
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62. Stadnicki A, Colman RW. Experimental models of inflammatory bowel disease. Arch Immunol Ther Exp (Warsz) 2003;51:149–55. 63. Kugathasan S, Amre D. Inflammatory bowel disease–environmental modification and genetic determinants. Pediatr Clin North Am 2006;53:727–49. 64. Van Kruiningen HJ, Freda BJ. A clustering of Crohn disease in Mankato, Minnesota. Inflamm Bowel Dis 2001;7:27–33. 65. Rushton G. Public health, GIS, and spatial analytic tools. Annu Rev Public Health 2003;24:43–56. 66. Green C, Elliott L, Beaudoin C, Bernstein CN. A population-based ecologic study of inflammatory bowel disease: searching for etiologic clues. Am J Epidemiol 2006;164:615–23; discussion 624–8. 67. Cosgrove M, Al-Atia RF, Jenkins HR. The epidemiology of paediatric inflammatory bowel disease. Arch Dis Child 1996;74:460–1. 68. Bjornsson S, Johannsson JH. Inflammatory bowel disease in Iceland, 1990–1994: a prospective, nationwide, epidemiological study. Eur J Gastroenterol Hepatol 2000;12:31–8. 69. Gottrand F, Colombel JF, Moreno L, Salomez JL, Farriaux JP, Cortot A. Incidence of inflammatory bowel diseases in children in the Nord-Pas-de-Calais region. Arch Fr Pediatr 1991;48:25–8. 70. Stordal K, Jahnsen J, Bentsen BS, Moum B. Pediatric inflammatory bowel disease in southeastern Norway: a five-year follow-up study. Digestion 2004;70:226–30. 71. Olafsdottir EJ, Fluge G, Haug K. Chronic inflammatory bowel disease in children in western Norway. J Pediatr Gastroenterol Nutr 1989;8:454–8. 72. Lindberg E, Lindquist B, Holmquist L, Hildebrand H. Inflammatory bowel disease in children and adolescents in Sweden, 1984–1995. J Pediatr Gastroenterol Nutr 2000;30:259–64. 73. Hildebrand H, Finkel Y, Grahnquist L, Lindholm J, Ekbom A, Askling J. Changing pattern of paediatric inflammatory bowel disease in northern Stockholm 1990–2001. Gut 2003;52:1432–4. 74. Hassan K, Cowan FJ, Jenkins HR. The incidence of childhood inflammatory bowel disease in Wales. Eur J Pediatr 2000;159:261–3. 75. Sood A, Midha V, Sood N, Bhatia AS, Avasthi G. Incidence and prevalence of ulcerative colitis in Punjab, North India. Gut 2003;52:1587–90. 76. Phavichitr N, Cameron DJ, Catto-Smith AG. Increasing incidence of Crohn disease in Victorian children. J Gastroenterol Hepatol 2003;18:329–32.
5 Early Onset Inflammatory Bowel Disease- Epidemiology and Clinical Features Melvin B. Heyman* and Neera Gupta
Introduction About 20–30% of individuals with inflammatory bowel disease (IBD) have symptom onset before 20 years of age. Ten to 15% of all IBD patients have an established diagnosis under the age of 18 years. Young children (i.e., under 6 years of age) with IBD represent a unique cohort of patients that is recognized as a valuable group to investigate due to their relative lack of environmental exposures compared with older patients. However, information is sparse regarding the presentation and course of disease in this subset of patients. We therefore present information on both early onset (0–5 years) and later onset (6–18 years) pediatric IBD.
Epidemiology of Pediatric Inflammatory Bowel Disease Incidence of Disease and Family History The epidemiology of pediatric IBD has been described in population-based studies from European centers. In an earlier report from Denmark, data collected between 1962 and 1987 revealed that the mean incidence of IBD among children below 15 years was 2.2/100,000, 2.0 for UC and 0.2 for CD. At diagnosis, children with UC had more extensive disease than adults (P < 0.05) [1]. A similar study on the incidence of Crohn disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC) in children was conducted in western Norway in 1984–85 [2]. During this two-year study period, 27 new cases of IBD were diagnosed in children aged 15 years or less, 10 new cases of CD, and 17 of UC. The mean annual incidence of CD in the child population was 2.5/100,000/year, whereas the incidence of UC in the child population was 4.3/100,000/year [2]. In a similar study Sawczenko, et al., reported on a 13-month prospective survey to determine the incidence of childhood IBD in the United Kingdom and the Republic of Ireland, finding an incidence of 5.2/100,000 per year in children younger than 16 years of age from 1998–1999. Of the 739 evaluable pediatric subjects reported, 4% were under 5 and 17% were 5-10 years ∗ Department of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, University of California, San Francisco, San Francisco, CA 94143-0136, Phone: 415-476-5892, Fax: 415-476-1343, Email:
[email protected] Supported in part by NIH Grants K24-DK060617 (mbh) and T32-DK007762 (ng).
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of age [3]. Data from a 12-year period in Sweden showed an annual incidence of 5.8/100,000 in children 15 years of age or less [4]. The data suggested increasing incidence of IBD from 4.6/100,000 in 1984–86 to 7.0/100,000 in 1993–5 [4]. Most of the increase was among those with UC, with an increase in incidence from 1.4 to 3.2 per 100,000 per year [4]. In contrast, in North America, most available information originates primarily from singlecenter studies that are inadequate to generate incidence or prevalence data. However, Kugathasan, et al., studied a population-based cohort and found an overall incidence of IBD of 7.05/100,000, noting that the incidence of Crohn disease (4.56/100,000) was more than double that of ulcerative colitis (2.14/100,000) [5]. Furthermore, the overall incidence of IBD was less than 5 per 100,000 until age 8 years, increasing to an incidence of 13 per 100,000 by 10 years of age. The 15-year old age group had the highest age-related occurrence of new-onset pediatric IBD, likely because older children are often referred to adult gastroenterologists. Most (89%) of the new IBD diagnoses had no family history of IBD [5]. Paul et al. analyzed data from 413 consecutive pediatric IBD outpatients attending their center between 1995–2000. 50 patients were diagnosed before the age of 5 years. First-degree family history was highest in early-onset (diagnosis before age 5 years) UC (26%) compared with the older (5–15 years) UC group (11%) [6]. Similarly, Heyman et al. found the subgroup of children younger than 3 years of age with UC had the highest prevalence of first-degree relatives with IBD (44%) compared with the other age groups [7]. However, Paul et al. found that familial aggregation overall was more frequent in CD than in UC [6].
Age of Diagnosis The most common age of diagnosis among pediatric populations tends to favor young teens, possibly because older teens are lost to pediatric practices as they are referred to adult gastroenterologists. However, young children and infants are not infrequently diagnosed with IBD. Heyman et al. reported on 1739 IBD patients from a large mutlicenter registry, finding that 6.1% of the patients were diagnosed with IBD at age less than 3 years [7]. Similarly, diagnosis was established in 211 (15.4%) prior to 6 years of age, 654 (47.7%) between 6 and 12 years, and 505 (36.9%) 13 to 17 years of age [7]. Lindberg, et al., found that of 639 children diagnosed with IBD in Sweden between 1984 and 1995, 7.5% were under 6 years of age, 30.2% were 6–10 years of age, and 62.3% were 11 years or older at diagnosis [4]. Kugathasan et al. reported that 20% of all pediatric cases were diagnosed before 10 years of age [5].
Disease Distribution and IBD Classification The intestinal distribution of disease varies by age. Younger children appear to have more colonic disease and specifically UC, IC or Crohn colitis. In contrast, older children appear to have more diffuse disease, with Crohn colitis being more prevalent. Paul, et al. compared disease distribution in children with early onset IBD (0–5 yrs) to children with later-onset IBD (5–15 yrs). They reported 66% of children with early onset IBD had a diagnosis of UC, while 67% of cases in the later-onset group had a diagnosis of CD. Furthermore, they reported isolated colonic disease was most common in the younger CD age group (76.5%), compared with ileocolic disease (45.5%) in the older CD age group [6]. Gryboski, et al., in early reports noted more UC in younger children and CD predominating in older children among pediatric patients with IBD [8]. In the largest pediatric report to date, Heyman et al. noted that 63% of children with IBD who were under 8 years of age had isolated colonic disease (UC, IC or Crohn colitis) at the time of diagnosis compared with 35% of children 8 years of age and older (p<0.0001) [7] Overall, 58% of the patients were ultimately diagnosed with CD, 29% with UC and 13% with IC [7]. Sawczenko et al. found an equivalent distribution: 58% were CD, 29% UC, and 12% IC [3].
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Clinical Features of Pediatric Inflammatory Bowel Disease Presentation Inflammatory bowel disease can present at any age, including infancy. In children a delay in diagnosis of 5 months is typical, and diagnostic delays may even extend beyond two years [9]. Sawczenko and Sandhu found a negative correlation (p<.001) between the length of delay in diagnosis and the age of onset of symptoms (determined by recall), suggesting it was more difficult to recognize IBD in younger children [9]. Heyman, et al., reported that 37 (2.7%) of 1370 pediatric patients in a large registry had IBD-specific symptoms before 1 year of age [7]. The most common symptoms at presentation are abdominal pain, diarrhea, weight loss, fever, and in ulcerative colitis bloody stool. Children and adolescents, but not adults, are at risk for significant growth retardation and growth failure. In a cohort of children 5 years of age and younger, Mamula et al. reported that failure to thrive (poor weight gain) at initial presentation was more frequent in those with CD or IC than with UC (p = 0.004) [10]. In this cohort, patients initially diagnosed with UC who had failure to thrive as a presenting symptom typically had their diagnosis changed to IC or CD [10]. Delayed growth is much more common in patients with CD compared with UC [9]. Chronic fever was associated with CD but not with UC or IC, and vomiting was associated with CD or IC but not UC (p = 0.01) in patients 5 years of age and younger [10]. The utility of laboratory tests in early onset IBD requires further investigation. Erythrocyte sedimentation rate (ESR) and C-reactive protein may be normal. Albumin levels may be normal or low. However, Paul et al. reported no significant differences in hemoglobin, albumin, or ESR between age groups or disease groups [6]. Antibody testing for IBD in younger children appears to be a poor marker for either UC or CD compared with older patients, although a recent report by Amre, et al., suggests that Anti-Saccharomices cerevisiae antibody (ASCA) may predict more severe disease with rapid progression in pediatric patients [11]. Growth Children and adolescents with IBD, particularly those with CD, are prone to poor linear growth, delayed puberty, and loss of bone mass, all of which can have deleterious physiological and psychosocial effects on the patients [12–14]. Pediatric gastroenterologists are and must be acutely aware of these aspects of pediatric IBD and apply treatment regimens that appropriately help to reverse and prevent these effects from occurring. Delayed diagnosis has been correlated with lower height z scores at diagnosis [15]. The mean adult height of patients with onset of symptoms before the age of 16 has been reported to be reduced [16]. While the etiology of growth failure in IBD is multifactorial, the most likely reasons are anorexia resulting in decreased nutrient intake, the inflammatory process resulting in excessive energy and protein expenditure, intestinal nutrient losses, secondary hypopituitarism and medications, mainly use of corticosteroids. Most children with UC will improve growth with treatment of the colitis. Treatment of CD including topical steroids, immunosuppressant medications, anti-TNF antibody, enteral nutrition, surgical resection, and growth hormone have some role but variable efficacy in inducing remission, restoring nutritional status and promoting linear growth [17–19]. While outcome studies remain to be performed, investigators have suggested that earlier intervention especially in children with CD may help to reverse some of the growth faltering that has been reported in IBD [20]. Medical Management Response to treatments is variable, as in adults. It is important that providers caring for pediatric patients with IBD remain vigilant in evaluating patients for disease activity, growth, nutrition
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status, and social issues (that may, particularly in teenagers, lead to non-compliance) in order to optimize therapy. Adverse reactions to medications may manifest in adolescents, even after many years on the same medications, as they progress through puberty and their metabolism changes. Age-specific treatment regimens will likely evolve over the next few years as we learn more about the course and response of early onset IBD. Surgery in Pediatric Patients with IBD Crohn Disease: Gryboski reported that 42% of the CD patients required surgical procedures, although a time frame was not specified in this retrospective study [15]. Gupta et al. reported that in a cohort of 989 pediatric patients with CD, the cumulative incidence of surgery was 17% at 5 years and 28% at 10 years [21]. Younger age at the time of diagnosis was associated with a decreased risk for surgery [21]. The relationship of genetic markers such as CARD15(NOD2) gene mutations and risk for surgery due to stricturing or fistulizing disease in pediatric patients requires further study. The role of newer agents, particularly the biologic therapies, in preventing the need for surgery in CD remains to be determined. Ulcerative Colitis: Only 5% (2/40) of patients with UC required surgery in Gryboski’s report [8]. In contrast, pediatric patients with UC are also reported to be more likely to have severe disease, including pancolitis, compared with adults, with surgery required in up to 20% in the first few years of disease [22, 23]. At one center, a retrospective review of children and adolescents with UC revealed a decrease in the frequency of colectomy from 48.9% from 1955 through 1964 to 26.2% from 1965 through 1974 [24]. Hyams and colleagues, in a retrospective review, reported that the 5-year colectomy rate in patients with mild disease at presentation was 8% compared with 26% in patients with moderate to severe disease at presentation [25]. A more recent but retrospective review of 73 children with UC between the ages of 1 and 18 years revealed that the combination of steroid dependency and pancolitis was associated with an increased need for colectomy [26]. Risk of Cancer The risk of colon cancer in UC or small intestinal and colon cancer in CD is increased in patients with disease of long duration. Thus, children with early onset IBD may have greater lifetime risk for development of cancer due to the length of time they have disease compared with later onset IBD. Few cases of colon cancer are described in the pediatric literature. However, ongoing surveillance colonoscopy is recommended for all children with disease of 8–10 years duration. Prospective, longitudinal studies of very young children with IBD including surveillance for potential surrogate markers for cancer and the cumulative effects of immunomodulatory and newer biologic agents are needed. References 1. Olafsdottir EJ, Fluge G, Haug K. Chronic inflammatory bowel disease in children in western Norway. J Pediatr Gastroenterol Nutr 1989;8(4):454–8. 2. Langholz E, Munkholm P, Krasilnikoff PA, Binder V. Inflammatory bowel diseases with onset in childhood. Clinical features, morbidity, and mortality in a regional cohort. Scand J Gastroenterol 1997;32(2):139–47. 3. Sawczenko A, Sandhu BK, Logan RF, et al. Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet 2001;357(9262):1093–4. 4. Lindberg E, Lindquist B, Holmquist L, Hildebrand H. Inflammatory bowel disease in children and adolescents in Sweden, 1984–1995. J Pediatr Gastroenterol Nutr 2000;30(3):259–64. 5. Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr 2003;143(4):525–31.
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6. Paul T, Birnbaum A, Pal D, Pittman N, Ceballos C, LeLeiko N, Benkov K. Distinct Phenotype of Early Childhood Inflammatory Bowel Disease. J Clin Gastroenterol 2006; 40:583–586. 7. Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr 2005;146(1):35–40. 8. Gryboski JD. Crohn disease in children 10 years old and younger: comparison with ulcerative colitis. J Pediatr Gastroenterol Nutr 1994;18(2):174–82. 9. Sawczenko A, Sandhu BK. Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child 2003;88(11):995–1000. 10. Mamula P, Telega GW, Markowitz JE, et al. Inflammatory bowel disease in children 5 years of age and younger. Am J Gastroenterol 2002;97(8):2005–10. 11. Amre DK, Lu SE, Costea F, Seidman EG. Utility of serological markers in predicting the early occurrence of complications and surgery in pediatric Crohn disease patients. Am J Gastroenterol 2006;101(3):645–52. 12. Bland RM, Evans TJ, Raine P, Weaver LT. Inflammatory bowel disease in Scottish children. Health Bull (Edinb) 1999;57(6):365–73. 13. Stephens M, Batres LA, Ng D, Baldassano R. Growth failure in the child with inflammatory bowel disease. Semin Gastrointest Dis 2001;12(4):253–62. 14. Griffiths AM. Specificities of inflammatory bowel disease in childhood. Best Pract Res Clin Gastroenterol 2004;18(3):509–23. 15. Sawczenko A, Ballinger AB, Savage MO, Sanderson IR. Clinical features affecting final adult height in patients with pediatric-onset Crohn disease. Pediatrics 2006;118(1):124–9. 16. Sawczenko A, Ballinger AB, Croft NM, Sanderson IR, Savage MO. Adult height in patients with early onset of Crohn disease. Gut 2003;52(3):454–5; author reply 5. 17. Calenda KA, Schornagel IL, Sadeghi-Nejad A, Grand RJ. Effect of recombinant growth hormone treatment on children with Crohn disease and short stature: a pilot study. Inflamm Bowel Dis 2005;11(5):435–41. 18. Cezard JP, Touati G, Alberti C, Hugot JP, Brinon C, Czernichow P. Growth in paediatric Crohndisease. Horm Res 2002;58 Suppl 1:11–5. 19. Newby EA, Sawczenko A, Thomas AG, Wilson D. Interventions for growth failure in childhood Crohn disease. Cochrane Database Syst Rev 2005(3):CD003873. 20. Brain CE, Savage MO. Growth and puberty in chronic inflammatory bowel disease. Baillieres Clin Gastroenterol 1994;8(1):83–100. 21. Gupta N, Cohen SA, Bostrom AG, et al. Risk factors for initial surgery in pediatric patients with Crohn disease. Gastroenterology 2006;130(4):1069–77. 22. Fonkalsrud EW. Long-term results after colectomy and ileoanal pull-through procedure in children. Arch Surg 1996;131(8):881–5; discussion 5–6. 23. Stordal K, Jahnsen J, Bentsen BS, Moum B. Pediatric inflammatory bowel disease in southeastern Norway: a five-year follow-up study. Digestion 2004;70(4):226–30. 24. Michener WM, Farmer RG, Mortimer EA. Long-term prognosis of ulcerative colitis with onset in childhood or adolescence. J Clin Gastroenterol 1979;1(4):301–5. 25. Hyams JS, Davis P, Grancher K, Lerer T, Justinich CJ, Markowitz J. Clinical outcome of ulcerative colitis in children. J Pediatr 1996;129(1):81–8. 26. Falcone RA, Jr., Lewis LG, Warner BW. Predicting the need for colectomy in pediatric patients with ulcerative colitis. J Gastrointest Surg 2000;4(2):201–6.
6 The Natural History of Pediatric Crohn Disease James Markowitz∗
Introduction Determining the natural history of Crohn disease involves the consideration of a number of different factors: disease activity over time, frequency of complications, the need for surgery and the risk of disease recurrence following both medically induced and surgically induced remission. In children, evaluation of the natural history also must include the effects of Crohn disease on growth and development and on quality of life. The true natural history of Crohn disease remains largely unknown, however, primarily because there are virtually no data describing the long-term course of untreated children or adults with this illness. The data that do exist arise from early clinical experience treating patients with corticosteroids and 5-aminosalicylate medications, and from a small number of placebo-controlled treatment trials.
Disease Activity Spontaneous remission in the absence of specific treatment can occur in Crohn disease. Two early adult trials, the National Cooperative Crohn’s Disease Study (NCCDS) [1] and the European Cooperative Crohn’s Disease Study (ECCDS) [2], included placebo treatment arms enrolling a total of less than 300 adult subjects. Among the 135 subjects with active disease at entry into the 2 trials, 26–42% achieved clinical remission after 3–4 months of placebo treatment, and 18% in both studies remained in clinical remission at 1 year [1, 2]. Prolonged spontaneous remission therefore appears to occur in only a small number of adults with Crohn disease. However, in the NCCDS, among the subgroup of 20 subjects with active disease who achieved clinical remission by 17 weeks, 75% remained in remission at 1 year, and 63% at 2 years [1]. Similarly, among the 153 subjects in the NCCDS and ECCDS who had inactive disease when randomized into the placebo arms of a maintenance study, 52–64% remained in remission at about 1 year and 35–40% at about 2 years [1, 2]. No comparable data from untreated or exclusively placebo treated children exist. However, in children with moderate-severe disease activity who achieve remission after a course of prednisone, ∗
Professor of Pediatrics, NYU School of Medicine, Attending Pediatrician, North Shore – LIJ Health System, Division of Pediatric Gastroenterology, Schneider Children’s Hospital, New Hyde Park, New York, E-mail:
[email protected]
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Figure 6.1. Yearly Crohn disease activity over the first 10 years after diagnosis in a Danish population of children diagnosed prior to 15 years of age. Data from Langholz et al. [5] [figure redrawn]. Reprinted from Inflammatory Bowel Diseases with Onset in Childhood Clinical features, morbidity and mortality in a regional cohort by Langholz E, Munholm P, Krasilnikoff PA, Binder V from Scan J Gastroenterology, www.tandf.no/gastro, 1997; 32, 139–147 by permission of Taylor & Francis
the likelihood of prolonged remission without ongoing therapy appears lower than in adults. Newly diagnosed children randomized to the control arm of a multicenter trial received prednisone for induction of remission and were then maintained only on placebo [3]. One year following the course of corticosteroids, only 43% remained in remission. Similarly, 95% of a cohort of Italian children maintained on mesalamine following an 8-week course of corticosteroids relapsed by 1 year [4]. Periods of active Crohn disease continue to be a problem beyond the first year after diagnosis. Disease activity over time has been described in a report derived from a large population based inception cohort of patients with inflammatory bowel disease diagnosed and treated in Copenhagen County, Denmark between 1962 and 1987 [5]. While useful, the data describing the course of pediatric Crohn disease in this study are based on observations of only 23 children. At diagnosis, 82.6% had disease activity characterized as moderate to severe. In each of the succeeding 9 years, only about 50% of the cohort were characterized as inactive during any given year, while roughly 20–35% had periods of high disease activity despite treatment (Figure 6.1). Observations in the larger, primarily adult onset cohort from the same geographic area revealed that individual patients had different patterns of clinical activity over time: some experienced frequent relapses, some only occasional relapses, and others had prolonged periods of disease quiescence [6]. In this cohort, relapse in any given year after diagnosis increased the risk of relapse in the following year. Relapse rate in the first year after diagnosis also correlated with relapse rate in the next 5–7 years. A review of North American experience revealed similar patterns of disease, with most patients having a chronic intermittent disease course, but 13% of patients having an unremitting disease course and only 10% experiencing a prolonged remission [7].
Evolution of Disease Phenotype At the time of initial diagnosis, the vast majority of children have an inflammatory disease phenotype. However, as time goes on, an increasing proportion expresses a changing phenotype, characterized as either stricturing or penetrating. This phenotypic change may be associated with the presence of specific genetic allelic variants. For instance, patients with NOD2/CARD15 variants appear to be at increased risk for fibro-stenosing complications [8, 9], while those with
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abnormalities in the IBD5 gene may be more likely to develop perianal fistulae [10]. Children at risk for stricturing or internal penetrating complications have also been shown to be more likely to have increased immune responses to microbial antigens, characterized by the presence of high titer antibodies such as anti-ompC and anti-I2 [11].
Growth For a significant subgroup of children with Crohn disease, growth impairment is an important characteristic of the disease’s natural history. While acute weight loss commonly is present in children with both ulcerative colitis and Crohn disease, impairment in linear growth is primarily a problem in the latter condition. At the time of initial diagnosis, about a third of children with Crohn disease has already dropped two or more major growth channels from their pre-illness growth percentiles [12, 13]. More dramatically, 88% have delayed height velocity at diagnosis [14]. Over time, periods of significantly impaired growth can be seen in about 60% of children and adolescents [15]. While catch-up growth is often possible, 7–35% of young adults diagnosed with Crohn disease during childhood have final heights that are significantly shorter than expected [13]. As a group, young adults who develop Crohn disease as children have adult heights skewed towards the lowest percentiles. In reports from both Chicago and New York, ∼ 50% of young adults with childhood onset Crohn disease have final adult heights less than the 10% for the general population, and ∼ 25% have adult heights less than the 5% [12, 13].
Corticosteroid Dependence An important characteristic of Crohn disease in children as well as adults is the tendency to develop corticosteroid dependence. Population based studies in adults from both Olmstead County, Minnesota [15] and Copenhagen County, Denmark [16] demonstrate similar findings. These studies document that acute response to corticosteroid therapy in adults with Crohn disease is reasonably good (complete remission in 48–58%, partial remission in 26–32% and no response in 12–20%). However, long term response is less optimal, with rates of corticosteroid dependence of 28–36% at 1 year [15, 16]. A similar risk for corticosteroid dependence is evident in children. As in adults, acute response to a course of corticosteroids is good. In data derived from a multicenter North American observational registry, among newly diagnosed children with moderate-severe Crohn disease activity treated with corticosteroids, 60% have a complete and 24% a partial clinical response by 3 months after initiation of treatment [17]. However, despite concomitant use of immunomodulators in many of these children, 31% are corticosteroid dependent at 1 year. In fact, without infliximab, only 46% of the children in this study maintained a corticosteroid free remission 1 year following an initial course of corticosteroids [17].
Surgery The need for surgery represents another important aspect of the natural history of Crohn disease in children. Table 6.1 summarizes published rates for surgery in children from a variety of different countries. Data from Denmark estimate a mean yearly operation rate of approximately 13%. The cumulative probability of surgery in this Danish cohort at 20 years was estimated to be 47% [5]. A more recent multicenter experience from the US estimates the cumulative incidence of surgery to be 6% at 1 year, 17% at 5 years and 28% at 10 years after diagnosis [18]. The presence of variant NOD2/CARD15 alleles appear to increase the risk for surgery, presumably due to the known
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Table 6.1. Surgical frequency in Crohn disease. Author
# Children Observed (Period studied) % Operated % Permanent Stomas
Farmer [40] (US) Ferguson [41] (UK) Griffiths [26] (Canada) Besnard [42] (France) Langholz [5] (Denmark) Gupta [18] (US)
522 50 275 119 23 989
(1955–1974) (1968–1983) (1970–1987) (1975–1994) (1962–1987) (1987–2003)
67% 78% 32% 30% 43% 13%
Not reported 30% 2% 2% Not reported 10%
association of these genetic polymorphisms with the development of fibrostenotic ileal disease [8, 9]. The presence of anti-Saccharomyces cerevisiae antibodies also appear to be associated with increased risk for surgery [11, 18].
Postoperative Recurrence Although there is little hard data published to document clinical experience, following surgery, the natural history of Crohn disease is to recur both endoscopically and symptomatically. In retrospective adult studies, symptomatic recurrence of Crohn disease following so-called “curative resection” (complete resection of all visibly evident disease) is reported to be 20–30% within the first year after surgery, with increasing likelihood in each subsequent year [19]. One or more additional surgeries are required in 15–45% of adults within 3 years, 26–65% in 10 years, and 33–82% in 15 years [20]. Controlled trials document severe endoscopic recurrence after placebo treatment in 43–79% of adult subjects by 1 year after surgery and in 42–85% of subjects after 2 years [21–25]. In children, the overall rate of clinical recurrence is estimated to be 50% at 5 years after initial resection [26]. However, the site and extent of preoperative Crohn disease can affect the recurrence free interval, such that it is estimated that 50% of children with extensive ileocolitis recur within 1 year, compared to a 50% recurrence rate after 5 years in children with ileocecal disease, and a 50% recurrence rate after 6 years if preoperative disease is confined to the small bowel [26]. Additional risk factors for postoperative recurrence in children are summarized in Table 6.2.
Cancer Risk Whether children with Crohn disease are at increased risk for malignancy over their lifetime is unknown. No data derived from a population with childhood onset Crohn disease have been reported. Studies in adults, however, suggest that Crohn disease patients do have an excess of malignancies compared to the general population. In a population-based cohort from the Upsala region of Sweden, there was an increased relative risk of colorectal cancer of 2.5 (95% confidence interval 1.3–4.3) in patients with Crohn disease [27]. Duration of illness and gender did not affect risk, but those subjects with colonic disease had a greater risk of colorectal cancer than those with only small bowel involvement. Of note, however, among those subjects with any colonic involvement diagnosed with Crohn disease before the age of 30 years, the relative risk of colorectal cancer increased to 20.9 (95% Confidence interval 6.8–48.7) [27]. By contrast, a similar population-based study from Denmark identified a relative risk of colorectal cancer of only 1.1 (95% confidence interval 0.6–1.9), and no risk differences were noted in different subgroups of patients [28]. A similar modest increase in colorectal cancer risk (1.9; 95% confidence interval 0.7–4.1) was found in a population-based study from Olmstead County, Minnesota [29].
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Table 6.2. Risk factors for postoperative recurrence in children. Author
N
Ages (yrs)
Risk Factors for Recurrent Crohn Disease
Griffiths [26] (Canada)
89
5.9–19
Besnard [42] (France)
30
7.5–16.5
Baldassano [43](US)
79
0.3–21
Effect of initial disease location on RFI*: extensive ileocolonic = 1 yr ileo/ileocecal = 5 yrs small bowel = 6 years Effect of surgical indication on RFI: Specific intestinal indication (e.g. stricture, fistula) = 6 years Failed medical therapy = 1.7 years Effect of preoperative duration of disease on RFI: <1 year = 8+ years >1 year = 3 to 4 years No difference on RFI found for: Age, Pathologic features, Pre-op bowel rest Multifocal disease pre-operatively: 12/12 recurrences with upper GI or perianal disease No difference found for: Age, Pre-operative disease duration, Disease Activity, Extension, Pre-operative nutritional support, Pre-operative mesalamine or azathioprine Effect of pre-operative 6-MP on RFI: No pre-operative 6-MP = 4.45 yrs Pre-operative 6-MP = 1 yr If 6-MP discontinued post-operatively, 5/6 relapse in 8 months If 6-MP continued post-operatively, 1/3 relapse at 2.5 yrs Effect of initial disease location on RFI: Colonic = 1.16 yr Ileocecal = 4.36 yr Colon/small bowel = 2.95 yr No difference found for: Age, Race, Gender, Appendecto my, Pre-operative disease duration, Indication for surgery, pathology
* RFI = recurrence free interval Reprinted from Workshop report: prevention of postoperative recurrence in Crohn’s Disease by Markowitz, J. et al. from Journal of Pediatric Gastroenterology and Nutrition, 2005, Aug; 41[2]: 145–151 by permission of Lippincott Williams & Wilkins [44]
By contrast, the risk of small bowel cancer consistently appears increased in patients with Crohn disease. In part because the rate of small bowel cancer in the general population is very low (estimated to be 0.005% at 5 years and 0.03% at 25 years according to data cited in reference 29), the relative increased risk for small bowel cancers in Crohn disease patients are significantly elevated. In the Danish study cited above, the relative increased risk for small bowel cancer was 17.9 (95% CI 4.8–42) [28]. In Olmstead County, the relative risk was found to be 40.6 (95% CI 4.4–118) [29]. Duration of Crohn disease did not appear to influence risk of developing a small bowel cancer. Adenocarcinoma, carcinoid, leiomyosarcoma and primary intestinal lymphoma have all been reported. The effect of age at Crohn disease onset on the risk of developing small bowel cancer has not been reported. There may also be a slight increase in risk of developing lymphoma. Among 454 adults living in Olmstead County who developed Crohn disease between 1950 and 1993, 1 developed a nonHodgkin’s lymphoma, resulting in a slight increase in relative risk (2.4; 95% CI 0.1–13) compared
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to the general population [30]. In this report, however, the referral practice of the same group of investigators revealed that development of lymphoma was associated with treatment with immune modifiers in about 5% of cases [30]. A recent meta-analysis utilizing data from 6 studies estimates the risk of lymphoma in IBD patients treated with azathioprine or 6-mercaptopurine to be increased about fourfold (4.18; 95% CI 2.07–7.51) [31]. Infliximab may add an additional element of risk, especially for children and young adults, in whom the development of a hepatosplenic T-cell lymphoma has been described [32]. Whether these risks to children with Crohn disease are due to the nature of the illness in children, their frequent need for potent immune modifier and biologic therapy, or both is not known.
Quality of Life In addition to imposing significant physical morbidity, the natural history of Crohn disease in childhood imposes potentially dramatic psychosocial burdens as well. Health related quality of life (HRQOL) scores, as measured by the IMPACT questionnaire (a validated, pediatric IBD health related quality of life questionnaire) [33] correlate with physician’s global assessment of disease severity, such that children with moderate-severe activity have the poorest HRQOL scores [34]. Over the first year after diagnosis, age also appears to be an independent factor affecting HRQOL scores, with older children reporting poorer IMPACT scores [34]. While treatment results in significant improvement in IMPACT scores in the first year after diagnosis, it is unknown whether further improvements in HRQOL occur over time. Children frequently report being bothered by having a chronic illness, by having to undergo tests, and by feeling tired. Over time, they also report feeling that it is unfair that they have their illness, and that they experience problems revolving around having to keep their illness a secret from others [34]. Other studies have noted that children with Crohn disease experience frequent absences from school, that they frequently require home tutoring, and that they commonly cannot participate fully or at all in physical education classes [35, 36]. Children express fears concerning everyday childhood activities, schooling and ability to get a job [37]. Fifty seven percent of a cohort was reported to have had an absence from school of at least 2 months duration, and in this same cohort, 8% were involuntarily unemployed as young adults [38]. Similar impairments are described in adult Crohn disease populations, with 15% of a Danish population on disability by 15 years after diagnosis, 25% reporting some inability to work in any given year of follow-up, and 50% reporting 1 or more years during first decade of disease with at least some inability to work [39]. References 1. Summers RW, Switz DM, Sessions JT Jr, et al. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterol 1979;77(4 Pt 2):847–869. 2. Malchow H, Ewe K, Brandes JW, et al. European Cooperative Crohn’s Disease Study (ECCDS): results of drug treatment. Gastroenterol 1984;86(2):249–266. 3. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterol 2000;119:895–902. 4. Romano C, Cucchiara S, Barabino A, et al. Usefulness of -3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn’s disease: A double-blind, randomized, placebo-controlled study. World J Gastroenterol 2005;11(45): 7118–7121. 5. Langholz E, Munkholm P, Krasilnikoff PA, et al. Inflammatory bowel diseases with onset in childhood. Clinical features, morbidity, and mortality in a regional cohort. Scand J Gastroenterol 1997;32:139–147. 6. Munkholm P, Langholz E, Davidsen M, et al. Disease activity courses in a regional cohort of Crohn’s disease patients. Scand J Gastroenterol 1995l;30(7):699–706. 7. Loftus EV Jr, Schoenfeld P, Sandborn WJ. The epidemiology and natural history of Crohn’s disease in population-based patient cohorts from North America: a systematic review. Aliment Pharmacol Ther 2002;16(1):51–60.
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8. Kugathasan S, Collins N, Maresso K, et al. CARD15 gene mutations and the risk for early surgery in pediatric-onset Crohn’s disease. Clin Gastroenterol Hepatol 2004;2:1003–1009. 9. Russell RK, Drummond HE, Nimmo EE, et al. Genotype-phenotype analysis in childhood-onset Crohn’s disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflamm Bowel Dis 2005;11(11):955–964. 10. Vermeire S, Pierik M, Hlavaty T, et al. Association of organic cation transporter risk haplotype with perianal penetrating Crohn’s disease but not with susceptibility to IBD. Gastroenterol 2005;129(6): 1845–1853. 11. Dubinsky MC, Lin YC, Dutridge D, et al. Serum immune responses predict rapid disease progression among children with Crohn’s disease: immune responses predict disease progression. Am J Gastroenterol 2006;101(2):360–367. 12. Kirschner BS. Growth and development in chronic inflammatory bowel disease. Acta Paediatr Scand Suppl 1990;366:98–104. 13. Markowitz J, Grancher K, Rosa J, et al. Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993;16(4):373–380. 14. Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn’s disease. Gastroenterology 1988;95(6):1523–1527. 15. Faubion WA Jr, Loftus EV Jr, Harmsen WS, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001;121(2):255–260. 16. Munkholm P, Langholz E, Davidsen M, et al. Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut 1994;35(3):360–362. 17. Markowitz J, Hyams J, Mack D, et al. Corticosteroid therapy in the age of infliximab: acute and 1 year outcomes in newly diagnosed children with Crohn disease. Clin Gastroenterol Hepatol 2006;4(9): 1124–1129. 18. Gupta N, Cohen SA, Bostrom AG, et al. Risk factors for initial surgery in pediatric patients with Crohn’s disease. Gastroenterology. 2006;130(4):1069–1077. 19. Becker JM. Surgical therapy for ulcerative colitis and Crohn’s disease. Gastroenterol Clin North Am 1999;28(2):371–390, viii–ix. 20. Chardavoyne R, Flint GW, Pollack S, et al. Factors affecting recurrence following resection for Crohn’s disease. Dis Colon Rectum 1986;29(8):495–502. 21. Brignola C, Cottone M, Pera A, et al. Mesalamine in the prevention of endoscopic recurrence after intestinal resection for Crohn’s disease. Italian Cooperative Study Group. Gastroenterology 1995;108:345–349. 22. Caprilli R, Andreoli A, Capurso L, et al. Oral mesalazine (5-aminosalicylic acid: Asacol) for the prevention of post-operative recurrence of Crohn disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Aliment Pharmacol Ther 1994;8:35–43. 23. Rutgeerts P, Heile M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995;108:1617–1621. 24. Rutgeerts P, Van Assche G, Vermeire S, et al. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2005;128(4):856–861. 25. Hanauer SB, Korelitz BI, Rutgeerts P, et al. Postoperative maintenance of Crohn’s disease remissions with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterol 2004;127:723–729. 26. Griffiths AM. Factors that influence the postoperative recurrence of Crohn’s disease in childhood. In Inflammatory Bowel Disease and Coeliac Disease in Children. Hadziselimovic F, Herzog B, BurginWolff A (eds). Boston: Kluwer Academic Publishers, 1990, pp. 131–136. 27. Ekbom A, Helmick C, Zack M, et al. Increased risk of large-bowel cancer in Crohn’s disease with colonic involvement. Lancet 1990;336:357–359. 28. Mellemkjaer L, Johansen C, Gridley G, et al. Crohn’s disease and cancer risk (Denmark). Cancer Causes and Control 2000;11:145–150. 29. Jess T, Loftus EV, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota. Gastroenterol 2006;130:1039–46. 30. Loftus EV Jr, Tremaine WJ, Habermann TM, et al. Risk of lymphoma in inflammatory bowel disease. Am J Gastroenterol 2000;95:2308–2312.
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31. Kandiel A, Fraser AG, Korelitz BI, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005;54(8):1121–1125. 32. Thayu M, Markowitz JE, Mamula P, et al. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr 40:220–222. 33. Otley A, Smith C, Nicholas D, et al. The IMPACT questionnaire: a valid measure of health-related quality of life in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002;35:557–563. 34. Otley A, Griffiths AM, Hyams J, et al. Health-related quality of life in the first year following a diagnosis of pediatric inflammatory bowel disease. Inflamm Bowel Dis;12(8):684–691. 35. Rabbett H, Elbadri A, Thwaites R, et al. Quality of life in children with Crohn disease J Pediatr Gastroenterol Nutr 1996;23:528–533. 36. Akobeng AK, Suresh-Babu MV, Firth D, et al. Quality of life in children with Crohn’s disease: a pilot study. J Pediatr Gastroenterol Nutr 1999;28:S37–S39. 37. Moody G, Eaden JA, Mayberry JF. Social implications of childhood Crohn’s disease. J Pediatr Gastroenterol Nutr 1999;28:S43–S45. 38. Ferguson A, Sedgwick DM, Drummond J, et al. Morbidity of juvenile onset inflammatory bowel disease: effects on education and employment in early adult life. Gut 1994;35:665–8. 39. Munkholm P, Langholz E, Davidsen M, et al. Disease activity courses in a regional cohort of Crohn’s disease patients. Scand J Gastroenterol 1995;30:699–706. 40. Farmer RG, Michener WM. Prognosis of Crohn’s disease with onset in childhood or adolescence. Dig Dis Sci 1979;24(10):752–757. 41. Ferguson A, Sedgwick DM. Juvenile-onset inflammatory bowel disease: predictors of morbidity and health status in early adult life. J R Coll Physicians Lond 1994;28(3):220–227. 42. Besnard M, Jaby O, Mougenot JF, et al. Postoperative outcome of Crohn’s disease in 30 children. Gut 1998;43(5):634–638. 43. Baldassano RN, Han PD, Jeshion WC, et al. Pediatric Crohn’s disease: risk factors for postoperative recurrence. Am J Gastroenterol. 2001;96(7):2169–2176. 44. Markowitz J, Markowitz JE, Bousvaros A, et al. Workshop report: prevention of postoperative recurrence in Crohn’s disease. J Pediatr Gastroenterol Nutr 2005;41(2):145–151.
7 Natural History of Pediatric Ulcerative Colitis Jeffrey S. Hyams∗
Introduction Defining the natural history of a chronic disease is made difficult by the continuously changing landscape of available therapies, earlier recognition of disease by more sensitive diagnostic techniques, and changes in intrinsic biological behavior. The natural history of ulcerative colitis following therapy with aminosalicylates and corticosteroids as were used in the 1960s and 1970s would be expected to differ from that following the current widespread use of immunomodulators and biological therapy. The data presented in this chapter reflect what we know of natural history now, and will likely be different than what we might describe in 10 years. Discussion of drugs will mostly focus on maintenance of remission. Whether course of disease in children is different than in adults is not clear, but will also be examined in this discussion. Lastly, possible methodology to predict response to therapy and alter natural history will be addressed.
Historical Perspective – Children In 1973 a report from Scotland described 25 children who had ulcerative colitis severe enough to be hospitalized [1]. Four had a single attack and 19 had chronic intermittent disease. During the follow-up period, averaging 24 years, 5 (20%) had died, usually in the post-operative period following colectomy. In 1979 a report from the Cleveland Clinic was published [2] describing the course of 336 patients diagnosed with ulcerative colitis before age 21 years between 1955 and 1974. Eleven per cent were deemed to have had a single episode of disease, 20% intermittent episodes returning to normal between bouts, 51% chronic but not incapacitating disease, and 18% chronic and incapacitating disease. Thirty five per cent underwent surgery. Five per cent of the patients died during the study period, most commonly from carcinoma of the colon (50%), lymphoma (6%), or chronic disease (27%). A report in 1996 of 171 subjects seen at two large pediatric inflammatory bowel disease centers in the Northeastern United States presented a somewhat more encouraging picture [3]. In this cohort, 43% had mild disease and 57% moderate or severe disease at presentation. Forty three percent had pancolitis. Over 80% had resolution of
*Professor of Pediatrics, University of Connecticut School of Medicine, Head, Division of Digestive Diseases and Nutrition, Connecticut Children’s Medical Center, 282 Washington Street, Hartford, Connecticut 06106, Tel.: (860) 545 9532, Fax.: (860) 545 9561, Email:
[email protected]
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Figure 7.1. Cumulative probability of colectomy at yearly intervals following diagnosis as a function of disease activity at diagnosis. Original population: mild disease, n = 73, moderate disease, n = 98. Confidence intervals: mild disease: 1 year (0 to 4%), 5 years (2% to 16%); moderate/severe disease: 1 year (3% to 13%), 5 years (16% to 36%). Mild disease vs. moderate/severe disease, p < 0.03. From Hyams JS et al. [3], with permission.
symptoms within 6 months of diagnosis and during subsequent yearly follow-up intervals 55% were symptom free, 38% had chronic intermittent symptoms, and 7% had continuous symptoms. Corticosteroid therapy was used in 27% of those with initially mild disease and 70% of those with moderate/severe disease by 1 year. Eleven per cent of those with moderate/severe disease received additional immunomodulatory therapy (azathioprine/6-mercaptopurine or cyclosporine) during the first year. By 1 year following diagnosis, 1% of those with initial mild disease and 8% of those with moderate/severe disease had required colectomy; at 5 years the risk of colectomy was 9% and 26% in the two groups, respectively (Figure 7.1). A report from Denmark in 1997 describing 80 children with ulcerative colitis demonstrated a cumulative colectomy rate of 6% and 23% at 1 and 5 years, respectively [4].
Historical Perspective – Adults The first report of the use of corticosteroids in the treatment of ulcerative colitis in adults appeared in the mid 1950s [5]. Truelove and Witts reported their experience using cortisone (100 mg per day) and demonstrated improvement or remission in 69% of treated subjects compared to 40% of controls. However, 6% of the cortisone treated patients and 15% of the control patients died during the 9 month study period. The largest report of the natural history of ulcerative colitis in adults appeared in 1994 and documented the course of 1161 patients diagnosed in Denmark between 1962 and 1987 [6]. Slightly less than half had distal disease at diagnosis, defined by rigid proctosigmoidoscopy and double contrast barium enema. Only 18% had pancolitis. During each year of follow-up beyond the first year, approximately 50% of patients were in clinical remission, 30–40% with intermittent symptoms, and 10% with continuous symptoms. Very few patients had a single episode of disease. The colectomy rate was 9% in the year of diagnosis, 3% per year in the following 4 years, and 1% per year subsequently. At 10 and 15 years from diagnosis, the cumulative colectomy rate was 24% and 30%, respectively.
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Clinical Characteristics Influencing Course Extent of Disease There are limited data on proctitis in children. In one report of 34 children with limited disease approximately 55% of patients were in remission in any one year following initial therapy, 40% had chronic intermittent symptoms, and 5% had continuous symptoms [7]. Proximal extension of disease was noted in 30% of patients over a 5-year period. Severity of Disease at Presentation Moderate to severe disease activity at presentation is common in children with ulcerative colitis. There is evidence to suggest that more severe disease at diagnosis is associated with a higher colectomy rate (9%) at one year than is mild disease at presentation (1%) [3].
Drug Modification of Natural History Aminosalicylates Maintenance therapy with sulfasalazine has been used for many years and is effective in up to 65 to 80% of adult patients [8]. Higher doses are more effective but may also be associated with greater side-effects. Clinical experience suggests mesalamine is also an effective maintenance therapy for mild to moderate ulcerative colitis [9]. There are no prospective, controlled trials examining the efficacy of mesalamine in maintaining remission of ulcerative colitis in children, though this therapy is commonly used. Corticosteroids Corticosteroids remain the mainstay of therapy for moderate to severe ulcerative colitis and therefore understanding the course of disease following these medications is critical to understanding natural history. The outcome of corticosteroid therapy for adults with UC in a populationbased study in Olmsted County, Minnesota was published in 2001 [10]. In this study of 185 patients diagnosed with UC over a 23-year period, only 63 (34%) received corticosteroids. Fiftyfour per cent of subjects receiving corticosteroids had a complete clinical response by 30 days, 30% a partial response, and 16% no response. By one year 49% had a prolonged response, 22% were termed corticosteroid-dependent, and 29% had undergone colectomy. Immunomodulators were used in very few of these patients. In children with ulcerative colitis treated with corticosteroids within 30 days of diagnosis, disease activity at 3 months was inactive in 60%, mild in 27%, and moderate/severe in 11% of patients in one study [11]. At one year, 31/62 (50%) of the corticosteroid treated patients were considered corticosteroid-responsive and 28 (45%) corticosteroid-dependent. A total of 4 patients receiving corticosteroids (5%) required colectomy in the first year. Immunomodulators were used in 61% of all corticosteroid treated patients. Thus, it is clear that response to corticosteroids plays a large role in defining natural history. It has recently been proposed that the multi-drug resistance (MDR) gene (MDR-1) may play an important role in determining response to corticosteroids [12, 13]. The MDR-1 gene codes for a 170-kilodalton cell membrane drug efflux pump P-glycoprotein 170 that transports MDR substrates out of cells, lowering their intracellular concentration. This glycoprotein is expressed in the apical surface of intestinal epithelium as well as in peripheral blood lymphocytes. Corticosteroids, cyclosporine, and methotrexate are all MDR substrates. Patients with ulcerative colitis refractory to corticosteroids have been shown to have higher MDR expression compared to controls [12].
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Immunomodulators The past 15 years has seen a great increase in the use of immunomodulators to treat ulcerative colitis, largely based on the previous positive experience in Crohn disease. A recently published review of 7 blinded, controlled trials of azathioprine in ulcerative colitis highlighted the methodological issues with many of the early studies which left unanswered the question of whether this drug was useful in maintaining remission [14]. A review of the 30 year experience with azathioprine in a large cohort of patients in Oxford, England suggested significant utility of azathioprine in maintaining remission [15]. Almost two-thirds of patients maintained remission for up to 5 years, and median time to relapse upon stopping the drug with 18 months. The addition of the 5-aminosalicylate olsalazine to azathioprine does not improve the maintenance of remission rate compared to azathioprine alone in steroid dependent adults with ulcerative colitis [16]. No controlled data are available in children. Two small retrospective series support the use of azathioprine in steroid dependent disease in children [17, 18]. Though cyclosporine is widely accepted as effective therapy for inducing remission in severe ulcerative colitis, controlled data supporting this assumption are limited [19, 20]. In children the experience is limited to retrospective chart review [21]. However, nephrotoxicity, increased susceptibility to infection, and other side-effects generally preclude its use as maintenance therapy. Therefore, monotherapy with cyclosporine to maintain remission is not indicated, and patients with cyclosporine induced remission are often transitioned to azathioprine for maintenance [22, 23]. Nonetheless, it is not clear whether long-term outlook is improved as many patients requiring cyclosporine therapy require colectomy within 2–3 years [21, 24]. Biologic Therapy While initial studies of infliximab for the treatment of ulcerative colitis were conflicting [25–27], more recent data have suggested efficacy. In 2005, two randomized, double-blind, placebo controlled studies, ACT 1 and ACT 2, were published in a single paper evaluating the efficacy of infliximab for induction and maintenance in 728 adults with active ulcerative colitis (Mayo score 6–12) [28]. Clinical response at 8 weeks (decrease in Mayo score by 3 points) was observed in approximately 65% of subjects receiving a 3-dose induction of infliximab (either 5 mg/kg/dose or 10 mg/kg/dose) compared to approximately 33% of placebo patients. Clinical remission at week 8 (Mayo score of 2 or lower, no item more than 1) was observed in approximately 33% of infliximab treated patients versus 10% in the placebo group. Mucosal healing at week 8 was seen in approximately 60% of infliximab treated patients versus 30% of placebo treated patients. Week 54 data were available for 364 ACT 1 patients; 42% of infliximab treated patients were in remission compared to 20% of those treated with placebo. Clinical remission without corticosteroids was seen in 9% of placebo treated patients, 26% of those receiving 5 mg/kg maintenance doses of infliximab every 8 weeks and 16% of those receiving 10 mg/kg doses. At the start of ACT 1 and ACT 2 approximately 30% of patients were felt to have corticosteroid refractory disease, 50-60% were taking corticosteroids at the time infliximab was initiated, and 70% were receiving 5-aminosalicylate preparations and 40–50% immunomodulators. Average disease duration was approximately 6 years. Longer term follow-up will be required to determine if this degree of disease suppression remains. In one study of hospitalized adults with severe ulcerative colitis refractory to corticosteroid therapy, the addition of infliximab was superior to placebo in preventing colectomy (Odds ratio 4.9, range 1.4–17) [29]. There are no comparable data for pediatric patients. No placebo controlled data are currently available for pediatric ulcerative colitis. Reported data from open-label experience demonstrate short-term improvement in 75–80% of subjects and longer term improvement in 60% [30–33]. It has been suggested that patients with chronic corticosteroid dependent disease are less likely to respond to infliximab than those with short-term disease [30].
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However, these observations were based on very small patient numbers and will require further study. Long-term data will be required to see whether the frequency of corticosteroid dependency or need for colectomy will decrease compared to the pre-biological therapy era, and whether long-term safety can be demonstrated. Additional biological agents have also been evaluated in limited clinical trials. MLN02 is a humanized monoclonal antibody that specifically recognizes the 4 7 heterodimer and selectively blockades the interaction between leukocytes and vascular endothelium in inflamed gut. One hundred eighty one adult patients with active ulcerative colitis, not receiving corticosteroids or immunomodulators, received either placebo or one of two doses of MLN02 (Day 1, 29). Clinical remission at week 6 was 14% in the placebo group and 32% in the treated groups [34]. Visilizumab is a humanized anti-CD3 antibody that selectively induces apoptosis in activated T cells. Phase I/II studies showed efficacy in corticosteroid resistant UC. Cytokine release syndrome and elevations in EBV DNA levels were observed [35].
Can We Predict the Course of Disease? Being able to predict the course of those patients who present with severe disease might be helpful in designing treatment strategies. Both clinical paradigms and laboratory evaluation have been examined in this regard. In 1977, Werlin and Grand reported 19 children with severe colitis (14 ulcerative colitis, 5 Crohn disease) defined as having 4 out of the following 5 features: ≥5 bloody stools per day, oral temperature >100°F, pulse ≥90, hematocrit ≤30%, albumin ≤3.0 g/dl [36]. One-third of their patients responded to therapy (bowel rest, parenteral nutrition, corticosteroids) and the remainder underwent colectomy within 2 years. In adults a duration of acute symptoms for more than 6 weeks, deep rectocolonic ulcers, or the presence of Truelove and Witts criteria [5] for severe disease had an 85% chance of medical failure with conventional therapy [37]. In another study of adults the presence of pedal edema, transverse colon dilatation (>5 cm), high C-reactive protein, low serum fibrinogen, prolonged prothrombin time, and Truelove and Witts criteria for severe disease predicted failure of medical therapy [38]. Similar findings on day 3 after hospital admission all predict a higher likelihood of requiring colectomy [39, 40]. Attempts have also been made to try to correlate disease course with genetic profiles. An association between severe and extensive disease and the major histocompatability complex (MHC) genes DRB1*0103 and DRB1*15 has been identified [41–43]. A structural polymorphism in the IKBL (inhibitor of B-like) gene, located in the central region of the MHC locus, has also been associated with severe disease [44]. Refractory ulcerative colitis has been associated with a polymorphism in the hMLH1 gene, a mismatch repair gene [45]. To date, no specific data on genetic associations and course of pediatric ulcerative colitis have been identified.
Summary Short of a cure, the ideal therapy for ulcerative colitis quickly induces and then effectively maintains remission with healing of the colonic mucosa and presents minimal toxicity to the patient. No current therapy meets all these requirements. The natural history of ulcerative colitis will continue to change as newer therapies are introduced. At present, aminosalicylates should be used to maintain remission given their favorable side-effect profile. Immunomodulators also appear to be effective in those patients failing aminosalicylates, as is infliximab. Long term safety data will be required to better understand the risk-benefit ratio of these therapies. In the future clinicians may be able to obtain a genetic profile of their patients that will help predict response to various therapies and thereby decrease the likelihood of treatment failure and complications of ineffective treatments. As was recently noted in a review article on severe colitis in children,
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“only scientifically proven data developed in children will allow us to safely and convincingly move from experience derived from adult studies to the pediatric population” [46]. References 1. Goel KM, Shanks RA. Long-term prognosis of children with ulcerative colitis. Arch Dis Child 1973;48:337–42. 2. Michener WM, Farmer RG, Mortimer EA. Long-term prognosis of ulcerative colitis with onset in childhood or adolescence. J Clin Gastroenterol 1979;1:301–5. 3. Hyams JS, Davis P, Grancher K, Lerer T, Justinich CJ, Markowitz J. Clinical outcome of ulcerative colitis in children. J Pediatr 1996;129:81–8. 4. Langholz E, Munkholm P, Krasilnikoff PA, Binder V. Inflammatory bowel diseases with onset in childhood. Clinical features, morbidity, and mortality in a regional cohort. Scand J Gastroenterol 1997;32:139–47. 5. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;1041–8. 6. Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology 1994;107:3–11. 7. Hyams J, Davis P, Lerer T, et al. Clinical outcome of ulcerative proctitis in children. J Pediatr Gastroenterol Nutr 1997;25:149–52. 8. Sutherland L, Roth D, Beck P, May G, Makiyama K. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2002;CD000544. 9. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 1997;92:204–11. 10. Faubion WA, Jr., Loftus EV, Jr., Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001;121:255–60. 11. Hyams J, Markowitz J, Lerer T, et al. The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol 2006;4:1118–23. 12. Farrell RJ, Murphy A, Long A, et al. High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy. Gastroenterology 2000;118:279–88. 13. Farrell RJ, Kelleher D. Glucocorticoid resistance in inflammatory bowel disease. J Endocrinol 2003;178:339–46. 14. Sands BE. Immunosuppressive drugs in ulcerative colitis: twisting facts to suit theories? Gut 2006;55:437–41. 15. Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002;50:485–9. 16. Mantzaris GJ, Sfakianakis M, Archavlis E, et al. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. Am J Gastroenterol 2004;99:1122–8. 17. Kader HA, Mascarenhas MR, Piccoli DA, Stouffer NO, Baldassano RN. Experiences with 6mercaptopurine and azathioprine therapy in pediatric patients with severe ulcerative colitis. J Pediatr Gastroenterol Nutr 1999;28:54–8. 18. Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr 1990;117:809–14. 19. D’Haens G, Lemmens L, Geboes K, et al. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology 2001;120:1323–9. 20. Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–5. 21. Treem WR, Cohen J, Davis PM, Justinich CJ, Hyams JS. Cyclosporine for the treatment of fulminant ulcerative colitis in children. Immediate response, long-term results, and impact on surgery. Dis Colon Rectum 1995;38:474–9. 22. Fernandez-Banares F, Bertran X, Esteve-Comas M, et al. Azathioprine is useful in maintaining longterm remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol 1996;91:2498–9.
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23. Arts J, D’Haens G, Zeegers M, et al. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis 2004;10:73–8. 24. Stack WA, Long RG, Hawkey CJ. Short- and long-term outcome of patients treated with cyclosporin for severe acute ulcerative colitis. Aliment Pharmacol Ther 1998;12:973–8. 25. Chey WY. Infliximab for patients with refractory ulcerative colitis. Inflamm Bowel Dis 2001;7 Suppl 1:S30–3. 26. Su C, Salzberg BA, Lewis JD, et al. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol 2002;97:2577–84. 27. Probert CS, Hearing SD, Schreiber S, et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut 2003;52:998–1002. 28. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76. 29. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005;128:1805–11. 30. Russell GH, Katz AJ. Infliximab is effective in acute but not chronic childhood ulcerative colitis. J Pediatr Gastroenterol Nutr 2004;39:166–70. 31. Mamula P, Markowitz JE, Cohen LJ, von Allmen D, Baldassano RN. Infliximab in pediatric ulcerative colitis: two-year follow-up. J Pediatr Gastroenterol Nutr 2004;38:298–301. 32. Serrano MS, Schmidt-Sommerfeld E, Kilbaugh TJ, Brown RF, Udall JN, Jr., Mannick EE. Use of infliximab in pediatric patients with inflammatory bowel disease. Ann Pharmacother 2001;35:823–8. 33. Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis 2005;11:213–8. 34. Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med 2005;352:2499–507. 35. Sandborn WJ, Baumgart DC, Targan SR, et al. Long-term outcome following visilizumab for the treatment of intravenous steroid-refractory ulcerative colitis (IVSRUC). Gastroenterology 2007;132:A506. 36. Werlin SL, Grand RJ. Severe colitis in children and adolescents: diagnosis. Course, and treatment. Gastroenterology 1977;73:828–32. 37. Carbonnel F, Lavergne A, Lemann M, et al. Colonoscopy of acute colitis. A safe and reliable tool for assessment of severity. Dig Dis Sci 1994;39:1550–7. 38. Kumar S, Ghoshal UC, Aggarwal R, Saraswat VA, Choudhuri G. Severe ulcerative colitis: prospective study of parameters determining outcome. J Gastroenterol Hepatol 2004;19:1247–52. 39. Travis SP, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut 1996;38:905–10. 40. Ho GT, Mowat C, Goddard CJ, et al. Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery. Aliment Pharmacol Ther 2004;19:1079–87. 41. Bouma G, Crusius JB, Garcia-Gonzalez MA, et al. Genetic markers in clinically well defined patients with ulcerative colitis (UC). Clin Exp Immunol 1999;115:294–300. 42. Trachtenberg EA, Yang H, Hayes E, et al. HLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish caucasian populations. Hum Immunol 2000;61:326–33. 43. Ahmad T, Armuzzi A, Neville M, et al. The contribution of human leucocyte antigen complex genes to disease phenotype in ulcerative colitis. Tissue Antigens 2003;62:527–35. 44. de la Concha EG, Fernandez-Arquero M, Lopez-Nava G, et al. Susceptibility to severe ulcerative colitis is associated with polymorphism in the central MHC gene IKBL. Gastroenterology 2000;119:1491–5. 45. Bagnoli S, Putignano AL, Melean G, et al. Susceptibility to refractory ulcerative colitis is associated with polymorphism in the hMLH1 mismatch repair gene. Inflamm Bowel Dis 2004;10:705–8. 46. Kugathasan S, Dubinsky M, Keljo D, et al. Severe colitis in children. J Pediatr Gastroenterol Nutr 2005;41:375–85.
8 Natural History of Pediatric Indeterminate Colitis Michael D. Kappelman∗ and Richard J. Grand
Introduction The term “Indeterminate Colitis” (IC) refers to a heterogeneous subset of patients with inflammatory bowel disease (IBD) who, for a number of different reasons, cannot be classified as either Crohn disease or ulcerative colitis. These patients have primarily colonic disease involvement, but several clinical, anatomic, endoscopic, or histologic features such as nonspecific gastritis, ileal inflammation or minor ulceration, rectal sparing, or growth failure make the diagnosis of ulcerative colitis uncertain. Not only are these patients a heterogeneous group; so too are their physicians. Because there are no established criteria for diagnosing IC, individual clinicians may vary on how, when, and how frequently they use this term. [1] As an example of this subjectivity, consider the child with pancolitis and mild histologic inflammation of the terminal ileum. One clinician may diagnose “ulcerative colitis with backwash ileitis”, another may diagnose indeterminate colitis, and a third may consider this a case of Crohn disease. [1] The heterogeneity of clinical presentations that have been described as IC, as well as the diagnostic subjectivity, limit the ability to describe the natural history of this condition. For example, are these patients at increased risk of disease recurrence and/or pouchitis following surgery? How will they respond to biologics and other therapies that have only been studied in patients with classical CD or UC? As a result, patients with IC and their physicians are often frustrated, especially when trying to understand disease prognosis, plan for the future, and weigh the risks/benefits of certain medical and surgical therapies. An additional concern is that these patients are often excluded from clinical trials, limiting their access to emerging therapeutics. In this chapter, we will explore the factors which lead to the diagnosis of indeterminate colitis, review the definitions of IC that have been used in the literature, describe the epidemiology of this condition relative to that of CD and UC, discuss the natural history of IC (subject to the limitations described above), and summarize the recommendations of the combined CCFA/NASPGHAN
∗
Assistant Professor of Pediatrics, University of North Carolina Chapel Hill, 5143 Bioinformatics Bldg; CB#7229, Chapel Hill, NC 27599, E-mail:
[email protected] Supported in part by AHRQ Grant No. T32 HS000063-12 to the Harvard Pediatric Health Services Research Fellowship Program, General Clinical Research Center Grant M01 RR002172, and the Wolpow Family Fund.
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Table 8.1. Summary of studies describing reclassification of patients initially diagnosed with IC. Author
Population
Moum (15) Joosens (17) Meucci (16) Total adult Lindberg (19) Carvalho (13) Mamula (18)
Adult Adult Adult
Total children
Pediatric Pediatric Pediatric (≤5 years)
Initial dx IC
Follow-up dx UC
Follow-up dx CD
Other follow-up dx (IC, not IBD, probable IBD)
35 97 48 180 171 74 19
12 14 17 43 (24%) 23 9 1
6 17 20 43 (24%) 6 16 4
17 66 11 94 (52%) 142 49 14
264
33(12.5%)
26 (10%)
205 (77.5%)
working group on the differentiation between ulcerative colitis, Crohn disease, and indeterminate colitis in children and young adults.
Factors Leading to a Diagnosis of Indeterminate Colitis Several endoscopic and histologic factors contribute to difficulty in distinguishing between CD and UC and lead to the diagnosis of IC, particularly in the pediatric and adolescent age range. Other factors, however, are the subject of considerable confusion among clinicians and pathologists, and may result in the inappropriate diagnosis of IC. First, there is increasing debate over the necessary findings of UC, which have traditionally included rectal involvement and continuous, distal to proximal distribution. This may be especially true for pediatric patients, as in one study up to 21% of newly diagnosed children with patchy colonic disease carried the diagnosis of UC. In this same study, the authors allowed for relative rectal sparing in 23% and absolute rectal sparing in 3%. [2] Non-classical findings such as these may cast doubt on a diagnosis of UC or raise the suspicion for Crohn disease, resulting in a provisional diagnosis of IC. Secondly, the relative infrequency of granulomas in colonic biopsy specimens in patients with colitis may lead to an overdiagnosis of IC in cases that would have ordinarily been diagnosed as Crohn colitis. Two recent reports demonstrated that the frequency of granulomas detected in colonic biopsies of patients with CD was between 21.7 and 30.2%. [3, 4] Of note, the addition of upper gastrointestinal and ileal biopsies increased the likelihood of granuloma detection to 43.8% in one of these studies. [3] Although these authors recommend Esophagogastroduodenoscopy (EGD) with biopsy and Terminal ileum (TI) intubation with biopsy for all patients with possible IBD, this practice is not yet universally accepted. [3, 4] Another reason for the diagnosis of IC is that the classical pathologic features of ulcerative colitis are often obscured in surgical resection specimens in patients with fulminant UC due to early superficial ulceration, transmural inflammation, and even rectal sparing. [5] Other, less appropriate reasons for the diagnosis of indeterminate colitis include the misinterpretation of pathologic features that are accepted variants of ulcerative colitis such as “backwash ileitis”, “gastritis”, and periappendiceal inflammation (commonly referred to as the “cecal patch”), and failure to use “hard” criteria such as transmural inflammation, granulomas, deep fissuring ulceration, ileal involvement, or segmental disease as representative of CD. [1, 5]
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Children with initial diagnosis of IC 264 patients
Follow up diagnosis of UC 33 patients (12.5%)
Follow up diagnosis of CD 26 patients (10%)
Other follow up diagnosis 205 patients (77.5%)
Definitions Because no standard definition for indeterminate colitis exists, our understanding of the epidemiology and natural history of this condition is limited. Originally, IC was purely a “histopathologic” diagnosis, established only after the examination of surgical specimens. Since the majority of these patients were operated because of fulminant colitis, the disease spectrum was limited to patients with severe colitis. Although many authors still support this original definition, other investigators are now using the term IC more broadly, including all cases with endoscopic, radiographic, and histologic evidence of IBD confined to the colon but features that make the clinician uncertain as to whether the diagnosis is CD or UC. [6] For example, in a prospective, population-based study of newly diagnosed IBD patients in Norway, Moum et al. defined the diagnostic criteria for IC as “endoscopy and histopathology were either inconclusive or divergent with regard to the diagnosis of UC or CD”. [7] Similarly, Kugathasan et al, in a community based study of the epidemiology of pediatric IBD in Wisconsin, defined indeterminate colitis as “inflammatory colitis in the setting of histopathological changes indicative of chronic IBD colitis, containing both endoscopic and histologic findings that were consistent with both CD and UC”. [8] By allowing the inclusion of all patients, not just those who have undergone surgery, “clinicopathologic” definitions such as these have expanded the subgroup of patients (and the spectrum of disease) categorized as indeterminate colitis. Finally, it should be emphasized that some experts believe that IC is not a distinct disease entity with specific diagnostic criteria. Rather, they believe that IC is a provisional descriptive term used until the true nature of the patient’s underlying type of IBD becomes apparent, usually within a few years following diagnosis. [5]
Epidemiology As illustrated by the discussion above, disagreement concerning the definition(s) of IC has lead to varying estimates of the incidence and prevalence of this disorder, not to mention uncertainty regarding the natural history. For the remainder of this chapter, our discussion will concentrate on patients who meet the broader, “clinicopathologic” diagnostic criteria, as we believe this definition is more useful to clinicians concerned with diagnostic and therapeutic decisions. There are only a few studies examining the incidence of IC. Moum et al. prospectively registered all new cases of UC and IC in a population based study in southeastern Norway. The study population consisted of a total of 525 cases of UC and 93 cases of IC. The mean annual incidence of IC was 2.4 per 100,000, comprising 13% of all newly diagnosed cases of IBD. [7] It should be noted that the average age of onset was 35 years indicating that the study population was predominantly adults.
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In the Wisconsin-based pediatric study, 10 out of 199 incident IBD cases (5%) were classified as IC, with an overall incidence of 0.35 per 100,000. [8] Another prospective study of pediatric IBD in Sweden reported a similar overall incidence of pediatric IBD; however, in this study approximately 25% of patients were classified as IC. [9] Additional reports from the pediatric literature estimate the proportion of newly diagnosed cases of IBD cases categorized as IC to be anywhere between 3.3% and 30%. [10–13] We believe that these widespread differences in the proportion of incident IBD cases categorized as IC, despite relatively similar overall IBD incidence rates, represents extremes in diagnosis and categorization rather than actual “biologic” differences. This variation underscores not only the heterogeneity of conditions labeled as IC, but also the inadequacy of the current classification system. The prevalence of IC is affected not only by the number of new cases, but also by the number of cases exiting the prevalent pool. Because of the chronic nature of this illness, patients leave the pediatric prevalence pool only under a limited number of circumstances: 1) becoming adults, 2) death (uncommon), and 3) having their diagnosis changed to CD or UC. Therefore, estimates of prevalence are limited not only by the diagnostic concerns addressed above, but also by the natural history and disease evolution which will be the subject of the next section.
Natural History Both for prognostic and therapeutic purposes, it is important to understand the natural history of indeterminate colitis. Are these patients more likely to follow a Crohn disease clinical course, or an ulcerative colitis-like course? Or, do these patients comprise a distinct subgroup and follow a unique clinical course? Many authors believe that patients with indeterminate colitis have a more severe clinical course than those with UC. For example, Stewenius et al. followed a cohort of 354 patients with IC, UC, and probable UC. After ten years of follow up, the relapse risk in patients with IC was twice as high as in patients with definite UC (relative risk, 1.9, 95% confidence interval, 1.6–2.4). [14] Other important questions regarding the natural history of indeterminate colitis include the following: How will these patients respond to medical therapy? What about surgical therapy? Are these patients at increased risk for post-operative complications such as pouch failure and postoperative fistulas? Our discussion of the natural history of IC will focus on three elements: 1) Diagnostic reclassification based on the development of features typical of UC or CD, 2) Response to medical management, and 3) Surgical outcomes.
Diagnostic Reclassification Several studies have attempted to determine what proportion of patients initially diagnosed with indeterminate colitis is ultimately re-classified as either CD or UC (Table 8.1). Of course, this depends on whether the diagnosis of IC was a pathologic one, based on colectomy specimens, or a clinicopathologic one, based on clinical, radiographic, endoscopic, and histologic data. In this section, we will discuss only the studies which classify patients according to clinicopathologic criteria. In 1997, Moum et al. offered clinical follow up one to two years following a diagnosis of IBD to a cohort of adult patients in south eastern Norway. Of the 36 cases of indeterminate colitis, 35 were available for clinical follow up. One third of these were reclassified as UC, 17% as CD, 29% as possible IBD, and 14% as non-IBD. Only 6% remained classified as IC. In contrast, less than 1% of patients with CD or UC were reclassified as IC during the follow up period. [15]
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In a multi-center, retrospective study based in Northern Italy, Meucci et al. analyzed the frequency of re-classification within eight years of an initial diagnosis of IC. In this study, fifty out of 1113 adult IBD patients were initially diagnosed as having indeterminate colitis (4.6%). Of these, 72.5% had their diagnosis changed to either CD or UC during the follow up period. [16] More recently, Joossens et al. prospectively followed 97 adult patients with indeterminate colitis in three European centers. During a mean follow up period of 2.4 years, 31 patients (32%) received a definitive diagnosis. Of these, 55% were reclassified as CD and 45% were reclassified as UC. [17] In the largest pediatric study, Lindberg et al. prospectively followed children with IBD between the years 1984 and 1995. Of the 171 children initially diagnosed with IC, 23 (13%) had their diagnosis changed to UC, 6 (4%) had their diagnosis changed to CD, and 3 (2%) had their diagnosis changed to probably CD. [9] Recently, Carvalho published a retrospective database analysis of 250 children with IBD diagnosed between 1996 and 2001. Of these, 74 (29.6 %) had IC. After a median follow-up of 1.9 years, 33.7% of these were reclassified as CD (n = 16) or UC (n = 9). [13] Mamula et al. reported on the reclassification of children with early onset IBD (five years of age and younger). In this retrospective study of 82 patients, 19 (23%) were initially diagnosed with indeterminate colitis. Of these, 26% were ultimately reclassified over a median follow up period of 7.5 years (range 6 months to 23 yr); 80% of these had a final diagnosis of CD and 20% UC. The majority of patients in whom the diagnosis was changed had the initial diagnosis made before 1991. This finding may be explained either by the longer duration of follow-up in children diagnosed before 1991 or by recent improvements in the technical aspects of pediatric colonoscopy allowing a more precise initial diagnosis in patients diagnosed after 1991. [18] Taken together, these studies indicate that diagnostic re-classification is common for patients with indeterminate colitis, reinforcing the sentiment that IC is often a provisional diagnosis. However, the rate of re-classification and the proportion of cases ultimately diagnosed as either CD or UC varies with each study, precluding any definitive conclusions. Generally, it appears that at least half of adult patients and ¼ of pediatric patients will ultimately be reclassified as either CD or UC. One exception may be very young children, who appear more likely to receive a final diagnosis of CD; however, this finding is based on a limited population and should be confirmed. Response to Medical Management There are no randomized clinical trials of medical therapy for indeterminate colitis. In fact, patients with IC are generally excluded from clinical trials. Therefore, little is known about the response of these patients to conventional medical therapies. It is frequently assumed that because many patients with indeterminate colitis will eventually be diagnosed with either CD or UC, any therapy that is effective in both diseases may be useful for the treatment of IC as well. Burakoff advocates that the approach to medical treatment should be based on the anatomic distribution of disease and the severity of relapse. [19] Our anecdotal experience confirms that these patients often respond to steroids, salicylates (oral and topical), and immunosuppressives such as 6 mercaptopurine and azathioprine; however, no data exist on the response rate of patients with IC compared to that of patients with CD or UC. Recently, Black et al. reported the results of an open label trial of infliximab in the treatment of medically refractory indeterminate colitis. Of 20 patients treated with infliximab, 14 (70%) had a complete response, 2 (10%) had a partial response, and 4 (20%) had no response. Of note, half of the enrolled patients were ultimately diagnosed with CD, though the response rate was no different in these patients compared to those who retained a diagnosis of IC. [20] Therefore, although
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limited studies and no controlled trials prove that patients with IC respond to conventional IBD therapies, we believe that a high percentage of these patients will respond to medical therapy and agree with Burakoff that therapy should be based on both anatomic location and disease severity. Surgical Outcomes Several studies have examined the surgical outcomes and complications of patients with indeterminate colitis following colectomy and ileal pouch-anal anastomosis (IPAA); however, there are no reports on the natural history of children with IC who underwent these operative procedures. Although these studies are all limited by their retrospective design, we will summarize and interpret their major findings in the remainder of this section. Yu et al. retrospectively studied 1437 adult patients with chronic UC and 82 patients with IC between 1981 and 1995. Median follow up time was 6.9 years. At ten years, patients with IC had significantly more episodes of pelvic sepsis (17% vs 7%; p < .01), pouch fistula (31% vs 9%; p < .01), and pouch failure (27 vs 11 %; p < .01). In this study, there were no significant differences in the rate of pouchitis between the two groups. Importantly, 15% of the IC patients had their diagnosis changed to CD during follow-up, compared to only 2% of those originally diagnosed with UC (p < .01). When the patients re-classified as CD were removed from analysis, patients with persistent IC did not have significantly different outcomes when compared to patients with chronic UC. Therefore, in this study it appears that the higher rate of surgical complications is limited to the subgroup of patients who were ultimately diagnosed with Crohn disease. [21] In another study, McIntyre et al. compared the outcomes of 71 adult IC patients and 1232 UC patients following IPAA. Mean follow up was 56 months for the IC group and 60 months for the UC group. The number of bowel movements and incontinence rates were similar in both groups; however, failure rate was higher in the IC group compared to the UC group (19% vs 8%). [22] A third study retrospectively compared complication rates in 140 adult patients with IC and 231 UC patients matched for age, sex, method of anastomosis, presence of defunctioning stoma, and length of follow up. The IC patients were more likely to develop minor perianal fistulae and pelvic abscess, but not anastomotic leak or major fistulae. There were no significant differences in the rate of pouch failure. As in previous studies, the proportion of patients who were diagnosed with CD following surgery was greater in IC patients than the UC controls. The same authors also compared 115 IC patients with 1399 UC controls in a prospective analysis, and found no significant differences in functional outcomes, quality of life, or satisfaction with IPAA surgery. [23] Taken together, these studies suggest that post-surgical complications such as pouch failure, fistula, and pelvic sepsis may be higher in adult IC patients undergoing colectomy and IPAA when compared to UC patients; however, these studies suggest that the higher complication rate may be limited to the subset of patients who ultimately receive a diagnosis of Crohn disease. This underscores the importance of complete pre-surgical evaluation, as proper classification prior to surgery may lead to improved risk assessment. Regardless of the complication rates, several of these studies have demonstrated that IC and UC patients have similar functional status, satisfaction, and quality of life following surgical treatment, and therefore, patients with IC should not be precluded from undergoing colectomy and restorative IPAA. Additional data concerning the natural history of children with IC following surgery are desperately needed before any generalizations can be made about pediatric patients with indeterminate colitis, particularly in very young children who may be at higher risk of Crohn disease when compared to older children and adults.
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Recommendations To address the questions, inconsistencies, and controversies in the diagnosis and classification of pediatric inflammatory bowel disease, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn and Colitis Foundation of America (NASPGHN) (CCFA) jointly organized a working group of 10 pediatric gastroenterologists, one adult gastroenterologist, one epidemiologist, and four GI pathologists which met in December of 2003. The goals of this working group were to establish an agreed upon set of definitions and phenotypes, and to develop an algorithm that would improve inter observer agreement in the diagnosis and classification of CD, UC, and IC. Although the working group was unable to determine evidence-based criteria for diagnosing IC, they put forth several general recommendations. First, the group suggested that clinicians try to avoid overuse of the diagnosis of IC, and specifically stated that the following criteria do not preclude a diagnosis of UC in children with colitis: backwash ileitis, rectal sparing, histologic patchiness, appendiceal inflammation, and gastritis. The committee also recommended that for patients diagnosed with IC based on symptoms highly atypical for UC such as ileal apthae, backwash ileitis in a patient with left sided colitis, profound growth failure, large oral apthae, or absolute rectal sparing, clinicians should precisely specify the reason(s) for this diagnosis rather than UC or CD. The committee further recommended patients given a provisional diagnosis of IC undergo additional endoscopic and radiographic evaluation after one year or during the next disease exacerbation to try to establish a definitive diagnosis, while acknowledging that partially treated disease may have a patchy distribution.
Summary Patients with indeterminate colitis are a heterogeneous group, and controversy exists regarding the diagnostic criteria for this condition. Marked variability in the usage of this term among physicians has resulted in widespread differences in the prevalence of this condition and has limited our understanding of the natural history. Additionally, patients with IC are often excluded from clinical trials, further limiting our understanding of both the clinical course and response to therapy, and this lack of evidence is particularly problematic in the pediatric population. We conclude that efforts should be made to standardize diagnostic criteria and to prospectively characterize the clinical course and response to therapy by a combination of observational and randomized studies. In the meantime, we believe that indeterminate colitis represents a mixture of patients with UC, patients with CD, and patients in whom, after several years of follow-up and re-evaluation, the diagnosis remains “indeterminate”. It appears that patients with IC are ultimately more likely to be diagnosed with UC rather than CD; however, the reverse may be true in very young children. We advocate medical treatment with agents that are effective in both CD and UC (i.e. steroids, salicylates, immunomodulators, and infliximab), with specific therapies chosen based on disease location, severity, and estimation of risk for recurrence. Although IC patients who undergo surgical therapy such as colectomy and IPAA may be at higher risk of post-operative complications, they appear to have similar functional outcomes. As such, surgical therapy should not be withheld from IC patients with refractory disease, once an attempt has been made to re-classify their disease status. References 1. Bousvaros A, Antonioli D, Colletti RB, et al. The differentiation between colitis, Crohn disease, and indeterminate colitis in childern and young adults. Report of a combined CCFA/NASPHGAN working group, and a proposed classification scheme and algorithm.
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2. Glickman JN, Bousvaros A, Farraye FA, et al. Pediatric patients with untreated ulcerative colitis may present initially with unusual morphologic findings. The American journal of surgical pathology, 2004;28(2):190–7. 3. De Matos V, Baldassano RN, Russo PA. Granuloma Prevalence and Distribution in Pediatric Crohn Diseaes: Importance of Upper Endoscopy and Terminal Ileal Biposies: 181. Journal of Pediatric Gastroenterolgy and Nutrition, 2005;41(4):549. 4. Shaoul R, Karban A, Weiss B, et al. NOD2/CARD15 mutations and presence of granulomas in pediatric and adult Crohn disease. Inflammatory Bowel Diseases, 2004;10(6):709–14. 5. Odze RD. Pathology of indeterminate colitis. Journal of Clinical Gastroenterology, 2004;38(5 Suppl):S36–S40. 6. Geboes K, De Hertogh G. Indeterminate colitis. Inflammatory Bowel Diseases, 2003; 9(5):324–31. 7. Moum B, Vatn MH, Ekbom A, et al. Incidence of inflammatory bowel disease in southeastern Norway: evaluation of methods after 1 year of registration. Southeastern Norway IBD Study Group of Gastroenterologists. Digestion, 1995;56(5):377–81. 8. Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. The Journal of Pediatrics, 2003;143(4):525–31. 9. Lindberg E, Lindquist B, Holmquist L, Hildebrand H. Inflammatory bowel disease in children and adolescents in Sweden, 1984–1995. Journal of Pediatric Gastroenterology and Nutrition, 2000;30(3):259–64. 10. Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. The Journal of Pediatrics, 2005;146(1):35–40. 11. Hildebrand H, Finkel Y, Grahnquist L, Lindholm J, Ekbom A, Askling J. Changing pattern of paediatric inflammatory bowel disease in northern Stockholm 1990–2001. Gut 2003;52(10):1432–4. 12. van der Zaag-Loonen HJ, Casparie M, Taminiau JA, Escher JC, Pereira RR, Derkx HH. The incidence of pediatric inflammatory bowel disease in the Netherlands: 1999–2001. Journal of Pediatric Gastroenterology and Nutrition, 2004;38(3):302–7. 13. Carvalho RS, Abadom V, Dilworth HP, Thompson R, Oliva-Hemker M, Cuffari C. Indeterminate colitis: a significant subgroup of pediatric IBD. Inflammatory Bowel Diseases, 2006;12(4):258–62. 14. Stewenius J, Adnerhill I, Ekelund GR, et al. Risk of relapse in new cases of ulcerative colitis and indeterminate colitis. Diseases of the Colon and Rectum, 1996;39(9):1019–25. 15. Moum B, Ekbom A, Vatn MH, et al. Inflammatory bowel disease: re-evaluation of the diagnosis in a prospective population based study in south eastern Norway. Gut, 1997;40(3):328–32. 16. Meucci G, Bortoli A, Riccioli FA, et al. Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in northern Italy. GSMII (Gruppo di Studio per le Malattie Infiammatorie Intestinali). European Journal of Gastroenterology & Hepatology, 1999;11(8):909–13. 17. Joossens S, Reinisch W, Vermeire S, et al. The value of serologic markers in indeterminate colitis: a prospective follow-up study. Gastroenterology, 2002;122(5):1242–7. 18. Mamula P, Telega GW, Markowitz JE, et al. Inflammatory bowel disease in children 5 years of age and younger. The American Journal of Gastroenterology, 2002;97(8):2005–10. 19. Burakoff R. Indeterminate colitis: clinical spectrum of disease. Journal of Clinical Gastroenterology, 2004;38(5 Suppl):S41–3. 20. Black A, Bhayani H, Ryder C, Pugh M, Gardner-Medwin J, Southwood T. Infliximab in the Treatment of Medically Refractory Indeterminate Colitis. Alimentary Pharmacology & Therapeutics, 2003;18(7):741–8. 21. Yu CS, Pemberton JH, Larson D. Ileal pouch-anal anastomosis in patients with indeterminate colitis: long-term results. Diseases of the Colon and Rectum, 2000;43(11):1487–96. 22. McIntyre PB, Pemberton JH, Wolff BG, Dozois RR, Beart RW, Jr. Indeterminate colitis. Longterm outcome in patients after ileal pouch-anal anastomosis. Diseases of the Colon and Rectum, 1995;38(1):51–4. 23. Delaney CP, Remzi FH, Gramlich T, Dadvand B, Fazio VW. Equivalent function, quality of life and pouch survival rates after ileal pouch-anal anastomosis for indeterminate and ulcerative colitis. Annals of Surgery, 2002;236(1):43–8.
9 Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease Shervin Rabizadeh and Maria Oliva-Hemker∗
Introduction Inflammatory bowel disease (IBD) is not just a disorder of one organ system, but rather a multisystemic disease. In addition to the more typical gastrointestinal involvement which can present with symptoms such as abdominal pain, chronic diarrhea, or bloody stools, other organs can be involved as well, including the eyes, skin, joints, kidneys and liver. In fact, these extraintestinal manifestations may become the predominant source of morbidity for a given patient. The pathogenesis of the extraintestinal manifestations, like the etiology of IBD, is unknown. It is postulated that the inflammatory response in IBD patients leads to the inability of the intestine to act as a selective barrier. Hence the uptake of bacterial products or dietary antigens can induce circulating immune complexes or a systemic inflammatory response [1]. Another theory involves the cross-reaction with a bacterial epitope leading to autoimmunity directed against an antigen shared among the intestine, skin, synovium, eye and biliary system [2]. An autoimmune reaction to an isoform of tropomyosin which is expressed in the eye (non-pigmented cilliary epithelium), skin (keratinocytes), joints (chondrocytes), biliary epithelium, and the gut is speculated as the focal point for this theory [3]. Similarly, extraintestinal manifestations may share a common pathway with the bowel disease in that recruitment of mucosal memory and/or effector T cells to various tissues via the expression of endothelial adhesion molecules that are usually restricted to the gut may lead to destruction from the influx of inflammatory cells [4]. There is a strong genetic influence on extraintestinal manifestations with reports of 83% concordance between siblings [5]. The Human leukocytes antigens (HLA) system is postulated as a link between IBD and certain extraintestinal manifestations, especially ocular and articular manifestations [5]. HLA-A2, -DR1, and -DQw5 are more commonly associated with extraintestinal co-morbidities in Crohn patients. On the other hand genotypes HLA-DRB1, -B27, and -B58 are linked with extraintestinal manifestations of ulcerative colitis. Primary sclerosing cholangitis as well as other autoimmune disorders (e.g. celiac disease, autoimmune hepatitis, myasthenia gravis) have been associated with IBD patients with haplotype HLA B8/DR3 while HLA B27 is reported in 50–80% of IBD patients with ankylosing spondylitis [3]. ∗
Division of Pediatric Gastroenterology and Nutrition, The Johns Hopkins University School of Medicine, 600 N Wolfe St., Brady 320, Baltimore, MD 21287-2631, Phone: 410-955-8765, Fax: 410-955-1464, E-mail:
[email protected]
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Table 9.1. Common extraintestinal manifestations of IBD in children and their relative prevalence. Extraintestinal Manifestation
Prevalence
Growth Failure Sacroiliitis Osteoporosis/Osteopenia Peripheral Joint Inflammation Aphthous Lesions Primary Sclerosing Cholangitis Granulomatous Skin Lesion Erythema Nodosum Pyoderma Gangrenosum Uveitis/Episcleritis Ankylosing Spondylitis
++++ ++++ +++ +++ +++ ++* ++ ++ + + +
*Adult Data
The incidence of developing any extraintestinal manifestation in IBD is estimated to be approximately 30% [6]. These manifestations have been classified in various ways such as their relationship with the degree of inflammation of the underlying bowel disease or by the location of the bowel disease, for example, colonic versus small intestinal [7]. Over 130 extraintestinal manifestations have been reported in the literature associated with IBD but fortunately most of these are rare [8]. Several excellent comprehensive reviews are available on the extraintestinal manifestations of IBD [9–13]. This chapter will focus on the more common extraintestinal manifestations found in the pediatric population and present them by the affected system and descending order of prevalence (Table 9.1).
Growth Failure Extraintestinal manifestations of pediatric IBD patients can not be discussed without first mentioning growth failure which is estimated to occur in 30% of children with Crohn disease and in 5–10% with ulcerative colitis [6]. Children can present with an obvious lack of growth such as a height below the 5th percentile for age, or growth changes can be more subtle with a gradual flattening of the child’s height velocity that is only evident upon plotting of multiple height measurements on a growth chart. Some children can have delays in bone maturation and pubertal development. It is important to not merely assume that growth failure is a consequence of gastrointestinal manifestations as decreases in weight and height velocities can precede any clinical evidence of bowel disease [14]. Thus, the concept of viewing growth failure as an independent manifestation of IBD will help health care providers develop a higher index of suspicion for the diagnosis of IBD in children presenting in this manner, even if they do not have gastrointestinal complaints. IBD-associated growth failure could be secondary to deficient nutrient intake, poor digestion and absorption as well as increased metabolic demands, however, the most likely etiology remains chronic caloric insufficiency [15]. Unfortunately, treatment for the IBD, especially with chronic corticosteroids, can have deleterious effects on overall growth and this needs to be weighed against the detrimental effects of the inflammatory process on growth. In addition to consideration of immunomodulator (e.g. 6-mercaptopurine) use earlier in the disease course of pediatric patients, administration of oral or enteral formula feedings should be considered to rehabilitate the growthstunted patient.
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Joint Manifestations Joint inflammation is a commonly seen extraintestinal manifestation of IBD in both adults and children [6]. Arthralgias are a frequent complaint and in fact arthritis occurs in up to a quarter of children with IBD [16]. Similar to most other extraintestinal manifestations, symptoms of joint inflammation may occur before or after the development of bowel disease. Joint manifestations can be divided into an axial form (involvement of the axial spine and sacroiliac joints) and a peripheral form (involvement of larger joints such as the knees, ankles, hips, wrists and elbows). The axial form of joint involvement includes ankylosing spondylitis and sacroiliitis. Ankylosing spondylitis, which is associated with the HLA-B27 antigen, is more commonly associated with ulcerative colitis and occurs in less than 2% of IBD patients. Symptoms include back stiffness, pain, and eventually stooped posture as well as peripheral joint complaints. Almost all of these patients will have involvement in their sacroiliac joints. On the other hand, asymptomatic sacroiliitis is more common with an estimated incidence of 10 to 52% [5]. Sacroiliitis is often not diagnosed especially in its early stages unless sought after with bone scans. Isolated sacroiliitis seems not to be associated with HLA-B27 [3]. Asymptomatic HLA-B27 negative patients with normal spinal mobility do not require specific treatment. Though ankylosing spondylitis has been shown to respond to sulfasalazine in multiple double-blind studies, none of the studies addressed ankylosing spondylitis in IBD patients [17]. In fact, therapy for IBD-related symptomatic axial disease primarily involves physical therapy and an exercise program to stop the progression of any disability and deformation. Peripheral joint inflammation is most frequently reported with Crohn disease and is most typically associated with colonic inflammation although can also be associated with small bowel disease [5]. The patient usually presents with erythema, swelling, and decreased range of motion in an asymmetric pauciarticular pattern. Fortunately, joint deformity is uncommon. The arthritis tends to worsen during times of increasing bowel disease and there is an association with other extraintestinal manifestations such as those of the skin, mouth, and ocular systems. Primary treatment of the bowel inflammation with aminosalicylate medications, corticosteroids or other immunomodulating agents is the first course of action for joint inflammation [6]. Often resolution is achieved with this approach in less than 8 weeks [16]. Treatment with non-steroidal inflammatory agents and cyclooxygenase-2-inhibitors have the potential for gastrointestinal mucosal injury and should be avoided if possible. In refractory cases, consideration is given to methotrexate and intraarticular corticosteroid injections. Recent studies have also shown that infliximab is efficacious in the treatment of spondyloarthropathies such as the articular and musculoskeletal findings in IBD [5].
Bone Disease There has been recent increasing interest in identifying osteopenia and osteoporosis in patients with IBD. In adult populations, the overall prevalence of osteoporosis in IBD is estimated between 4 to 40% with increasing prevalence in older patients [3]. A large population-based adult study reported an osteoporosis prevalence of 15% and relative risk of 1.4 for fractures in IBD patients compared to the general population [18]. Prevalence of osteopenia and osteoporosis in the pediatric population is estimated between 8 to 30% based on several smaller studies [19]. IBD commonly presents during adolescence and young adulthood when bone mass is being rapidly attained. IBD patients have inadequate intake or malabsorption of calcium and vitamin D. Also these patients are potentially prone to low bone mineral density secondary to corticosteroid use, low estrogen states in females, and effect of circulating proinflammatory cytokines [20]. Hence, IBD patients, especially those with Crohn disease, are at higher risk of eventually developing osteoporosis. This can make the patients prone to bone fracture, bone deformities, and chronic pain.
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Diagnosis of osteopenia/osteoporosis is made with dual-energy x-ray absorptiometry (DEXA) which measures bone mineral density in the spine, femoral neck or other bones rapidly and with low amounts of radiation. Treatment with calcium and vitamin D may prevent further deterioration of bone but not necessarily help in recovery of lost bone density. Prevention has not been well studied in IBD patients but it would be prudent to ensure intake of at least the recommended daily requirement for age of calcium and vitamin D, proper exercise, and minimization of corticosteroid usage to maximize the pediatric patient’s potential in achieving an appropriate peak bone mass. Other bone complications in IBD patients are osteonecrosis of the femoral head, hypertrophic osteoarthropathy, and chronic recurrent multifocal osteomyelitis (CRMO). Osteonecrosis of the femoral head is usually associated with patients who have received chronic steroids and have complaints of hip or knee pain. Clubbing or hypertrophic osteoarthropathy is another bone manifestation associated with IBD especially with small intestinal Crohn disease. The etiology, though unknown is postulated to involve increased blood flow to the fingers and hence increased connective tissue growth secondary to circulating cytokine production [6]. Chronic recurrent multifocal osteomyelitis (CRMO), rarely described in children with IBD, is an aseptic inflammatory bone disease that typically affects the long bones and clavicles [21].
Oral Lesions Recurrent aphthous lesions are the most common oral lesions associated with IBD. The reported incidence is approximately 20% of patients with Crohn disease and significantly less in those with ulcerative colitis [8]. Aphthous lesions tend to parallel intestinal disease though they often can predate intestinal symptoms. Other oral lesions can consist of lip swelling, fissures, and gingivitis which can demonstrate granulomas on histology [22]. Orofacial granulomatosis is a rare syndrome with chronic swelling of the lips and lower half of the face combined with oral ulcerations and hyperplastic gingivitis that has been reported in three dozen Crohn cases [23]. Another rare disorder seen in association with ulcerative colitis patients is pyostomatitis vegetans which can present with oral and cutaneous findings in the axillae, genital areas and scalp. The oral lesions consist of multiple neutrophil and eosinophil-filled pustules on erythematous bases which can erode and fuse to form shallow ulcers that have been described as being “snail track” configuration [24]. Treatment of oral lesions is usually reserved for those causing significant discomfort and may involve topical, intralesional or systemic corticosteroids, or aminosalicylate preparations directed at the bowel disease.
Skin Lesions Cutaneous manifestations of IBD can be classified into three principal groups: granulomatous, reactive, and secondary to nutritional deficiency. Granulomatous skin manifestations have the same histological features as the bowel disease and can include perianal and peristomal ulcers and fistulas, oral granulomatous ulcers, and metastatic Crohn disease. The latter is a rare complication that manifests as subcutaneous nodules or ulcers mainly in the lower extremities and on occasion can occur in the genital areas. It appears unrelated to bowel activity and can be treated successfully with corticosteroids, antibiotics, azathioprine, methotrexate, and infliximab [5]. Reactive skin manifestations of IBD include erythema nodosum (Figure 9.1), pyoderma gangrenosum (Figure 9.2), and Sweet’s syndrome. Of all the skin manifestations associated with IBD, erythema nodosum and pyoderma gangrenosum are the most common, however, in the
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pediatric patient, erythema nodosum, which is more commonly associated with Crohn disease than with ulcerative colitis, is encountered more frequently [6]. Erythema nodosum presents as tender, subcutaneous, erythematous nodules, usually on the extremities, especially the lower legs and the majority of patients with this skin manifestation will have associated joint pain or develop arthritis. Children may appear systemically ill with fever. Over days to weeks, the nodules will flatten, turn brown or gray and can be mistaken for bruises. Histologically, erythema nodosum is as a septal panniculitis consisting of a lymphohistiocytic infiltrate. The prevalence in all IBD patients, adult and pediatric, is estimated between 4% and 15% [25]. Exacerbations of erythema nodosum correlate most often with increased intestinal inflammation, hence treatment towards the bowels is considered a primary form of management. Recent reports in children have shown good response to infliximab [25]. Pyoderma gangrenosum is an ulcerating lesion often correlating with exacerbations of the bowel disease however it can persist for long periods while the intestinal inflammation is clinically quiescent. The lesions are often painful and located on the lower extremities. Histopathology reveals endothelial injury with fibrinoid necrosis of blood vessels and marked neutrophilic and lymphocytic infiltrates. Treatment is difficult and patients may require large doses of systemic corticosteroids or immunomodulators as well as topical ulcer care. Infliximab has shown to be effective in refractory cases [5, 25]. Some extreme cases might require skin grafting. Fortunately, pyoderma gangrenosum is a rare extraintestinal manifestation of IBD with a reported incidence of 2% in UC patients and a smaller number in Crohn patients [25]. Sweet’s syndrome is another very rare reactive cutaneous disorder associated with IBD. It is a neutrophilic dermatosis presenting with painful erythematous plaques or nodules often associated with fever and leukocytosis. Usually there is good response to corticosteroids. Nutritional issues, such as trace mineral and vitamin deficiencies, can be common in children with IBD, especially Crohn disease, however skin disorders secondary to these are unusual. There are rare reported cases of acrodermatitis enteropathica, pellagra and scurvy secondary to zinc, niacin, and vitamin C deficiency, respectively.
Figure 9.1. Erythema nodosum, Courtesy of Dr. Edwin King, www.dermatlas.org.
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Figure 9.2. Pyoderma gangrenosum, Courtesy of Dr. Rachel Nussbaum, Johns Hopkins Univeristy.
Eye Lesions The most common eye manifestations of IBD are episcleritis and uveitis [6]. These are often associated with other extraintestinal manifestations, especially arthritis and erythema nodosum. Episcleritis (Figure 9.3), inflammation of the blood-rich episclera, tends to parallel bowel activity. It is often confused with conjunctivitis as the patients present with eye redness and burning. Patients with episcleritis have no impairment of vision and usually respond clinically to topic corticosteroids. If visual impairment is present, the possibility of scleritis, which can occur with protracted intestinal disease, needs to be considered and an emergent evaluation by an ophthalmologist is required to evaluate for retinal detachment or optic nerve swelling. Uveitis, unlike episcleritis, is usually independent of the bowel activity and inflammation. Anterior uveitis involves inflammation of the iris and the ciliary body. Symptoms can include acute or subacute eye pain, headache, photophobia and blurred vision or occasionally decreased vision, however, many patients may be asymptomatic. Complications of uveitis can be serious and include
Figure 9.3. Episcleritis, Courtesy of Dr. Rachel Nussbaum, Johns Hopkins Univeristy.
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iris atrophy, synechiae, pigment deposits, glaucoma, cataracts and permanent visual deficits. Attention must be paid for early signs of uveitis which can include a cellular or proteinaceous exudate of inflammatory cells in the anterior chamber of the eye. An evaluation of 147 children with IBD who had no ophthalmologic complaints revealed a prevalence of uveitis of 6.1% in patients with Crohn disease [26]. Uveitis was not diagnosed in any child with ulcerative colitis. Like scleritis, acute anterior uveitis is an ophthalmologic emergency. Treatment involves covering the eye to reduce pain and photophobia, pupillary dilatation, and the use of topical or systemic corticosteroids.
Liver Disease Liver pathology, including hepatitis, fatty liver, cholelithiasis, amyloidosis and primary sclerosing cholangitis, is found in less than 5% of patients with IBD [6]. Screening with periodic checks of serum aminotransferases, alkaline phosphatase, gamma glutamyltransferase, and bilirubin is necessary as many of the children with liver disease are asymptomatic. Children with IBD are at risk for primary sclerosing cholangitis (PSC) and this is the most common extraintestinal liver manifestation of IBD. PSC is a chronic, fibrosing inflammation of unknown etiology affecting both intra- and extrahepatic bile ducts. Cirrhosis develops after obliteration of the bile duct lumen. PSC is more frequently associated with ulcerative colitis (reported incidence of 2–7% in adult studies) as compared to Crohn disease (reported incidence of 0.7–3.4% in adult studies) [5]. The presenting symptoms are often nonspecific but patients may present with fatigue, anorexia, jaundice, pruritus, and hepatomegaly. Laboratory analysis can reveal a persistent elevation in alanine aminotransferase, alkaline phosphatase and gamma glutamyltransferase. A study of 52 children with PSC, in which 81% also had IBD, suggested that lower platelet count, older age at presentation, and splenomegaly are risk factors associated with a poor outcome [27]. Interestingly, 20% of the children in this series were diagnosed with PSC prior to their diagnosis of IBD. Hence a diagnosis of PSC in a child should lead to an evaluation for IBD. This study’s reported prevalence of IBD in PSC patients is comparable to adult data in which 70% of patients with PSC have ulcerative colitis. Besides laboratory analysis, the work-up for PSC should include a cholangiogram by magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and/or intraoperative cholangiogram. Histology can demonstrate focal concentric (onion skin) edema and fibrosis around intralobular bile ducts and less commonly the pathognomonic fibrous-obliterative cholangitis. Overall the prognosis of PSC tends to be poor. Adults have a reported median survival time of 9-12 years from the time of PSC diagnosis, [5] however, pediatric patients can remain stable for many years without development of cirrhosis [6]. PSC is a risk factor for cholangiocarcinoma as it is reported in 6 to 11% of adult PSC patients [28]. Treatment of PSC with the choleretic agent, ursodeoxycholic acid, has improved symptoms and laboratory markers in small studies [17]. The treatment of choice for patients who develop end stage liver disease from PSC is liver transplantation. Thirty percent of patients in one pediatric series were transplanted or listed for liver transplantation due to rapid progression to cirrhosis or a high-grade extrahepatic biliary stricture [27]. PSC may lead to the development of biliary strictures which may be treated with balloon dilatation and stent placement, or in severe cases, with surgical biliary reconstruction [6]. Unfortunately, PSC does not improve with remission of intestinal inflammation and proctocolectomy does not have a beneficial effect. Other therapeutic agents such as corticosteroids, azathioprine, cyclosporine, and D-penicillamine, have shown no benefit in PSC. Management of end-stage liver disease complications that may arise from PSC is similar to the management of those complications in other forms of liver disease.
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Rare manifestations of liver disease described in both adult and pediatric IBD patients include gallstones, fatty liver, chronic active hepatitis, granulomatous hepatitis, amyloidosis, cholangiocarcinoma (most often related to PSC), and liver abscesses [29]. Patients with Crohn disease are at risk for cholelithiasis due to malabsorption of bile salts from the inflamed terminal ileum. In fact, it is reported to occur in up to 25% of adult Crohn patients [29]. Severely ill patients with poor nutrition and concomitant steroid therapy are at risk for fatty infiltration of the liver. Hepatic abscesses are very rare and have been reported in ∼60 cases [29]. Most of these patients were male and had Crohn disease.
Other Extraintestinal Manifestations Many other systems, listed below, have had reported involvement in IBD but they have been reported to occur in less than 1% of pediatric IBD patients [6]. Hematologic Abnormalities Anemia, thrombocytosis, and leukocytosis are common hematologic abnormalities in IBD patients and can be seen in up to half the patients with active disease [6]. Usually the anemia is secondary to iron, vitamin B12, and folic acid deficiency as well as anemia of chronic disease. The thrombocytosis is postulated to result from circulating inflammatory cytokines that stimulate platelet production. Similarly, leukocytosis can occur as a result of generalized inflammation. On the other hand, patients should be monitored for leucopenia on certain treatment regimens such as 6-mercatopurine. Vascular Patients with IBD have been reported to have a 3 fold increased risk of venous thrombosis compared to matched controls [30]. Interestingly, this increased risk is specific for IBD as it is not seen with other inflammatory conditions such as rheumatoid arthritis or other bowel disorders such as celiac disease. Deep venous thrombosis and pulmonary embolism are the most common complications resulting from an overall increased coagulation in IBD patients. Coagulation factors may be elevated as part of an acute phase response. Factor V Leiden, a genetic disorder characterized by an impaired anticoagulant response to protein C leading to a prothrombotic state, may be increased in Crohn patients [30]. Furthermore, IBD patients might have higher levels of homocysteine, which can be a potential cause of thrombosis [30]. Another vascular complication, arteritis of small or large vessels, has been reported in children with IBD [31]. Pancreatitis Most commonly, pancreatitis in patients with IBD appears to be associated with medications such as 5-aminosalicylate preparations or 6-mercaptopurine. As this is presumed to be an idiosyncratic reaction discontinuation of the medication is indicated. However, IBD patients appear to have a small increased risk for idiopathic pancreatitis. Although pancreatic autoantibodies have been found in up to 40% of Crohn patients their significance remains unclear. In one series, patients with Crohn who were pancreatic antibody positive had a higher rate of pancreatic exocrine insufficiency than those who were antibody negative [3]. Furthermore, chronic pancreatitis has also been reported in a series of six adult IBD patients, five of whom had changes on pancreatic pathology samples [32].
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Renal IBD patients, especially those with extensive ileal disease or ileal resection with significant fat malabsorption or fluid losses, are at risk for developing calcium oxalate and uric acid stones. Glomerulonephritis with immune complex deposition can also be seen which can progress to severe renal disease. Other renal diseases, described in children with IBD, include renal artery stenosis, amyloidosis leading to renal failure, ureteral compression and perinephritic abscesses secondary to abscesses or inflammation surrounding the terminal ileum [33]. Pulmonary Pulmonary manifestations associated with IBD, including reactive airway disease, bronchitis, bronchiectasis, tracheal obstruction, granulomatous lung disease, interstitial or hypersensitivity pneumonitis, and bronchiolitis obliterans are being reported at an increasing frequency [3, 6, 34–36]. However, the latter two have been associated with 5-aminosalicylate products and methotrexate used in the treatment of IBD [3, 36]. Similar to other extraintestinal manifestations, pulmonary disease can predate the bowel disease by months or years. Most pulmonary manifestations respond to corticosteroids via an inhaled, oral, or intravenous route. Neurologic Peripheral nerve disorders, myopathy, multiple sclerosis, optic neuritis, and epilepsy have been described in IBD patients [37]. A retrospective cross-sectional study of adult patients with IBD reported an odds ratio of 1.67 for developing multiple sclerosis, optic neuritis, or a demyelinating disorder [3]. Cardiac Rarely children with IBD can develop myopericarditis and pleuropericarditis with symptoms of chest pain and dyspnea. Cardiac manifestations are not necessarily associated with active bowel disease and respond to corticosteroids and nonsteroidal anti-inflammatory agents, which need to be used with caution in IBD patients.
Summary Crohn disease and ulcerative colitis are associated with numerous extraintestinal manifestations. It is clearly evident that IBD is a multi-systemic disease that stretches beyond the gastrointestinal tract. Knowledge about extraintestinal manifestations is critical as patients can present with these instead of the classical bowel symptoms. Furthermore, these extraintestinal manifestations of IBD are a cause of major morbidity in patients and need to be considered and addressed at all points of care. References 1. Levine JB, Lukawski-Trubish D. Extraintestinal considerations in inflammatory bowel disease. Gastroenterol Clin North Am 1995;24:633. 2. Bhagat S, Das KM. A shared and unique peptide in the human colon, eye, and joint detected by a monoclonal antibody. Gastroenterology 1994;107:103. 3. Rothfuss KS, Stange EF, Herrlinger KR. Extraintestinal manifestations and complications in inflammatory bowel disease. World J Gastroenterol 2006;12:4819. 4. Adams DH, Eksteen B. Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease. Nat Rev Immunol 2006;6:244.
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5. Danese S, Semeraro S, Papa A, Roberto I, Scaldaferri F, Fedeli G, Gasbarrini G, Gasbarrini A. Extraintestinal manifestations in inflammatory bowel disease. World J Gastroenterol 2005;11:7227. 6. Oliva-Hemker M. More than a gut reaction: Extraintestinal complications of IBD. Contemporary Pediatrics 1999;16:45. 7. Lichtman SN, Sartor RB: Extraintestinal manifestations of inflammatory bowel disease: clinical aspects and natural history. In Targan S and Shanahan F (eds): Inflammatory Bowel Disease: From Bench to Bedside, Baltimore, MD, Williams and Wilkins, 1994. 8. Hyams JS. Extraintestinal manifestations of inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr 1994;19:7. 9. Kethu SR. Extraintestinal manifestations of inflammatory bowel disease. J of Clinical Gastroenterology 2006;40: 467. 10. Urlep D, Mamula P, Baldassano R. Extraintestinal manifestations of inflammatory bowel disease. Minerva Gastroenterologica e Dietologica 2005;51:147. 11. Loftus EV. Management of extraintestinal manifestations and other complications of inflammatory bowel disease. Current Gastroenterology Reports 2004;6:506. 12. Hoffmann RM, Kruis W. Rare extraintestinal manifestations of inflammatory bowel disease. Inflammatory Bowel Diseases 2004;10:140. 13. Su CG, Judge TA, Lichtenstein GR. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterology Clinics of North America 2002;31:307. 14. Kanof ME, Lake AM, Bayles TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn disease. Gastroenterology 1988;95:1523. 15. Oliva MM, Lake AM. Nutritional considerations and management of the child with inflammatory bowel disease. Nutrition 1996;12:151. 16. Passo MH, Fitzgerald JF, Brandt KD. Arthritis associated with inflammatory bowel disease in children— relationship of joint disease to activity and severity of bowel lesion. Dig Dis Sci 1986;31:492. 17. Juillerat P, Mottet C, Froehlich F, Felley C, Vader J, Burnand B, Gonvers J, Michetti P. Extraintestinal manifestations of Crohn disease. Digestion 2005;71:31–36. 18. Bernstein CN. Osteoporosis and other complications of inflammatory bowel disease. Current Opinion in Gastroenterology 2002;18:428. 19. Gokhale R, Favus MJ, Karrison T, et al. Bone mineral density assessment in children with inflammatory bowel disease. Gastroenterology 1998;114:902 20. Hyams JS, Wyzga N, Kreutzer, et al. Alterations in bone metabolism in children with inflammatory bowel disease: an in vitro study. J Pediatr Gastroenterol Nutr 1997;24:289. 21. Bousvaros A, Marcon M, Treem W, Waters P, Issenman R, Couper R, Burnell R, Rosenberg A, Rabinovish E, Kirschner B. Chronic recurrent multifocal osteomyelitis associated with chronic inflammatory bowel disease in children. Digestive Diseases and Science 1999;44:2500–07. 22. Plauth M, Jenss H, Meyle J. Oral manifestations of Crohn disease. J Clin Gastroenterol 1991;13:29. 23. Grilich C, Bogenrieder T, Palitzsch KD, Scholmerich J, Lock G. Orofacial granulomatosis as initial manifestation of Crohn disease: a report of two cases. European Journal of Gastroenterology & Hepatology 2002;13:873–76. 24. Storwick GS, Prihoda MB, Fulton RJ, et al. Pyodermatitis-pyostomatitis vegetans: a specific marker for inflammatory bowel disease. J Am Acad Dermatol 1994;31:336. 25. Kugathasan S, Miranda A, Nocton J, Drolet BA, Raasch C, Binion DG. Dermatologic manifestations of Crohn disease in children: response to infliximab. J of Pediatr Gastroenterol Nutr 2003;37:150–154. 26. Hofley P, Roarty J, McGinnity G, et al. Asymptomatic uveitis in children with chronic inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993;17:397. 27. Feldstein AE, Perrault J, El-Youssif M, et al. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology 2003;38:210 28. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 2000;31:7. 29. Margalit M, Elinav H, Ilan Y, Shalit M. Liver abscess in inflammatory bowel disease: report of two cases and review of the literature. J of Gastroenterology and Hepatology 2004;19:1338. 30. SriRajaskanthan R, Winter M, Muller AF. Venous thrombosis in inflammatory bowel disease. Eur J of Gastroenterology and Hepatology 2005;17:697.
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31. Mader R, Segol O, Adawi M, Trougoboff P, Nussinson E. Arthritis or vasculitis as presenting symptoms of Crohn disease. Rheumatol Int 2005;25:401–05. 32. Barthet M, Hastier P, Bernard JP, et al. Chronic pancreatitis and inflammatory bowel disease: true or coincidental association? Am J Gastroenterol 1999;94:2141–8 33. Kuzmic AC, Kolacek S, Brkljacic B, Juzjak N. Renal artery stenosis associated with Crohn disease. Pediatr Nephrol 2001;16:371–73. 34. Camus P, Piard F, Ashcroft T, et al. The lung in inflammatory bowel disease. Medicine 1993;72:151. 35. Al-Binali AM, Scott B, Al-Garni A, Montgomery M, Robertson M. Granulomatous pulmonary disease in a child: an unusual presentation of Crohn disease. Pediatr Pulmonol 2003;36:76–80. 36. Haralambou G, Teirstein AS, Gil J, Present D. Bronchiolitis obliterans in a patient with ulcerative colitis receiving mesalamine. Mt Sinai J Med 2001;68:384–88. 37. Lossos A, River Y, Eliakim A, et al. Neurologic aspects of inflammatory bowel disease. Neurology 1995;45:416.
10 Growth Impairment in Pediatric Inflammatory Bowel Disease Thomas D. Walters and Anne M. Griffiths∗
Introduction The clinical course and severity of inflammatory bowel disease (IBD) vary widely in children and in adults [1, 2]. Unique to pediatric patient populations, however, is the potential for linear growth impairment as a complication of chronic intestinal inflammation. The challenge in treating each child or adolescent is to employ pharmacologic, nutritional, and where appropriate surgical interventions, to not only decrease mucosal inflammation and thereby alleviate symptoms, but also to optimize growth and normalize associated pubertal and social development. Indeed, normal growth is a marker of therapeutic success. This chapter reviews the prevalence of growth impairment in pediatric IBD, discusses its pathophysiology, and outlines strategies for its prevention and management.
Normal Growth and Pubertal Development “Normal” children grow at very different rates. Patterns of growth and pubertal progression in young patients with IBD can only be accurately recognized as pathologic, if the variations in normal development of healthy children and adolescents are first appreciated. A child’s growth is the result of both genes and environment; it appears principally mediated by hormones and nutrition [3]. Linear growth can be represented by stature (attained height) or by the rate of growth (height velocity). A child’s attained height represents the culmination of growth in all preceding years; height velocity reflects growth status at a particular point in time. Growth can be conceptualized as the product of three overlapping biological phases: infancy, childhood, and puberty. Final height represents the sum of each of the individual components. The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis plays a pivotal role in normal postnatal growth. IGF-1 stimulates mitosis of epiphyseal chondrocytes resulting in linear bone growth [4]. Thyroxine, cortisol and sex steroids are also implicated in the maintenance of normal linear growth. Linear growth velocity decreases from birth onwards, punctuated by a short period of growth acceleration (the “adolescent growth spurt”) just prior to completion of growth. As the rapid
*Anne M. Griffiths MD, FRCP(C), Professor of Paediatrics, Division of Gastroenterology/Nutrition, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada, Phone: 416-8137734, Fax: 416-813-6531, E-mail:
[email protected]
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growth of infancy tails off, the steady growth of childhood predominates. Healthy children grow at a consistent rate in the range of 4 to 6 centimeters annually from six years of age until the onset of puberty [5]. At puberty there is a rapid alteration in body size, shape and composition; for a year or more height velocity approximately doubles. The age of onset of puberty, and hence of the pubertal growth spurt, vary among normal individuals and between ethnic populations. Puberty begins earlier in girls than in boys; moreover the pubertal growth spurt occurs in mid-puberty (prior to menarche) in girls but in late puberty (after Tanner stage 4) in boys [5]. There is hence quite consistently a two year difference in the timing of peak height velocity (PHV) in girls compared to boys [5]. In North American females PHV occurs at a mean age of 11.5 years but in males not until 13.5 years (2SD = 1.8 years) [5]. The occurrence of menarche is an indication that linear growth is nearing completion; usually girls gain only 5 to 8 cm more in height within the two subsequent years [5]. Monitoring and Assessment of Growth Standardized charts are available for graphically recording height, weight and height velocity such that an individual child’s growth can be compared to normative values [6–8]. Wherever possible, reference data most appropriate to the child being monitored should be utilized. An individual child’s growth measurement can be represented as a percentile or as a standard deviation score, a quantitative expression of distance from the reference population mean (50th percentile) for the same age and gender [9]. Healthy children grow steadily along the same height percentile and hence maintain the same standard deviation score for height from early childhood through until adulthood. Combined parental heights can be used to estimate a child’s potential height [9]. Some temporary deviation from the usual growth channel may occur if the pubertal growth spurt occurs particularly early (temporary increase in height velocity and height centile) or late (temporary decrease in height velocity and height centile). Definitions of Impaired Growth Within a large patient group, skewing of standard deviation scores (SDS) for height below population reference values is evidence of disease-associated growth impairment. Mean height SDS of a population characterized by normal growth approximates zero. Growth disturbance in an individual child is indicated by an abnormal growth rate [9]. A definition in terms of static height measurement, although sometimes used, may be misleading, since it is so influenced by parental heights. An individual child may be normally short; conversely a previously tall child may not have increased his height in two years, but still be of average stature. A shift from higher to lower centiles on a growth chart of height attained more sensibly signifies growth faltering. Height velocity, expressed either as a centile or as a standard deviation score for age and gender, is the most sensitive parameter by which to recognize impaired growth.
Growth in Pediatric IBD Prevalence of Growth Impairment in IBD Inflammatory disease occurring during early adolescence is likely to have a major impact on nutritional status and growth because of the very rapid accumulation of lean body mass that normally occurs at this time. Further, boys are more vulnerable to disturbances in growth than girls because their growth spurt comes later and is ultimately longer and greater [5].
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Crohn Disease Several studies have characterized the growth of children with Crohn disease as treated in the 1980’s and into the 1990’s [1,10–15]. These studies are important as a benchmark of outcomes with traditional therapy. It is to be hoped that the now better understanding of the pathogenesis of growth impairment, together with the greater efficacy of current therapeutic regimens in healing intestinal inflammation, may lead to enhanced growth of young patients diagnosed in the present decade. As summarized in Table 10.1, the percentage of patients with Crohn disease, whose growth is affected, varies with the time of assessment, the definition of growth impairment and with the nature of the population under study (tertiary referral center versus population-based) [1,10–19]. It has nevertheless been consistently observed that impairment of linear growth is common prior to recognition of Crohn disease as well as during the subsequent years, and that height at maturity has often been compromised [1,10–19]. At the time of diagnosis mean standard deviation score (SDS) for height is reduced among children with Crohn disease as a group compared to reference populations (Table 10.2), an indication of the growth retardation occurring prior to recognition and treatment of intestinal inflammation [1,11,12,15–17]. During the decade 1990–1999 in Toronto, mean SDS for height at time of diagnosis among 161 Tanner stage 1 or 2 children was –0.74 +/– 1.2, [15] indicating overall lesser growth delay in comparison to the earlier decade [1]. Nevertheless the percentage of children with height less than the 5th centile (SDS score < –1.8), based on Center for Disease Control 2000 data, was still 22% [15]. Mean SDS for height among 333 patients aged less than 16 years was –0.54 (95% CI –0.67 to –0.41) in a 1998–1999 population-based surveillance study of incident IBD in the United Kingdom [16]. Thirteen percent were below the third centile (SDS < –1.96) for height based on data from Child Growth Foundation, London [16]. In Israel SDS for height at diagnosis among a cohort of 93 patients aged less than 18 years was –0.56 +/– 1.16, but 20% had SDS score < –2.0 [17]. Taken together these data confirm that growth delay prior to diagnosis still occurs and remains a challenge [15–17]. Delay in epiphyseal closure allows growth to continue longer than normal. Hence mean SDS for height may improve over the course of treatment, when the chronic inflammation can be controlled [1, 12, 15]. No population-based cohort studies have compared pre-illness height centiles with final adult stature in order to determine how often catch-up growth is complete. In spite of gains, mean adult height of patients with prepubertal onset of disease remains reduced compared to population reference data [1, 12, 15, 18, 19]. Studies suggesting otherwise have included patients with post-pubertal onset of disease, and therefore not at risk for growth impairment [20]. Ulcerative Colitis Cohort data are sparse in comparison to Crohn disease, but in general at diagnosis no significant reduction is observed in height-for-age standard deviation scores among young patients with ulcerative colitis compared to the reference population [12, 14, 16]. As an example, SDS for height was not reduced (mean –0.12, 95%CI –0.30 to 0.05) in 143 children and adolescents with incident UC in the British paediatric surveillance study [16]. In follow-up growth impairment remains a less frequent complication, although relatively few studies have carefully described linear growth in ulcerative colitis as compared to the abundance of studies in Crohn disease. Hildebrand et al. observed that 11 (24%) of 45 children had a height velocity < –2.0 SD during at least one year [12]. Final attained mean height was comparable to reference population data in this study [12]. Why linear growth impairment is less common in ulcerative colitis than in Crohn disease is not entirely clear. The usual colitic symptom of bloody diarrhea is more promptly investigated than
Table 10.1. Prevalence of linear growth impairment in pediatric Crohn disease. Varying definitions and times of assessment (at the time of diagnosis and during follow-up) are applied. Study Details [ref] Baltimore, USA 1961 to 1985 [11] Toronto, Canada 1980 to 1988 [1] Sweden 1983 to 1987 [12] New York, USA 1979 to 1989 [13] Toronto, Canada 1990 to 1999 [15] United Kingdom 1998 to 1999 [16] Israel 1991 to 2003 [17]
Time of assessment
Patients studied
n
Definition of linear growth impairment
At diagnosis
Prepubertal (Tanner I or II)
50
During follow-up
Prepubertal (Tanner I or II)
100
During follow-up
Population-based cohort <16yrs at Dx
46
At Maturity
Children in Tertiary Care
38
During follow-up
Prepubertal (Tanner I or II)
161
At Diagnosis
Population-based cohort <16yrs at Dx
338
Decrease in height velocity prior to diagnosis Height velocity ≤ 2 SD for age for ≥ 2 years Height velocity ≤ 2 SD for age for 1 year Failure to reach predicted adult height Height velocity ≤ 2 SD for age for ≥ 2 years Height SDS < –1.96
At Diagnosis
Children in Tertiary Care
93
Height SDS < –2.0
Percentage with growth impairment 88% 49% 65% 37% 54% 13% 20%
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Table 10.2. Mean Height Standard Deviation scores for height in children diagnosed with Crohn disease prior to or in early puberty (Tanner stage I or II). Study [ref]
Baltimore, USA 1961 to 1985 [11] Toronto, Canada 1980 to 1988 [1] Sweden 1983 to 1987 [12] Toronto, Canada 1990 to 1999 [15] United Kingdom 1998 to 1999 [16] Israel 1991 to 2003 [17] Leiden, The Netherlands Reported in 2002 [19] London, UK 1996 to 2002 [18]
Patients studied
N
Mean Height SDS (SD) At diagnosis
At maturity
Prepubertal (Tanner I or II)
50
–0.48
Not assessed
Prepubertal (Tanner I or II)
100
–1.1 (1.3)
–0.82 (1.1)
Population-based cohort <16yrs at Dx
46
–0.5 (1.4)
–0.4 (1.1)
Prepubertal (Tanner I or II)
161
–0.74 (1.2)
–0.70 (1.2)
Population-based cohort <16yrs at Dx
338
–0.54
Not assessed
Children in Tertiary Care
93
–0.56 (1.16)
Not assessed
Children in Tertiary Care
64
Not reported
–0.9 (1.2)
Prepubertal Children in Tertiary Care
20
Not reported
–0.57 (0.3)
the often subtle presenting symptoms of Crohn disease, accounting at least in part for the lesser effect on growth prior to diagnosis. Disease-related differences in cytokine production may also be important.
Pathophysiology of Growth Impairment in IBD As summarized in Table 10.3, several interrelated factors contribute to linear growth impairment in children with IBD. The fundamental mechanisms have recently been comprehensively reviewed [21]. Chronic Caloric Insufficiency Chronic undernutrition has long been implicated and remains an important and remediable cause of growth retardation [22]. Multiple factors contribute to malnutrition. However, reduced intake, rather than excessive losses or increased needs, is the major cause of the caloric insufficiency. Kirschner et al. reported caloric intakes of growth-impaired patients to average 54% of that recommended for children of similar height age [23]. Disease-related anorexia may be profound. Cytokines produced by the inflamed bowel are likely responsible. Work in a rat model of colitis suggests that tumour necrosis factor alpha (TNF-alpha) interacts with hypothalamic appetite pathways [24]. Significant intestinal fat malabsorption is uncommon, [25] but leakage of protein is frequent [26]. In general, resting energy expenditure (REE) does not differ from normal in patients with inactive disease, but can exceed predicted rates in the presence of fever and sepsis. Furthermore, in comparison to comparably malnourished patients with anorexia nervosa, a lack of compensatory reduction in REE has been described in adolescents with Crohn disease [27]. Reduction in REE is a normal biologic response to conserve energy. Production of inflammatory mediators may explain the lack of REE adaptation in patients with Crohn disease, and further augment the ongoing malnutrition.
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Table 10.3. Factors contributing to growth impairment in children with Crohn disease. Factor Pro-inflammatory cytokines Decreased food intake Stool losses Increased nutritional needs Corticosteroid treatment
Explanation Direct interference with IGF-1 mediation of linear growth Cytokine-mediated anorexia, fear of worsening gastrointestinal symptoms Mucosal damage leading to protein-losing enteropathy; diffuse small intestinal disease or resection leading to steatorrhea Fever; required catch-up growth Interference with growth hormone and insulin-like growth factor-1
Direct Cytokine Effects A simple nutritional hypothesis fails to explain all the observations related to growth patterns among children with IBD. Within the past decade the direct growth-inhibiting effects of proinflammatory cytokines released from the inflamed intestine have been increasingly recognized and are now the focus of intriguing research [28–31]. IGF-1, produced by the liver in response to growth hormone (GH) stimulation, is the key mediator of GH effects at the growth plate of bones. GH binds to hepatic GH receptors (GHR) and activates JAK2 kinase. This in turn leads to the phosphorylation and nuclear translocation of signal transducer and activator of transcription (STAT) protein 5, resulting in the upregulation of anabolic target genes including IGF-1 and acid labile subunit (ALS) [32–34]. Most IGF-1 circulates as a 150kDa ternary complex composed of IGF-1, IGF-binding protein 3 (IGFBP-3) and an acid-labile subunit (ALS) [35]. This complex significantly increases the half-life of IGF-1 [35]. An association between impaired growth in children with Crohn disease and low IGF-1 levels is well recognized [36]. However, GH production in this setting has been shown to be normal [37]. The molecular mechanisms by which cytokines induce this state of “GH resistance” have not yet been completely elucidated. Conceptually, they could involve downregulation of the GH receptor (GHR), up-regulation of post-receptor inhibitory proteins, reduced protein synthesis and/or increased protein degradation. Information from animal models supports each of these potential mechanisms. TNF-alpha has been demonstrated to down regulate GHR formation [38]. Suppressors of cytokine signaling (SOCS) proteins are cytokine/growth factorinducible post-receptor inhibitors of cell signaling that mediate their effect via the JAK/STAT pathway [39]. Interleukine-6 and TNF-alpha can upregulate the expression of SOCS-3 and cytokine-inducible SH2-containing protein (CIS)1 [34, 40]. Both of these proteins have, in turn, been shown to inhibit GH signaling by blocking the phosphorylation of STAT5 [39, 41, 42]. Interleukine-1 (IL-1), on the other hand, has been shown to reduce IGF-1 mRNA levels, but does not appear to do so by either upregulation of SOCS nor by impairment of JAK2/STAT5 signaling [43]. Early studies emphasized the role of malnutrition in suppression of IGF-1 production [36]. Recently transgenic mice with defective growth were found to over-express interleukin-6 (IL-6). Antibody to IL-6 partially corrected the growth defect, whereas administration of IL-6 led to a decrease in IGF-1 before food intake was affected [28]. Further, IGF-1 levels were negatively correlated with IL-6 among children with juvenile rheumatoid arthritis [28]. The exact mechanism for this observation, however, is not clear. Whilst these, and other data, [44] suggest an IL-6 mediated decrease in IGF-1 production; [28] more recent work by DeBenedetti et al. suggests the primary mechanism is a reduction in IGFBP-3 levels due to reduced production and/or increased proteolysis [45]. Previously, low levels of IGFBP-3 have been associated with accelerated clearance, and hence low levels, of IGF-1 [45].
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The relative contributions of malnutrition and inflammation to linear growth delay have been recently explored by Ballinger et al. using a rat model of TNBS colitis [29]. Two control groups were used: healthy controls with free access to food, and a pair-fed group comprised of healthy animals with daily food intake restricted to match that of colitic rats [29]. In the colitic rats IGF-1 levels were reduced to 35% of control values. Comparison with the healthy but undernourished pair-fed rats, suggested that malnutrition accounted for 53% of the total depression of IGF-1 in colitic rats, with the remaining 47% attributable to inflammation [29]. There is evidence that inflammatory cytokines also inhibit linear growth through pathways other than IGF-1 production. Animal experiments have shown that TNF- and interleukin-1 (IL-1) increase chondrocyte death and thus may have a deleterious effect on growth [30]. In an organ culture model of fetal rat parietal bone, marked impairment in osteoblast function and bone growth was observed with addition of serum from children with Crohn disease, but not from children with ulcerative colitis, nor from healthy controls [31]. Cytokines appear to impair end-organ responsiveness to circulating testosterone, thereby compounding the effects of undernutrition in delaying progression through puberty [46]. Corticosteroid-suppression of Linear Growth Chronic daily corticosteroid administration in children augments the growth impairment associated with inflammatory disease. The growth suppressive effects of glucocorticoids are multifactorial and include: central suppression of GH release; decreased hepatic transcription of GH receptor, such that production of IGF-1 is decreased; and decreased IGF-1 binding in cartilage [47]. Hence exogenous corticosteroids create a state of functional GH deficiency [47]. Endocrine Mediators of Growth Impairment It is evident from the above discussion that reduced plasma concentrations of IGF-1, as a result of inflammatory cytokines and/or malnutrition and/or exogenous corticosteroids, play a central role in mediating growth impairment in IBD. GH levels in response to provocative testing are normal [37]. Thyroid gland function is normal. Sex steroids may play a role in the delayed pubertal growth spurt. Influence of Genetic Factors Russell et al. [48] and Tomer et al. [49] have both suggested that NOD2/CARD15 polymorphisms may be determinants of growth impairment, but neither analysis controlled for disease location, the phenotypic characteristic clearly influenced by NOD2/CARD15 [50]. A subsequent careful analysis of growth prior to and following diagnosis found no association of growth impairment with the three common Crohn disease associated NOD2/CARD15 polymorphisms [17]. Recent Scottish paediatric data suggest an association of the IBD5 susceptibility locus with low anthropometric centiles at diagnosis [51]. Given the role of inflammatory mediators in growth, it is feasible that common genetic polymorphisms which alter cytokine expression may contribute to growth impairment, rather than influencing disease susceptibility. A recent study of Israeli patients suggests that relatively common variations in the promoter region for TNF- may have an independent effect on linear growth outcomes [52]. Similarly, data from Sawczenko et al. demonstrate a potential causal relationship between variation in the promoter region for IL-6, subsequent IL-6 expression, and a differential in linear growth impairment during active inflammation [44]. Confirmation of these and similar findings are awaited, and may help better elucidate the complex molecular interactions pertinent to the pathophysiology of growth impairment.
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Facilitation of Normal Growth in IBD The Importance of Prompt Recognition of IBD The clinical presentation of childhood Crohn disease may be subtle and varied. Impairment of linear growth and concomitant delay in sexual maturation may precede the development of intestinal symptoms and dominate the presentation. Prompt diagnosis is important in avoiding a long period of growth retardation. The greater the height deficit at diagnosis, the greater is the demand for catch-up growth. The Importance of Monitoring Growth In caring for children with IBD, it is important to obtain pre-illness heights, so that the impact of the chronic intestinal inflammation can be fully appreciated. Following diagnosis and institution of treatment, regular measurement and charting of height, together with calculation of height velocity, are central to management. A properly calibrated wall-mounted stadiometer is required for accurate and reproducible serial measurements. Part of the assessment of response to therapy in children with IBD is a regular analysis of whether rate of growth is normal for age and pubertal stage and whether catch-up growth to pre-illness centiles is being achieved. Height velocity should be appraised in the context of current pubertal stage, because of the variation in normal rates of growth before puberty, during puberty and near the end of puberty. If growth and puberty appear either delayed or very advanced, radiologic determination of bone age can be used to indicate the remaining growth potential. One of the difficulties in evaluating growth in response to a therapy is the relatively long interval of time required for valid assessment. Published normal standards for height velocity throughout childhood are based on height increments during twelve month periods [53]. When growth velocity is calculated over short time periods, small errors in individual measurements are significantly magnified, and the normal seasonal variation in growth is overlooked. The consensus from paediatric endocrinologists is that height velocity should be calculated over intervals no shorter than six months [53]. On a research basis, efforts to reflect growth changes over intervals shorter than six months have focused on measuring changes in lower leg length by knemometry and on determination of circulating levels of markers of collagen metabolism [53]. A valid indicator of anticipated linear growth would allow more timely change in therapy. Psychosocial Impact of Impaired Growth Growth impairment and accompanying pubertal delay have a significant psychosocial impact on adolescents, as the physical differences between them and healthy peers become progressively more obvious. In the development process of a disease-specific health related quality of life instrument for pediatric IBD, body image issues including height and weight were among the concerns most frequently cited by adolescents with Crohn disease [54].
General Principles of Management Prior to recognition of the direct influences of pro-inflammatory cytokines on linear growth, management of growth-impaired children focused on nutritional restitution [22, 23]. Improved growth following supplementary enteral or parenteral nutrition is well documented [55–57], but the relative contribution of improved nutrition versus reduced inflammation is uncertain and may vary between patients. A recent study demonstrated that decrease in inflammatory parameters and increase in IGF-1 occurred very early during exclusive enteral nutrition and preceded changes in nutritional parameters [58]. Moreover, a subset of patients fails to grow despite nutritional
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repletion, because intestinal inflammation remains chronically active. In the management or prevention of growth impairment attention needs to focus on treatment of inflammatory disease using the most appropriate pharmacologic, nutritional or surgical intervention [59]. Separation of anti-inflammatory and nutritional effects is somewhat artificial, moreover, because of the important interactions between cytokines and nutrition. Nutrition and inflammation constitute a bi-directional pathway [60]. Treatments of paediatric IBD will be briefly discussed with respect to their effects on growth. Anti-inflammatory Treatments and Effects on Growth Few interventions have been tested in the randomized controlled trial setting in children, and hence the effects of therapies on growth have seldom been rigorously assessed. The one exception is enteral nutrition as primary therapy of paediatric Crohn disease. For most other therapies, growth outcomes have been reported only in observational studies. To date, the key different in management of IBD in children and young adolescents compared to adults have included greater attention to avoidance of longterm corticosteroid therapy, more frequent use of enteral nutrition as an alternate primary therapy in Crohn disease, and earlier consideration of resection of localized Crohn disease and steroid-dependent ulcerative colitis [59]. These strategies are all aimed at optimizing growth prior to completion of puberty. New biologic therapies, particularly anti-TNF alpha have brought the management of Crohn disease into a new era. Children whose disease remains chronically active despite use of immunomodulatory drugs now benefit from such therapy. Ongoing monitoring of long-term safety issues will determine whether infliximab and other biologic agents in future should have a special place in paediatric treatment regimens in order to improve disease-related outcomes including growth and quality of life. Enteral Nutrition Prior to availability of infliximab, acute treatment options for moderately to severely active Crohn disease were limited. The appeal of enteral nutrition as primary therapy among paediatric patients, relates to avoidance of steroids, both because of their unwanted cosmetic side effects and their propensity to interfere with growth [59]. Aminoacid based and peptide-based formulae are administered by nocturnal nasogastric infusion, but more palatable polymeric formulae can be consumed orally, and appear comparably efficacious [61]. Open trials in children have documented endoscopic healing and decreased mucosal cytokine production following exclusive enteral nutrition [62]. Some have argued that active Crohn disease occurring in children is more responsive than that occurring in adults, where corticosteroid therapy more often induces clinical remission [63, 64]. It seems likely, however, that other factors, such as small bowel localization and recent onset of Crohn disease, rather than young age per se, influence responsiveness of intestinal inflammation to exclusive enteral nutrition [65, 66]. Nevertheless, enteral nutrition does seem to be more feasible in paediatric patients. Children quickly become adept at swallowing the silastic catheter required for nasogastric feeding regimens, and can remove it each morning before school. If enteral nutrition is to facilitate growth, remission must be maintained. One of the limitations of liquid diet therapy has been the observed tendency for symptoms to recur promptly following its cessation [67]. Chronic intermittent bowel rest with nocturnal infusion of an elemental diet one month out of four was reported as a means of sustaining remission and facilitating growth [56]. In a multi-centre Canadian paediatric study, children achieving clinical remission with either prednisone or enteral nutrition, were randomized to receive long-term either low dose (0.3 mg/kg) prednisone on alternate days or exclusive enteral nutrition one month out of four [68]. In the eighteen month study, 67% of the children treated with cyclical enteral nutrition remained in
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continuous clinical remission compared with 47% of those receiving alternate day prednisone [68]. Although this difference in relapse rate was not statistically significant in the total of 35 patients studied, linear growth was significantly better in the children receiving liquid diet therapy [68]. Another nutritional strategy, continuation of nocturnal nasogastric feeding four to five times weekly as supplement to an unrestricted ad lib daytime diet was also associated with prolonged disease quiescence and improved growth in a historical cohort study [57]. Corticosteroids Conventional corticosteroids are still the most commonly used drug to treat acute disease exacerbations of paediatric Crohn disease and ulcerative colitis. Resolution of inflammation, if sustained following a short course of steroids, will be associated with normal linear growth. Chronic daily administration of corticosteroids to control intestinal inflammation is clearly contraindicated in paediatric IBD because of the interference with linear growth in addition to the other unwanted long-term adverse effects common to children and adults. Alternate day administration was long ago advocated as a means of controlling inflammation in Crohn disease without suppression of IGF-1 [69]. This strategy, inferior to cyclical enteral nutrition [68], has been abandoned in favour of other therapeutic approaches to corticosteroid dependency in children with Crohn disease. Because of the limited other medical options, it may be reasonable to employ low dose alternate day prednisone for a limited time period in some children with steroid-dependent ulcerative colitis, as long as linear growth rate is carefully monitored and found to be maintained. Children with moderate symptoms of active Crohn disease localized to the ileum and/or right colon may respond to short-term treatment with controlled ileal release budesonide. Cosmetic effects of steroids are spared in this context, even if efficacy is overall less than with conventional corticosteroids [70, 71]. Studies in adults demonstrate little benefit in comparison to placebo in maintaining remission. Limited clinical experience with maintenance budesonide in children raised concern that linear growth was impaired during therapy in spite of good weight gain [72]. Azathioprine and 6-Mercatopurine The immunomodulatory drugs, azathioprine and 6-mercaptopurine, are increasingly used to maintain remission in children and adolescents with Crohn disease, a reflection of the increased body of evidence in support of both their therapeutic efficacy and safety profile. In a multi-centre trial newly diagnosed children with moderately severe Crohn disease treated with an initial course of prednisone were randomized to receive either concomitant 6-mercaptopurine or placebo [73]. A beneficial effect on linear growth was not clearly apparent in this study in spite of the steroidsparing effect and improved control of intestinal inflammation, perhaps a function of sample size and difficulties inherent in comparing growth rates among patients of varying ages and pubertal stages [53]. Level one evidence of efficacy of azathioprine/6-mercaptopurine in ulcerative colitis has been relatively sparse even in adult patients, but is accumulating [74]. In clinical practice immunomodulatory drugs are also employed in children whose ulcerative colitis remains steroid dependent despite optimization of 5-aminosalicylic acid or sulfasalazine therapy. Surgery Optimal management of young patients with IBD includes appropriate and timely referral for intestinal resection. Sustained steroid-dependency and associated impairment of linear growth should not be tolerated in children with ulcerative colitis, where colectomy cures the disease and restores growth [75]. For children with Crohn disease, the possibility of a significant asymptomatic interval, during which normal growth and pubertal development can resume, makes intestinal resection an attractive therapeutic option, despite the likelihood of eventual disease recrudescence.
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In three paediatric studies, anatomic distribution of Crohn disease was the most important factor influencing duration of post-operative clinical remission [76–78]. Patients with extensive ileocolonic involvement experienced an excess of early clinical recurrences (50% by 1 year) in comparison to children with pre-operative disease in the terminal ileum +/– right colon or in the more proximal small intestine (50% by 5 years) [76]. Children undergoing resection because of stenosing or fistulizing complications (e.g. bowel obstruction or intra-abdominal abscess) had delayed recrudescence of disease in comparison to those operated upon simply for inflammatory symptoms refractory to medical therapy [76]. An early operative approach to localized disease and for complications of chronic inflammation is supported by these data [76–78]. Significant improvements in height velocity post-operatively compared to pre-operatively are observed in prepubertal or early pubertal children [76–78]. Anti-tumour Necrosis Factor Alpha (Anti-TNF-alpha) Within the spectrum of paediatric Crohn disease is a subgroup of patients with chronically active extensive disease not amenable to resection, and refractory to previously available medical therapies. At the Hospital for Sick Children in Toronto, such patients comprised 16-17% of all prepubertal children with Crohn disease diagnosed during each of two decades [1, 15]. These patients, as expected, were also the most likely to have sustained growth impairment [1, 15]. The development of anti-cytokine therapies, such as infliximab, with the potential to achieve mucosal healing, even in otherwise treatment refractory patients constitutes a tremendous advance. The ability of repeated infliximab infusions to sustain clinical remission is well documented in adults, and clinical experience in children is similar. Both observational [79–82] and clinical trial [83] data demonstrate that a beneficial effect on linear growth is observed, if treatment is undertaken early enough prior to or during puberty. These observations are cause for optimism that the medical therapy for Crohn disease available in the present decade will reduce the prevalence of sustained growth impairment in paediatric patients. Hormonal Interventions Given that corticosteroids interfere with the GH-IGF-1 axis at a number of sites, there is a small experience with the use of exogenous recombinant growth hormone (rGH) therapy for growth failure associated with ongoing steroid therapy in a number of paediatric conditions [46]. Mauras et al. reported improvement in IGF-1 levels and height velocity in a pilot study of 10 children with Crohn disease, whose growth had been impaired in the context of steroid dependency [84]. Beyond its “anti-glucocorticoid” effects, it is possible that GH has a direct therapeutic effect in IBD. A randomized controlled clinical trial by Slonim in 2000 demonstrated a possible positive effect of GH on disease activity in adults with Crohn disease [85]. Recent experimental data supports this finding; suggesting an IGF-1 independent pathway where GH directly inhibits IL-6 activation of the STAT3 pro-inflammatory pathway [86]. Despite the possible benefits, GH therapy may also introduce a variety of risks and complications. Described adverse systemic effects of GH include altered carbohydrate metabolism with glucose intolerance, a transient increase in total body fluid, hypertension, cardiac disease, stimulation of autoimmune disease and increased malignancy risk. GH should be considered experimental in the setting of IBD, and is still best limited to formal investigative study settings. Three to six months of testosterone therapy, carefully supervised by pediatric endocrinologists, has been used in boys with extreme delay of puberty and has been associated with a growth spurt [47]. It must be emphasized, however, that children requiring consideration of these adjunctive hormonal therapies should be encountered increasingly less commonly. Treatment of intestinal inflammation and assurance of adequate nutrition are of much greater importance.
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Summary Increased understanding of the mechanisms of linear growth impairment associated with chronic inflammatory disease points the way toward better management. Early recognition of Crohn disease remains an important challenge. Following diagnosis of IBD, restoration and maintenance of a child’s pre-illness growth pattern indicate success of therapy. Current treatment regimens limit use of corticosteroids, via optimization of immunomodulatory drugs, use of enteral nutrition in Crohn disease, and, if necessary, surgery for ulcerative colitis and for intestinal complications of localized Crohn disease. Biologic agents with the potential for mucosal healing hold promise of growth enhancement even among patients with otherwise refractory disease, whose growth was previously compromised. For all interventions, there is a window of opportunity, which must be taken advantage of before puberty is too advanced. References 1. Griffiths AM, Nguyen P, Smith C, MacMillan JH, Sherman PM. Growth and clinical course of children with Crohn disease. Gut 1993; 34:939–43. 2. Hyams JS, Davis P, Grancher K, Lerer T, Justinich CJ, Markowitz J. Clinical outcome of ulcerative colitis in children. J Pediatr 1996; 129:81–8. 3. Karlberg J, Jalil F, Lam B, Low L, Yeung CY. Linear growth retardation in relation to the three phases of growth. Eur J Clin Nutr 1994; 48 Suppl 1:S25–43; discussion S43–4. 4. Wang J, Zhou J, Cheng CM, Kopchick JJ, Bondy CA. Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth. J Endocrinol 2004; 180:247–55. 5. Rogol AD, Roemmich JN, Clark PA. Growth at puberty. J Adolesc Health 2002; 31:192–200. 6. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 1976; 51:170–9. 7. Centers for Disease Control and Prevention NCfHS. CDC growth charts: United States, http://www.cdc.gov/growthcharts/.30–5-2000. 8. Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, Preece MA. Cross sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995; 73:17–24. 9. Zeferino AM, Barros Filho AA, Bettiol H, Barbieri MA. [Monitoring growth]. J Pediatr (Rio J) 2003; 79 Suppl 1:S23–32. 10. Kirschner BS. Growth and development in chronic inflammatory bowel disease. Acta Paediatr Scand Suppl 1990; 366:98–104; discussion 105. 11. Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn disease. Gastroenterology 1988; 95:1523–7. 12. Hildebrand H, Karlberg J, Kristiansson B. Longitudinal growth in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1994; 18:165–73. 13. Markowitz J, Grancher K, Rosa J, Aiges H, Daum F. Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993; 16:373–80. 14. Motil KJ, Grand RJ, Davis-Kraft L, Ferlic LL, Smith EO. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993; 105:681–91. 15. Kundhal P, Critch J, Hack C, Griffiths A. Clinical course and growth of children with Crohn disease. Can J Gastroenterol 2002. 16. Sawczenko A, Sandhu BK. Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child 2003; 88:995–1000. 17. Wine E, Reif SS, Leshinsky-Silver E, et al. Pediatric Crohn disease and growth retardation: the role of genotype, phenotype, and disease severity. Pediatrics 2004; 114:1281–6. 18. Sawczenko A, Ballinger AB, Croft NM, Sanderson IR, Savage MO. Adult height in patients with early onset of Crohn disease. Gut 2003; 52:454–5; author reply 455. 19. Alemzadeh N, Rekers-Mombarg LT, Mearin ML, Wit JM, Lamers CB, van Hogezand RA. Adult height in patients with early onset of Crohn disease. Gut 2002; 51:26–9. 20. Ferguson A, Sedgwick DM. Juvenile onset inflammatory bowel disease: height and body mass index in adult life. BMJ 1994; 308:1259–63.
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21. Ballinger A. Fundamental mechanisms of growth failure in inflammatory bowel disease. Horm Res 2002; 58 Suppl 1:7–10. 22. Kelts DG, Grand RJ, Shen G, Watkins JB, Werlin SL, Boehme C. Nutritional basis of growth failure in children and adolescents with Crohn disease. Gastroenterology 1979; 76:720–7. 23. Kirschner BS, Klich JR, Kalman SS, deFavaro MV, Rosenberg IH. Reversal of growth retardation in Crohn disease with therapy emphasizing oral nutritional restitution. Gastroenterology 1981; 80: 10–5. 24. Ballinger A, El-Haj T, Perrett D, et al. The role of medial hypothalamic serotonin in the suppression of feeding in a rat model of colitis. Gastroenterology 2000; 118:544–53. 25. Filipsson S, Hulten L, Lindstedt G. Malabsorption of fat and vitamin B12 before and after intestinal resection for Crohn disease. Scand J Gastroenterol 1978; 13:529–36. 26. Griffiths AM, Drobnies A, Soldin SJ, Hamilton JR. Enteric protein loss measured by fecal alpha 1-antitrypsin clearance in the assessment of Crohn disease activity: a study of children and adolescents. J Pediatr Gastroenterol Nutr 1986; 5:907–11. 27. Azcue M, Rashid M, Griffiths A, Pencharz PB. Energy expenditure and body composition in children with Crohn disease: effect of enteral nutrition and treatment with prednisolone. Gut 1997; 41:203–8. 28. De Benedetti F, Alonzi T, Moretta A, et al. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J Clin Invest 1997; 99:643–50. 29. Ballinger AB, Azooz O, El-Haj T, Poole S, Farthing MJ. Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis. Gut 2000; 46:694–700. 30. Martensson K, Chrysis D, Savendahl L. Interleukin-1beta and TNF-alpha act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones. J Bone Miner Res 2004; 19:1805–12. 31. Varghese S, Wyzga N, Griffiths AM, Sylvester FA. Effects of serum from children with newly diagnosed Crohn disease on primary cultures of rat osteoblasts. J Pediatr Gastroenterol Nutr 2002; 35:641–8. 32. Teglund S, McKay C, Schuetz E, et al. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 1998; 93:841–50. 33. Bergad PL, Schwarzenberg SJ, Humbert JT, et al. Inhibition of growth hormone action in models of inflammation. Am J Physiol Cell Physiol 2000; 279:C1906–17. 34. Denson LA, Held MA, Menon RK, Frank SJ, Parlow AF, Arnold DL. Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3. Am J Physiol Gastrointest Liver Physiol 2003; 284:G646–54. 35. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16:3–34. 36. Kirschner BS, Sutton MM. Somatomedin-C levels in growth-impaired children and adolescents with chronic inflammatory bowel disease. Gastroenterology 1986; 91:830–6. 37. Tenore A, Berman WF, Parks JS, Bongiovanni AM. Basal and stimulated serum growth hormone concentrations in inflammatory bowel disease. J Clin Endocrinol Metab 1977; 44:622–8. 38. Denson LA, Menon RK, Shaufl A, Bajwa HS, Williams CR, Karpen SJ. TNF-alpha downregulates murine hepatic growth hormone receptor expression by inhibiting Sp1 and Sp3 binding. J Clin Invest 2001; 107:1451–8. 39. Ram PA, Waxman DJ. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J Biol Chem 1999; 274:35553–61. 40. Colson A, Le Cam A, Maiter D, Edery M, Thissen JP. Potentiation of growth hormone-induced liver suppressors of cytokine signaling messenger ribonucleic acid by cytokines. Endocrinology 2000; 141:3687–95. 41. Cohney SJ, Sanden D, Cacalano NA, et al. SOCS-3 is tyrosine phosphorylated in response to interleukin2 and suppresses STAT5 phosphorylation and lymphocyte proliferation. Mol Cell Biol 1999; 19: 4980–8. 42. Ram PA, Waxman DJ. Role of the cytokine-inducible SH2 protein CIS in desensitization of STAT5b signaling by continuous growth hormone. J Biol Chem 2000; 275:39487–96. 43. Shumate ML, Yumet G, Ahmed TA, Cooney RN. Interleukin-1 inhibits the induction of insulin-like growth factor-I by growth hormone in CWSV-1 hepatocytes. Am J Physiol Gastrointest Liver Physiol 2005; 289:G227–39.
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44. Sawczenko A, Azooz O, Paraszczuk J, et al. Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C polymorphism in children. Proc Natl Acad Sci U S A 2005; 102:13260–5. 45. De Benedetti F, Meazza C, Oliveri M, et al. Effect of IL-6 on IGF binding protein-3: a study in IL-6 transgenic mice and in patients with systemic juvenile idiopathic arthritis. Endocrinology 2001; 142:4818–26. 46. Mauras N. Growth hormone therapy in the glucocorticosteroid-dependent child: metabolic and linear growth effects. Horm Res 2001; 56 Suppl 1:13–8. 47. Ballinger AB, Savage MO, Sanderson IR. Delayed puberty associated with inflammatory bowel disease. Pediatr Res 2003; 53:205–10. 48. Russell RK, Drummond HE, Nimmo EE, et al. Genotype-phenotype analysis in childhood-onset Crohn disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflamm Bowel Dis 2005; 11:955–64. 49. Tomer G, Ceballos C, Concepcion E, Benkov KJ. NOD2/CARD15 variants are associated with lower weight at diagnosis in children with Crohn disease. Am J Gastroenterol 2003; 98:2479–84. 50. Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP. Differential effects of NOD2 variants on Crohn disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol 2004; 99:2393–404. 51. Russell RK, Drummond HE, Nimmo ER, et al. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease. Gut 2006; 55:1114–23. 52. Levine A, Shamir R, Wine E, et al. TNF promoter polymorphisms and modulation of growth retardation and disease severity in pediatric Crohn disease. Am J Gastroenterol 2005; 100:1598–604. 53. Griffiths AM, Otley AR, Hyams J, et al. A review of activity indices and end points for clinical trials in children with Crohn disease. Inflamm Bowel Dis 2005; 11:185–96. 54. Griffiths AM, Nicholas D, Smith C, et al. Development of a quality-of-life index for pediatric inflammatory bowel disease: dealing with differences related to age and IBD type. J Pediatr Gastroenterol Nutr 1999; 28:S46–52. 55. Aiges H, Markowitz J, Rosa J, Daum F. Home nocturnal supplemental nasogastric feedings in growthretarded adolescents with Crohn disease. Gastroenterology 1989; 97:905–10. 56. Belli DC, Seidman E, Bouthillier L, et al. Chronic intermittent elemental diet improves growth failure in children with Crohn disease. Gastroenterology 1988; 94:603–10. 57. Wilschanski M, Sherman P, Pencharz P, Davis L, Corey M, Griffiths A. Supplementary enteral nutrition maintains remission in paediatric Crohn disease. Gut 1996; 38:543–8. 58. Bannerjee K, Camacho-Hubner C, Babinska K, et al. Anti-inflammatory and growth-stimulating effects precede nutritional restitution during enteral feeding in Crohn disease. J Pediatr Gastroenterol Nutr 2004; 38:270–5. 59. Walker-Smith JA. Management of growth failure in Crohn disease. Arch Dis Child 1996; 75:351–4. 60. Gassull MA, Stange EF. Nutrition and diet in inflammatory bowel disease. In: Satsangi J, Sutherland LR, eds. Inflammatory Bowel Diseases. London, UK: Elsevier, 2003:461–74. 61. Zachos M, Tondeur M, Griffiths AM. Enteral nutritional therapy for inducing remission of Crohn disease. Cochrane Database Syst Rev 2001:CD000542. 62. Fell JM, Paintin M, Arnaud-Battandier F, et al. Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn disease. Aliment Pharmacol Ther 2000; 14:281–9. 63. Heuschkel RB, Menache CC, Megerian JT, Baird AE. Enteral nutrition and corticosteroids in the treatment of acute Crohn disease in children. J Pediatr Gastroenterol Nutr 2000; 31:8–15. 64. Griffiths AM, Ohlsson A, Sherman PM, Sutherland LR. Meta-analysis of enteral nutrition as a primary treatment of active Crohn disease. Gastroenterology 1995; 108:1056–67. 65. Seidman E, Griffiths AM, Jones A. Semi-elemntal diet versus prednisone in the treatment of acute Crohn disease in children and adolescents. Gastroenterology 1993; 104:A778. 66. Griffiths AM. Enteral nutrition: the neglected primary therapy of active Crohn disease. J Pediatr Gastroenterol Nutr 2000; 31:3–5.
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67. Rigaud D, Cosnes J, Le Quintrec Y, Rene E, Gendre JP, Mignon M. Controlled trial comparing two types of enteral nutrition in treatment of active Crohn disease: elemental versus polymeric diet. Gut 1991; 32:1492–7. 68. Seidman E, Jones A, Issenman R. Cyclical exclusive enteral nutrition versus alternate day prednisone in maintaining remission of pediatric Crohn disease. J Pediatr Gastroenterol Nutr 1996; 23:A344. 69. Whittington PF, Barnes HV, Bayless TM. Medical management of Crohn disease in adolescence. Gastroenterology 1977; 72:1338–44. 70. Escher JC. Budesonide versus prednisolone for the treatment of active Crohn disease in children: a randomized, double-blind, controlled, multicentre trial. Eur J Gastroenterol Hepatol 2004; 16:47—54. 71. Papi C, Luchetti R, Gili L, Montanti S, Koch M, Capurso L. Budesonide in the treatment of Crohn disease: a meta-analysis. Aliment Pharmacol Ther 2000; 14:1419–28. 72. Kundhal P, Zachos M, Holmes JL, Griffiths AM. Controlled ileal release budesonide in pediatric Crohn disease: efficacy and effect on growth. J Pediatr Gastroenterol Nutr 2001; 33:75–80. 73. Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn disease. Gastroenterology 2000; 119:895–902. 74. Sands BE. Immunosuppressive drugs in ulcerative colitis: twisting facts to suit theories? Gut 2006; 55:437–41. 75. Nicholls S, Vieira MC, Majrowski WH, Shand WS, Savage MO, Walker-Smith JA. Linear growth after colectomy for ulcerative colitis in childhood. J Pediatr Gastroenterol Nutr 1995; 21:82–6. 76. Griffiths AM, Wesson DE, Shandling B, Corey M, Sherman PM. Factors influencing postoperative recurrence of Crohn disease in childhood. Gut 1991; 32:491–5. 77. Davies G, Evans CM, Shand WS, Walker-Smith JA. Surgery for Crohn disease in childhood: influence of site of disease and operative procedure on outcome. Br J Surg 1990; 77:891–4. 78. Baldassano RN, Han PD, Jeshion WC, et al. Pediatric Crohn disease: risk factors for postoperative recurrence. Am J Gastroenterol 2001; 96:2169–76. 79. Walters TD, Gilman AR, Griffiths AM. Linear growth improves during infliximab therapy in children with chronically active severe Crohn disease inflammatory bowel diseases April 2007, Vol 13(4): 424–430. 80. de Ridder L, Escher JC, Bouquet J, et al. Infliximab therapy in 30 patients with refractory pediatric crohn disease with and without fistulas in The Netherlands. J Pediatr Gastroenterol Nutr 2004; 39:46–52. 81. Borrelli O, Bascietto C, Viola F, et al. Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn disease. Dig Liver Dis 2004; 36:342–7. 82. Cezard JP, Nouaili N, Talbotec C, et al. A prospective study of the efficacy and tolerance of a chimeric antibody to tumor necrosis factors (remicade) in severe pediatric crohn disease. J Pediatr Gastroenterol Nutr 2003; 36:632–6. 83. Griffiths AM, Hyams JS, Crandall W. Height of children with Active Crohn Disease Improves During Treatment with Infliximab. Gastroenterology 2006; 130 Suppl2:A59. 84. Mauras N, George D, Evans J, et al. Growth hormone has anabolic effects in glucocorticosteroiddependent children with inflammatory bowel disease: a pilot study. Metabolism 2002; 51:127–35. 85. Slonim AE, Bulone L, Damore MB, Goldberg T, Wingertzahn MA, McKinley MJ. A preliminary study of growth hormone therapy for Crohn disease. N Engl J Med 2000; 342:1633–7. 86. Han X, Sosnowska D, Bonkowski EL, Denson LA. Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis. Gastroenterology 2005; 129:185–203.
11 Skeletal Health in Pediatric Inflammatory Bowel Disease Francisco Sylvester*
Introduction The skeleton serves as a scaffold for soft tissue, is the largest calcium reservoir in the body, and it harbors the hematopoietic bone marrow. In addition, bone tissue is metabolically active and susceptible to regulation by local and systemic signals. Consequently, the integrity of the skeleton is vulnerable to the effects of disease and treatment factors, which can influence bone cell function. Childhood is characterized by active bone metabolism and growth in size and width due to the combined activities of bone cells and the growth plate. Bone modeling, which is the main process responsible for bone tissue expansion in childhood, involves both bone-forming osteoblasts and bone-resorbing osteoclasts, with both cell types active at the same time on bone surfaces with net gain in bone mass [1] (Figure 11.1). Bone modeling and growth plate functions may be sensitive to disease and treatment effects in children with IBD, impairing both bone formation and linear growth [2, 3]. Bone remodeling, which occurs in both adults and children, is on the other hand a slow process that aims to maintain existing bone mass and architecture. It involves the sequential activities of osteoclasts and osteoblasts, so that resorption by osteoclasts precedes bone formation by osteoblasts. Osteoclasts first dissolve a quantum of stressed or micro-fractured bone, which is then followed by bone matrix formation by osteoblasts [1]. In adults with IBD, bone resorption is increased [4]. Both modeling and remodeling may be affected by multiple influences, including malnutrition, inflammation, inactivity, and hypogonadism, and medications such as corticosteroids [5]. In this chapter we will review current clinical and experimental evidence of the effects of IBD on the pediatric skeleton.
Growth, Bone Modeling and Remodeling Childhood is a time of skeletal growth and maturation. After rapid growth in the third trimester of gestation and in the early neonatal period, bone growth rate falls sharply until puberty. Sexual maturation is associated with a dramatic acceleration of longitudinal bone growth until it ceases when growth plates become fused. Consequently, bone mass is gained rapidly during adolescence. Peak bone mass is achieved after a period of consolidation at the end of the second decade of life in females and at the beginning of the third decade of life in males [6]. Consequently, gains in ∗ Associate Professor of Pediatrics, Connecticut Childrens Medical Center, 282 Washington Street, Hartford, CT 06106, Phone: 860-545-9560, Fax: 860-545-9561, E-mail:
[email protected]
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Microfracture Resorption Trabecular Bone
Growth Plate
Compact Bone
Formation
Formation
Resorption
Restoration
Figure 11.1. Bone Modeling and Remodeling occurs uniquely in children and results from the combined activities of osteoblasts, osteoclasts and the growth plate cells. Its result is bone that grows in length, width, and is reshaped (striped arrows). Compared to remodeling, it is a fast process in which all bone surfaces are active and osteoblasts and osteoclasts work at the same time. In contrast, bone remodeling takes place in both adults and children. It can occur in either trabecular or cortical bone as a consequence of microfractures or mechanical stress. Small amounts of bone are dissolved by osteoclasts, which are followed by bone-forming osteoblasts. The protein matrix released by osteoblasts then becomes calcified, restoring the original bone mass.
skeletal mass may occur after epiphyseal closure and cessation of linear growth. After a period of stability that lasts for about two decades, bone loss occurs after menopause in women and in elderly men. Loss of mineral mass is accompanied by deterioration of bone microarchitecture and increased propensity to fractures with age, which defines osteoporosis [7]. This process of bone deterioration may be enhanced by IBD in adults, but the effects of the disease in children are probably different (please see below). Although the total amount of bone tissue grows with the individual, the material density of bone (e.g., in g/cm3 ) remains relatively constant in children until the latter stages of sexual maturation, when it rises modestly [8, 9]. The measurement of true volumetric bone density is not routinely available clinically. Dual X-ray absorptiometry (DXA), a precise and accurate method commonly used to assess bone mass measures bone mineral content, which is divided by bone area (e.g., DXA “density” is expressed as g/cm2 , or “areal” bone density, not a true material density). DXA produces a two-dimensional projection of three-dimensional bones, so larger bones with equal material density to smaller bones will be measured as “denser” by this method. Therefore, diseases like IBD that can affect linear growth and bone size may affect DXA measurements by underestimating bone mass in smaller children. This requires correction of DXA readings for patient’s size, sex, and sexual maturation [10] (see Chapter 21). Bone mass is maintained by bone remodeling, characterized by the formation of a functional unit that consists of osteoclasts and osteoblasts (the bone remodeling unit) (Figure 11.1). In response to damage or mechanical strain, osteoclasts resorb bone and form resorption pits. This is followed by recruitment of osteoblasts that fill in bone divots with a specialized protein matrix (osteoid, composed primarily of type I collagen). Osteoid later becomes relatively stiff by deposition of
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hydroxyapatite [1]. Some osteoblasts undergo apoptosis, while others become embedded in the newly formed bone matrix and become osteocytes. Osteocytes are interconnected by cellular processes, and sense mechanical strain [11]. The process of remodeling typically takes several months, and generates quantum amounts of bone. In bone remodeling, the activities of osteoblasts and osteoclasts are sequentially coordinated, so formation follows resorption. Only about 20% of bone surfaces in the body are actively engaged in this process at any given time. Bone remodeling occurs both in adults and children, and can take place in cortical or trabecular bone [12]. However, gains in bone mass in childhood are largely due to a combination of the action of the growth plate and a distinct process called bone modeling, which is exclusive to children (Figure 11.1). Bone modeling can be compared to the process of erecting a skyscraper, with construction occurring on both ends of the edifice and from the center out, while bone remodeling is akin to maintaining the building’s structural integrity over time by occasional repairs. In children, accumulation of bone mass is largely a consequence of linear growth [9]. Longitudinal growth occurs due to the production of a cartilaginous scaffold by the growth plate that is calcified, remodeled, and turned into trabecular bone. Trabeculae act as struts, columns and joists to distribute mechanical load from the epiphysis to the compact bone shaft. Linear growth and bone modeling occur simultaneously, with osteoblasts laying down new bone matrix in the periosteal surface, while osteoclasts reshape the bone by resorbing endosteal and metaphyseal bone (metaphyseal inwaisting). Bone modeling occurs in 100% of bone surfaces, and both osteoclasts and osteoblasts are active at the same time [13]. These significant physiological differences between pediatric and adult bone have important implications for children with IBD. Disease and treatment factors influence both modeling and remodeling, but the major impact in children is likely to be on growth plate cells and bone formation, the two most active processes during growth.
Bone Cells and Inflammation Osteoclasts and the RANKL/OPG System Both bone remodeling and modeling involve the activity of osteoclasts and osteoblasts. Osteoclasts are cells from the macrophage/monocyte lineage, which secrete and are regulated by cytokines [14]. Osteoclasts are formed primarily by stimulation of precursor cells with receptor activator of nuclear factor B-ligand (RANKL) in the presence of macrophage stimulating factor (M-CSF) [15] (Figure 11.2). RANKL, a member of the tumor necrosis factor receptor superfamily is produced by osteoblasts, stromal cells, and activated T cells [16], and stimulates osteoclast differentiation, activation, and survival. RANKL deficient mice have hyperdense bones secondary to lack of osteoclasts [17]. RANKL has been implicated as a key factor in the pathogenesis of bone loss associated with increased resorption, like in post-menopausal osteoporosis [18] and inflammation [19]. Multiple inflammatory cytokines (tumor necrosis factor-, interleukin 1-) work via RANKL to increase osteoclast formation [20–23]. TNF- can also modestly stimulate osteoclastogenesis directly [24], and TNF−/− mice and mice lacking the p55 TNF receptor are resistant to the bone effects of estrogen deficiency in mice [25], suggesting an important role for this cytokine in bone loss due to increased bone resorption. Osteoprotegerin (OPG) is a soluble decoy receptor for RANKL produced by osteoblasts and stromal cells [26]. OPG serves as an inhibitor of osteoclast development. OPG transgenic mice have hyperdense bones, a phenotype that can be replicated by systemic administration of OPG to normal mice [26]. OPG-null mice on the other hand are profoundly osteopenic due to unopposed osteoclast activity [27, 28]. Consequently, OPG is a key regulator of bone resorption. Besides OPG, another control switch in osteoclast development is interferon (INF)-, which is induced by RANKL binding to its receptor RANK on osteoclast precursors [29]. INF- interferes with
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IL-10 IL-12 IL-18 INF-γ TGF-β
RANKL TNF-α M-CSF
Bone Formation
Bone Resorption
Osteoclast Precursors RANKL
Osteoclasts
OPG TNF-α
Osteoblasts
IGF-I
TNF-α, IL-1β, IL-6, IL-7 Vitamin D Prostaglandin E2
BMP Wnt
Osteoblast Precursors
Figure 11.2. Regulation of Bone Cells by Cytokines both osteoblasts and osteoclasts are tightly regulated by a host of systemic and local factors. For osteoclasts, the “gatekeeper” regulator is RANKL. Cytokines and other factors influence osteoclast differentiation and activity by interacting with the RANKL pathway. Cytokines can either stimulate or inhibit osteoclastogenesis. RANKL is secreted by osteoblasts, stromal cells and activated T cells. Osteoblasts also release OPG, which neutralizes RANKL before it can bind to RANK on the surface of osteoclast precursors. Osteoblast formation is induced by IGF-I, bone morphogenetic proteins, Wnt and other growth factors. Inflammatory cytokines such as TNF- can inhibit osteoblast formation by multiple mechanisms. Therefore, inflammation can affect both osteoblast and osteoclast function.
the activity of c-fos, a transcription factor that is essential for osteoclast formation. Other factors, such as TGF- and Wnt inhibit osteoclastogenesis by upregulating the production of OPG by osteoblasts [30, 31] and Wnt by repressing RANKL expression [32]. In addition, several cytokines relevant to the pathogenesis of IBD inhibit osteoclast differentiation, including INF- [33], IL-10 [34, 35], and IL-12 [36, 37]. Therefore, osteoclast formation is subject to multiple regulatory controls by cytokines that play a role in inflammation. These pathways are an example of the close physiological ties between the immune system and bone cells. However, it is not yet known whether these mechanisms are engaged in regulating bone mass in children with IBD. The RANKL/OPG system also plays important roles outside of bone. This is evidenced by the lack of peripheral lymph nodes and impaired development of lactating mammary glands in RANKL or RANK-null mice [38]. In addition, RANKL/OPG may be involved in the formation of calcified atherosclerotic plaques [27, 39, 40]. RANKL contributes to normal dendritic cell function and survival, and the early development of B and T cells [17, 41]. In addition, RANKL/RANK may play a role in intestinal mucosal tolerance [42]. OPG also has a role in the regulation of the immune response. Both B cells and dendritic cells secrete OPG, and this secretion is regulated by the CD40 receptor [43]. Also, dendritic cells isolated from OPG−/− mice more efficiently present antigen in vitro and secrete more inflammatory cytokines when stimulated with bacterial products or soluble RANKL in vitro [43]. Collectively, this suggests that RANKL/RANK/OPG play an important role in the regulation of the immune response, and in pathways involving the mobilization of calcium [44]. A role for the RANKL/OPG system is emerging in inflammatory bowel disease. Circulating OPG levels are elevated in patients with IBD [3, 45, 46], and expression of OPG and RANKL
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is increased in colonic macrophages and dendritic cells [46, 47]. Currently it is not clear whether circulating OPG in patients with IBD represents spillover from intestinal inflammatory activity, or it comes from bone, or both. The function of RANKL/OPG in the pathogenesis of intestinal inflammation deserves further study. Osteoblasts Osteoblasts are cells from mesenchymal origin. Several factors and hormones regulate osteoblast formation [48] (Figure 11.2). Insulin-like growth factor-I (IGF-I), is secreted by the liver in response to stimulation by growth hormone, and enhances the expression of the mature osteoblast phenotype [49]. Serum IGF-I is frequently reduced in children with active IBD [2] due to growth hormone insensitivity in the liver [50]. Consequently, relative IGF-I deficiency in children with IBD may negatively affect osteoblast differentiation and function. TNF-, an important cytokine in the pathogenesis of IBD inhibits osteoblast development by inducing the degradation of Runx2, a critical transcription factor in osteoblast development [51]. TNF- also regulates a number of inflammatory chemokines and cytokines, inflammatory genes, transcriptional regulators, boneremodeling genes, signal transducers, cytoskeletal genes, and genes involved in apoptosis in the preosteoblast cell line MC3T3-E1 [52]. Based on these studies, theoretically the blockade of TNF- may improve bone formation. Emerging clinical data support this hypothesis. Infliximab, a TNF- neutralizing antibody, rapidly improves bone formation in adults with IBD [53, 54] and is associated with increased bone mass [55]. However, the effects of infliximab may be a product of improved disease control and not specific effects of this drug on bone metabolism in these patients. T Cells and Bone Loss T cells are emerging as important regulators of bone cell function [19]. Activated T cells can regulate osteoclast formation and activity by several mechanisms, both RANKL-dependent and independent [44, 56]. Activated T cells secrete RANKL, and consequently can promote osteoclast differentiation and survival. Both soluble and membrane-bound RANKL is produced by activated CD4+ and CD8+ T cells [16]. T cell-induced bone resorption has been implicated in tissue injury in animal models of arthritis and periodontal disease [57]. T cells may also play an important role in bone loss associated with estrogen deficiency, where osteoclast activity is upregulated. This is suggested by experiments performed in ovariectomized mice, where absence of T cells prevents bone loss [21]. In this model, the expansion of a TNF- producing T cell pool appears to be essential [58] and may occur as a result of upregulation of antigen presentation [59]. The nature of the activating antigen(s) is not yet known, but it is possible that both self and foreign epitopes (including intestinal bacterial products) may play a role [59]. The concept that T cells activated by bacterial antigens may regulate bone cell function is intriguing. In IBD, it is possible that activated T cells may serve as “inflammatory shuttles” between intestine and bone, since circulating T cells produce cytokines that can regulate both osteoblasts and osteoclasts [3]. This possibility awaits additional research.
Effects of Intestinal Inflammation on Bone Animal Models IBD is a complex clinical entity, where multiple disease and treatment factors contribute to affect bone cell biology and ultimately skeletal health. In an effort to study mechanistic questions, animal models of intestinal inflammation have been used by several groups. A brief description of their observations follows.
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Studies in both rat and mouse models suggest that intestinal inflammation can decrease bone mass by impairing bone formation. Lin et al. induced colitis in rats by rectal instillation of TNBS [60] to study its effects on bone mass, assessed by quantitative histomorphometry. After 3 weeks rats with colitis had a loss of trabecular bone of 33% in the tibia compared with agematched, pair-fed control animals. This was associated with a marked suppression of the trabecular bone formation rate. As the colitis healed, bone formation became more active and bone mass normalized after 12 weeks. In IL-10−/− mice with colitis Dresner-Pollak et al. performed bone densitometry, ash weight, histomorphometry analysis and mechanical fragility testing [61]. They observed that bone mass decreased secondary to decreased bone formation in 8 and 12 week old mice; bone resorption was not increased in mice with colitis compared to wild type controls. Long bones were more fragile in IL-10−/− with colitis, an ash weight was reduced. Two reports using adoptive transfer models of colitis suggest that bone mass decreases secondary to increased bone resorption. In the first paper, Ashcroft et al. studied IL-2−/− mice with colitis at 4, 7, and 9 weeks of age, and compared X-ray, histomorphometry with IL-2−/+ and wild type mice. IL-2−/− mice develop colitis, but also have splenomegaly, anemia and other signs of systemic inflammation [62]. They observed a decrease in trabecular bone volume in IL-2−/− with colitis compared with the other two groups of mice at 7 and 9 weeks of age. C57BL/6-Rag1−/− mice transplanted with CD3+ cells from IL-2−/− had significantly lower femoral BMD and % trabecular volume 6-8 weeks post-grafting. Serum OPG and osteoclast number were significantly higher in mice engrafted with T cells from IL-2−/− mice compared to IL-2+/+ . In this model, treatment with OPG was associated with both improved bone mass and decreased intestinal inflammation. These results point to a possible role between T cells and bone loss in the context of intestinal inflammation, and suggest a possible anti-inflammatory role for OPG. In the second study, Byrne et al. transferred CD4+ CD45RBHi or CD4+ CD45RBLo from CB6F1 mice to C.B.17 scid/scid mice [63]. CD4+ CD45RBHi , but not CD4+ CD45RBLo caused colitis in recipient mice, and mice with colitis had lower bone mineral density in the femur/tibia. To treat bone loss, mice received Fc-OPG 3.4–5 mg/kg SC three times weekly for 34 days. OPG had no effect on the severity of colitis, but significantly improved BMD. Collectively, these observations suggest that intestinal inflammation can directly affect bone mass in rodents. Mechanisms may include decreased bone formation or increased bone resorption, depending on the model. It appears that intestinal inflammation present at an early age is associated with decreased bone formation. Administration of exogenous OPG increases bone mass in older mice with certain forms of colitis. However, this may be a non-specific effect of OPG on normally active osteoclasts and by itself does not establish that increased bone resorption is responsible for bone loss in rodent models of colitis. In addition, in adoptive transfer models of colitis, it is not possible to distinguish whether intestinal inflammation in the recipient animals caused bone loss or if colitogenic T cells directly migrated into the bone marrow influenced bone cell function. However, it is interesting that in the CD4+ CD45RBHi model [63] there is an inflammatory infiltrate in the bone marrow containing TNF--producing cells. This provides proof of principle that intestinal inflammation is associated with the presence of activated T cells in the bone marrow that secrete pro-inflammatory cytokines which may influence the function of bone cells. The presence of these cells awaits studies in other murine models of intestinal inflammation and in humans. Human Studies Several studies have measured bone mineral density in children with IBD, both in incident and in prevalent cohorts (Table 11.1). Most of these studies are cross-sectional, and used DXA to measure BMD. These studies suggest that decreased bone mineral density is common in children with Crohn disease at the time of diagnosis, especially in those patients with delays in growth and sexual maturation, and those with decreased lean tissue mass [3, 64, 65]. Some of these studies
Table 11.1. Studies on bone density in children with IBD. Cohort
n
Age (years)
M/F
Normative data
CD
I
17
Mean 13.9 ± 2.1
17
CD UC
I P@
123
(Mean ± SD) Crohn 11.8 ± 2.9 (M), 11.9 ± 2.4 (F), UC10.1 ± 2.8 (M), 11.7 ± 2.6 (F)
Crohn 43/39, UC 22/19
CD
I
18
Mean (range)12.9 (5.5 – 16.8)
11/7
GE Lunar Database
CD
I
23
Mean ± SD 12.58 ± 2.37
15/8
CD UC
P
47 CD 26 UC
Healthy controls; Van der Sluis (80) GE Lunar Database
#
46/27
Healthy controls Hologic database Healthy controls
Z-score Lower bone mineral content/bone width Crohn, spine Z-score −1.44 ± 0.97 (M), −1.37 ± 1.22 (F)*. UC, spine Z-score −0.93 ± 1.10 (M), Z-score −0.56 ± 0.89 (F) Body −0.24 ± 0.79 Spine −0.99 ± 1.1**
Body 0.36 ± 1.99 Spine −0.14 ± 1.04 §
CD −2.0 (−3.8, −0.3) UC 1.2 (−3.2, 0.8)
Risk Factors
Ref
N/A
[64]
Male, Relatively young at diagnosis, No immunomodulator
[79]
Low BMI, weight, height, lean body mass, Delayed puberty, Decreased physical activity Low BMI
[65]
Short stature, Low BMI
[66]
[3]
(continued)
Table 11.1. (continued) Cohort
n
CD
P
29
CD UC
P
CD
P
28 CD 10 UC 119
CD UC
P
22 CD 33 UC
Age (years) Median (range)15.18 (13.85 – 17.18) Median (range)13 (5–18)
4−18
M/F
Normative data
Z-score
Corticosteroids
[81]
N/A
[83]
72/47
38/119 <−2.0 81/119 <−1.0
[84]
34/21
Body SDS −0.95 Spine SDS –0.75
Weight and height Z scores, male sex Corticosteroids, BMI SDS, Crohn disease
N/A
GE Lunar Database Faulkner (82)
¶
Single photon densitometry was used to measure bone mineral mass at the 1/3 distal radius. Longitudinal 2-year study. Mean follow-up approximately 4 years ∗ Spine BMD Z-score significantly lower in children with Crohn than in those with UC § BMD expressed as median standard deviation score (90th percentile, 10th percentile), CD significantly different than UC (P < 0.05) ¶ Results expressed as median N/A Not available ∗∗ P = 0.002 @
Ref
Body −1.20 Spine −2.10 18/28 CD 8/10 UC had “low Z-scores”
20/9
I = incident cohort P = prevalent cohort CD = Crohn disease UC = Ulcerative colitis #
Risk Factors
[85]
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were performed in incident cohorts of treatment-naïve patients, and suggest that disease factors can affect bone mass in children with IBD prior to the initiation of treatment. Collectively, they suggest that children with Crohn disease are at greater risk for decreased bone mass than children with ulcerative colitis. Since patients with low body mass index appear to be at particular risk for decreased BMD, these children may be selected for DXA scanning. In addition to measuring bone mass, body composition data provided by the instrument may be helpful in guiding the nutritional rehabilitation of these patients. In most of these studies, investigators took care of adjusting DXA BMD measurements to patient size, gender, and sexual maturation. This is important, because in any given patient with IBD, the challenge is to distinguish between small, normal bones and abnormally thin bones [66]. Taken together, these studies indicate that the observed reduction of BMD in children with IBD can be attributed in part to decreased bone size. However, it is important to note that smaller bones may be weaker, and their physical properties may not be normal. It is not yet known whether smaller bone size leads to increased fracture risk in children with IBD. Indirect markers of bone cell function, including osteocalcin and bone alkaline phosphatase for osteoblasts and products of type-I collagen degradation for osteoclasts suggest that children with Crohn disease have decreased bone turnover at diagnosis [3]. This indicates that the observed reduction in BMD in children with IBD is probably secondary to decreased bone formation. Although bone biopsy studies have not been performed in children with IBD to confirm this, in adults bone formation may also be decreased [67]. However, in this study patients were taking prednisolone at the time of biopsy, so it is difficult to distinguish between treatment and disease effects. Laboratory observations suggest that systemic factors impair bone formation in IBD. For example, serum from newly diagnosed children decreases markers of osteoblastic activity in bone explants [68] and in isolated osteoblasts [69], while indicators of bone resorption are not increased. IL-6, a proinflammatory cytokine, appears to play an important role in these effects, in cooperation with other factors present in intact bone [70]. In consequence, IBD may have systemic effects on linear growth and direct effects on bone cells in children, thereby decreasing bone mass. Although globally both bone formation and bone resorption appear lower in children with IBD at diagnosis, it is possible that in some regions of the skeleton bone resorption may be increased, resulting in thinner bone cortices and mechanical fragility. While systemic and local humoral factors can directly influence bone cell function in IBD, other influences, albeit indirect, may also be significant. For example, an important stimulus for bone formation is mechanical loading by the expanding muscle forces during puberty [13]. Muscle volume (lean body mass) normally expands during sexual maturation, and its growth precedes gains in bone mass. Children with IBD often present with malnutrition, with significant losses in both the fat and lean tissue compartments and decreased body mass index. With treatment and clinical improvement, children gain weight but deficits in lean body mass persist [71, 72]. This may result in decreased mechanical loading on bone and be a reason for decreased bone formation in children. In addition, children with IBD may be less active than their peers when they don’t feel well, which may also affect gains in muscle and bone mass over time. Nutritional factors may also negatively impact bone mass. For example, vitamin D is essential for normal osteoid mineralization and may have immunoregulatory effects [73]. Vitamin D deficiency is common in children with IBD, especially in northern latitudes [74]. These patients may spend more time indoors during disease exacerbations, affecting their exposure to sunlight and cutaneous synthesis of vitamin D. In addition, their intake of dairy products fortified with vitamin D may be limited due to secondary lactase deficiency. It is not clear whether children with IBD are at increased risk of fractures. Population-based studies in adults with IBD suggest that the risk of fractures appears to be modestly increased [75] or not elevated [76]. However, a study of vertebral fracture assessment in adults with Crohn disease indicated high prevalence of asymptomatic vertebral fractures [77]. Vertebral fractures have been
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reported in children [78], but no systematic fracture prevalence study has been performed. Risk factors for fractures for adults and children with IBD may be different, and the risk of fracture for a given decrease in bone mass may vary depending on age. Since fracture is the only clinically relevant manifestation of decreased bone mass, it would be important to examine fracture risk (including asymptomatic vertebral collapse) in children with IBD in the future.
Conclusions Inflammatory bowel disease can negatively affect bone development in children through multiple mechanisms. Due to differences in bone metabolism in children and adults, IBD impacts bone metabolism differently in these two age groups. In children, decreased BMD is probably the result of both impaired growth and decreased osteoblast function. Current therapies, including corticosteroids and immunomodulators may not be optimal for promoting normal body composition and skeletal health in children with IBD. Preliminary data indicate that targeted biological therapies may be more effective in this regard. In children, careful attention to disease control, nutrition (including calcium and vitamin D), and activity level is probably appropriate to improve skeletal mass. Antiresorptive agents such as bisphosphonates may be helpful in selected children (e.g., those with fragility fractures), but should not be started in children without input from experts in pediatric metabolic bone diseases. References 1. Seeman E, Delmas PD. Bone quality–the material and structural basis of bone strength and fragility. N Engl J Med 2006;354(21):2250–61. 2. Kirschner BS, Sutton MM. Somatomedin-C levels in growth-impaired children and adolescents with chronic inflammatory bowel disease. Gastroenterology 1986;91(4):830–6. 3. Sylvester FA, Davis PM, Wyzga N, Hyams JS, Lerer T. Are activated T cells regulators of bone metabolism in children with Crohn disease? J Pediatr 2006;148(4):461–6. 4. Dresner-Pollak R, Karmeli F, Eliakim R, Ackerman Z, Rachmilewitz D. Increased urinary N-telopeptide cross-linked type 1 collagen predicts bone loss in patients with inflammatory bowel disease. Am J Gastroenterol 2000;95(3):699–704. 5. Sylvester FA. IBD and skeletal health: children are not small adults! Inflamm Bowel Dis 2005;11(11):1020–3. 6. Bachrach LK. Osteoporosis and measurement of bone mass in children and adolescents. Endocrinol Metab Clin North Am 2005;34(3):521–35. 7. Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement 2000;17(1):1–45. 8. Lu PW, Briody JN, Ogle GD, Morley K, Humphries IR, Allen J, et al. Bone mineral density of total body, spine, and femoral neck in children and young adults: a cross-sectional and longitudinal study. J Bone Miner Res 1994;9(9):1451–8. 9. Seeman E. Clinical review 137: Sexual dimorphism in skeletal size, density, and strength. J Clin Endocrinol Metab 2001;86(10):4576–84. 10. Herzog D, Bishop N, Glorieux F, Seidman EG. Interpretation of bone mineral density values in pediatric Crohn disease. Inflamm Bowel Dis 1998;4(4):261–7. 11. Stains JP, Civitelli R. Cell-to-cell interactions in bone. Biochem Biophys Res Commun 2005;328(3):721–7. 12. Parfitt AM, Travers R, Rauch F, Glorieux FH. Structural and cellular changes during bone growth in healthy children. Bone 2000;27(4):487–94. 13. Rauch F, Bailey DA, Baxter-Jones A, Mirwald R, Faulkner R. The ‘muscle-bone unit’ during the pubertal growth spurt. Bone 2004;34(5):771–5. 14. Tanaka Y, Nakayamada S, Okada Y. Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy 2005;4(3):325–8. 15. Feng X. Regulatory roles and molecular signaling of TNF family members in osteoclasts. Gene 2005;350(1):1–13.
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38. Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000;103(1):41–50. 39. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 2004;95(11):1046–57. 40. Sandberg WJ, Yndestad A, Oie E, Smith C, Ueland T, Ovchinnikova O, et al. Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol 2006;26(4):857–63. 41. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997;390(6656):175–9. 42. Williamson E, Bilsborough JM, Viney JL. Regulation of mucosal dendritic cell function by receptor activator of NF-kappa B (RANK)/RANK ligand interactions: impact on tolerance induction. J Immunol 2002;169(7):3606–12. 43. Yun TJ, Chaudhary PM, Shu GL, Frazer JK, Ewings MK, Schwartz SM, et al. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. J Immunol 1998;161(11):6113–21. 44. Theill LE, Boyle WJ, Penninger JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 2002;20:795–823. 45. Bernstein CN, Sargent M, Leslie WD. Serum osteoprotegerin is increased in Crohn disease: a populationbased case control study. Inflamm Bowel Dis 2005;11(4):325–30. 46. Moschen AR, Kaser A, Enrich B, Ludwiczek O, Gabriel M, Obrist P, et al. The RANKL/OPG system is activated in inflammatory bowel disease and relates to the state of bone loss. Gut 2005;54(4):479–87. 47. Franchimont N, Reenaers C, Lambert C, Belaiche J, Bours V, Malaise M, et al. Increased expression of receptor activator of NF-kappa B ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin in the colon of Crohn disease patients. Clin Exp Immunol 2004;138(3):491–498. 48. Canalis E. The fate of circulating osteoblasts. N Engl J Med 2005;352(19):2014–6. 49. Zhao G, Monier-Faugere MC, Langub MC, Geng Z, Nakayama T, Pike JW, et al. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 2000;141(7):2674–82. 50. Difedele LM, He J, Bonkowski EL, Han X, Held MA, Bohan A, et al. Tumor Necrosis Factor alpha Blockade Restores Growth Hormone Signaling in Murine Colitis. Gastroenterology 2005;128(5): 1278–1291. 51. Kaneki H, Guo R, Chen D, Yao Z, Schwarz EM, Zhang YE, et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 2006;281(7): 4326–33. 52. Shen F, Ruddy MJ, Plamondon P, Gaffen SL. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-{alpha}-induced genes in bone cells. J Leukoc Biol 2005;77(3): 388–399. 53. Franchimont N, Putzeys V, Collette J, Vermeire S, Rutgeerts P, De Vos M, et al. Rapid improvement of bone metabolism after infliximab treatment in Crohn disease. Alimentary Pharmacology and Therapeutics 2004;20(6):607–614. 54. Ryan BM, Russel MG, Schurgers L, Wichers M, Sijbrandij J, Stockbrugger RW, et al. Effect of antitumour necrosis factor-alpha therapy on bone turnover in patients with active Crohn disease: a prospective study. Aliment Pharmacol Ther 2004;20(8):851–7. 55. Bernstein M, Irwin S, Greenberg GR. Maintenance infliximab treatment is associated with improved bone mineral density in Crohn disease. Am J Gastroenterol 2005;100(9):2031–5. 56. Weitzmann MN, Cenci S, Rifas L, Haug J, Dipersio J, Pacifici R. T cell activation induces human osteoclast formation via receptor activator of nuclear factor kappaB ligand-dependent and -independent mechanisms. J Bone Miner Res 2001;16(2):328–37. 57. Takayanagi H. Inflammatory bone destruction and osteoimmunology. J Periodontal Res 2005;40(4): 287–93. 58. Roggia C, Tamone C, Cenci S, Pacifici R, Isaia GC. Role of TNF-alpha producing T-cells in bone loss induced by estrogen deficiency. Minerva Med 2004;95(2):125–32. 59. Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 2006;116(5):1186–1194.
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60. Lin CL, Moniz C, Chambers TJ, Chow JW. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology 1996;111(5):1263–71. 61. Dresner-Pollak R, Gelb N, Rachmilewitz D, Karmeli F, Weinreb M. Interleukin 10-deficient mice develop osteopenia, decreased bone formation, and mechanical fragility of long bones. Gastroenterology 2004;127(3):792–801. 62. Ashcroft AJ, Cruickshank SM, Croucher PI, Perry MJ, Rollinson S, Lippitt JM, et al. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity 2003;19(6):849–61. 63. Byrne FR, Morony S, Warmington K, Geng Z, Brown HL, Flores SA, et al. CD4+CD45RBHi T cell transfer induced colitis in mice is accompanied by osteopenia which is treatable with recombinant human osteoprotegerin. Gut 2005;54(1):78–86. 64. Issenman RM, Atkinson SA, Radoja C, Webber CE. Spinal Bone Mass During The First Two Years of Treatment in Pediatric Crohn Disease. J Pediatr Gastroenterol Nutr 1996. 65. Harpavat M, Greenspan SL, O’Brien C, Chang CC, Bowen A, Keljo DJ. Altered bone mass in children at diagnosis of Crohn disease: a pilot study. J Pediatr Gastroenterol Nutr 2005;40(3):295–300. 66. Ahmed SF, Horrocks IA, Patterson T, Zaidi S, Ling SC, McGrogan P, et al. Bone mineral assessment by dual energy X-ray absorptiometry in children with inflammatory bowel disease: evaluation by age or bone area. J Pediatr Gastroenterol Nutr 2004;38(3):276–80. 67. Croucher PI, Vedi S, Motley RJ, Garrahan NJ, Stanton MR, Compston JE. Reduced bone formation in patients with osteoporosis associated with inflammatory bowel disease. Osteoporos Int 1993;3(5): 236–41. 68. Hyams JS, Wyzga N, Kreutzer DL, Justinich CJ, Gronowicz GA. Alterations in bone metabolism in children with inflammatory bowel disease: an in vitro study. J Pediatr Gastroenterol Nutr 1997;24(3):289–95. 69. Varghese S, Wyzga N, Griffiths AM, Sylvester FA. Effects of serum from children with newly diagnosed Crohn disease on primary cultures of rat osteoblasts. J Pediatr Gastroenterol Nutr 2002;35(5):641–8. 70. Sylvester FA, Wyzga N, Hyams JS, Gronowicz GA. Effect of Crohn disease on bone metabolism in vitro: a role for interleukin-6. J Bone Miner Res 2002;17(4):695–702. 71. Burnham JM, Shults J, Semeao E, Foster B, Zemel BS, Stallings VA, et al. Whole body BMC in pediatric Crohn disease: independent effects of altered growth, maturation, and body composition. J Bone Miner Res 2004;19(12):1961–8. 72. Burnham JM, Shults J, Semeao E, Foster BJ, Zemel BS, Stallings VA, et al. Body-composition alterations consistent with cachexia in children and young adults with Crohn disease. Am J Clin Nutr 2005;82(2):413–420. 73. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81(3):353–73. 74. Sentongo TA, Semaeo EJ, Stettler N, Piccoli DA, Stallings VA, Zemel BS. Vitamin D status in children, adolescents, and young adults with Crohn disease. Am J Clin Nutr 2002;76(5):1077–81. 75. Bernstein CN, Blanchard JF, Leslie W, Wajda A, Yu BN. The incidence of fracture among patients with inflammatory bowel disease. A population-based cohort study. Ann Intern Med 2000;133(10):795–9. 76. Loftus EV, Jr., Crowson CS, Sandborn WJ, Tremaine WJ, O’Fallon WM, Melton LJ, 3rd. Long-term fracture risk in patients with Crohn disease: a population-based study in Olmsted County, Minnesota. Gastroenterology 2002;123(2):468–75. 77. Klaus J, Armbrecht G, Steinkamp M, Bruckel J, Rieber A, Adler G, et al. High prevalence of osteoporotic vertebral fractures in patients with Crohn disease. Gut 2002;51(5):654–8. 78. Semeao EJ, Stallings VA, Peck SN, Piccoli DA. Vertebral compression fractures in pediatric patients with Crohn disease. Gastroenterology 1997;112(5):1710–3. 79. Gupta A, Paski S, Issenman R, Webber C. Lumbar spine bone mineral density at diagnosis and during follow-up in children with IBD. J Clin Densitom 2004;7(3):290–5. 80. van der Sluis IM, de Ridder MA, Boot AM, Krenning EP, de Muinck Keizer-Schrama SM. Reference data for bone density and body composition measured with dual energy x ray absorptiometry in white children and young adults. Arch Dis Child 2002;87(4):341–7; discussion 341–7. 81. Bourges O, Dorgeret S, Alberti C, Hugot JP, Sebag G, Cezard JP. [Low bone mineral density in children with Crohn disease]. Arch Pediatr 2004;11(7):800–6.
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82. Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C, Wilkinson AA. Bone densitometry in Canadian children 8–17 years of Age. Calcif Tissue Int 1996;59(5):344–51. 83. Scheer K, Kratzsch J, Deutscher J, Gelbrich G, Borte G, Kiess W. Bone metabolism in 53 children and adolescents with chronic inflammatory bowel disease. Klin Padiatr 2004;216(2):62–6. 84. Semeao EJ, Jawad AF, Zemel BS, Neiswender KM, Piccoli DA, Stallings VA. Bone mineral density in children and young adults with Crohn disease. Inflamm Bowel Dis 1999;5(3):161–6. 85. Boot AM, Bouquet J, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density and nutritional status in children with chronic inflammatory bowel disease. Gut 1998;42(2):188–94.
12 Puberty and Pediatric-Onset Inflammatory Bowel Disease Barbara S. Kirschner* and Barry H. Rich
Introduction The term “delayed growth and sexual maturation” is cited extensively in literature describing inflammatory bowel disease (IBD) with onset during childhood and adolescence. Indeed, evidence suggests that many of the nutritional, inflammatory/immunologic and endocrine factors which result from IBD affect both growth and the onset and progression of puberty. This chapter will address how puberty is affected and influences other aspects of health in the pediatric-age population with IBD.
The Pubertal Process in Healthy Children and Adolescents Puberty is defined as the sequential biologic processes that ultimately lead to reproductive capacity [1]. The onset of puberty is initiated following the synthesis and secretion of luteinizing hormone releasing hormone (LHRH, also called gonadotropin releasing hormone, GnRH), in the hypothalamus and its transport to gonadotrophs within the anterior pituitary. Pralong et al. suggested, based on experimental studies in prepubertal rats, that neuropeptide Y (NPY) found in hypothalamus may affect (inhibit) LHRH secretion and delay sexual maturation [2]. In a limited study, girls with constitutional delay in puberty had higher levels of NPY than those with normal course of puberty [3]. Once stimulated by LHRH, the gonadotrophs secrete the gonadotropins LH and FSH which regulate ovarian and testicular function. Pituitary sensitivity to LHRH varies throughout life but increases prior to the onset of puberty. At this time, luteinizing hormone (LH) begins to be secreted in a pulsatile manner during sleep but subsequently changes to a pulsatile pattern throughout the day as puberty progresses [4]. FSH causes growth of granulosa cells in the ovarian follicle and estrogen production (estrone or E1 and estradiol or E2). In the female, LH stimulates theca cells in the ovary to produce androgens which diffuse to granulosa cells for conversion into estrogens. In the male, FSH stimulates the seminiferous tubules to produce sperm. LH controls testosterone production by Leydig cells in the testis. Testosterone undergoes 5-reduction to dihydrotestosterone which induces secondary sex characteristics. ∗ Professor of Pediatrics, Section of Pediatric Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, The University of Chicago, The University of Chicago Comer Children’s Hospital, 5839 S. Maryland Avenue, Chicago, IL 60637, Phone: 773-702-6152, Fax: 773-702-0666, Email:
[email protected]
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Adrenarche is the onset of ACTH-dependent adrenal 17-ketosteroid and androgen production. Most often this occurs between 6 and 9 years of age with elevation of circulating dehydroepiandrosterone sulfate (DHAS) [5]. While adrenal androgen production is a minor component of mid-pubertal male testosterone level, the adrenal contributes about half the total testosterone produced in the female. This may contribute significantly to the timing of the appearance of pubic hair. Since the adrenal production is ACTH dependent, this synthesis is subject to suppression with exogenous glucocorticoid therapy. Adrenal androgen production has also been shown to be affected by other hormones, such as insulin, growth hormone (GH) and Insulin-like growth factor 1 (IGF-1), and indirectly to nutritional status [6]. In normal maturation, DHAS is the most abundant circulating adrenal steroid after onset of adrenarche and often reflects endogenous glucocorticoid secretory capacity.
Table 12.1. Hormone levels in puberty. Hormone Dehydroepiandrosterone Sulfate (DHAS)
Luteinizing Hormone (LH) Pediatric
Follicle Stimulating Hormone (FSH) Pediatric
Estradiol (E2) Pediatric
Estrone (E1)
Testosterone (Te)
IGF–1
Stage Preadrenarche 6–9 years Tanner III Tanner V Tanner I Tanner II Tanner III Tanner IV Tanner V Tanner I Tanner II Tanner III Tanner IV Tanner V Tanner I Tanner II Tanner III Tanner IV Tanner V Tanner I Tanner II Tanner III Tanner IV Tanner V Tanner I Tanner II Tanner III Tanner IV Tanner V Tanner I Tanner II Tanner III Tanner IV Tanner V
Male <40 <145 60–505 65–500 <0.4 0.2–4.8 0.6–3.7 0.5–7.1 1.5–7.0 <1.9 0.7–4.6 2.0–10.4 1.7–10.4 1.5–7.0
<23 <70 15–280 105–545 268–800 109–485 174–512 230–818 396–776 402–839
Female <20 mcg/dL <140 20–585 75–530 <0.2 IU/L 0.2–4.1 0.2–4.1 0.7–15.0 0.3–29.4 <3.4 IU/L 1.7–4.6 2.5–7.0 1.3–7.4 1.0–9.2 <10 pg/ml 5–115 5–180 25–345 40–410 <15 pg/ml 10–33 15–43 16–77 30–77 <20 ng/dL <30 10–30 10–40 15–40 128–470 ng/ml 186–695 292–883 394–920 308–1138
Modified from Endocrinology: Quest Diagnostic Manual, 3rd edition (2004), Delbert A. Fisher (Ed), Quest Diagnostics Inc., San Juan Capistrano CA. Caution is suggested in differentiating puberty from pre-puberty, especially with regard to LH, FSH, E2 and Te. The assays must be sufficiently specific as well as sensitive for the normally low prepubertal and early pubertal levels. In addition these hormones are secreted episodically with short half-lives in the blood. Early morning testing is recommended.
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A summary of normal hormone levels in puberty is seen in Table 12.1. Since in early puberty increased gonadotropin pulse amplitude increases first during sleep, gonadal steroid secretion at this point of development is maximal in the very early morning hours and may wane to low, prepubertal levels by 0900. The adrenal steroid DHAS, however, does not follow this pattern because of its long plasma half-life and a meaningful level may be determined throughout the day. Brain et al. stated that the onset of puberty is associated with Tanner Stage 2 for breast development in girls and testicular volume of 4 mL in boys [7]. The mean age of onset of puberty in healthy children in this study was 11.1 years for girls and 12.4 years for boys. The standard deviation for all pubertal milestones is about one year [8, 9]. Thus, girls older than about 13 years and boys older than 14.5 years without evidence of Tanner II development are considered to have delayed puberty. The mean age of menarche in the United States was observed to be 12.8 ± 0.05 and 12.9 ± 0.1 years by Frisch, and Zacharias et al. [10, 11] The mean age for spermarche is between 13.5 and 14.5 years [1]. The average duration of puberty in girls is 4 years (range 1.5 to 8 years) and for boys 3 years (range 2 to 5 years) [1]. This is important as it reflects the wide range in maturation of normal, healthy individuals as well as the variation in duration to completion [12–14]. For distinguishing different phases of pubertal development most reports in the pediatric gastroenterology literature have used Tanner Stages which rely on visual observation of the progression of pubic hair character and distribution, breast size and contour and testicular size [15]. Recently, Schall et al. studied the validity of self-assessment of sexual maturity in 100 patients, age 8 to 18 years, with Crohn disease [16]. The instrument included drawings and written description of Tanner stages. Patients self assessments were compared with those of a designated pediatrician. Agreement varied between 74% to 85% depending on sex and sexual maturity status with children and overweight boys overestimating their sexual maturity status (SMS). Rapkin et al. also noted that self-staging of Tanner stage was as accurate as circulating estradiol and FSH measurements in 124 healthy girls, aged 8 to 18 years [17].
The Influence of Inflammatory Bowel Disease on Puberty From the viewpoint of this author, one of the most interesting studies which assessed the effect of IBD on puberty is that of Hildebrand et al. [18] This unique study obtained height and weight data collected from birth through final adult height in 46 patients with childhood onset Crohn disease (CD) and 60 patients with childhood onset ulcerative colitis (UC). The age at peak height velocity (PHV) was stated to represent the middle of puberty. Individual values for height were converted into standard deviation scores (SDS) using the infancy-childhood-puberty (ICP) growth standard of Karlberg et al. [19] The authors reported that the PHV for healthy children in Sweden is 12.05 ± 0.88 years for girls and 14.15 ± 0.98 for boys. Delayed puberty was defined as a delayed age at PHV of >2.0 SDS. No significant delay was noted in children with UC with age at PHV 11.9 ± 1.1 years for girls and 14.0 ± 1.2 years for boys. In contrast, mean age at PHV was later in patients with Crohn disease: 12.7 ± 1.4 years for girls and 14.9 ± 1.2 years for boys. The delay was >2.0 SDS in 23% of children with CD. The authors observed that onset of disease during the pre-pubertal period was frequently associated with subnormal growth. Within this group, growth velocity was –2.0 SDS in 24% of children with UC and 40% of children with CD [20, 21]. Kanoff et al. and Kirschner had previously reported impaired growth in 68% to 88% of pre-pubertal children with CD [20, 21]. Within a group of pre-pubertal patients, Saha et al. noted the poorest growth in those with severe Crohn disease when compared with UC [22]. Interestingly, no difference was seen between patients with and without corticosteroid treatment. In contrast, Motil et al. and Sentongo et al. reported that the prevalence of growth failure was equal regardless of the stage of pubertal development [23, 24].
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Normal prepubertal growth velocity after 3 years of age averages about 5 cm/year. The pubertal growth spurt provides an additional 15–25 cm growth above basal rate [9,12–14]. Target heights are midparental +6.5 cm for boys and midparental – 6.5 cm for girls. Delayed puberty is often associated with lower peak height velocity. Sawczenko et al. studied the effect of CD on final height in 123 patients who were designated “pre-pubertal” based on age at onset of symptoms: <13 years for boys and <11 years for girls [25]. Nineteen per cent had a final height 8.0 centimeters (cm) or more below the targeted or mid-parental height. Boys were overrepresented with an O.R. of 3.70. In an earlier report, Griffiths et al. had also observed less catch-up growth in boys than girls [26]. In the study of Sawczenko, children with prepubertal onset of symptoms who had received steroid therapy were not significantly shorter than other children at final height. The authors also concluded that there was no evidence to suggest that the judicious use of systemic steroids would cause significant long-term growth delay [25]. Ferguson and Sedgwick described delayed puberty based on a retrospective survey of adults with a history of pediatric-onset UC and CD [27]. Their results were different from other published reports in several ways. Adult stature achieved by 67 of 70 patients was similar to normal adults and no difference was seen whether the patients had CD or UC. Delayed puberty was based on patients recall many years later. Pubertal delay was reported as follows: Crohn disease, 11/28 (39%) of men and 13/22 (59%) of women compared with 2/9 (22%) of men and 3/11 (27%) of women with UC. These numbers were not statistically different. Age at menarche was reported to be >16 years in 8 of 11 (73%) of women whose menarche occurred after the diagnosis of CD. Brain et al. observed several alterations in pattern of puberty among pediatric patients with IBD [7]. The mean age at onset of puberty was delayed for both female and male patients when compared to healthy controls: 12.6 years v. 11.1 years in girls and 13.2 years v. 12.4 years in boys. The duration of puberty was prolonged, especially in adolescents with frequent relapses during puberty [7]. Some patients with IBD took up to 4 years to progress from Tanner stage 2 to stage 4. Peak height velocities during puberty reached rates >12 cm/yr in patients who remained in remission in contrast to as little as 1–2 cm/yr in those with relapsing disease. When surgical resection was indicated in 11 pre-pubertal children with Crohn disease, puberty started within one year of resection. Homer et al. reported similar findings but noted that catch-up, even in prepubertal patients, occurred only in those with sustained clinical remission [28]. Brain et al. postulated that if the onset of puberty was delayed beyond fourteen years that the final height may be “irreparably compromised” [7]. Our data would confirm that statement. We observed that there was a strong correlation between age at menarche and height gain [29]. When menarche occurred at < 13 years of age, the mean increment in height was 10 cm compared with 3.0 cm in those aged > 15 years.
Pubertal Arrest GnRH response is blunted in malnourished state and improves with weight gain [30]. This may be a more complex issue with weight not the sole independent variable. Stress and inflammation may also have important roles. In addition to delays in the onset of puberty, slowing or cessation of sexual maturation may occur in patients with IBD. For example, secondary amenorrhea is a well-recognized complication of weight loss.
Potential Causes of Pubertal Delay in Patients with IBD The complex interactions between severity of disease, fluctuations in inflammatory cytokines and their effect on nutritional status and hormonal profile make it difficult to determine how individual factors influence the onset and progression of puberty in pediatric patients with IBD.
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As a consequence, while nutritional deficits are well described in patients, other aspects such as the potential role of inflammatory cytokines on puberty are often extrapolated from animal models [31]. Nutritional Causes of Pubertal Delay Undernutrition in the absence of disease may cause delay in menarche and sexual maturation. Frisch reported that during the adolescent growth spurt prior to menarche there is a continuous decline in the percent body water and increase in body fat resulting in a change in the ratio of lean body weight from 5:1 to 3:1 and a mean percent body fat at menarche of 22% [32–34]. She noted that the mean weight at menarche in girls in the United States was 47.8 ± 0.5 kg [32–34]. A possible relationship between body fat and menarche was suggested by adipose tissue being a significant extra-gonadal site of estrogen production through conversion of androgen into estrogen. She postulated that the decrease in age at menarche (approximately 3–4 months each decade over the past 100 years) is due to girls reaching the weight earlier due to improved nutrition. For girls with primary amenorrhea due to undernutrition, a minimal equivalent of 17% body fat may be necessary for menarche to occur [32–34]. For girls experiencing secondary amenorrhea, resumption of menses usually occurred when weight gain was 10 percent higher than the weight at menarche. Dreizen et al. compared the age at menarche of 30 girls with “chronic undernutrition” with 30 “well-nourished” girls living in north central Alabama [35]. The average age at menarche was 14.5 years in the former group and 12.4 years in the latter group. Interestingly, standing heights which had differed by 9.2 cm at 12.5 years decreased to 3.5 cm at 14.5 years and were not significantly different (1.1 cm) at 17 years. Similarly, skeletal age was delayed in the undernourished group but at the time those girls reached menarche the bone age was only 3.8 months younger than the well-nourished group. Complete fusion of the epiphyses was delayed in the malnourished group to 17.6 years versus 15.9 years for healthy controls. Therefore, although the time of the adolescent growth spurt was delayed by undernutrition, final height (in the absence of underlying disease) was not significantly reduced. An earlier study by the same authors in undernourished boys also showed delayed epiphyseal fusion to 18.7 years versus 17.0 years and a mean difference in height between the groups of 2.68 inches at 16 years [36]. Unfortunately, final adult heights were not reported. Similar delays in menarche (with onset averaging 15.1 ± 0.5 years) are seen in ballet dancers, swimmers and runners whose training and low calorie intakes begin prior to menarche [33, 34]. Frisch postulated that these females have a raised lean/fat ratio. Both increased nutrition and reduction in the intensity of training may restore menses. Athletic amenorrhea is a hypothalamic reversion to a more immature pattern in GnRH response. Normalization may occur with reduction in exercise and/or other stress without the weight change estimated by Frisch. Reduction in calorie intake has been documented in many studies of pediatric-onset IBD, especially CD [37–39]. Thus, undernutrition is likely to be one of the contributing factors leading to delay in the onset and progression of puberty. Similarly, secondary amenorrhea seen in female patients with IBD may be caused by weight loss, a frequent complication of IBD in adolescents. Sentango et al. used dual energy x-ray absorptiometry (DEXA) and anthropometric measures to compare fat mass (FM) and fat-free mass (FFM) in 132 pediatric patients with IBD and 66 healthy controls [24]. They found that patients had normal fat stores but reduced FFM, consistent with “inflammatory cachexia” [24]. They cited data suggesting that proinflammatory muscle-active cytokines may impair accretion of lean tissue. Burnham et al. compared 104 patients with Crohn disease (CD) to 233 healthy control subjects and documented delayed maturation in the CD group [40]. Patients within Tanner stages 2 to 4 averaged 1.4–1.5 years older than control subjects at the same pubertal stages. Lean mass was reduced by 8% in the patient CD group.
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It is the opinion of the authors that the role of undernutrition in both growth failure and sexual maturation may be underestimated if these complications are compared only with documented weight loss. Failure to gain weight (without a history of weight loss) may also adversely affect the timing of menarche and the progression of puberty. Advancement in puberty may also be related to excess weight gain [41]. Early adrenarche appears to be related to excess weight gain and may be accompanied by skeletal advancement and possibly earlier true puberty. This may be related to peripheral aromatization of adrenal androgens to estrogens in fat. Endocrine Aspects of Pubertal Delay Most studies of endocrine function in children and adolescents with IBD have been performed to investigate the causes of growth failure rather than the onset and progression of puberty [37–39, 42–46]. These reports in growth-impaired patients have generally demonstrated normal growth hormone (GH) secretion, thyroid function, cortisol response to hypoglycemia and gonadotropin response to luteinizing hormone releasing hormone (LHRH). What changes were observed such as reduced amplitude of the GH pulse or increase in reverse (rT3 ) triiodothyronine were not associated with reduced growth velocity [44]. We observed that weight loss could be associated with pre-pubertal levels of circulating sex hormones despite previous physical signs of pubertal progression [45]. Insulin-like growth factor I (IGF-1) may be significantly reduced in children and adolescents with IBD [31, 45, 47, 48]. This usually occurs despite the presence of adequate circulating levels of GH and is known as “growth hormone resistance”. Since IGF-1 is modulated by both growth hormone (GH) and nutritional status, it is not clear whether GH resistance is secondary to active disease or the decrease in calorie intake (or both) is causing the reduction in IGF-1 seen in this population [31, 45]. IGF-1 improves with nutritional restitution in children with IBD. Others have suggested that the IGF-1 rise following enteral nutrition or surgical resection in children with active IBD precedes improvement in nutritional status (based on anthropometric measures); however, more rapid indices of nutritional restitution such as prealbumin were not measured in those studies. Corkins et al. noted the major binding protein for IGF-1 (IGFBP-3) was also reduced at diagnosis in children with IBD which would result in a reduced half-life for circulating IGF-1 [47]. Recent evidence using a knockout mouse lacking only liver-derived IGF-1 demonstrated normal growth and development, suggesting an important role for paracrine or autocrine production of IGF-1 by nonhepatic tissues [49]. The use of IGF-1 as a potential therapeutic agent is hampered by concerns regarding an increased risk for colon cancer and other malignancies [50]. In a trinitrobenzene sulfonate (TNBS) model of experimental colitis in rats, Azooz et al. noted that puberty was delayed but plasma concentrations of gonadotropins were similar to healthy controls [51]. Interestingly, delayed puberty and reduced levels of plasma testosterone and 17estriol levels were present in both colitic and non-colitic pair-fed rats, compared to healthy controls, emphasizing the importance of caloric sufficiency. The frequency of delayed puberty was less in the food-restricted rats (28%) versus the colitis rats (57%), suggesting an independent role for inflammation in this process. However, the authors also noted that administering testosterone subcutaneously on a daily basis to the colitis rats normalized the onset of puberty. Pro-inflammatory Cytokines-Endocrine Interactions Recent in vitro studies have elucidated ways in which pro-inflammatory cytokines, known to elevated in patients with IBD such as tumor necrosis factor- (TNF-), interleukin-6 (IL-6) and interleukin-1 (IL-1 )), affect endocrine function. Several of these findings may be applicable to explaining pubertal delay in patients with chronic inflammatory bowel disease [52].
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TNF- has inhibitory effects on GH and sex hormone function. Transgenic mice overexpressing TNF- (or IL-6) are growth-impaired and have low IGF-1 levels despite normal GH because of inhibition of GH signaling within hepatocytes [53]. Denson et al. showed that TNF- suppressed GH receptor expression by inhibiting Sp1/Sp3 transactivators [54]. It has been suggested that GH therapy may overcome hepatic GH resistance induced by IL-6 [55]. TNF- decreased androgen receptor protein as well as dihydrotestosterone activation to induce cell proliferation. TNF-, IL-6 and IL-1 reduce testosterone synthesis in Leydig cells and steroidogenesis in cells in the ovary. TNF- and IL-1 induce anorexia. IL-6 inhibits hepatic GH signally by inducing a suppressor of cytokine-inducible signaling (SOCS-3) and reduces the half-life of IGF-1 by increasing the catabolism of its binding protein, IGFBP-3. TNF- and IL-6 also reduce IGF-1 action by inhibiting insulin receptor substrate 1 which influences IGF-1 binding to its receptors and interleukin-1 (IL-1 ).
Psyschosocial Issues and Puberty There is extensive literature describing dynamic changes in the psychosocial interests and concerns of adolescents. Shafer and Irwin addressed these issues and emphasized how they develop and are different among adolescents during early adolescence (ages 10–13 years), middle adolescence (ages 14–16 years) and late adolescence (ages 17–21 years) [56]. Delayed sexual maturation may have significant adverse effects on self-esteem and socialization [57]. Nottelmann, et al. studied the relationship between adolescent psychosocial adjustment and chronologic age, pubertal status and serum hormone levels [58]. In boys, adjustment problems were associated with low sex hormones or lower pubertal stage in conjunction with higher chronologic age. These included sadness/anxiety, problems with body and self-image. In girls, adjustment problems in social relationships were also associated with lower pubertal stage and higher age. Both groups had elevated levels of androstenedione, an adrenal hormone responsive to stress, which the authors suggested may be due to self-comparison with same-age peers. They speculated that boys may be more sensitive to hormonal influences and girls to environmental influences. In addition to the psychological response to pubertal delay, stress itself may interfere with functioning of the brain-pituitary-gonad axis. Evidence suggests that this may be mediated by elevated cortisol levels over a protracted period of time. Consten et al. noted that cortisol administration to male carp caused delayed testicular development, reduced testosterone levels and impaired maturation of pituitary gonadotrophs [59].
Therapeutic Approach to Addressing Pubertal Issues in IBD The observations and studies described above suggest that prolonged control of active inflammation and providing adequate nutrient intake are both essential in promoting normal puberty. Alperstein et al. reported that it took 2.5 to 10 years for 5 of 9 children with growth delay who were Tanner stage 1 to attain their pre-illness height percentile following surgery [60]. Often final height preservation is at odds with desire to pubesce. In our experience GH treatment is of little value unless there is reasonable disease control. Steroid-related growth effects may in part be ameliorated with GH treatment [61]. Artificial induction of puberty with estrogen or testosterone runs the risk of skeletal advancement without commensurate growth. An anabolic steroid such as oxandrolone (Anavar® ), which does not advance bony maturation as much in modest dose might be of some value. Prospective studies of the effects of testosterone and estradiol administration on the initiation and progression of puberty, growth and changes in skeletal maturation have not been reported in pediatric patients with IBD. However, a limited
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study involving five male adolescents with cystic fibrosis showed that growth velocity increased from a mean to 2.2 cm/yr to 7.2 cm/yr [62]. Ballinger et al. describe their current approach to “young patients with IBD” as including a 3 to 6 month course of 100–125 mg/month of intramuscular testosterone ester (enanthate or cypionate) in boys and ethynylestradiol 4–6 mcg/day for the same length of time in girls [63]. The publication of results from this regimen may provide important new information in the treatment of pubertal delay in pediatric patients with IBD. References 1. Irwin CE Jr, Shafer M. Adolescent health problems. In: Harrison’s Principals of Internal Medicine. 14 ed. New York: McGraw Hill; 1998:30–3. 2. Pralong FP, Voirol M, Giacomini M, et al. Acceleration of pubertal development following central blockade of the Y1 subtype of neuropeptide Y receptors. Regulatory Peptides 2000;95(1–3):47–52. 3. Blogowska A, Rzepka-Gorska I, Krzyzanowska-Swiniarska B. Is neuropeptide Y responsible for constitutional delay of puberty in girls? A preliminary report. Gynecol Endocrinol 2004;19(1):22–5. 4. Boyar R, Finkelstein J, Roffwarg H, Kapen S, Weitzman E, Hellman L. Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Engl J Med 1972;287(12):582–6. 5. Reiter EO, Fuldauer VG, Root AW. Secretion of the adrenal androgen, dehydroepiandrosterone sulfate, during normal infancy, childhood, and adolescence, in sick infants, and in children with endocrinologic abnormalities. J Pediatr 1977;90(5):766–70. 6. Guercio G, Rivarola MA, Chaler E, Maceiras M, Belgorosky A. Relationship between the growth hormone/insulin-like growth factor-I axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal girls. J Clin Endocrinol Metab 2003;88(3):1389–93. 7. Brain CE, Savage MO. Growth and puberty in chronic inflammatory bowel disease. Bailliere’s Clinical Gastroenterology 1994;8(1):83–100. 8. MacMahon B. Age at Menarche: United States, 1960–1970. Vital Health Statistics 11 1973;133:1–36. 9. Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;107(3):317–29. 10. Frisch RE, Revelle R. Height and weight at menarche and a hypothesis of menarche. Arch Dis Child 1971;46(249):695–701. 11. Zacharias L, Rand WM, Wurtman RJ. A prospective study of sexual development and growth in American girls: the statistics of menarchie. Obstet & Gynecol Survey 1976;31(4):325–37. 12. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44(235):291–303. 13. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970;45(239):13–23. 14. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 1976;51(3):170–9. 15. Tanner JM. Growth at Adolescence. 2 ed. Oxford: Blackwell Scientific Publications; 1962. 16. Schall JI, Semeao EJ, Stallings VA, et al. Self-assessment of sexual maturity status in children with Crohn disease. J Pediatr 2002;141(2):223–9. 17. Rapkin AJ, Tsao JC, Turk N, et al. Relationships among self-rated Tanner staging, hormones, and psychosocial factors in healthy female adolescents. J Pediatr Adoles Gynecol 2006;19(3):181–7. 18. Hildebrand H, Karlberg J, Kristiansson B. Longitudinal growth in children and adolescents with inflammatory bowel disease. J Ped Gastroenterol Nutr 1994;18(2):165–73. 19. Karlberg J, Fryer JG, Engstrom I, et al. Analysis of linear growth using a mathematical model. II. From 3 to 21 years of age. Acta Paed Scand 1987;337:12–29. 20. Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn disease. Gastroenterology 1988;95(6):1523–7. 21. Kirschner BS. Growth and development in chronic inflammatory bowel disease. Acta Paed Scand 1990;366:98–104. 22. Saha MT, Ruuska T, Laippala P, et al. Growth of prepubertal children with inflammatory bowel disease. J Ped Gastroenterol Nutr 1998;26(3):310–4.
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23. Motil KJ, Grand RJ, Davis-Kraft L, et al. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993;105(3):681–91. 24. Sentongo TA, Semeao EJ, Piccoli DA, et al. Growth, body composition, and nutritional status in children and adolescents with Crohn disease. J Pediatr Gastroenterol Nutr 2000;31(1):33–40. 25. Sawczenko A, Ballinger AB, Savage MO, et al. Clinical features affecting final adult height in patients with pediatric-onset Crohn disease. Pediatrics 2006;118(1):124–9. 26. Griffiths AM, Nguyen P, Smith C, et al. Growth and clinical course of children with Crohn disease. Gut 1993;34(7):939–43. 27. Ferguson A, Sedgwick DM. Juvenile onset inflammatory bowel disease: height and body mass index in adult life. BMJ (Clinical research ed 1994;308(6939):1259–63. 28. Homer DR, Grand RJ, Colodny AH. Growth, course, and prognosis after surgery for Crohn disease in children and adolescents. Pediatrics 1977;59(5):717–25. 29. Kirschner BS, Uebler N, Sutton MM. Growth after menarche in pediatric patients with chronic inflammatory bowel disease. Gastroenterology 1993;104:A629. 30. Beumont PJ, George GC, Pimstone BL, Vinik AI. Body weight and the pituitary response to hypothalamic releasing hormones in patients with anorexia nervosa. The J Clin Endocrinol Metab 1976;43(3):487–96. 31. Ballinger AB, Camacho-Hubner C, Croft NM. Growth failure and intestinal inflammation. QJM 2001;94(3):121–25. 32. Frisch RE. Fatness, menarche, and female fertility. Perspectives Biol Med 1985;28(4):611–33. 33. Frisch RE, Gotz-Welbergen AV, McArthur JW, et al. Delayed menarche and amenorrhea of college athletes in relation to age of onset of training. JAMA 1981;246(14):1559–63. 34. Frisch RE, Wyshak G, Vincent L. Delayed menarche and amenorrhea in ballet dancers. N Engl J Med 1980;303(1):17–19. 35. Dreizen S, Spirakis CN, Stone RE. A comparison of skeletal growth and maturation in undernourished and well-nourished girls before and after menarche. J Pediatr 1967;70(2):256–63. 36. Dreizen S, Stone R. Human Nutritive and Growth Failure. Postgrad Med 1962:381–6. 37. Kelts DG, Grand RJ, Shen G, et al. Nutritional basis of growth failure in children and adolescents with Crohn disease. Gastroenterology 1979;76(4):720–7. 38. Kirschner BS, Voinchet O, Rosenberg IH. Growth retardation in inflammatory bowel disease. Gastroenterology 1978;75(3):504–11. 39. Thomas AG, Taylor F, Miller V. Dietary intake and nutritional treatment in childhood Crohn disease. J Pediatr Gastroenterol Nutr1993;17(1):75–81. 40. Burnham JM, Shults J, Semeao E, et al. Whole body BMC in pediatric Crohn disease: independent effects of altered growth, maturation, and body composition. J Bone Miner Res 2004;19(12):1961–8. 41. Kaplowitz P. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics 2001;108:347–53. 42. Chong SK, Grossman A, Walker-Smith JA, et al. Endocrine dysfunction in children with Crohn disease. J Ped Gastroenterol Nutr 1984;3(4):529–34. 43. Farthing MJ, Campbell CA, Walker-Smith J, et al. Nocturnal growth hormone and gonadotrophin secretion in growth retarded children with Crohn disease. Gut 1981;22(11):933–8. 44. Gotlin RW, Dubois RS. Nyctohemeral growth hormone levels in children with growth retardation and inflammatory bowel disease. Gut 1973;14(3):191–5. 45. Kirschner BS, Sutton MM. Somatomedin-C levels in growth-impaired children and adolescents with chronic inflammatory bowel disease. Gastroenterology 1986;91(4):830–6. 46. Tenore A, Berman WF, Parks JS, et al. Basal and stimulated serum growth hormone concentrations in inflammatory bowel disease. J Clin Endocrinol Metab 1977;44(4):622–8. 47. Corkins MR, Gohil AD, Fitzgerald JF. The insulin-like growth factor axis in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2003;36(2):228–34. 48. Thomas AG, Holly JM, Taylor F, et al. Insulin like growth factor-I, insulin like growth factor binding protein-1, and insulin in childhood Crohn disease. Gut 1993;34(7):944–7. 49. Yakar S, Liu JL, Stannard B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Nat Acad Sci 1999;96(13):7324–9. 50. Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 2001;131(11 Suppl):3109S–20S.
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51. Azooz OG, Farthing MJ, Savage MO, et al. Delayed puberty and response to testosterone in a rat model of colitis. Am J Physiol 2001;281(5):R1483–91. 52. Wong SC, MacRae VE, McGrogan P, et al. The role of pro-inflammatory cytokines in inflammatory bowel disease growth retardation. J Pediatr Gastroenterol Nutr 2005;43:144–155. 53. Wang P, Li N, Li JS, et al. The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity. World J Gastroenterol 2002;8(3):531–6. 54. Denson LA, Menon RK, Shaufl A, et al. TNF-alpha downregulates murine hepatic growth hormone receptor expression by inhibiting Sp1 and Sp3 binding. J Clin Invest 2001;107(11):1451–8. 55. Theiss AL, Fruchtman S, Lund PK. Growth factors in inflammatory bowel disease: the actions and interactions of growth hormone and insulin-like growth factor-I. Inflammatory Bowel Diseases 2004;10(6):871–80. 56. Shafer M, Irwin C. The adolescent patient. In: Rudolph A, ed. Rudolph’s Pediatrics. 14 ed: Norwalk, Appleton and Lange; 1995. 57. Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterology Clin N Amer 2003;32(3):967–95. 58. Nottelmann ED, Susman EJ, Inoff-Germain G, et al. Developmental processes in early adolescence: relationships between adolescent adjustment problems and chronologic age, pubertal stage, and pubertyrelated serum hormone levels. J Pediatr 1987;110(3):473–80. 59. Consten D, Bogerd J, Komen J, et al. Long-term cortisol treatment inhibits pubertal development in male common carp, Cyprinus carpio L. Biology of Reproduction 2001;64(4):1063–71. 60. Alperstein G, Daum F, Fisher SE, et al. Linear growth following surgery in children and adolescents with Crohn disease: relationship to pubertal status. J Pediatr Surg 1985;20(2):129–33. 61. Allen DB, Julius JR, Breen TJ, Attie KM. Treatment of glucocorticoid-induced growth suppression with growth hormone. National Cooperative Growth Study. J Clin Endocrinol Metab1998;83(8):2824–9. 62. Landon C, Rosenfeld RG. Short stature and pubertal delay in male adolescents with cystic fibrosis. Androgen treatment. Amer J Dis Child (1960) 1984;138(4):388–91. 63. Ballinger AB, Savage MO, Sanderson IR. Delayed puberty associated with inflammatory bowel disease. Pediatr Res 2003;53(2):205–10.
13 Classification of Pediatric Inflammatory Bowel Disease Athos Bousvaros∗
Introduction The correct phenotyping and classification of children with inflammatory bowel disease (IBD) remains problematic, especially for the child with IBD limited to the colon. In a child presenting with bloody diarrhea and endoscopic evidence of colitis, even an experienced clinician may have trouble distinguishing acute self-limited colitis from inflammatory bowel disease, or ulcerative colitis from Crohn disease (CD). This chapter will review, in sequence: the diagnostic evaluation of IBD; the differentiation of acute self -limited colitis from Crohn disease; the differentiation of ulcerative colitis (UC) from Crohn disease; the classification of ulcerative colitis into subtypes; and the classification and phenotyping of Crohn disease. The reader is also referred to additional papers that discuss these issues in more detail: the recommendations for diagnosing IBD written by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) IBD working group, and the classification working group of the 2005 montreal world congress of gastroenterology [1, 2]. Much of this chapter is based on another manuscript this author and his colleagues prepared for the Journal of Pediatric Gastroenterology and Nutrition, which was recently published [3].
Diagnostic Evaluation of Inflammatory Bowel Disease Discussed elsewhere in the book, the diagnostic evaluation of inflammatory bowel disease involves both gathering evidence to support the diagnosis of CD or UC, and also gathering data to exclude other confounding conditions (e.g. tuberculosis, Clostridium difficile infection). Initially, a clinician must suspect the diagnosis of IBD on the basis of history, examination, and preliminary laboratory testing (hematocrit, erythrocyte sedimentation rate, albumin), and then exclude other intercurrent illnesses. At that point, the physician has a choice of a wide variety of diagnostic modalities to help the clinician in determining whether or not a patient has IBD (Table 13.1). The standard evaluation of an inflammatory bowel disease patient, however, consists of two tests: colonoscopy with biopsy, and radiographic imaging of the small bowel with contrast. Many clinicians also choose to perform an esophagogastroduodenoscopy with biopsy at the time of
*Athos Bousvaros, MD, MPH, Associate Director, Inflammatory Bowel Disease Center, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02421, Phone: 617 355 2962, Fax: 617 730 0494, E-mail:
[email protected]
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Table 13.1. Tests currently utilized in the diagnosis of IBD. Blood or serum Complete blood count Serum albumin Erythrocyte sedimentation rate C-reactive protein Serologies Anti-neutrophil cytoplasmic antibody Anti-Saccharomyces cerevisiae antibody Antibodies to outer membrane porin Antibodies to flagellin NOD 2 genetics (principally used in research studies) Radiographic Studies Barium contrast radiography Abdominal computed tomography Abdominal magnetic resonance imaging Radionuclide scintigraphy with Tc99 labeled white blood cells. Endoscopy and histology Upper endoscopy with biopsies Colonoscopy with biopsies Video capsule endoscopy
diagnosis also, because it frequently provides useful clinical information as to the disease type and severity. Most published studies regarding diagnosis involve the interpretation of these three tests, and this chapter will focus on how these are properly interpreted. Despite the wide availability of a multitude of diagnostic modalities, the correct diagnosis of inflammatory bowel disease rests on the accurate interpretation and correlation of endoscopic and histologic findings.
Distinguishing Acute Self-limited Colitis from Inflammatory Bowel Disease Involving the Colon It is now recognized that our current culture methods are capable of identifying only a small subset of microorganisms that inhabit the intestine, and we cannot reliably culture all pathogens from a stool sample. In addition, a small number of documented cases of infectious colitis last longer than thirty days [4, 5]. Therefore, not every patient with bloody diarrhea and negative stool cultures has inflammatory bowel disease as the cause of their colitis. To definitively state a patient has UC in epidemiologic studies, some investigators have utilized very strict criteria (e.g. bloody diarrhea for over 6 weeks, or greater than two episodes of colitis within a six month period) [6, 7]. However, for the practicing clinician trying to determine whether or not to treat his/her patient for IBD, waiting 6 weeks or more for a patient to “declare themselves” as having IBD is not appropriate. In patients with bloody diarrhea and negative stool cultures, performance of colonoscopy with random biopsies for histology early in the course of suspected IBD is important. Studies suggest that colonoscopy with careful examination of biopsy samples will allow differentiation between acute self-limited colitis (ASLC) and IBD. In a cohort of 114 adults with acute colitis of less than 5 days duration, Mantzaris et al. performed colonoscopy at disease onset and subsequent flexible sigmoidoscopies at 1, 3, 6, and 18–24 months after initial illness. At 12 months after the onset of illness, a total colonoscopy was performed. Ultimately 68 patients were diagnosed with ASLC, and 46 patients were diagnosed with IBD (42 UC, 4 Crohn ileocolitis). Patients with UC had a significantly higher prevalence of diffuse erythema (100% vs. 25%),
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granularity (100% vs. 8%), and friability (100% vs. 12%) than patients with ASLC; in contrast, patients with self-limited colitis had a significantly higher prevalence of patchy erythema and microaphthoid ulcerations [8]. Histologic features identified reported in chronic inflammatory bowel disease but not in acute self-limited colitis include: basal plasmacytosis, basal lymphoid aggregates, crypt branching, crypt atrophy, and the presence of Paneth cells in the left colon. [5–10]. Other findings, such as focal crypt destruction or superficial aphthous lesions, do not reliably differentiate between ASLC and IBD [11]. In one pediatric study, 8 of 29 patients with focal active colitis (cryptitis with an adjacent increase in lamina propria macrophages and T lymphocytes) were ultimately diagnosed with Crohn disease; thus, while focal active colitis suggests the possibility of IBD, it is not a specific finding [12]. In summary, in a child with bloody diarrhea and negative stool cultures, the performance of colonoscopy with random biopsies throughout the colon may provide the clinician and pathologist with evidence that proves or disproves the diagnosis of inflammatory bowel disease. Endoscopic findings suggesting IBD include erythema, granularity, and friability, and histologic evidence supporting an IBD diagnosis include crypt distortion, crypt branching, and basal lymphoplasmacytic infiltrate.
Distinguishing Ulcerative Colitis from Crohn Disease Endoscopy and Biopsy It is usually straightforward in most patients to differentiate UC from CD on colonoscopy. In most cases of Crohn disease, the inflammation is limited to the ileum, cecum, and ascending colon. In contrast, classic ulcerative colitis typically begins in the rectum, extends proximally, is in a diffuse continuous distribution, and does not involve the small bowel. Even if Crohn disease is limited to the colon, the endoscopic appearance will help differentiate the two diseases; Crohn disease is characterized by aphthae, deep fissures, and cobblestoning, while UC is characterized by superficial inflammation, granularity, and friability. Evidence of ileal stenosis or ulceration, perianal disease, or granulomatous inflammation also helps establish the diagnosis of Crohn disease. Clinical, endoscopic, and histologic features that assist the clinician in differentiating these two conditions were summarized by the ESPGHAN working group, and are given in Table 13.2 [1]. However, a subset of patients with IBD involving the colon will have certain “non-classical” features that may make the clinician less certain as to whether the patient has ulcerative colitis or Crohn disease. These are summarized in Table 13.3; all of these findings have been reported in ulcerative colitis. While it may be tempting to give a patient a diagnosis of “indeterminate colitis” if a patient has any of these atypical features, such a diagnosis makes it more difficult to enter such a patient into clinical trials or epidemiologic registries. Therefore, the author of this chapter suggests that a physician considers classifying such a patient as ulcerative colitis, documents the nonclassical finding, and follow up the patient to see if the finding resolves or evolves over time. Some of these nonclassical findings (ileitis, gastritis, periappendiceal inflammation, rectal sparing, and “patchy” histology) are discussed in more detail below. “Backwash Ileitis” Versus Crohn of the Ileum “Backwash ileitis” was originally used to describe an abnormal appearance of the terminal ileum observed on radiologic testing or endoscopically in patients with ulcerative pancolitis. The term derives from the original contention that the ileitis resulted as a reaction to “the reflux of colonic contents into the terminal ileum”. Currently such ileitis in UC is considered to be primary ileal mucosal inflammation. The prevalence of backwash ileitis in both children and adults has been
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Table 13.2. Endoscopy and histology in inflammatory bowel disease. Crohn disease Endoscopy (and visualization Ulcers (aphthous, linear, or stellate) of oral and/or perianal regions) Cobblestoning Skip lesions Strictures Fistula Abnormalities in oral and/or perianal regions Segmental distribution Histology
Ulcerative colitis Ulcers Erythema Loss of vascular pattern granularity Friability Spontaneous bleeding Pseudopolyps Continuous with variable proximal extension from rectam Mucosal involvement Crypt distortion Crypt abscess
Submucosal (biopsy with suffcient submucosal tissue) or transmural involvement (surgical specimen) Ulcers, crypt distortion Gobler cell depletion Crypt abscess Mucin granulomas (rare) Granulomas (non-caseating, nonmucin) Continuous distribution Focal changes (within biopsy) Patchy distribution (biopsies)
Histology for both Crohn disease and ulcerative colitis included acute and chronic inflammation with architectural changes, loss of glands, and branching of crypts. Crohn disease abnormalities in oral region included lip swelling, gingival hyperplasia, aphthous ulcers: Crohn disease abnormalities in perianal region included tags, fissures, fistulae, and abscess. Source: Reprinted from: Inflammatory Bowel Disease Working Group of ESPGHAN. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis–the Porto criteria. J Pediatr Gastroenterol Nutr 2005;41(1): 1–7. Table 2. page 4. with permission. Lippincott Williams & Wilkins publishers.
evaluated in several studies. The most comprehensive study in adults was performed by Heuschen, et al. who evaluated 590 adults with UC undergoing colonic resection. In this study. 107 of 476 patients with pancolitis (22%) had evidence of backwash at colectomy; in contrast, backwash ileal inflammation was not seen in any patients with left sided ulcerative colitis [13]. The prevalence of backwash is similar in children [14]. In backwash ileitis, radiographic studies of the terminal ileum demonstrate a normal caliber ileum without stenosis or cobblestoning; however, a rough “sandpaper” appearance may be present in the terminal ileum [13, 15, 16]. At endoscopy, a patient with backwash ileitis has a normal ileocecal valve without signs of stricture, stenosis, or ulceration. In backwash ileitis, normal lymphoid nodules may be present, but no linear ulcerations, deep fissures, or areas of cobblestoning are seen. The histology of backwash ileitis, and what specific features differentiate this entity from CD of the ileum, is unclear. Studies suggest that changes seen in “backwash ileitis are usually mild, consisting of villous atrophy, increased mononuclear cells, and scattered crypt abscesses” [17]. One group has suggested that pyloric metaplasia seen in ileal biopsies is suggestive of CD [18]. Some investigators automatically classify a patient as having Crohn disease or indeterminate colitis if there is any histologic inflammation on an ileal biopsy [19, 20]. In the opinion of a recent NASGHAN working group, identification of nonspecific or microscopic ileitis in a patient with typical features of UC does not warrant a change of diagnosis, unless there are specific features suggesting Crohn disease (e.g. linear ulcers, cobblestoning, or granulomas). Rather, if nonspecific ileitis is identified, the term “UC with backwash ileitis” is more appropriate. Suggested standard descriptions of ileal inflammation are provided in Table 13.4.
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Table 13.3. Non-classical findings at presentation in UC patients, which do not exclude the diagnosis of UC. 1. Clinical Small anal fissures or skin tags (<5 mm in size) Oral ulcers Growth impairment Diarrhea without macroscopic or microscopic blood 2. Endoscopic Gastritis without aphthae “Backwash ileitis” – ileal erythema without linear ulceration Periappendiceal inflammation in a patient without pancolitis Rectal inflammation less severe than in the more proximal colon (relative rectal sparing) 3. Histologic Microscopic ileitis without granuloma Microscopic gastritis without granuloma “Relative rectal sparing” (histologic inflammation less severe in the rectum). “Patchiness” (normal colonic mucosa in between two areas of colonic inflammation) Source: Reprinted with permission from Table 4, Journal pediatric GI and Nutrition 2007; 44: 660 Lippincott Williams & Wilkins publishers.
Gastritis in Patients with Inflammatory Bowel Disease Esophagogastroduodenoscopy (EGD) is increasingly being performed as part of the initial evaluation in children with suspected inflammatory bowel disease, especially if a child is under anesthesia. Performing an EGD in an intubated child adds very little time to the initial diagnostic evaluation, and may identify gastric pathology that requires additional medical treatment (e.g. proton pump inhibitors or immunomodulators). The Porto working group of ESPGHAN has recommended routine upper endoscopy at initial presentation to aid in the diagnosis of pediatric IBD [1]. However, in certain patients, the endoscopic or histologic findings seen on EGD may raise uncertainty as to whether the patient has CD or UC. It is now well documented that patients with both CD and UC may have upper GI tract inflammation, and that the prevalence of inflammation seen in the esophagus, stomach, and duodenum is comparable in both CD and UC. Both nonspecific gastritis and focally enhanced gastritis (defined as perifoveolar or periglandular mononuclear or neutrophilic infiltrate around gastric crypts) may be identified in the gastric biopsies of patients with IBD. Focal gastritis is more common in the gastric biopsies of patients with Crohn disease than patients with ulcerative colitis [1, 21, 22]. In a retrospective study of 238 children with UGI biopsies, focal gastritis was present in 5/24 (20.8%) of patients with UC, but it was more common in CD patients (28/43 or 65.1%) compared to 2.3% of controls without IBD and one of 39 with Helicobacter pylori [23]. The most useful histologic finding on upper endoscopy in the IBD patient is the identification of granulomas on routine biopsy of the esophagus, stomach, or duodenum. The performance of such biopsies in IBD patients at initial diagnosis will identify non-caseating granulomas in 12 to 28% of patients, which will establish the formal diagnosis of Crohn disease [21–27]. In one study by Kundhal et al., 39 children with ulcerative or indeterminate colitis and normal barium small bowel radiographs underwent upper endoscopy. Granulomas were present on antral biopsy in five patients (14%), thus changing the diagnosis to CD [25]. In a review of duodenal, antral and esophageal biopsies from children with CD and UC in whom Helicobacter pylori infection had been excluded, Tobin noted granulomas in 40% of patients. While the majority of these were identified in the stomach, granulomas could also be identified in the esophagus or duodenum [27]. While granulomas may also be seen in other conditions, including H. pylori disease and
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Table 13.4. Ileitis – suggested descriptions. 1. Normal ileum - an ileum that is both MACROSCOPICALLY and MICROSCOPICALLY normal, without features of inflammation. Lymphoid nodularity of the terminal ileal Peyer’s patches should be considered a normal finding. 2. Histologic backwash ileitis (microscopic inflammation of the ileum) - Active ileitis (focal or diffuse) with or without features of chronicity identified on histologic examination, with an endoscopically NORMAL ileum. 3. Endoscopic and histologic backwash ileitis - Endoscopic erythema and granularity of the terminal ileum, confirmed upon histology with findings of active or chronic ileitis. 4. Crohn disease of the ileum - linear ulceration, cobblestoning, and narrowing of the ileum, often associated with ulceration of the ileocecal valve. These findings may be demonstrated either by endoscopy of the terminal ileum, or by barium upper GI with small bowel follow-through contrast study. The histology may be normal (due to the focal nature of the inflammation), or demonstrate acute and chronic ileitis. The presence of non-caseating granulomas on ileal biopsy automatically classifies a patient as having CD of the ileum. Source: Reprinted from Table 6, JPGN 2007; volume 44: page 662. Differentiating ulcerative colitis from Crohn disease in children and young adults: a report of a working group of the North American Society of Pediatric Gastroenterology Hepatology and Nutrition, and the Crohn and Colitis Foundation of America.
sarcoidosis, the identification of upper GI tract granulomas on upper endoscopy strongly suggests Crohn disease in a child with IBD. Periappendiceal Inflammation in Ulcerative Colitis The finding of right colonic inflammation in a patient with disease limited to the left colon suggests a skip area, which should suggest Crohn disease. However, patients with UC that does not extend to the cecum may have an inflamed distal (left) colon, a normal transverse and ascending colon, and evidence of periappendiceal and cecal inflammation (a.k.a. a “cecal patch”). The finding of a “cecal patch” was well documented on studies of colectomy specimens, which demonstrate appendiceal involvement as a “skip lesion” that can be seen in UC [28–32]. More recently, prospective and retrospective studies of colonoscopy and histology have confirmed that periappendiceal inflammation is common in UC [32–38]. One pediatric study examined appendiceal from resected intestinal specimens of patients with IBD who failed medical therapy and found that all the patients in the study (17 UC, 24 CD) had appendiceal involvement [39]. Therefore, the clinician should be aware that mild periappendiceal inflammation can occur in both CD and UC. In CD, this appendiceal inflammation usually occurs in conjunction with more extensive inflammation of the ileum and cecum, with a more normal distal colon. In contrast, in UC, the appendiceal inflammation is seen in association with diffuse continuous disease, pancolitis in the colon. Rectal Sparing and Patchiness The classic definition of ulcerative colitis requires diffuse continuous disease that begins in the rectum and extends proximally, to some point higher up in the colon, without “skip areas.” “Rectal sparing”, where the rectum is not inflamed (absolute rectal sparing), or inflamed less severely than the more proximal colon (relative rectal sparing) was thought to be suggestive of Crohn disease. Recent studies emphasize that colonic inflammation may be less severe in children than in adults with new onset UC, leading to relative or absolute rectal sparing. Three of these studies compared new onset UC in children to that in adults, and all three suggested less severe and less diffuse architectural abnormalities in children. Two of these studies demonstrated a higher prevalence of rectal sparing in children compared to adults [40–42].
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The term “patchiness” refers areas of normal mucosa (either endoscopically or histologically) between two areas of colonic inflammation. As with rectal sparing, the finding of histologic “patchiness” was originally thought to be suggestive of a Crohn disease skip area. However, a number of studies suggest that rectal sparing and patchiness can be seen in acute self-limited colitis, new onset untreated ulcerative colitis in children, and medically treated ulcerative colitis in adults [41–44]. In the study by Glickman, et al. 16% of children with new onset treatment naïve UC had patchy chronic colitis, compared to no adults. The precise reason why the histology of new onset UC differs between children and adults is unclear, though it may be a function of younger age and shorter duration [42]. It is important to emphasize the effects of treatment on a patient with either CD or UC. Certain treatments, particularly immunomodulators and infliximab, are highly effective at inducing mucosal healing. Even milder medical therapies such as aminosalicylates may cause attenuation of inflammation, resulting in patchiness [43, 45]. Therefore, the best opportunity to distinguish CD from UC is at the initial endoscopic evaluation. Radiographic Imaging Studies in the Differentiation of UC from CD The role of barium radiography in differentiating between CD and UC is well established, and it is recommended by many experts that all children with IBD undergo an upper GI with small bowel follow through at the time of initial diagnosis. In Crohn disease of the ileum, the terminal ileum, ileocecal valve, and cecum demonstrate various degrees of narrowing, ulceration, and stenosis [46]. In contrast, in UC with backwash ileitis the terminal ileum has a granular appearance, the ileocecal valve is wide open, and the cecum is normal in caliber. Some authors have questioned the utility of barium radiography in otherwise healthy patients with a normal ileoscopy, because it is unclear how often the findings of a barium study change the diagnosis [46]. The role of other imaging modalities (ultrasound, nuclear medicine, computed tomography, and magnetic resonance imaging studies) in the differentiation of CD from UC varies greatly from center to center. All of these modalities have been utilized in the diagnosis of IBD patients, with good results [15, 47–49]. However, the benefits in diagnosis must be weighed against the cost and radiation exposure to the patient. Of the above modalities, MRI scan of the bowel offers the potential benefit of accurate anatomic localization without radiation. Recent studies suggest that MRI can differentiate between CD of the ileum and backwash ileitis by evaluating bowel wall thickness of the ileum [15, 48]. Serologies and Genetic Testing A number of serum markers of variable sensitivity and specificity are currently available as a “diagnostic panel for inflammatory bowel disease.” Serology is discussed in greater detail elsewhere in this book. The utility of serology in differentiating between CD and UC is highly controversial, and there remains doubt if this test has utility in routine clinical practice [50]. The Perinuclear anti neutrophil cytoplasmic antibody (pANCA) is identified in approximately 75% of patients with ulcerative colitis, and up to 20% of patients with Crohn disease [51–53]. In contrast, antibodies to Saccharomyces cerevisiae antibody (ASCA) are present in 40–80% of patients with Crohn disease, are rarely if ever seen in UC, and are preferentially associated with ileocecal Crohn disease. While in some children, antibody testing may assist in the diagnostic classification, the current diagnosis of CD and UC is based on endoscopy and histology, NOT on serology. Genetic testing for NOD 2 reliably identifies 25% of CD patients, principally patients with distal ileal and fibrostenosing disease [54]. In contrast, patients with UC do not have an increased prevalence of mutations in NOD2. At this time, genetic testing cannot reliably differentiate UC from CD of the colon, and is not routine recommended for use in clinical practice.
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Video Capsule Endoscopy Video capsule endoscopy is increasingly being utilized in the detection of obscure small bowel lesions, and now has a proven role in the identification of Crohn disease of the small intestine. The sensitivity of this technique at identifying small bowel ulceration or stricture appears to be superior to conventional barium radiography and enteroclysis [55, 56]. In one study of 20 adults, the yield of capsule endoscopy was 3 times that of enteroclysis in identifying small bowel Crohn disease [56]. The biggest concern with capsule endoscopy is that the capsule may become impacted in a patient with a small bowel stricture. For this reason, our approach is to initially perform a barium small bowel series as the initial study. If Crohn is strongly suspected, colonoscopy fails to identify disease, and a barium study shows no inflammation or stricture, we then perform a capsule study to evaluate for mid-small bowel Crohn disease.
“Indeterminate Colitis” or “Colonic IBD Type Unclassified” In some cases, a clinician is uncomfortable making a firm diagnosis of Crohn or ulcerative colitis based on the clinical presentation. These patients have traditionally received the diagnosis of “indeterminate colitis” (IC). The prevalence of “indeterminate colitis” appears to be higher in pediatric than in adult case series. In most adult epidemiologic studies, the prevalence of IC ranges from 5–10%, while pediatric series report a prevalence as high as 30% [57, 58]. It is highly unclear whether not this dramatic difference in the reported prevalence of IC between children and adults represent differences in biology or differences in what internists and pediatricians classify as UC. As the number of routine tests used in the diagnostic evaluation of IBD has grown, so has diagnostic uncertainty. While use of the “indeterminate colitis” classification may be easy for the clinician, this author recommends against overusing it. Specifically, classifying all UC patients as “indeterminate colitis” on the basis of nonspecific findings (e.g. nonspecific gastritis, patchiness, or backwash ileitis) may render a patient ineligible for clinical studies (which usually exclude patients with indeterminate colitis). In addition, overusing the IC classification will make epidemiologic studies of pediatric UC and CD more difficult in the future. The NASPGHAN working group has developed an algorithm to allow clinicians to differentiate CD from UC (Figure 13.1) [3]. The ongoing development of molecular genetic and serologic markers further complicates the differentiation of UC from CD from IC. For example, what if a patient with classical UC pancolitis is ASCA positive? This area remains controversial, and is the topic of ongoing active research. A recent consensus conference from Montreal concluded that the term “indeterminate colitis” be reserved for patients who have undergone colectomy, and that the term “colonic IBD type unclassified” be utilized in patients who have undergone endoscopy but still have an uncertain diagnosis [2]. In conclusion, further research studies are needed to develop reliable molecular and serum markers that will differentiate UC from CD. In the meantime, a patient may be given a putative diagnosis of indeterminate colitis if they have inflammatory bowel disease limited to the colon, and clinical features that are inconsistent with the diagnosis of UC (for example, ileal aphthae in left sided colitis, small perianal tags in a patient with pancolitis, severe growth failure in UC, or unusually severe focal gastritis). If the clinician decides to classify a patient as indeterminate colitis, it is suggested the physician clearly record the precise piece of clinical data that prompted the use of the IC diagnosis (e.g. absolute rectal sparing, small ileal ulcers without strictures or cobblestoning, backwash ileitis in a patient with left sided disease, growth failure). In the future, such a patient may benefit from additional evaluation to see if the finding prompting the IC diagnosis has changed or resolved. This may allow the clinician to establish a definitive diagnosis of CD or UC in the future, which may prove helpful to the patient.
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1 Patient with suspected inflammatory bowel disease - initial evaluation
2
1. Colonoscopy with biopsies. 2. Barium upper gastrointestinal series with small bowel follow-through 3. Consider upper endoscopy with biopsies
3
4 Are noncaseating granulomas (that are not adjacent to ruptured crypts) present in any of the mucosal biopsies?
Crohn disease (identify disease locations, utilize Montreal classification)
YES
NO 5
6 Is there radiographic or endoscopic evidence of small bowel stricturing, linear ulceration, fistulization, or cobblestoning?
Crohn disease (identify disease locations, utilize Montreal classification)
YES
NO 8
7 Is there evidence of perianal fistulae, abscess, or large (> 5 mm) skin tags?
Crohn disease (identify disease locations, utilize Montreal classification)
YES
NO 9 10 Is there definite cobblestoning or stricturing in the terminal ileum or colon, or segmental colitis at time of colonoscopy and ileoscopy?
Crohn disease (identify disease locations, utilize Montreal classification)
YES
NO 11 Is there diffuse continuous superficial inflammation of the colon beginning at the anus and extending proximally, WITHOUT endoscopic or histologic evidence of ileal inflammation?
12 Probable ulcerative colitis without backwash (subclassify into proctitis, left sided colitis, and pancolitis).
YES
NO 13 14 Is there diffuse pancolitis with superficial mucosal inflammation of the ileum identified by endoscopy or histology? (Upper GI series demonstrates a normal caliber ileum with a widely patent ileocecal valve)
Probable ulcerative colitis with backwash (typically occurs in patients with pancolitis).
YES
15 Are features that raise the question of Crohn disease and are uncommonly seen in ulcerative colitis (e.g. absolute rectal sparing, growth failure, "focal active gastritis") present in the patient's diagnostic evaluation?
16
YES
1. Classify as indeterminate colitis for now. 2. Carefully document the feature in the evaluation that raises diagnostic uncertainty. 3. Repeat diagnostic evaluation in the future to attempt to classify patient more definitively.
NO 17 Ulcerative colitis
Figure 13.1. Algorithm for differentiating UC from CD – from reference 3. Reprinted with permission from: J. Pediatric Gastroenterolgy Nutr. 2007; Figure 6, page 668–669, publisher Lippincott Williams & Wilkins.
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Subclassification of Ulcerative Colitis and Crohn Disease The Montreal working group recommends subclassifying patients with UC into one of 3 categories: Ulcerative proctitis (E1), left sided UC (E2), and extensive UC (E3). This classification is based on ENDOSCOPIC appearance, rather than histology. The inflammation in proctitis is limited to the rectum (typically the last 15 cm of colon). Left sided disease (E2) has endoscopic inflammation distal to the splenic flexure, while extensive disease (E3) extends proximally to the splenic flexure [2]. The term “pancolitis” is commonly used to define a patient whose entire colon is inflamed, and there is evidence that pancolitis is more common in children than in adults [41, 59]. Crohn disease is commonly subtyped on the basis of disease location (jejunal, ileal, ileocecal, ileocolonic, colonic only, or perianal), and disease behavior (inflammatory, penetrating, or stricuring). In an attempt to standardize reporting in the literature, a group of experts developed the “Vienna” classification [60]. This classification system was revised in 2005, resulting in the “Montreal classification” for IBD (Table 13.5). The Montreal classification assigns a code based on three variables: age (<16 years, 17–40, >40), location (ileum, colon, ileocolon, or upper gastrointestinal tract, and behavior (inflammatory, stricturing, penetrating). One major difference from the Vienna classification is that perianal complications by themselves no longer automatically place a patient into the “penetrating” disease behavior group. Rather, the penetrating phenotype is reserved for patients who develop internal fistulae or abdominal abscesses, and perianal disease is treated as a modifier. The current Montreal system still has some drawbacks; for example, it does not differentiate a patient with classic ileocecal Crohn disease from a patient with “UC-like” pancolitis and ileitis in whom granulomas are identified on biopsy. Undoubtedly, additional modifications and improvements to the current phenotyping system will be included over time. In spite of its these issues is a state of the act consensus document by experts. Therefore, we recommend the “Montreal classification” be used for clinical and epidemiologic studies.
Table 13.5. Subclassification of Crohn disease – the “Montreal Classification”. Age at diagnosis (A) A1 16 years or younger A2 17–40 years A3 Over 40 years Location (L) L1 L2 L3 L4
Terminal ileum Colon Ileocolon UpperGI
Behaviour (B) B1∗ B2 B3
Nonstricturing, nonpenetrating Stricturing Penetrating
Upper GI modifier (L4) L1 + L4 L2 + L4 L3 + L4 – Perianal disease modifier B1p B2p B3p
Terminal ileum+ Upper GI Colon + Upper GI Ileocolon + Upper GI –
Nonstricturing, nonpenetrating+trating+perianal Stricturing + perianal Penetrating + perianal
∗ B1 category should be considered ‘interim’ until a prespecified time has elapsed from the time of diagnosis. Such a time period may vary from study to study (eg.5–10 years is suggested) but should be defined in order for B1 behaviour to be considered ‘definitive’. GI Gastrointestinal Source: Reprinted from reference 2. with permission of author and pulsus publishing group
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Summary The correct classification of a patient with inflammatory bowel disease requires careful attention to detail. Patients presenting with signs and symptoms that suggest IBD need to be evaluated in full with a physical examination, supportive laboratory testing, stool cultures, radiographic studies, and endoscopy. If feasible, we recommend upper GI series with small bowel follow through, upper endoscopy, and colonoscopy at the time of disease onset. Two or three biopsies should be taken from each region of the bowel, and given to the pathologist, with a careful endoscopic description that will allow correlation of endoscopy and histology. Patients with colitis and nonspecific findings such as gastritis and backwash ileitis can still have ulcerative colitis. Criteria from the Porto and Montreal groups will help reduce inter-observer variability. Additional research involving imaging, capsule endoscopy, serology, and genetics may prove helpful in the future. However, in 2007, the cornerstone of IBD classification is careful endoscopic evaluation and microsopic examination of biopsied tissue. References 1. Inflammatory Bowel Disease Working Group of ESPGHAN. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis–the Porto criteria. J Pediatr Gastroenterol Nutr 2005;41(1):1–7. 2. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005;19 Suppl A:5–36. 3. Bousvaros A, Antonioli D, Colletti C, et al. NASPGHAN Clinical Report: Differentiating ulcerative colitis from Crohn disease in children and young adults: Report of a working group of the North American Society for Pediatric Gastroenterology Hepatology and Nutrition, and the Crohn and Colitis Foundation of America. J Pediatr Gastroenterol Nutr, 2007, 44: 653–674. 4. Drake AA, Gilchrist MJ, Washington JA, 2nd, Huizenga KA, Van Scoy RE. Diarrhea due to Campylobacter fetus subspecies jejuni. A clinical review of 63 cases. Mayo Clin Proc 1981;56(7):414–23. 5. Nostrant TT, Kumar NB, Appelman HD. Histopathology differentiates acute self-limited colitis from ulcerative colitis. Gastroenterology 1987;92(2):318–28. 6. Garland CF, Lilienfeld AM, Mendeloff AI, Markowitz JA, Terrell KB, Garland FC. Incidence rates of ulcerative colitis and Crohn disease in fifteen areas of the United States. Gastroenterology 1981;81(6):1115–24. 7. Loftus EV, Jr., Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Ulcerative colitis in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gut 2000;46(3):336–43. 8. Mantzaris GJ, Hatzis A, Archavlis E, et al. The role of colonoscopy in the differential diagnosis of acute, severe hemorrhagic colitis. Endoscopy 1995;27(9):645–53. 9. Konuma Y, Tanaka M, Saito H, Munakata A, Yoshida Y. A study of the histological criteria for ulcerative colitis: retrospective evaluation of multiple colonic biopsies. J Gastroenterol 1995;30(2):189–94. 10. Surawicz CM, Haggitt RC, Husseman M, McFarland LV. Mucosal biopsy diagnosis of colitis: acute self-limited colitis and idiopathic inflammatory bowel disease. Gastroenterology 1994;107(3):755–63. 11. Wong NA, Penman ID, Campbell S, Lessells AM. Microscopic focal cryptitis associated with sodium phosphate bowel preparation. Histopathology 2000;36(5):476–8. 12. Xin W, Brown PI, Greenson JK. The clinical significance of focal active colitis in pediatric patients. Am J Surg Pathol 2003;27(8):1134–8. 13. Heuschen UA, Hinz U, Allemeyer EH, et al. Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis. Gastroenterology 2001;120(4):841–7. 14. Alexander F, Sarigol S, DiFiore J, et al. Fate of the pouch in 151 pediatric patients after ileal pouch anal anastomosis. J Pediatr Surg 2003;38(1):78–82. 15. Laghi A, Borrelli O, Paolantonio P, et al. Contrast enhanced magnetic resonance imaging of the terminal ileum in children with Crohn disease. Gut 2003;52(3):393–7.
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16. Riddell RH. Pathology of idiopathic inflammatory bowel disease. In: Kirsner J, ed. Inflammatory Bowel Disease, 5th edition. Phildelphia: WB Saunders, 2000;427–50. 17. Haskell H, Andrews CW, Jr., Reddy SI, et al. Pathologic features and clinical significance of “backwash” ileitis in ulcerative colitis. Am J Surg Pathol 2005;29(11):1472–81. 18. Koukoulis GK, Ke Y, Henley JD, Cummings OW. Detection of pyloric metaplasia may improve the biopsy diagnosis of Crohn ileitis. J Clin Gastroenterol 2002;34(2):141–3. 19. Geboes K, Ectors N, D’Haens G, Rutgeerts P. Is ileoscopy with biopsy worthwhile in patients presenting with symptoms of inflammatory bowel disease? Am J Gastroenterol 1998;93(2):201–6. 20. Joossens S, Reinisch W, Vermeire S, et al. The value of serologic markers in indeterminate colitis: a prospective follow-up study. Gastroenterology 2002;122(5):1242–7. 21. Parente F, Cucino C, Bollani S, et al. Focal gastric inflammatory infiltrates in inflammatory bowel diseases: prevalence, immunohistochemical characteristics, and diagnostic role. Am J Gastroenterol 2000;95(3):705–11. 22. Pascasio JM, Hammond S, Qualman SJ. Recognition of Crohn disease on incidental gastric biopsy in childhood. Pediatr Dev Pathol 2003;6(3):209–14. 23. Sharif F, McDermott M, Dillon M, et al. Focally enhanced gastritis in children with Crohn disease and ulcerative colitis. Am J Gastroenterol 2002;97(6):1415–20. 24. Abdullah BA, Gupta SK, Croffie JM, et al. The role of esophagogastroduodenoscopy in the initial evaluation of childhood inflammatory bowel disease: a 7-year study. J Pediatr Gastroenterol Nutr 2002;35(5):636–40. 25. Kundhal PS, Stormon MO, Zachos M, Critch JN, Cutz E, Griffiths AM. Gastral antral biopsy in the differentiation of pediatric colitides. Am J Gastroenterol 2003;98(3):557–61. 26. Ruuska T, Vaajalahti P, Arajarvi P, Maki M. Prospective evaluation of upper gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn disease. J Pediatr Gastroenterol Nutr 1994;19(2):181–6. 27. Tobin JM, Sinha B, Ramani P, Saleh AR, Murphy MS. Upper gastrointestinal mucosal disease in pediatric Crohn disease and ulcerative colitis: a blinded, controlled study. J Pediatr Gastroenterol Nutr 2001;32(4):443–8. 28. Davison AM, Dixon MF. The appendix as a ‘skip lesion’ in ulcerative colitis. Histopathology 1990;16(1):93–5. 29. Goldblum JR, Appelman HD. Appendiceal involvement in ulcerative colitis. Mod Pathol 1992;5(6):607–10. 30. Groisman GM, George J, Harpaz N. Ulcerative appendicitis in universal and nonuniversal ulcerative colitis. Mod Pathol 1994;7(3):322–5. 31. Kroft SH, Stryker SJ, Rao MS. Appendiceal involvement as a skip lesion in ulcerative colitis. Mod Pathol 1994;7(9):912–4. 32. Perry WB, Opelka FG, Smith D, et al. Discontinuous appendiceal involvement in ulcerative colitis: pathology and clinical correlation. J Gastrointest Surg 1999;3(2):141–4. 33. Matsumoto T, Nakamura S, Shimizu M, Iida M. Significance of appendiceal involvement in patients with ulcerative colitis. Gastrointest Endosc 2002;55(2):180–5. 34. Okawa K, Aoki T, Sano K, Harihara S, Kitano A, Kuroki T. Ulcerative colitis with skip lesions at the mouth of the appendix: a clinical study. Am J Gastroenterol 1998;93(12):2405–10. 35. Scott IS, Sheaff M, Coumbe A, Feakins RM, Rampton DS. Appendiceal inflammation in ulcerative colitis. Histopathology 1998;33(2):168–73. 36. Yamagishi N, Iizuka B, Nakamura T, Suzuki S, Hayashi N. Clinical and colonoscopic investigation of skipped periappendiceal lesions in ulcerative colitis. Scand J Gastroenterol 2002;37(2):177–82. 37. Yang SK, Jung HY, Kang GH, et al. Appendiceal orifice inflammation as a skip lesion in ulcerative colitis: an analysis in relation to medical therapy and disease extent. Gastrointest Endosc 1999;49(6):743–7. 38. D’Haens G, Geboes K, Peeters M, Baert F, Ectors N, Rutgeerts P. Patchy cecal inflammation associated with distal ulcerative colitis: a prospective endoscopic study. Am J Gastroenterol 1997;92(8):1275–9. 39. Kahn E, Markowitz J, Daum F. The appendix in inflammatory bowel disease in children. Mod Pathol 1992;5(4):380–3. 40. Faubion WA, Jr., Loftus EV, Sandborn WJ, Freese DK, Perrault J. Pediatric “PSC-IBD”: a descriptive report of associated inflammatory bowel disease among pediatric patients with psc. J Pediatr Gastroen-
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terol Nutr 2001;33(3):296–300. 41. Glickman JN, Bousvaros A, Farraye FA, et al. Pediatric patients with untreated ulcerative colitis may present initially with unusual morphologic findings. Am J Surg Pathol 2004;28(2):190–7. 42. Robert ME, Tang L, Hao LM, Reyes-Mugica M. Patterns of inflammation in mucosal biopsies of ulcerative colitis: perceived differences in pediatric populations are limited to children younger than 10 years. Am J Surg Pathol 2004;28(2):183–9. 43. Odze R, Antonioli D, Peppercorn M, Goldman H. Effect of topical 5-aminosalicylic acid (5-ASA) therapy on rectal mucosal biopsy morphology in chronic ulcerative colitis. Am J Surg Pathol 1993;17(9):869–75. 44. Washington K, Greenson JK, Montgomery E, et al. Histopathology of ulcerative colitis in initial rectal biopsy in children. Am J Surg Pathol 2002;26(11):1441–9. 45. Kim B, Barnett JL, Kleer CG, Appelman HD. Endoscopic and histological patchiness in treated ulcerative colitis. Am J Gastroenterol 1999;94(11):3258–62. 46. Horton K, Jones B, Fishman E. Imaging of the inflammatory bowel diseases. In: Kirsner J, ed. Inflammatory Bowel Disease, 5th edition. Philadelphia: WB Saunders, 2000;479–500. 47. Charron M. Pediatric inflammatory bowel disease imaged with Tc-99m white blood cells. Clin Nucl Med 2000;25(9):708–15. 48. Darbari A, Sena L, Argani P, Oliva-Hemker JM, Thompson R, Cuffari C. Gadolinium-enhanced magnetic resonance imaging: a useful radiological tool in diagnosing pediatric IBD. Inflamm Bowel Dis 2004;10(2):67–72. 49. Parente F, Greco S, Molteni M, Anderloni A, Bianchi Porro G. Imaging inflammatory bowel disease using bowel ultrasound. Eur J Gastroenterol Hepatol 2005;17(3):283–91. 50. Sabery N, Bass D. Use of serologic markers as a screening tool in inflammatory bowel disease compared with elevated erythrocyte sedimentation rate and anemia. Pediatrics 2007;119(1):e193–9. 51. Dubinsky MC, Ofman JJ, Urman M, Targan SR, Seidman EG. Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease. Am J Gastroenterol 2001;96(3):758–65. 52. Vasiliauskas EA, Kam LY, Karp LC, Gaiennie J, Yang H, Targan SR. Marker antibody expression stratifies Crohn disease into immunologically homogeneous subgroups with distinct clinical characteristics. Gut 2000;47(4):487–96. 53. Zholudev A, Zurakowski D, Young W, Leichtner A, Bousvaros A. Serologic testing with ANCA, ASCA, and anti-OmpC in children and young adults with Crohn disease and ulcerative colitis: diagnostic value and correlation with disease phenotype. Am J Gastroenterol 2004;99(11):2235–41. 54. Abreu MT, Taylor KD, Lin YC, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn disease. Gastroenterology 2002;123(3):679–88. 55. Eliakim R, Fischer D, Suissa A, et al. Wireless capsule video endoscopy is a superior diagnostic tool in comparison to barium follow-through and computerized tomography in patients with suspected Crohn disease. Eur J Gastroenterol Hepatol 2003;15(4):363–7. 56. Marmo R, Rotondano G, Piscopo R, et al. Capsule endoscopy versus enteroclysis in the detection of small-bowel involvement in Crohn disease: a prospective trial. Clin Gastroenterol Hepatol 2005;3(8):772–6. 57. Hildebrand H, Fredrikzon B, Holmquist L, Kristiansson B, Lindquist B. Chronic inflammatory bowel disease in children and adolescents in Sweden. J Pediatr Gastroenterol Nutr 1991;13(3):293–7. 58. Carvalho RS, Abadom V, Dilworth HP, Thompson R, Oliva-Hemker M, Cuffari C. Indeterminate colitis: a significant subgroup of pediatric IBD. Inflamm Bowel Dis 2006;12(4):258–62. 59. Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr 2003;143(4):525–31. 60. Gasche C, Scholmerich J, Brynskov J, et al. A simple classification of Crohn disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000;6(1):8–15.
Section 3 Diagnosis
14 The History and Physical Exam in Pediatric Inflammatory Bowel Disease Cheryl Blank and David J. Keljo∗
Introduction The history and physical exam form the foundation for medical care. Physicians learn that a good history and physical exam can point to a diagnosis, even before other investigations have been undertaken. This is particularly true for the diagnosis of inflammatory bowel disease (IBD). There are some challenges in obtaining a good history that are more frequent in pediatrics. Children are often too young or too shy to provide the pertinent information. Parents and care givers are frequently relied upon to provide the necessary details, and their skills as observers and reporters can vary widely. Many gastrointestinal disorders, such as infectious gastroenteritis and eosinophilic enteritis, may mimic the signs and symptoms of IBD. Within the spectrum of IBD, Crohn disease (CD) and ulcerative colitis (UC) may have overlapping clinical presentations as well as similar extraintestinal manifestations. A proper history and physical exam will help narrow the differential diagnosis and help lead more rapidly to a correct diagnosis and proper treatment.
History Consensus based criteria for the diagnosis of IBD have been developed by the European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). These criteria were based on review of a prospective registry of children with IBD [1]. The group suggested that there should be a clinical suspicion of IBD in any child with persistent (≥ 4 weeks) or recurrent (≥ 2 episodes in 6 months) symptoms of abdominal pain, diarrhea, hematochezia and weight loss [1]. Other supporting symptoms and signs were weight loss, lethargy and anorexia. While abdominal pain, weight loss, rectal bleeding and diarrhea are the symptoms which have been most frequently associated with IBD, the typical pattern of symptoms differs between Crohn disease and ulcerative colitis. Weight loss is more common in patients with Crohn disease. Diarrhea and rectal bleeding are more common presenting symptoms in ulcerative colitis. Children ∗
Associate Professor of Pediatrics, University of Pittsburgh School of Medicine, Director, Inflammatory Bowel Disease Center, Department of Gastroenterology, Children’s Hospital of Pittsburgh of UMPC, 3705 Fifth Ave, Pittsburgh, PA 15213, Phone: 412-692-5180, Fax: 412-692-7355, E-mail:
[email protected]
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Table 14.1. Frequency of symptoms in newly diagnosed patients with inflammatory bowel disease in Wisconsin, United States and United Kingdom. Wisconsin N = 199
Abdominal pain Diarrhea Rectal Bleeding Weight loss Fatigue Aphthous lesions Anorexia Arthritis Nausea/Vomiting Constipation/Soiling Anal fistula Growth failure/Delayed puberty Anal abscess, ulcer Erythema nodosum, rash Liver disease Toxic megacolon
Great Britain N = 739
UC
CD
UC n = 172
IC n = 72
CD n = 379
43% 98% 83% 38% 2% 13%
67% 30% 43% 55% 13% 5%
72% 74% 84% 31% 12%
75% 78% 68% 35% 14%
72% 56% 22% 58% 27%
6% 6% 0.5%
13% 4% 1%
25% 7.5% 6% 1% 4.5% 4% 2% 1.5%
1%
1% 1.5% 2%
0.5% 3% 0.5%
3%
UC= ulcerative colitis, CD= Crohn disease, IC= indeterminate colitis.
with IBD may also present with sole findings of perirectal abscess, weight loss, arthritis or fever. Table 14.1. summarizes the frequency of symptoms in studies from Wisconsin, United States and the United Kingdom [2, 3]. Careful attention to pain patterns can yield important information. Patients with esophageal ulcerations may complain of odynophagia or dysphagia while eating, or heartburn after eating. Gastritis or duodenitis may result in early satiety or vomiting. Distal ileal stenosis or strictures will be associated with pain and nausea beginning an hour or more after a meal and may also be associated with abdominal distension and vomiting. Small bowel inflammation is frequently associated with a sensation of bloating and generalized malaise. Crampy lower abdominal pain reflecting colonic inflammation and rectal inflammation will additionally be marked by urgency of stooling and most commonly hematochezia. It is important to note that young children are frequently stoic and may under-report pain. They will also be less able than older children to describe or localize their pain. Questions regarding patient’s bowel movements are sometimes difficult to address but are necessary. Parents do not generally witness their child’s stools once toilet training has been completed and many adolescents never look at their stools let alone talk about them. Parents tend to say to the child when asked about stooling “You go every day, don’t you?” and it may require some effort to elicit the true pattern from the child. It is required not only to ask about the frequency of stooling but also to ask about the quality of the stool. Individuals have different definitions of diarrhea so it is important to ask a patient or care giver to describe the bowel movement in some detail. Stool diameter helps to get at issues of stool firmness or anal stenosis. “Does it fall apart when it hits the water?” is a question which is useful to distinguish between formed and loose stools. Nocturnal bowel movements are never normal, often reflect inflammation in the colon, and are highly suspicious for IBD. School-aged children may be afraid to report blood in the stools and adolescents may not look at their stools, so it is necessary to ask the patient if they are having bloody stools (and if they do not know to get them to look). Quantity of blood (Is it mostly blood or mostly stool?) and frequency of stooling can help to assess severity
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of colitis. Urgency, increased stooling frequency and tenesmus are symptoms indicative of rectal inflammation and may be seen in either CD or UC. Children with IBD often present with weight loss or poor weight gain, growth failure and pubertal delay. Growth failure is a unique characteristic of pediatric IBD, as opposed to adult IBD, and occurs in 10–40% of patients at the time of presentation [1]. While it can be seen both in CD and UC, it is more common in CD. When malnutrition and growth failure are the only signs, IBD is sometimes misdiagnosed as anorexia nervosa. IBD patients may present with non-specific symptoms or solely with the extra-intestinal manifestations of IBD. Fever of unknown origin (FUO) is defined as documented daily temperatures greater than 101 degrees Fahrenheit persisting for greater than 3 weeks without a cause despite an extensive work up. It has been estimated that 5% of children with FUO will ultimately be diagnosed with inflammatory bowel disease and that roughly 2% of patients diagnosed with IBD will present with fever alone [4]. Approximately 4% of patients with IBD will present with a predominant symptom of arthritis. The arthritis of IBD is typically pauciarticular and involving large joints. Arthritis pain tends to be worse in the morning. Distinction from infectious arthritis is obviously important. Patients with Crohn disease may present first to the surgeon with perianal abscess or an appendicitis-like picture. Free perforations are occasionally seen. Patients with IBD can develop fistulas, or communications between bowel and bowel, bowel and skin or bowel and urinary tract. Unless specifically asked, patients may not mention air or feces in the urine. They may be seen first by the dermatologists with painful and non-specific rashes, especially on the lower extremities. A large fraction of patients with erythema nodosum or pyoderma gangrenosum will be found to have IBD. Rare patients will have swelling of the lips as the only external manifestation of IBD. Along with the history of present illness, the family history may give clues to a diagnosis of IBD as well. Somewhere between 11 and 29% of newly diagnosed IBD patients will have a first or second degree relative with a history of IBD (2,5). Many parents with IBD worry about IBD in their children when they have any GI complaint. Symptoms in subsequent siblings tend to be more rapidly recognized than symptoms in probands. Social history and review of systems should be routinely obtained, as well as detailed allergy history.
Physical Exam The physical exam often confirms your suspicion after taking a thorough and complete history. The patient’s general appearance may reflect illness. Affect and energy are often lacking in ill patients. Significant anemia can manifest as pallor. Children with growth and pubertal delay may look much younger than their stated age. While the eye is a sensitive tool for nutritional assessment, careful measurement of height and weight are as important as obtaining of historical growth data. These must be plotted on growth and on height velocity charts. Decreased growth velocity is an important indicator of disease activity. With the recent increase in obesity incidence, normal nutritional status or even obesity does not exclude the possibility of IBD. Important changes may be seen in vital signs. Assessment of vital signs is also important. Fever can be a presenting sign of IBD and should be noted on exam. Tachycardia can indicate fever, anemia, hypoproteinemia or dehydration. Ocular findings of IBD include uveitis and episcleritis. A patient with newly diagnosed IBD should be referred to an ophthalmologist for a complete eye examination to evaluate for these extraintestinal manifestations of IBD and for baseline assessment for cataracts and glaucoma which can follow steroid therapy. Because these can be clinically silent, patients should follow up with their ophthalmologist yearly. The oral pharynx needs to be thoroughly examined looking
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for evidence of apthous lesions. Orofacial granulomatosis is an uncommon presentation of Crohn disease and appears as non-specific lip swelling [6]. It is important to assess cardiopulmonary status in any patient. IBD patients will rarely develop interstitial pneumonitis which may have minimal findings on exam or pericardial effusions which can manifest with friction rubs, muffled heart sounds or paradoxical changes in the blood pressure with respiration. The abdominal exam may be deceiving because the exam may be normal or exhibit only non-specific tenderness. Abdominal distension may be seen with obstruction, ileus, perforation, or toxic megacolon. The pitch of bowel sounds may be increased with distension of bowel loops. Bowel sounds may be diminished in frequency or absent with severe inflammation, peritonitis or ileus caused by medication or electrolyte imbalance. A “fullness” felt in the right lower quadrant may indicate thickened bowel in the area of the terminal ileum, an area often inflamed in patients with Crohn disease. A tender inflammatory mass may be clearly palpable in patients with CD which may indicate active inflammation or an abscess. Tenderness over an inflamed colon might be appreciated. A visual perianal exam and digital rectal exam, while unpleasant for the patient, are critical parts of the examination of patients with the potential diagnosis of IBD. Hemorrhoids are uncommon in children, are usually present only when straining and have the bluish discoloration reflecting venous distention. Small (<0.5 cm) skin tags may be present most commonly at 12 o’clock in patients with chronic constipation. Larger skin tags or skin tags in other locations are suggestive of Crohn disease. Deep perianal fissures are suggestive of and perianal fistulae are almost pathognomonic of Crohn disease. Occasionally perianal Crohn disease may not be painful and a patient may be unaware of the extent of their perianal disease. Perianal abscesses are generally marked by erythema, induration, fluctuance and severe tenderness. With significant perianal disease it may be impossible to perform a rectal exam in a conscious patient. When it can be performed reasonably comfortably, it may reveal important information regarding the presence or absence of blood in the stool, and presence or absence of anal stenosis. If the anal canal is stenotic and the small finger will pass through the anal canal the stenosis is usually not limiting of stool passage. During a digital rectal exam, the palpation of a tender mass or collection in the pelvis may facilitate distinction between ruptured appendix and IBD as causes of tenesmus. Examination of the skin, nails and joints may reveal important information. Finger clubbing may be present. Rashes, such as erythema nodosum and pyoderma gangrenosum, are found in patients with IBD and are relatively easily distinguishable from other, more common rashes. Joint effusions may be subtle.
Conclusion A careful history and physical examination may reveal important information regarding the diagnosis of IBD, distinction between Crohn Disease and ulcerative colitis and location of disease. Accurate assessment of disease activity and detection of complications will be facilitated by careful serial assessments of history and physical examination. References 1. IBD Working Group of the European Society for Paediatric Gastroenterology Hepatology and Nutrition. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis–the Porto criteria. Journal of Pediatric Gastroenterology & Nutrition 41(1):1–7, 2005. 2. Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. Journal of Pediatrics 143(4):525–31, 2003.
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3. Sawczenko A, Sandhu BK. Presenting features of inflammatory bowel disease in Great Britain and Ireland. Archives of Disease in Childhood 88(11):995–1000, 2003. 4. Miller LC, Sisson BA, Tucker LB, et al. Prolonged fevers of unknown origin in children: patterns of presentation and outcome. Journal of Pediatrics 129(3):419–23, 1996. 5. Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. Journal of Pediatrics 146(1):35–40, 2005. 6. Khouri JM, Bohane TD, Day AS. Is orofacial granulomatosis in children a feature of Crohn’s disease? Acta Paediatrica 94(4):501–4, 2005.
15 Differential Diagnosis of Pediatric Inflammatory Bowel Disease Thierry Lamireau∗
Introduction A diagnosis of inflammatory bowel disease (IBD) is usually suspected in patients with chronic digestive symptoms, especially diarrhea, with or without blood in the stool, abdominal pain, and poor weight gain. Numerous other diseases can have similar symptoms. For some of them, laboratory investigations, endoscopic, and even histological features may be difficult to distinguish from those of ulcerative colitis (UC) or Crohn disease (CD). In the short term the most important challenge is to rule out an infectious disease. In the long term, the differential diagnosis with other chronic diseases, such as eosinophilic gastroenteropathy, vasculitis, lymphoma, or immunodeficiency syndromes, may cause some difficulties. In some cases, the possibility of IBD, mostly CD, is considered in a child presenting with abdominal mass, isolated esophagogastroduodenal or perianal involvement.
Acute Onset Diarrhea In 10 to 20% of adults with IBD, patients present with apparently transient diarrhea, abdominal cramps, and low-grade fever [1]. In this acute onset disease, the diagnoses to be considered are mostly intestinal infection, food allergy and acute appendicitis. Intestinal Infection In the case of acute diarrhea, patients are thought to have viral gastroenteritis particularly if they appear to recover promptly. However, prolonged diarrhea, right lower quadrant tenderness or a slow recovery should alert the physician to the possibility of early IBD, although, in this setting, a bacterial or parasitic infection of the intestine is more likely to be responsible for prolonged symptoms. Stool sample should therefore be collected for culture and toxin assay that can identify one of the numerous pathogens responsible for intestinal infection (Table 15.1). According to the age, the severity of symptoms and the type of bacteria, an appropriate antibiotic treatment is then initiated. When no pathogen is present in the stools, an abdominal ultrasound is usually performed. It can show enlarged mesenteric lymph nodes, and thickening of the colonic and/or ∗ Division of Pediatric Gastroenterology,
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Children’s
Hospital,
Bordeaux,
France
E-mail:
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Table 15.1. Laboratory tests used to detect enteropathogens. Laboratory test
Organism suggested or identified
Microscopic stool examination fecal leukocytes trophozoïtes, cysts, oocysts, or spores spiral or S-shapped gram-negative bacilli Stool culture standard specific selective medium (to be specified to the laboratory) Stool cytotoxicity assay Culture of colonic biopsy sample Circulating antibodies
invasive or cytotoxin-producing bacteria Giardia lamblia, Entameoba histolytica, Schistosoma mansoni Campylobacter Escherichia coli, Shigella, Salmonella, Campylobacter, Yersinia Clostridium difficile, E coli O157:H7 Aeromonas, Plesiomonas shigelloïdes, Klebsiella oxytoca, Vibrio parahemolyticus Clostridium difficile (A or B toxin) Shigella, Salmonella, Campylobacter, Yersinia, Klebsiella oxytoca, E coli O157:H7, Mycobacterium tuberculosis Shigella, Salmonella, Campylobacter, Yersinia, Entameoba histolytica,
ileal wall, but these findings can be seen in infectious diseases as well as in IBD. Colonoscopy is then useful, enabling the visualization of colonic lesions and collection of biopsy samples for histology and culture. The endoscopist should describe the lesions precisely without directly stating a final diagnosis of IBD. Besides Clostridium difficile which is responsible for the typical pseudomembranous colitis, infection with numerous bacteria or parasites may lead to colonic lesions, which can be very similar to those of UC or CD [2] (Table 15.2). Moreover, intestinal infection is part of initial manifestations in 10 to 20% cases of IBD. When symptoms are severe, it is therefore justified to propose a short-course empiric treatment with ceftriaxone (or ciprofloxacin after 15 years of age), associated with metronidazol. If laboratory tests and evolution do not confirm the hypothesis of infection, the diagnosis can be changed to IBD because of histological findings. Acute inflammatory changes of cryptitis, and crypt abscesses with neutrophilic infiltration, are not specific and are seen in both entities. The Table 15.2. Main infectious agents responsible for IBD-like lesions during endoscopy. Microorganism Aeromonas Campylobacter Clostridium difficile Escherichia coli Klebsiella oxytoca Mycobacterium tuberculosis Plesiomonas shigelloides Salmonella enteritidis Shigella dysenteriae Vibrio parahemolyticus Yersinia enterocolitica Entamoeba histolytica Cytomegalovirus N = no Y = yes
possible Ileal involvement
Crohn-like aspect
UC-like aspect
N Y N N N Y N Y Y N Y N Y
+ ++ + + + +++ + + + + +++ + +
++ + + + + + +++ ++ +++ + + +++ +++
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more discriminatory findings in favor of a first manifestation of IBD are the presence of glandular bifurcations and distortions, an infiltration of the mucosa with plasmocytes, and the presence of granuloma [3, 4]. Nevertheless, these findings are rarely seen when endoscopy is performed at an early stage, and, in adults, most acute episodes of colitis remain initially unclassified. Half of these patients will relapse in the following three years, leading to a diagnosis of IBD, usually UC [5]. When the diagnosis is uncertain, one should avoid starting long lasting anti-inflammatory treatment and be cautious when giving information to the family. Food Allergy Food proteins, usually milk or soy, may produce an allergic colitis which is typically encountered in infants under the age of 2 with a family history of atopy [6–8]. Rectosigmoidoscopy usually shows mucosal erythema and nodularity [9], but lesions may include aphtous ulcerations that mimic UC. The diagnosis of allergy is suspected if an eosinophilic infiltration of the mucosa is present on histology [9, 10]. Patch tests using a panel of the main allergens responsible for food allergy in children can be used to direct the exclusion of the offending protein. A rapid disappearance of symptoms will then confirm the diagnosis [11]. Acute Appendicitis Acute appendicitis may cause some diarrhea, associated with the classic right lower quadrant pain and tenderness. If there is any doubt or the abdominal tenderness worsens, a laparotomy should be performed to avoid gangrenous or perforated appendicitis. In some rare cases, an ileal involvement of CD will be discovered during operation [12, 13].
Chronic or Recurrent Intestinal Symptoms Chronic or recurrent intestinal symptoms represent the most frequent presentation of IBD in the pediatric population, and include symptoms such as abdominal pain and diarrhea lasting sometimes for several months or years, especially in CD. This long delay until the diagnosis may be explained by the frequency of these symptoms as up to 10% of children between 7 and 11 years old seek medical attention for recurrent abdominal pain [14]. The periumbilical location of pain is not pathognomonic for functional abdominal pain since it is present in most children with IBD. In patients with uncomplicated abdominal pain, constipation, lactose intolerance, peptic disease, food allergy, pathology of the urinary tract, or psychosocial causes should be considered and eliminated. The presence of fever, anorexia, weight loss or growth disturbance, perineal involvement, blood in the stools, suggests the possibility of IBD. This diagnosis is strengthened by laboratory investigations showing anemia and increased inflammatory markers (C-reactive protein, erythrocyte sedimentation rate), or ultrasound examination of the abdomen showing a thickening of the intestinal wall. However, these features are not specific to IBD and further investigations are useful to eliminate other diseases (Table 15.3). Intestinal Infection Even in case of chronic digestive manifestations, an infectious disease remains the most frequent differential diagnosis to be considered [2, 15]. It is therefore important to collect stools for bacterial culture and parasitic pathogens at the initial evaluation of a patient with suspected IBD. Contrary to acute presentation, an anti-microbial treatment is generally not considered until laboratory tests have confirmed a specific infectious disease. According to the pathogen, the part of the gut involved and the symptoms may vary, leading to consideration of either CD or UC (Table 15.2).
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Table 15.3. Useful investigations for differential diagnosis of IBD in children with chronic diarrhea. Blood
polynuclear count and morphologic features lymphocyte count FACS enumeration of T and B lymphocytes serum electrophoresis IgG, A, M total haemolytic complement C3 , C4 concentrations Anti-Neutrophil Cytoplasm antibody Anti-Saccharomyces Cervisea antibody Anti-Transglutaminase antibody specific IgE against food allergens Anti-bacteria antibody (Shigella, Salmonella, Campylobacter, Yersinia, Entameoba histolytica)
Stools
fecal leukocytes microscopic examination standard and specific medium culture Clostridium difficile cytotoxin assay
Skin tests for
tuberculosis food allergens
Imaging of the abdomen
US examination CT-scan
Endoscopy
Oesogastroduodenoscopy biopsy for histology Ileo-colonoscopy biopsy for histology, bacterial culture
Infection with Yersinia enterocolitica is usually associated with a mild illness in children [16] but subacute and chronic ileitis or ileocolitis has been reported [16–18]. This can also be associated with erythema nodosum and arthritis, aphtous ulcers, and mucosal thickening of the terminal ileum and colon on US examination, mimicking CD [19]. Stool or biopsy sample cultures may require a specific enrichment medium, are time-consuming and not always positive. The diagnosis can be made by serology showing an increase (or a very high titre) of antibody titre in two successive sera. However, serology also has false positives (antigenic cross reaction with other bacteria), and false negatives (serology is specific for only three serotypes: Yersinia enterocolitica 03 and 09, and Yersinia pseudotuberculosis). Infection with enteropathogenic and enteroaggregative Escherichia coli (EPEC, EAEC) may be responsible for chronic diarrhea in children, especially when they live or travel in developing countries [20, 21]. Infection with Clostridum difficile leads to digestive disease ranging from self-limited diarrheal syndrome, to severe pseudomembranous colitis. Sometimes sustained symptoms lead to consideration of the possibility of IBD. Clostridum difficile infection must be sought in children receiving antibiotics, especially betalactamins, although it may occur without prior antibiotic therapy. Rectosigmoidoscopy, performed with care and minimal insufflation, reveals the presence of typical yellow-white pseudomembranes in approximately one third of patients [15] and infection is confirmed by the presence of the toxin A or B in stool. Nevertheless, Clostridium difficile infection can occasionally occur in patients with UC or CD, even without the use of antibiotics [22, 23], and stool toxin positivity has been reported in 5 to 25% of IBD patients with relapse, mostly after antibiotic exposure [22, 24]. Clinical symptoms are quite similar in both diseases,
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and it is recommended that stool cytotoxin assay for Clostridium difficile be obtained on children with IBD during acute relapses [22]. Giardia intestinalis infection can be associated with chronic diarrhea, abdominal pain and weight loss [25] which may occasionally lead one to consider the possibility of IBD. Giardia is found in most countries in the world, the prevalence being highest in developing countries. Trophozoites or cysts of Giardia intestinalis can be found in fresh stool specimens, or rectal biopsies. In some cases, it may be necessary to examine duodenal aspirate or biopsies. Jejunal morphology may be normal, although partial or even total villous atrophy has been reported [26, 27]. Failure to eradicate giardiasis can be due to hypogammaglobulinemia or deficit in secretory IgA. Entamoeba histolytica infection occurs mostly in developing countries. Infection may be asymptomatic, or lead to a dysenteric syndrome. Demonstration of Entamoeba histolytica trophozoites and cysts in stools remains the mainstay of diagnosis. Chronic amoebic colitis could lead to clinical, radiologic, and endoscopic findings that can be indistinguishable from those of IBD [28, 29]. However this differentiation is important because amoebiasis can become fulminant if the patient is treated with immunosupressive agents for a presumed IBD. In these chronic manifestations, the parasite can be difficult to find in stool samples or in rectal biopsies, even using a concentration technique. The presence of high titers of antibodies in the serum may then be helpful in the diagnosis of chronic amoebiasis. Intestinal tuberculosis remains a challenging diagnosis in developing countries, because treatments used for CD may adversely affect tuberculosis [30]. Intestinal tuberculosis involves the ileocecal region more frequently, isolated colonic location being present in only 10 to 25% of cases. Symptoms can be very similar to those of CD; these include diarrhea, abdominal pain, fever, weight loss, abdominal mass of the right iliac fossa, and even suppurative perineal lesions. The presence of intramural swelling, mesenteric thickness, stricture or fistula on x-ray or CT-scan can be encountered in both diseases [31], although the absence of, or minimal asymmetrical wall thickening, favors the diagnosis of tuberculosis [32]. Nodules, ulcers and strictures can be seen at ileocolonoscopy, or possibly at enteroscopy in the case of isolated jejunal lesions [33–36], but these lesions can be indistinguishable from those of CD. Skin reaction to antigen is present in only 70 to 80% of patients with intestinal tuberculosis. The diagnosis may be facilitated by the presence of active pulmonary tuberculosis (but this is only present in 20% of cases), or ascites, or large lymphadenopathy on imaging [32, 37]. Unfortunately, acid-alcohol-resistant bacilli are very rarely present on direct examination of intestinal biopsies, and culture is positive in only 40% of cases. PCR for Mycobacterium tuberculosis on intestinal biopsies is probably better, but it can be negative [36] and its diagnostic value remains to be evaluated. The characteristics of histologic lesions may be helpful [38]: in tuberculosis, granulomas are typically bigger, often confluent, located beneath the ulcerations, and absent in non-inflamed mucosa and half of them contain caseum. In cases of persistent doubt, empiric treatment with antituberculosis drugs is justified in countries where the prevalence of tuberculosis is high [34]. If the patient’s condition doesn’t improve, the diagnosis of CD should then be reconsidered. Primary intestinal infection with cytomegalovirus can occur in immunocompromised children but it is exceptional in immunocompetent children. Endoscopy reveals ulcerative and hemorrhagic colitis, and histological examination of the biopsy will confirm the infection with cytomegalovirus by finding typical intra-nuclear inclusions in the colonic mucosa, associated with immunostaining with a specific antibody. Cytomegalovirus may be present in the colonic mucosa at the initial manifestation or at relapses of UC [39]. The role of this virus in the severity of the lesions remains under debate: is it only an opportunistic agent present in inflamed tissues, or active infection which really worsens colonic lesions. In the case of manifestations of UC which are resistant to classic treatment, some authors recommend using a specific anti-viral therapy [39].
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Celiac Disease Celiac disease is easily recognized in the classic mode of presentation of infants who present with chronic diarrhea, anorexia, failure-to-thrive, and abdominal distension. Presentation is often less typical in older children who complain of abdominal pain, chronic diarrhea, anorexia, short stature, or iron-resistant anemia, symptoms that may also suggest IBD. In this situation, laboratory investigations should include specific antibodies, i.e. anti-gliadin, anti-endomysium and/or antitissue transglutaminase. If these antibodies are positive, the diagnosis of celiac disease will be further confirmed by jejunal biopsy showing total villous atrophy with increased number of intra-epithelial lymphocytes [40]. Eosinophilic Gastroenteropathy Eosinophilic gastroenteropathy is a rare condition characterized by infiltration of the gastrointestinal tract with eosinophils [41]. Most common symptoms are vomiting, abdominal pain and growth failure. Diarrhea associated with rectal bleeding is present in 23% of cases, especially in infants, and symptoms of protein-losing enteropathy are present in 33 to 100% of cases [42, 43]. Endoscopic examination may show nodularity, erythema, friability, erosions and ulcerations in the upper digestive tract and/or in the colon [9, 42, 44]. The diagnosis is strongly suggested by a context of food allergy or the association with hypereosinophilia in the blood, which is present in 70 to 100% of cases [42, 45]. The presence of excessive eosinophils in the digestive mucosa will confirm the diagnosis although it may also be encountered in CD. Gastric biopsies may demonstrate eosinophilic gastroenteropathy more consistently, most patients having more than 10 eosinophils per high power field in the antral or duodenal mucosa [42, 46]. Primary or Acquired Immunodeficiency Diseases The importance of the intestine as an immune barrier is highlighted by the proximity of gut-associated lymphoid tissue to the luminal surface of the gastrointestinal tract, an external environment which is rich in microbial pathogens and dietary antigens. Significant gastrointestinal disorders, leading to chronic diarrhea, malabsorption and failure-to-thrive, are frequently present in primary or acquired immunodeficiency diseases (Table 15.4). The most frequent diseases are recurrent, persistent, and severe or unusual infections [47]. Disturbance of the immune system in the gut may also lead to autoimmune diseases, excessive production of IgE, or malignancies [48, 49]. Immunodeficient patients may present with chronic non-specific enterocolitis, characterized at jejunal biopsy by subtotal villous atrophy with acute and chronic inflammatory cell infiltration of the lamina propria [47, 50–55]. This chronic non-specific enteropathy is non sensitive to a gluten-free diet and occurs in several immunodeficiency disorders, affecting humoral response (X-linked agammaglobulinemia, IgA deficiency, common variable immunodeficiency), T-cell function (Wiskott-Aldrich syndrome, Acquired Immuno Deficiency Syndrome), or both (combined immunodeficiency). In some cases, strictures of the intestine may develop [50, 56]. In these patients it is important to rule out infection with opportunistic bacteria or parasites, and also with more common pathogens, such as rotavirus, adenovirus, picornavirus [47, 55]. Enterocolitis that resembles CD is mostly associated with defects of phagocytic function. Patients with chronic granulomatous disease may present with chronic colitis, perirectal abscesses and fistulas and antrum narrowing [57, 58]. The similarity with CD also includes endoscopic appearance, radiographic abnormalities and even histologic features showing granulomas and giant cells in the digestive mucosa. Nevertheless, a paucity of neutrophils, an increased number of eosinophils, eosinophilic crypt abscesses, pigmented macrophages, and nuclear debris suggest chronic granulomatous disease [59]. Patients with CD11/CD18 Leucocyte Adhesion Molecule
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Table 15.4. Gastrointestinal manifestations in the main immunodeficiency syndromes. Immunodeficiency syndrome
Gastrointestinal manifestations
Predominantly antibody defects X-linked agammaglobulinemia IgA deficiency common variable immunodeficiency
persistent rotavirus, campylobacter or Giardia infection bacterial overgrowth gluten-sensitive enteropathy food allergies nodular lymphoid hyperplasia chronic non-specific colitis autoimmune diseases malignancies (gastric cancer, lymphoma) Crohn’s disease
Predominantly cellular defects severe combined immunodeficiency
severe, persistent opportunistic infections graft-versus-host disease
acquired immunodeficiency syndrome combined immunodeficiency Wiskott-Aldrich syndrome DiGeorge’s syndrome
persistent viral, parasitic, fungal or bacterial infections HIV enteropathy malignancies chronic non-specific colitis
Defects of phagocytic function congenital neutropenia
severe bacterial infections chronic diarrhea with malabsorption
chronic granulomatous disease CD11/CD18 leukocyte adhesion molecule deficiency Glycogen storage disease type 1b Hermansky-Pudlak syndrome
stomatitis, perineal abcesses Crohn-like colitis
Deficiency, a rare disorder of phagocytic function, present with oral and perineal involvement that may be mistaken for CD. These manifestations include stomatitis with pharyngitis, gingivitis with parodontitis, ischiorectal abscesses and distal ileocolitis [60]. Other disorders of neutrophils, such as glycogen storage disease type 1b and the Hermansky-Pudlack syndrome [61], and also IgA deficiency and acquired immunodeficiency syndrome may be associated with chronic colitis that resembles IBD [62, 63]. In patients presenting with digestive involvement resembling CD, a history of delayed umbilical cord separation (2 or 3 weeks), recurrent infections, and a young age, should alert the clinician to the possibility of an immunodeficiency disease and lead to prompt referral. Autoimmune Enteropathy Autoimmune enteropathy is characterized by severe persistent diarrhea associated with circulating auto-antibody against gut epithelial cell and/or another auto-immune disorder [64]. It may be an X-linked familial disease which includes polyendocrinopathy (IPEX syndrome) [65–67]. Although the colon is frequently involved [65, 68, 69], the lesions are predominant in the small intestine, with inflammatory cell infiltration of the mucosa, and subtotal or total villous atrophy [65, 66, 69], leading to secretory, protracted diarrhea in the first months of life [70, 71]. Nevertheless, antibodies
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to colonic epithelial cells have been also found in patients with UC [72], and 10% of IBD patients suffer from one or more auto-immune diseases [73], leading to some diagnostic difficulties in the older child. Intestinal Neoplasm Patients with intestinal lymphoma often present with chronic digestive symptoms, such as abdominal pain, distension, and/or diarrhea. Ultrasound examination and contrast study of the small bowel show a thickening of the intestinal wall, and/or narrowing of the lumen of the gut which can be very similar to CD [74]. Extension of the lesions is more precisely seen with a CT-scan of the abdomen, and upper digestive endoscopy and ileo-colonoscopy are mandatory to provide a histologic confirmation. Nevertheless, if the lesions are limited to part of the small intestine, the biopsy may require an enteroscopy or even a surgical procedure, by coelioscopy or laparotomy. Predisposing conditions for intestinal lymphoma in children include inherited or acquired immunodeficiency syndromes, immunosuppressive therapy, and Epstein-Barr Virus infection [75]. In developing countries, Mediterranean lymphoma is characterized by the proliferation of IgA-secreting B lymphocytes. The diagnosis is usually suspected because of the presence of alpha heavy chain in the serum [76]. Vasculitis Disorders Henoch-Schöenlein purpura (HSP) is a frequent vasculitis, involving the gut, skin, joints and kidney. Diagnosis is easily made in a child presenting with typical skin purpura. Gastrointestinal symptoms, i.e. colicky abdominal pain and bleeding, may precede the skin rash by a number of days, and some cases of isolated duodenojejunitis without purpura have been described [77]. In other less frequent systemic vasculitis, such as periarteritis nodosa [78–83], Wegener granulomatosis [84], Behcet’s disease [85–87], and lupus arteriosus [88, 89], intestinal involvement can lead to chronic abdominal pain associated with bleeding. Endoscopic and histological findings may be very similar to CD, even with the presence of granuloma. Extra-digestive manifestations, especially neurological, respiratory, renal and cutaneous lesions suggest systemic vasculitis (Table 15.5). On the other hand, extra-intestinal vasculitis can complicate IBD, involving the retina, brain, skin, muscle, joints and lung [44, 90–95]. Nevertheless, the differentiation between primary systemic vasculitis and IBD can be clinically challenging, but is important because their treatments and outcome are different [96]. The confirmation of the vasculitis process is more often evident on extra-intestinal biopsies (skin, muscle, kidney) than on intestinal biopsies, and on angiography showing aneurysms and caliber variation of visceral arteries [82].
Abdominal Mass The discovery of an abdominal mass has been found to reveal ileocolic CD in some adults and children [97–99]. Ultrasound examination and CT-scan of the abdomen are first line investigations which will exclude extra-digestive malignant tumors, such as lymphoma, sarcoma, nephroblastoma or neuroblastoma. When the mass is developed from the digestive tract, glandular lymphoma or adenocarcinoma of the colon, although rare in children, can be suspected [100, 101]. Radiologic findings may be very similar in some benign lesions, like leiomyoma, pseudoinflammatory tumor or tuberculosis [32, 102, 103]. Nevertheless, surgical exploration is generally required, leading to correct diagnosis after histologic examination of the excised tumor. Intestinal tuberculosis may be a challenging diagnosis because histologic findings may be very similar, although granulomas are typically larger and contain caseum in the case of tuberculosis [38]. Polymerase chain reaction for Mycobacterium tuberculosis should be systematically performed.
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Table 15.5. Extra-digestive manifestations and useful investigations for the diagnosis of systemic vasculitis in children with digestive symptoms resembling Crohn’s disease. Vasculitis
Extra-digestive manifestations
Investigations
Periarteritis nodosa
multiple neuritis myositis arterial hypertension skin ulcerations and gangrene
skin, muscle biopsy angiography
Wegener granulomatosis
epistaxis, sinusitis, otitis, hearing loss stridor, hoarseness cough, wheezing, dyspnea, hemoptysis necrotizing glomerulonephritis skin ulcerations and gangrene conjunctivitis, uveitis, optic neuritis pseudotumor cerebri
thoracic CT-scan c-ANCA nasal mucosa biopsy
Behcet’s disease
serious buccal aphtous genital ulcers uveitis thrombophlebitis menigoencephalitis
HLA-B5
Lupus arteriosus
typical facial erythema myocarditis, pericarditis, endocarditis pleuropneumonitis glomerulonephritis thrombophlebitis hemolytic anemia and thrombopenia keratoconjunctivitis, retinitis
antinuclear antibody anti-DNA antibody
Isolated Esophagogastroduodenal Involvement Esophagogastroduodenal involvement is present in about 25% of children with CD, usually discovered during upper digestive endoscopy with systematic biopsies, performed at initial workup [104–106]. More rarely, patients may present with symptoms suggestive of peptic disease, including epigastric burning pain and early satiety, these often being relieved by antacids or antisecretory treatment [107, 108]. Endoscopy can show heterogenous lesions, but irregularshaped ulcers and erosions in a disrupted mucosal pattern are suggestive of CD [105, 107, 109]. Uncommonly, patients present with an isolated gastric or duodenal ulcer [108]. In the case of long-lasting symptoms, altered growth rate, the possibility of CD should be kept in mind and a biopsy of the edge of the ulcer looking for the presence of granulomas should be performed [104, 105, 107].
Isolated Perianal Disease Skin tags, anal fissures, and perianal fistulae or abscesses are frequent in infants who are in diapers and/or have a history of constipation with hard stools. Such perianal lesions also occur in half of patients with CD, mostly in the context of colonic inflammation [110]. These lesions may precede other manifestations of intestinal disease in about one third of these patients [111]. In adolescents, perianal lesions can be severe [112, 113], hidden and unrecognized for several months. The diagnosis of CD should then be considered in the case of extensive or refractory perianal lesions occurring in older children. Confirmation of diagnosis will be obtained by the presence of granuloma on biopsies of perianal lesions that required surgery, and/or colonoscopy
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that will show colitis [111, 113]. More rarely, severe perianal lesions can be seen in tuberculosis [114], disorders of phagocytic function of neutrophil polynuclear [57, 58], or occur after trauma or sexual abuse [115, 116]. References 1. Schumacher G, Sandstedt B, Kollberg B. A prospective study of first attacks of inflammatory bowel disease and infectious colitis. Clinical findings and early diagnosis. Scand J Gastroenterol. 1994;29(3):265–74. 2. Rutgeerts P, Peeters M, Geboes K, Vantrappen G. Infectious agents in inflammatory bowel disease. Endoscopy. 1992;24(6):565–7. 3. Surawicz CM, Belic L. Rectal biopsy helps to distinguish acute self-limited colitis from idiopathic inflammatory bowel disease. Gastroenterology. 1984;86(1):104–13. 4. Nostrant TT, Kumar NB, Appelman HD. Histopathology differentiates acute self-limited colitis from ulcerative colitis. Gastroenterology. 1987;92(2):318–28. 5. Notteghem B, Salomez JL, Gower-Rousseau C, Marti R, Lemahieu M, Nuttens MC, et al. [What is the prognosis in unclassified colitis? Results of a cohort study of 104 patients in the Northern-Pas-de-Calais region]. Gastroenterol Clin Biol. 1993;17(11):811–5. 6. Goldman H, Proujansky R. Allergic proctitis and gastroenteritis in children. Clinical and mucosal biopsy features in 53 cases. Am J Surg Pathol. 1986;10(2):75–86. 7. Hill SM, Milla PJ. Colitis caused by food allergy in infants. Arch Dis Child. 1990;65(1):132–3. 8. Jenkins HR, Pincott JR, Soothill JF, Milla PJ, Harries JT. Food allergy: the major cause of infantile colitis. Arch Dis Child. 1984;59(4):326–9. 9. Odze RD, Bines J, Leichtner AM, Goldman H, Antonioli DA. Allergic proctocolitis in infants: a prospective clinicopathologic biopsy study. Hum Pathol. 1993;24(6):668–74. 10. Rosekrans PC, Meijer CJ, van der Wal AM, Lindeman J. Allergic proctitis, a clinical and immunopathological entity. Gut. 1980;21(12):1017–23. 11. Powell GK. Milk- and soy-induced enterocolitis of infancy. Clinical features and standardization of challenge. J Pediatr. 1978;93(4):553–60. 12. Fonkalsrud EW, Ament ME, Fleisher D. Management of the appendix in young patients with Crohn disease. Arch Surg. 1982;117(1):11–4. 13. Yang SS, Gibson P, McCaughey RS, Arcari FA, Bernstein J. Primary Crohn disease of the appendix: report of 14 cases and review of the literature. Ann Surg. 1979;189(3):334–9. 14. Apley J. The child with recurrent abdominal pain. Pediatr Clin North Am. 1967;14(1):63–72. 15. Tedesco FJ, Hardin RD, Harper RN, Edwards BH. Infectious colitis endoscopically simulating inflammatory bowel disease: a prospective evaluation. Gastrointest Endosc. 1983;29(3):195–7. 16. Marks MI, Pai CH, Lafleur L, Lackman L, Hammerberg O. Yersinia enterocolitica gastroenteritis: a prospective study of clinical, bacteriologic, and epidemiologic features. J Pediatr. 1980;96(1):26–31. 17. Vantrappen G, Ponette E, Geboes K, Bertrand P. Yersinia enteritis and enterocolitis: gastroenterological aspects. Gastroenterology. 1977;72(2):220–7. 18. Abdel-Haq NM, Asmar BI, Abuhammour WM, Brown WJ. Yersinia enterocolitica infection in children. Pediatr Infect Dis J. 2000;19(10):954–8. 19. Blaser MJ, Miller RA, Lacher J, Singleton JW. Patients with active Crohn disease have elevated serum antibodies to antigens of seven enteric bacterial pathogens. Gastroenterology. 1984;87(4):888–94. 20. Bhan MK, Raj P, Levine MM, Kaper JB, Bhandari N, Srivastava R, et al. Enteroaggregative Escherichia coli associated with persistent diarrhea in a cohort of rural children in India. J Infect Dis. 1989;159(6):1061–4. 21. Fang GD, Lima AA, Martins CV, Nataro JP, Guerrant RL. Etiology and epidemiology of persistent diarrhea in northeastern Brazil: a hospital-based, prospective, case-control study. J Pediatr Gastroenterol Nutr. 1995;21(2):137–44. 22. Gryboski JD. Clostridium difficile in inflammatory bowel disease relapse. J Pediatr Gastroenterol Nutr. 1991;13(1):39–41. 23. Greenfield C, Aguilar Ramirez JR, Pounder RE, Williams T, Danvers M, Marper SR, et al. Clostridium difficile and inflammatory bowel disease. Gut. 1983;24(8):713–7.
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50. Teahon K, Webster AD, Price AB, Weston J, Bjarnason I. Studies on the enteropathy associated with primary hypogammaglobulinaemia. Gut. 1994;35(9):1244–9. 51. Conley ME, Park CL, Douglas SD. Childhood common variable immunodeficiency with autoimmune disease. J Pediatr. 1986;108(6):915–22. 52. Bjarnason I, Sharpstone DR, Francis N, Marker A, Taylor C, Barrett M, et al. Intestinal inflammation, ileal structure and function in HIV. Aids. 1996;10(12):1385–91. 53. Kotler DP, Gaetz HP, Lange M, Klein EB, Holt PR. Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med. 1984;101(4):421–8. 54. Lim SG, Condez A, Poulter LW. Mucosal macrophage subsets of the gut in HIV: decrease in antigenpresenting cell phenotype. Clin Exp Immunol. 1993;92(3):442–7. 55. Ochs HD, Ament ME, Davis SD. Structure and function of the gastrointestinal tract in primary immunodeficiency syndromes (IDS) and in granulocyte dysfunction. Birth Defects Orig Artic Ser. 1975;11(1):199–207. 56. Abramowsky CR, Sorensen RU. Regional enteritis-like enteropathy in a patient with agammaglobulinemia: histologic and immunocytologic studies. Hum Pathol. 1988;19(4):483–6. 57. Mulholland MW, Delaney JP, Simmons RL. Gastrointestinal complications of chronic granulomatous disease: surgical implications. Surgery. 1983;94(4):569–75. 58. Johnson FE, Humbert JR, Kuzela DC, Todd JK, Lilly JR. Gastric outlet obstruction due to X-linked chronic granulomatous disease. Surgery. 1975;78(2):217–23. 59. Schappi MG, Smith VV, Goldblatt D, Lindley KJ, Milla PJ. Colitis in chronic granulomatous disease. Arch Dis Child. 2001;84(2):147–51. 60. Hawkins HK, Heffelfinger SC, Anderson DC. Leukocyte adhesion deficiency: clinical and postmortem observations. Pediatr Pathol. 1992;12(1):119–30. 61. Hazzan D, Seward S, Stock H, Zisman S, Gabriel K, Harpaz N, et al. Crohn-like colitis, enterocolitis and perianal disease in Hermansky-Pudlak syndrome. Colorectal Dis. 2006;8(7):539–43. 62. Sturgess I, Greenfield SM, Teare J, O’Doherty MJ. Ulcerative colitis developing after amoebic dysentery in a haemophiliac patient with AIDS. Gut. 1992;33(3):408–10. 63. Bernstein CN, Ament M, Artinian L, Ridgeway J, Shanahan F, Bernstein BB, et al. Milk tolerance in adults with ulcerative colitis Crohn ileitis in a patient with longstanding HIV infection. Am J Gastroenterol. 1994;89(6):872–7. 64. Unsworth DJ, Walker-Smith JA. Autoimmunity in diarrhoeal disease. J Pediatr Gastroenterol Nutr. 1985;4(3):375–80. 65. Powell BR, Buist NR, Stenzel P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr. 1982;100(5):731–7. 66. Satake N, Nakanishi M, Okano M, Tomizawa K, Ishizaka A, Kojima K, et al. A Japanese family of X-linked auto-immune enteropathy with haemolytic anaemia and polyendocrinopathy. Eur J Pediatr. 1993;152(4):313–5. 67. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002;39(8):537–45. 68. Hill SM, Milla PJ, Bottazzo GF, Mirakian R. Autoimmune enteropathy and colitis: is there a generalised autoimmune gut disorder? Gut. 1991;32(1):36–42. 69. Lachaux A, Loras-Duclaux I, Bouvier R. Autoimmune enteropathy in infants. Pathological study of the disease in two familial cases. Virchows Arch. 1998;433(5):481–5. 70. Catassi C, Fabiani E, Spagnuolo MI, Barera G, Guarino A. Severe and protracted diarrhea: results of the 3-year SIGEP multicenter survey. Working Group of the Italian Society of Pediatric Gastroenterology and Hepatology (SIGEP). J Pediatr Gastroenterol Nutr. 1999;29(1):63–8. 71. Ventura A, Dragovich D. Intractable diarrhoea in infancy in the 1990s: a survey in Italy. Eur J Pediatr. 1995;154(7):522–5. 72. Khoo UY, Bjarnason I, Donaghy A, Williams R, Macpherson A. Antibodies to colonic epithelial cells from the serum and colonic mucosal washings in ulcerative colitis. Gut. 1995;37(1):63–70. 73. Ricart E, Panaccione R, Loftus EV, Jr., Tremaine WJ, Harmsen WS, Zinsmeister AR, et al. Autoimmune disorders and extraintestinal manifestations in first-degree familial and sporadic inflammatory bowel disease: a case-control study. Inflamm Bowel Dis. 2004;10(3):207–14. 74. Sartoris DJ, Harell GS, Anderson MF, Zboralske FF. Small-bowel lymphoma and regional enteritis: radiographic similarities. Radiology. 1984;152(2):291–6.
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75. Isaacson PG. Gastrointestinal lymphomas of T- and B-cell types. Mod Pathol. 1999;12(2):151–8. 76. Martin IG, Aldoori MI. Immunoproliferative small intestinal disease: Mediterranean lymphoma and alpha heavy chain disease. Br J Surg. 1994;81(1):20–4. 77. Gunasekaran TS, Berman J, Gonzalez M. Duodenojejunitis: is it idiopathic or is it Henoch-Schonlein purpura without the purpura? J Pediatr Gastroenterol Nutr. 2000;30(1):22–8. 78. Dahlander B, Odeberg H, Hansen BU. Polyarteritis nodosa: ischaemic intestinal pain successfully treated with nitroglycerin. J Intern Med. 1996;240(1):31–2. 79. Gundogdu HZ, Kale G, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Intestinal perforation as an initial presentation of polyarteritis nodosa in an 8-year-old boy. J Pediatr Surg. 1993;28(4):632–4. 80. Lee EL, Smith HJ, Miller GL, 3rd, Burns DK, Weiner H. Ischemic pseudomembranous colitis with perforation due to polyarteritis nodosa. Am J Gastroenterol. 1984;79(1):35–8. 81. Mazy V, Delforge M, Demoulin JC, Fontaine F, Gillard V, Dreze C. [Ischemic necrosis of the intestine: expression of a vasculitis]. Rev Med Liege. 1994;49(7):412–21. 82. Brogan PA, Malik M, Shah N, Kilday JP, Ramsay A, Shah V, et al. Systemic vasculitis: a cause of indeterminate intestinal inflammation. J Pediatr Gastroenterol Nutr. 2006;42(4):405–15. 83. Blau EB, Morris RF, Yunis EJ. Polyarteritis nodosa in older children. Pediatrics. 1977;60(2):227–34. 84. Radhakrishnan KR, Kay M, Wyllie R, Hashkes PJ. Wegener granulomatosis mimicking inflammatory bowel disease in a pediatric patient. J Pediatr Gastroenterol Nutr. 2006;43(3):391–4. 85. Akay N, Boyvat A, Heper AO, Soykan I, Arica IE, Bektas M, et al. Behcet’s disease-like presentation of bullous pyoderma gangrenosum associated with Crohn disease. Clin Exp Dermatol. 2006;31(3):384–6. 86. Yim CW, White RH. Behcet’s syndrome in a family with inflammatory bowel disease. Arch Intern Med. 1985;145(6):1047–50. 87. Stringer DA, Cleghorn GJ, Durie PR, Daneman A, Hamilton JR. Behcet’s syndrome involving the gastrointestinal tract–a diagnostic dilemma in childhood. Pediatr Radiol. 1986;16(2):131–4. 88. Gladman DD, Ross T, Richardson B, Kulkarni S. Bowel involvement in systemic lupus erythematosus: Crohn disease or lupus vasculitis? Arthritis Rheum. 1985;28(4):466–70. 89. Sultan SM, Ioannou Y, Isenberg DA. A review of gastrointestinal manifestations of systemic lupus erythematosus. Rheumatology (Oxford). 1999;38(10):917–32. 90. Nelson J, Barron MM, Riggs JE, Gutmann L, Schochet SS, Jr. Cerebral vasculitis and ulcerative colitis. Neurology. 1986;36(5):719–21. 91. Garcia-Diaz M, Mira M, Nevado L, Galvan A, Berenguer A, Bureo JC. Retinal vasculitis associated with Crohn disease. Postgrad Med J. 1995;71(833):170–2. 92. Sargent D, Sessions JT, Fairman RP. Pulmonary vasculitis complicating ulcerative colitis. South Med J. 1985;78(5):624–5. 93. Speiser JC, Moore TL, Zuckner J. Ulcerative colitis with arthritis and vasculitis. Clin Rheumatol. 1985;4(3):343–7. 94. Weizman Z. Vasculitis involving muscle associated with Crohn colitis. Gastroenterology. 1982;82(6):1483–4. 95. Saulsbury FT, Hart MH. Crohn disease presenting with Henoch-Schonlein purpura. J Pediatr Gastroenterol Nutr. 2000;31(2):173–5. 96. Levine SM, Hellmann DB, Stone JH. Gastrointestinal involvement in polyarteritis nodosa (1986–2000): presentation and outcomes in 24 patients. Am J Med. 2002;112(5):386–91. 97. Gryboski JD, Fischer R. “Apple-core” lesion of the colon in Crohn disease. Am J Gastroenterol. 1986;81(2):130–2. 98. Martinez CR, Siegelman SS, Saba GP, Diaconis JN, Yardley JH. Localized tumor-like lesions in ulcerative colitis and Crohn disease of the colon. Johns Hopkins Med J. 1977;140(5):249–59. 99. Peterson IM, Milburn J, Reynolds M. Bowel obstruction and an apple-core lesion in an 18-year-old man. J Fam Pract. 1990;31(1):85–8. 100. Griffin PM, Liff JM, Greenberg RS, Clark WS. Adenocarcinomas of the colon and rectum in persons under 40 years old. A population-based study. Gastroenterology. 1991;100(4):1033–40. 101. Karnak I, Ciftci AO, Senocak ME, Buyukpamukcu N. Colorectal carcinoma in children. J Pediatr Surg. 1999;34(10):1499–504. 102. Chaimoff C, Dintsman M, Lurie M. Lesions mimicking malignant tumors of the large bowel. Am J Proctol Gastroenterol Colon Rectal Surg. 1981;32(6):12–5, 26.
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103. Ciftci AO, Akcoren Z, Tanyel FC, Senocak ME, Caglar M, Hicsonmez A. Inflammatory pseudotumor causing intestinal obstruction: diagnostic and therapeutic aspects. J Pediatr Surg. 1998;33(12):1843–5. 104. Lenaerts C, Roy CC, Vaillancourt M, Weber AM, Morin CL, Seidman E. High incidence of upper gastrointestinal tract involvement in children with Crohn disease. Pediatrics. 1989;83(5):777–81. 105. Mashako MN, Cezard JP, Navarro J, Mougenot JF, Sonsino E, Gargouri A, et al. Crohn disease lesions in the upper gastrointestinal tract: correlation between clinical, radiological, endoscopic, and histological features in adolescents and children. J Pediatr Gastroenterol Nutr. 1989;8(4):442–6. 106. Kirschner BS, Schmidt-Sommerfeld E, Stephens JK. Gastroduodenal Crohn disease in childhood. J Pediatr Gastroenterol Nutr. 1989;9(2):138–40. 107. Rutgeerts P, Onette E, Vantrappen G, Geboes K, Broeckaert L, Talloen L. Crohn disease of the stomach and duodenum: A clinical study with emphasis on the value of endoscopy and endoscopic biopsies. Endoscopy. 1980;12(6):288–94. 108. Grubel P, Choi Y, Schneider D, Knox TA, Cave DR. Severe isolated Crohn-like disease of the gastroduodenal tract. Dig Dis Sci. 2003;48(7):1360–5. 109. Danzi JT, Farmer RG, Sullivan BH, Jr., Rankin GB. Endoscopic features of gastroduodenal Crohn disease. Gastroenterology. 1976;70(1):9–13. 110. Markowitz J, Daum F, Aiges H, Kahn E, Silverberg M, Fisher SE. Perianal disease in children and adolescents with Crohn disease. Gastroenterology. 1984;86(5 Pt 1):829–33. 111. Galbraith SS, Drolet BA, Kugathasan S, Paller AS, Esterly NB. Asymptomatic inflammatory bowel disease presenting with mucocutaneous findings. Pediatrics. 2005;116(3):e439–44. Epub 2005 Aug 11. 112. Shetty AK, Udall J, Jr., Schmidt-Sommerfeld E. Highly destructive perianal Crohn disease. J Natl Med Assoc. 1998;90(8):491–2. 113. Markowitz J, Grancher K, Rosa J, Simpser E, Aiges H, Daum F. Highly destructive perianal disease in children with Crohn disease. J Pediatr Gastroenterol Nutr. 1995;21(2):149–53. 114. Gupta PJ. Ano-perianal tuberculosis - solving a clinical dilemma. Afr Health Sci. 2005;5(4):345–7. 115. Porzionato A, Alaggio R, Aprile A. Perianal and vulvar Crohn disease presenting as suspected abuse. Forensic Sci Int. 2005;155(1):24–7. 116. Muram D. Anal and perianal abnormalities in prepubertal victims of sexual abuse. Am J Obstet Gynecol. 1989;161(2):278–81.
16 Laboratory Evaluation of Pediatric Inflammatory Bowel Disease Jennifer Strople∗ and Benjamin D. Gold
Introduction Although clinical history and physical exam may raise suspicion of Crohn disease (CD) or ulcerative colitis (UC), a focused laboratory evaluation may facilitate further differentiation between inflammatory bowel disease (IBD) and non-inflammatory bowel disease–in particular, infectious processes and functional bowel disorders (Table 16.1). These blood and stool studies, in combination with clinical presentation (thorough history, including family history of IBD and physical examination), can help determine which child may require more invasive testing, such as radiological and endoscopic evaluation. Moreover, the blood and stool evaluations may also provide insight into the severity of disease, if indeed IBD (i.e., prognostication), and potentially aid in phenotyping the disease (CD versus UC). The first part of this review will focus on the evaluation of blood tests in the work-up of a child with suspected IBD. Initially, the non-specific markers of disease (e.g., anemia) and inflammation (e.g., C-reactive protein (CRP), and erythrocyte sedimentation rate, (ESR)) will be discussed. Subsequently, the more “specific” markers of IBD will be reviewed, and then stool tests which can be used to potentially delineate between IBD and non-IBD will be discussed.
Blood Tests Most clinicians, adult and pediatric, will agree that blood tests should be part of the initial screening process in children with symptoms compatible with UC or CD [1–6]. The specific blood evaluations performed should, at minimum, consist of a complete blood count, including white blood cell numbers with a differential, hemoglobin and hematocrit, and iron/red blood cell indices such as mean corpuscular volume. In addition, liver biochemistries: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin and total protein, and inflammatory indices, such as ESR and CRP should be included in the initial laboratory evaluation of a child with suspected IBD [6]. Although normal tests do not rule out the possibility of intestinal inflammation, if abnormalities are present, further investigative studies are generally warranted. Also, as several of these parameters are included in the Pediatric Crohn Disease
∗ Children’s Memorial Hospital, 2300 Children’s Plaza, Box 65, Chicago, IL 60614, Phone: (773) 880-4354, Fax: (773) 880-4036, Email:
[email protected]
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Table 16.1. Laboratory tests for suspected inflammatory bowel disease. Test
Findings
Significance
Complete blood count and differential
Anemia (microcytic, macrocytic, normocytic), thrombocytosis, leukocytosis
ESR and CRP
Elevation
Liver function tests
Hypoalbuminemia Elevated transaminases Elevated alkaline phosphatase/GGT
Stool Cultures—E. Coli, Salmonella, Shigella, Campylobacter, Yersinia species
Infection
Anemia: Assess severity of blood loss, evaluate for iron and other macronutrient deficiencies. Reported prevalence 16-77% in Crohn disease and 9–67% in ulcerative colitis [15, 16]. Thrombocytosis: Acute phase reactant, nonspecific measure of inflammation. Reported prevalence variable, occurring in up to 85% of patients with Crohn disease and 70% patients with ulcerative colitis [25, 26]. Nonspecific markers of inflammation, potential role in assessing disease activity, predicting disease relapse and monitoring therapeutic response [33, 34]. Hypoalbuminemia: Surrogate marker of nutrition, possibly indicative of decreased liver production (negative acute phase reactant) or intestinal protein losses due to inflammation [17, 44]. AST/ALT/Alkaline phosphatase/GGT: Role in evaluating for extraintestinal complications of inflammatory bowel disease [47–49]. Evaluate for primary infectious colitis, which may mimic inflammatory bowel disease and exclude co-infection, which may complicate disease [70, 71].
Clostridium difficile toxin
Infection
Stool calprotectin
Elevation
Stool lactoferrin
Elevation
IBD serologies
Positive ASCA (IgA or IgG), pANCA, anti-OmpC, anti-CBir
ESR: erythrocyte sedimentation rate CRP: C-reactive protein IBD: inflammatory bowel disease AST: aspartate aminotransferase ALT: alanine aminotransferase GGT: Gamma glutamyl transpeptidase ASCA: Anti-Saccharomyces cerevisisae (ASCA) pANCA: perinuclear anti-nuclear cytoplasmic antibody OmpC: outer membrane protein
Evaluate for primary infection and co-infection. In patients with inflammatory bowel disease, C. difficile is the most common infectious agent identified [9, 72]. Alternative inflammatory marker, which appears to be a direct measure of intestinal inflammation. Potential role in assessing disease activity and predicting relapse in patients with inflammatory bowel disease [82, 83, 86]. Another inflammatory marker that demonstrated in preliminary studies the potential of being utilized as a measure of intestinal inflammation. As with calprotectin, has the potential role of assessing response to therapy [89, 90, 91]. May aid in classifying disease subtype and play a role in therapeutic decisions (prognostic factor). Inadequate screening tool due to low sensitivity compared to clinical history and routine laboratory tests [1, 68, 69].
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Activity Index (e.g., albumin, ESR), these blood tests may offer additional insight into disease activity, and potentially, severity [6–8]. Anemia Anemia is a well known complication of inflammatory bowel disease occurring in both UC [9] and CD [10–16]. Anemia is generally defined as a hemoglobin value <120 grams per liter or hematocrit <0.4. With respect to IBD, severe anemia is defined as a hemoglobin level <100 grams per liter. For reasons that are not well characterized, many patients with IBD are intolerant of oral iron replacement therapy or their anemia is refractory to such supplementation [16]. The reported prevalence of anemia is variable in IBD. Anemia has been described occurring in 16–77% of patients with CD (16%, 58%, and 77% reported in pediatric cohorts) [13–20] and 9–67% of patients with ulcerative colitis (30% reported in one pediatric cohort) [16, 17, 20]. The cause of iron deficiency with or without frank anemia is likely multifactorial in both CD and UC. In CD, anemia may result from iron, folate or vitamin B12 micronutrient deficiencies which commonly accompany extensive small bowel disease, particularly if the ileum is involved. In addition, anemia may result from gross or occult gastrointestinal blood loss due to underlying intestinal inflammation. Finally, iron deficiency and/or anemia may be due to decreased overall iron stores due to chronic disease, and lack of appropriate dietary intake to replace iron stores. The anemia observed in ulcerative colitis is generally the result of iron losses from chronic intestinal bleeding, but as with CD can be due to anemia of chronic disease. Anemia of chronic disease is also believed to be multifactorial in its etiopathogenesis. Three potential mechanisms leading to the anemia associated with chronic disease have been postulated namely, 1) anemia results as a consequence of cytokine activation and subsequent alteration of iron homeostasis; 2) anemia occurs due to the inhibition of erythropoiesis and 3) a shortened red blood cell half life is associated with chronic disease and thereby results in the anemia [15]. As mentioned, anemia of chronic disease such as that in IBD involves erythropoiesis disturbance due to circulating inflammation mediators. In one recent study, erythropoietin (Epo) levels in children and adolescents with IBD were investigated and correlated to disease activity [21]. In this particular study by Tsitsika et al. [21]. thirty-three patients with IBD were evaluated (18 boys, 15 girls) ages 4 to 15 years (median 11 years). The authors separated the patients into two study groups related to their disease activity; those with active disease (n = 21), and those in remission (n = 12). Anemia of chronic disease was only present in patients with active disease, and compared with patients in remission, those with active disease had a higher frequency of altered Epo levels. This study provides compelling evidence that inhibition of erythropoiesis (i.e., by impairment of Epo production) is another possible mechanism for development of anemia of chronic disease in active IBD. Once the diagnosis of anemia is established the etiology should be further investigated so treatment can be initiated. For macrocytic anemias, folate, vitamin B12, and methylmalonic acid levels should be obtained. Iron studies including ferritin, total iron binding content (TIBC), and iron levels should be evaluated in cases of microcytic anemia. However, the results of these studies may be difficult to interpret, as ferritin, a measure of iron stores, is also an acute phase reactant and may be falsely elevated in inflammatory conditions. Thus, in patients with a microcytic anemia, obtaining a soluble transferrin receptor in addition to standard iron studies, may be helpful in differentiating iron deficiency anemia and anemia of chronic disease [22–24]. Soluble transferrin receptor concentration, which is not affected by inflammation, is elevated in iron deficiency anemia, but remains normal in anemia of chronic disease [22–24]. The therapy for anemia is directed towards treatment of the underlying inflammatory process, and in the case of anemia associated with IBD, therapy aimed at resolving the disease often results in anemia resolution as well. Supplemental therapy, depending on the type and severity of deficiency can also be implemented. Iron deficiency anemia should be treated initially with oral
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iron preparations. If however, the child’s anemia is unresponsive or other situations arise which result in inability to tolerate oral therapy or there is a demonstration of a lack of tolerance (e.g., gastrointestinal side effects), then therapy should be administered parenterally; i.e. with intravenous preparations. Intramuscular therapy has been abandoned due to high rate of complications. Intravenous therapy may be administered as a multiple-dose regimen (intravenous iron sucrose and gluconate) or as a single intravenous dose (iron dextran), which is associated with a higher risk of allergic infusion reactions and requires obligatory test dose administration. Treatment with erythropoietin is reserved for a select subgroup of patients with anemia of chronic disease. Acute Phase Reactants: Platelets In inflammatory conditions such as CD and UC, there is a rise in acute phase reactant proteins as result of cytokine stimulation. The assessment of acute phase reactants has been employed as laboratory tests in the standard work-up of the child with suspected IBD, as well as other inflammatory conditions (e.g., juvenile rheumatoid arthritis) [25, 26]. Reactive thrombocytosis, a nonspecific marker of inflammation, is a result of this acute phase response. Since the first published paper describing the association of thrombocytosis with chronic IBD by Morowitz et al. [27] the characterization of platelet elevation in the peripheral blood has been a “standard” part of the work–up of patients for suspected IBD, and, in the monitoring of their disease activity. However, more recently, studies of the pathogenesis of IBD have implicated platelets in the propagation of intestinal inflammation. In a murine model of intestinal inflammation, CD40CD40L signaling pathway appears to be involved in the pathogenesis of intestinal inflammation, and a major role of this pathway may be modulation of leukocyte and platelet recruitment by activated, CD40-positive endothelial cells in colonic venules [28]. In addition, Kayo et al. [29] recently evaluated the role of platelets in inflammation in peripheral blood and in the mucosa of a cohort of patients with active UC. These investigators compared the group of patients with active UC to patients with inactive UC and a small cohort of healthy controls. The authors observed a close association between activated platelets and neutrophils in both the affected colonic mucosa and peripheral blood of patients with active UC compared to the normal volunteers (i.e., healthy controls) and those with inactive UC. The investigators inferred from their study results that a platelet-neutrophil association may play a role in the progression of inflammation in UC [29]. Thus, platelets may in fact play more of a role in the propagation of intestinal inflammation, rather than being a simple “biomarker” of IBD [25]. In children referred for endoscopy for evaluation of abdominal pain, diarrhea, rectal bleeding, weight loss, or mouth ulcerations, 85% of patients with CD and 70% of patients with UC had elevated platelet counts compared to 6% of children with normal endoscopic assessment [17]. The presence of thrombocytosis may be overestimated in this study, or a unique response in the child with IBD as a lower prevalence of increased platelets in IBD is reported in adults [30–32]. However, an elevated platelet count in a child with chronic intestinal symptoms should raise clinical suspicion of underlying intestinal inflammation. In one study evaluating pediatric patients with chronic abdominal complaints, the presence of an abnormal hemoglobin and/or elevated platelet count on a routine CBC was able to differentiate between IBD and healthy controls, with 90.8% sensitivity and 80.0% specificity [33]. Furthermore, the platelet count may help differentiate between IBD and infectious processes, as thrombocytosis is a rare finding in diarrhea associated with enteric pathogens [30]. Acute Phase Reactants: Erythrocyte Sedimentation Rate and C-reactive Protein ESR and CRP are two other nonspecific measures of inflammation which should be included in the evaluation of patients with suspected IBD [34]. Both ESR and CRP have been investigated in IBD for a number of reasons, namely, i) diagnostic purposes, ii) determination of disease severity
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and potential disease related complications, iii) prognostication, and iv) for evaluating treatment response. CRP may be a better measure for assessing disease activity and predicting relapse. In CD in particular, CRP appears to correlates well with disease activity, and thus elevation of this acute phase reactant may be helpful in distinguishing IBD from non inflammatory conditions [35]. Additionally, in clinical trials with biological therapies, elevated CRP levels prior to initiation of therapy are associated with higher response rate, whereas normal CRP levels are associated with higher placebo response rates [35]. Both ESR and CRP can be elevated to varying degrees in IBD and therefore are helpful in distinguishing inflammatory from functional disorders. In a study of 91 children referred for chronic gastrointestinal symptoms the CRP was elevated in 100% of patients with CD and 60% UC, and ESR was elevated in 85% of patients with CD and 23% of patients with UC [17]. None of the patients with polyps or normal investigations had elevation of either marker. In adults with chronic abdominal symptoms, all patients with CD and 50% of patients with UC had elevated ESR and CRP, whereas none of the patients with functional disorders had elevation of both markers [36]. Therefore using these markers in combination may increase the diagnostic yield. Overall, the response in UC appears to be less robust, with elevated values found in more extensive colitis compared to limited disease [37–40]. However, the development of highly sensitive CRP assays may improve the sensitivity of this test, even in patients with limited disease [41]. In a study by Poullis et al. [41] the authors evaluated 224 adult patients and determined the accuracy of the CRP in distinguishing IBD from functional GI disease. Using a newly developed enzyme linked immunoassay approach to CRP measurement, the authors determined that a CRP cut-off value of 2.3 mg/l had a sensitivity of 100% and a specificity of 67% in differentiating functional bowel disease from new cases of IBD [41]. Compared to ESR, CRP has a shorter half life and thus returns to baseline values more rapidly once the inflammatory stimulus has resolved. Because of this rapid decline CRP therefore may be a better measure of remission and response to therapy than other inflammatory markers in patients with IBD [35]. Other Laboratory Evaluations Liver function tests and electrolyte panels may add additional information to aid the clinician in differentiating IBD from non-IBD and, in the determination of the IBD phenotype–i.e., presence or absence of extra-intestinal manifestations such as liver disease [42, 43]. Although severe liver disease can be the first presentation of IBD in pediatric patients, hypoalbuminemia, which may be due to liver parenchymal damage, and/or decreased production or bowel injury and/or increased fecal loss, is a more frequent finding at diagnosis [43]. Hypoalbuminemia is observed in both CD and UC; however it is present at a much higher frequency in CD. In pediatric cohorts, hypoalbuminemia has been reported in 35–64% of patients with CD and 15% of patients with UC [17, 18, 44–47]. In addition to being useful in the diagnosis of IBD compared to non-IBD, hypoalbuminemia when present may have value as a prognostic factor for both surgical risk [44] and for osteopenia and decreased bone mineral density scores [46]. As with anemia, the etiology of hypoalbuminemia is multifactorial, with protein loss from intestinal inflammation, decreased albumin production (negative acute phase response), and long term poor nutrition all contributing [38, 45, 47]. Elevation of AST and ALT may also be present on this initial screen in the evaluation of a patient with suspected IBD. In one recent study by Mendes et al. [48] the investigators determined the prevalence of abnormal hepatic biochemistries and chronic liver disease in a cohort of IBD patients in a somewhat case-control fashion. Patients with normal and abnormal liver biochemistries were compared. In this a cohort of 544 patients, almost one third of these patients had abnormalities of their liver biochemistries, and contrary to what the investigators hypothesized, abnormal liver biochemistries did not correlate with IBD activity. These authors recommended that persistently abnormal hepatic biochemistries should be evaluated, but to use caution and
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not immediately attribute these abnormal liver biochemistries to IBD activity [48]. Abnormal liver biochemistries may also be primarily related to poor nutrition as a result of active disease, and thus spontaneous resolution of these transient elevations are common [49]. However, when AST/ALT are persistently elevated or seen in association with an elevated alkaline phosphatase and/or -glutamyl transpeptidase, the extraintestinal complication of primary sclerosing cholangitis (PSC) or autoimmune hepatitis/overlap syndrome should be considered. PSC is reported complication in 3% of children with IBD and can occur coincident with diagnosis of IBD [50–52]. In a study of 32 children with PSC, Wilschanski et al. [52] demonstrated that the majority of patients were diagnosed in their second decade of life; however, approximately 13% of children in this small cohort were diagnosed prior to the age of two years. Seventeen of the 32 patients evaluated by these Toronto investigators had inflammatory bowel disease (IBD), and all patients with IBD had colitis (14 UC, 3 CD) [52]. In 8 patients, PSC preceded the diagnosis of IBD. In this cohort of Toronto children, the presentation of chronic liver disease was variable, with only 8 children presenting with clinically evident jaundice. Thus, of the hepatic pathologies reported associated with IBD in children and adults, PSC, as a pathologic diagnosis, remains the more common presentation. In one longitudinal, cohort study by Feldstein et al. [50] 52 children with cholangiography-proven PSC were followed to determine the long-term outcome (mean follow up was 16.7 years) of children with PSC diagnosed over a 20 year period. Eighty-one percent of the patients evaluated had IBD [50]. During follow-up, 11 children underwent liver transplantation for end-stage PSC and 1 child died. Overall the survival in children with PSC was significantly shorter when compared to an age and gender-matched population. Further analysis revealed that thrombocytopenia, splenomegaly and older age negatively affected survival whereas medical therapy had no effect. Thus, the authors concluded that PSC, whether associated with IBD or not, significantly decreases survival [50]. Renal disease may also be an extra-intestinal manifestation of IBD or can be an adverse event associated with IBD pharmacotherapy [53–57]. In one large British cohort evaluating 19,025 IBD patients who had used aminosalicylates (5-ASA), the incidence of renal disease was 0.17 cases per 100 patients per year. In the nested case control analysis comparing 5-ASA users to non-users, the crude odds ratio (OR) for renal disease in 5-ASA users was 1.60 (95% confidence interval 1.14–2.26). However, this OR lost significance when adjusted for IBD disease severity and concomitant therapies. The investigators concluded that overall, the incidence of 5-ASA associated renal disease in IBD is low and appears to be unrelated to dose of 5-ASA therapy [55]. Conversely, although small in sample size, Izzedine et al. [58] described 4 patients with severe interstitial nephritis demonstrated on histopathological examination of kidney biopsy specimens. In all patients, renal failure was diagnosed prior to mesalamine exposure, and it progressed to end-stage diseases in 3 of these patients [58]. Thus, with respect to appropriate adjunct or complementary lab tests to obtain in the work up of a child with suspected IBD, given the reports of interstitial nephritis in patients with Crohn disease in the absence of 5-aminosalicylate exposure, a baseline chemistry panel should be considered during the initial evaluation. The above paragraphs highlight the standard evaluation that should be performed in all children with history and physical exam findings suspicious for IBD. These diagnostic tests may aid the clinician in the differentiation UC and CD from functional bowel disorders and infectious etiologies. However, because the clinical presentation of IBD is so diverse and symptoms can be nonspecific, at times, it may be difficult to distinguish between inflammatory and functional disorders. Several other non-invasive studies have been proposed to aid in the diagnosis of inflammatory bowel disease including IBD serologies and fecal calprotectin. The following section briefly reviews these tests; a brief overview of the use of IBD serology and the evidence to support or disprove their use in the preliminary evaluation of the child with suspected IBD, and, stool tests, which is an essential part of the initial work up of the child with suspected IBD, and includes a discussion of a more novel marker of intestinal inflammation, fecal calprotectin, and fecal lactoferrin.
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Specific Blood Tests: Inflammatory Bowel Disease Serologies Anti-Saccharomyces cerevisisae (ASCA), an antibody response against Saccharomyces cerevisiae and perinuclear anti-nuclear cytoplasmic antibody (pANCA), an antibody response toward nuclear antigens with a perinuclear pattern, are two immunologic markers detected in IBD. At present, there is much debate in both the pediatric and adult clinical settings regarding the proper use of these serologies in the routine evaluation of IBD. There have been several studies assessing the accuracy and clinical utility of ASCA and pANCA in children with IBD [1, 5, 59–67]. Although these investigations differ in their study design and in some cases the type of serological profile obtained, overall, these markers appear to be reasonably specific for both CD and UC. In the reported studies, ASCA (IgG or IgA) specificity ranged from 88% to 97% for CD [61, 63–66] and pANCA specificity ranged from 65–95% for UC [60, 61, 63–66]. In children, the specificity of the combined serologies in differentiating IBD from non IBD has been reported to range from 84% to 95% [1, 5, 61, 63, 67]. Unfortunately, the sensitivity of these serologies has been shown to be poor with overall sensitivity ranges reported between 55%–78% [1, 5, 59, 61, 63, 67]. Therefore, a negative test result does not exclude the diagnosis of IBD, particularly in those patients with nonspecific symptoms such as abdominal pain and intermittent diarrhea. The development of a modified assay using different cut off values for ASCA and ANCA, may increase the sensitivity of the assay, improving the diagnostic yield, but the assay remains costly [62]. The more recent addition of anti Omp-C, an antibody to the outer membrane porin of Escherichia coli, appears to add little to the diagnostic accuracy of this serologic panel in children [65, 66]. In two pediatric studies, the overall sensitivity of anti-OmpC for both CD and UC was very low [65, 66]. However, the use of the additional IBD serologies may help identify a small number of IBD patients who had negative ASCA and pANCA [65, 66]. Moreover, with an increasing number of candidate genes being identified in patients with IBD, particularly CD, other serological markers have been identified that may increase the overall sensitivity of the assays [68]. For example, patients carrying the NOD2 mutations have an increased adaptive immune response to indigenous colonic microflora as measured by higher titers of antimicrobial antibodies, such as anti-CBir and ASCA [68]. Although their specificity is reasonable, overall ASCA and pANCA appear to be less sensitive than clinical history and routine laboratory tests (hemoglobin and ESR) in the evaluation of pediatric IBD. In a retrospective study, Khan et al. [67] evaluated 177 pediatric subjects who had pANCA and ASCA, hemoglobin, ESR and colonoscopy as part of their initial evaluation. In this study, ninety patients were diagnosed with IBD, and of those, 52 had UC and 39 were diagnosed with CD. Combining abnormal hemoglobin and/or ESR with rectal bleeding, the most distinguishing symptom for IBD in this study cohort, was more sensitive than positive ASCA and/or pANCA (86% versus 68%) and identified 86% of patients with IBD prior to endoscopy. A study by Sabery et al. [1] yielded similar findings. In this retrospective study which included 210 pediatric subjects, 40 with IBD, the sensitivity of ASCA and pANCA was again compared to hemoglobin and ESR [1]. The presence of an abnormal hemoglobin or ESR was the more sensitive screen, with a sensitivity of 83%, compared to 73% for the First Step® modified assay (Prometheus laboratories, San Diego, CA), and 60% for the confirmatory panel, which included anti-OmpC. In the subset of patients without rectal bleeding, a group whose symptoms may be more difficult to differentiate from functional disorders, the sensitivity of ASCA and pANCA decreased to 55% whereas the sensitivity of an abnormal hemoglobin or ESR remained high at 91%. Hemoglobin and ESR are both components of the PCDAI and therefore, have added value as markers of disease severity and clinical response. Given the cost of these tests and overall poor sensitivities documented in several pediatric studies, particularly compared to other clinical and laboratory parameters, currently, serology testing does not appear to have additive value as a screening test in the initial diagnostic work-up for patients with suspected IBD. It is unclear whether addition of antibodies to CBir1 flagellin,
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an antibody found in approximately 50% of adult patients with CD, will increase the diagnostic yield of this panel [69, 70]. In a study by Targan et al. [70] 484 sera previously employed for a study evaluating other serological markers of IBD (namely, ASCA, pANCA, OmpC) were tested for anti-CBir1 by enzyme-linked immunosorbent assay. Interestingly, the authors observed that the presence and level (i.e. titers) of immunoglobulin G anti-CBir1 were positively associated with CD independently, and was associated with a unique phenotype of CD, namely, smallbowel, internal-penetrating, and fibrostenosing disease. The role of this additional serological marker, anti-CBir1 may be a prognosticator of disease as a recent study by Papadakis et al. [69] demonstrated that anti-CBir1 serum reactivity in Crohn disease patients was independently and significantly associated with fibrostenosing disease and complicated small bowel Crohn. Unfortunately, at the time of this review, the ability to make an overall recommendation regarding the utility of these additional serological markers independently or as a group of assays for the differentiation between IBD and functional disease, and for phenotyping of IBD cannot be made as there is limited published pediatric data. Perhaps for now, the use these serologies should be reserved as an aid in classifying disease subtype in children with indeterminate colitis and assisting in therapeutic decisions such as colectomy.
Stool Evaluation The presentation of pediatric inflammatory bowel disease can be quite heterogeneous; however, those children who present with classic gastrointestinal complaints such as diarrhea and abdominal pain should have a thorough stool evaluation to rule out bacterial and parasitic etiologies of these symptoms. Standard stool cultures to look for enterohemorrhagic Escherichia. coli, Salmonella, Shigella, Yersinia, and Campylobacter species, Clostridium difficile toxin assay and ova and parasite studies to look for Entameoba histolytica and other parasites are a necessary part of the work-up of the child to differentiate infectious versus inflammatory enterocolitis and should be obtained prior to invasive procedures. In particular, Yersinia enterocolitica infections may mimic CD and thus specific emphasis should be placed on looking for this organism as isolation can be increased by using selective media [71, 72]. Also, defects in mucosal barrier function can predispose patients with IBD to infectious colitis, and Clostridium difficile is the most common infectious agent identified [9, 73]. In addition to differentiating between infectious colitis and IBD, there has been a lot of recent attention towards infectious agents in the etiopathogenesis of IBD; with focus either being on enteric microflora (i.e., commensals) as compared to infecting pathogens in the genetically susceptible host [4, 74]. Moreover, there has been a recent resurgence of interest in the organism Mycobacterium avium subspecies paratuberculosis and its role as a trigger, and/or modulator of IBD, particularly CD [75–77]. This renewed interest has been specifically fueled by a recent report of a several month course of triple therapy antibiotics which successfully resolved CD at short term follow up in a small cohort of Australian adults [76]. A positive stool test does not rule out the possibility of IBD, and thus patients with a suspicious clinical history who do not improve with appropriate treatment of stool pathogens should have further diagnostic evaluations. Fecal Calprotectin Calprotectin, a calcium binding protein in the S100 family, is an abundant protein in neutrophils, and to a lesser extent, macrophages and monocytes, accounting for approximately 60% of the cytosolic protein in neutrophils [78–80]. Calprotectin has bacterostatic and anti-fungal properties, and thus likely contributes to neutrophilic defenses [80]. In healthy individuals, concentrations of calprotectin are approximately six times higher in stool than plasma [80]. In IBD, a spot fecal calprotectin level correlates well with fecal excretion of 111 indium white cells, suggesting this
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protein can be an alternative marker of intestinal inflammation [82, 83]. Fecal calprotectin is easy to measure, resistant to proteolysis and stable in stool for 7 days, and thus has been proposed as a simple noninvasive investigative tool, which may help distinguish inflammatory from functional disorders [33, 80, 84–86]. Several studies have shown elevated fecal calprotectin levels in patients with both UC and CD compared to healthy controls and patients with irritable bowel syndrome [34, 84–86]. In one large study of 602 new patient referrals who had symptoms compatible with either irritable bowel syndrome or organic disease, including 189 patients later diagnosed with IBD, fecal calprotectin levels of > 10 mg/L had a sensitivity of 89% and specificity of 79% for organic diseases [87]. This test was more sensitive than either ESR or CRP and an abnormal fecal calprotectin had an odds ratio for disease of 27.8 [87]. A similar, but small cohort sized study by Carroccio et al. [88] using the newer fecal calprotectin assay yielded a somewhat lower sensitivity for organic disease (sensitivity 66%), but similar specificity (84%). However, in the small subset of 9 adult patients with inflammatory bowel disease, the sensitivity and specificity of fecal calprotectin was 100% and 95%, respectively [88]. Finally, in this study, which included 50 children with chronic diarrhea, the assay had a higher sensitivity (70%) and specificity (93%) in pediatric patients than in adults. Other pediatric studies have reported even higher sensitivities with similar specificities of the fecal calprotectin assay. Fagerberg et al. [84] obtained fecal calprotectin levels in 36 pediatric patients with gastrointestinal symptoms who underwent colonoscopy for suspected inflammation. Using the standard upper reference limit of <50 μg/g for the modified assay, the test has a sensitivity and specificity for inflammation of 95% and 93%, respectively. Using the older assay, Bunn et al. [89] reported a sensitivity of 90% and specificity of 100% for identifying intestinal inflammation in 36 pediatric patients who underwent either colonoscopy or [100]Tc-labeled white blood scans for suspected inflammatory bowel disease. As there was a strong suspicion of IBD in both of these studies, there may be some selection bias, which resulted in these higher sensitivities and specificities; however, based on these results, it appears fecal calprotectin correlates well with histologic inflammation in pediatric patients. Therefore, the assay offers an advantage over other nonspecific inflammatory markers as is appears to be a direct measure of intestinal inflammation and consequently may be followed prospectively in patients as a marker of disease activity and relapse. Although larger prospective pediatric clinical studies need to be performed, fecal calprotectin appears to offer promise in the evaluation of patients with suspected IBD. Fecal Lactoferrin Another potentially useful stool marker in patients with IBD is fecal lactoferrin. This protein was shown in an adult study to be the most useful of neutrophil-derived proteins in stool as a marker of intestinal inflammation [90]. In a case series of five pediatric patients with CD, fecal lactoferrin significantly decreased in response to infliximab therapy [91]. More recently, in a large pediatric study in 148 children with CD, UC, irritable bowel syndrome, and healthy volunteers, fecal lactoferrin was shown to be a useful marker of inflammation in diagnosis and interval assessment, and it correlated well with the clinical activity indices and ESR [92].
Summary In the preceding paragraphs, we attempted to provide an overview of the laboratory tests available that can be used in the initial work up of the child with suspected inflammatory bowel disease. Although a thorough clinical history and physical exam can raise suspicion of CD or UC it is important to include a focused laboratory evaluation. A combination of blood and stool tests (markers of inflammation i.e., fecal calprotectin, fecal lactoferrin or of infectious etiologies
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i.e. stool cultures) may further differentiate between IBD and non-IBD–in particular, infectious processes and functional bowel disorders. Not only can a carefully chosen combination of blood and stool studies help determine which child may require more invasive testing, but they can also be used in the initial phenotyping of the disease i.e., CD versus UC. Moreover, there are laboratory tests available, specifically IBD serologic markers such as ASCA and anti-CBir1, which can be employed to subtype CD and potentially provide the clinician with the ability to prognosticate disease severity. The definitive diagnosis of IBD is made by combining historical features, physical examination, radiological findings and endoscopy and biopsy. However, laboratory investigations provide important information about inflammation and function of other organ systems that may or may not be involved with the child with IBD, which ultimately helps guide the clinician toward more invasive testing. References 1. Sabery N, Bass D. Use of serologic markers as a screening tool in inflammatory bowel disease compared with elevated erythrocyte sedimentation rate and anemia. Pediatrics 2007;119:e193–9. 2. Hait E, Bousvaros A, Grand R. Pediatric inflammatory bowel disease: what children can teach adults. Inflamm Bowel Dis 2005;11:519–27. 3. Auvin S, Molinie F, Gower-Rousseau C et al. Incidence, clinical presentation and location at diagnosis of pediatric inflammatory bowel disease: a prospective population-based study in northern France (1988–1999). J Pediatr Gastroenterol Nutr 2005;41:49–55. 4. Oliva-Hemker M, Fiocchi C. Etiopathogenesis of inflammatory bowel disease: the importance of the pediatric perspective. Inflamm Bowel Dis 2002;8:112–28. 5. Dubinsky MC, Ofman JJ, Urman M, Targan SR, Seidman EG. Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease. Am J Gastroenterol 2001;96:758–65. 6. Hyams J, Markowitz J, Otley A et al. Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience. J Pediatr Gastroenterol Nutr 2005;41:416–21. 7. Hyams JS, Ferry GD, Mandel FS et al. Development and validation of a pediatric Crohn’s disease activity index. J Pediatr Gastroenterol Nutr 1991;12:439–47. 8. Griffiths AM, Otley AR, Hyams J et al. A review of activity indices and end points for clinical trials in children with Crohn’s disease. Inflamm Bowel Dis 2005;11:185–96. 9. Mylonaki M, Langmead L, Pantes A, Johnson F, Rampton DS. Enteric infection in relapse of inflammatory bowel disease: importance of microbiological examination of stool. Eur J Gastroenterol Hepatol 2004;16:775–8. 10. Roy CN, Weinstein DA, Andrews NC. 2002 E. Mead Johnson Award for Research in Pediatrics Lecture: the molecular biology of the anemia of chronic disease: a hypothesis. Pediatr Res 2003;53:507–12. 11. Koutroubakis IE, Karmiris K, Kouroumalis EA. Treatment of anaemia in inflammatory bowel disease. Aliment Pharmacol Ther 2006;23:1273–4; author reply 1274–5. 12. Wells CW, Lewis S, Barton JR, Corbett S. Effects of changes in hemoglobin level on quality of life and cognitive function in inflammatory bowel disease patients. Inflamm Bowel Dis 2006;12:123–30. 13. Thayu M, Leonard MG, Baldassano RN, Mamula P. Prevalence of Anemia in Incident Pediatric Crohn Disease. J Pediatr Gastroenterol Nutr 2005;41:547. 14. Thayu M, Mamula P. Treatment of iron deficiency anemia in pediatric inflammatory bowel disease. Curr Treat Options Gastroenterol 2005;8:411–7. 15. Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut 2004;53:1190–7. 16. Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am J Med 2004;116 Suppl 7A:44S–49S. 17. Beattie RM, Walker-Smith JA, Murch SH. Indications for investigation of chronic gastrointestinal symptoms. Arch Dis Child 1995;73:354–5. 18. Burbige EJ, Huang SH, Bayless TM. Clinical manifestations of Crohn’s disease in children and adolescents. Pediatrics 1975;55:866–71. 19. Dyer NH, Child JA, Mollin DL, Dawson AM. Anaemia in Crohn’s disease. Q J Med 1972;41:419–36.
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20. Thomson AB, Brust R, Ali MA, Mant MJ, Valberg LS. Iron deficiency in inflammatory bowel disease. Diagnostic efficacy of serum ferritin. Am J Dig Dis 1978;23:705–9. 21. Tsitsika A, Stamoulakatou A, Kafritsa Y et al. Erythropoietin levels in children and adolescents with inflammatory bowel disease. J Pediatr Hematol Oncol 2005;27:93–6. 22. Margetic S, Topic E, Ruzic DF, Kvaternik M. Soluble transferrin receptor and transferrin receptorferritin index in iron deficiency anemia and anemia in rheumatoid arthritis. Clin Chem Lab Med 2005;43:326–31. 23. Markovic M, Majkic-Singh N, Subota V. Usefulness of soluble transferrin receptor and ferritin in iron deficiency and chronic disease. Scand J Clin Lab Invest 2005;65:571–6. 24. Baillie FJ, Morrison AE, Fergus I. Soluble transferrin receptor: a discriminating assay for iron deficiency. Clin Lab Haematol 2003;25:353–7. 25. Matsumoto T. Platelets in inflammatory bowel disease. J Gastroenterol 2006;41:91–2. 26. Danese S, Scaldaferri F, Papa A et al. Platelets: new players in the mucosal scenario of inflammatory bowel disease. Eur Rev Med Pharmacol Sci 2004;8:193–8. 27. Morowitz DA, Allen LW, Kirsner JB. Thrombocytosis in chronic inflammatory bowel disease. Ann Intern Med 1968;68:1013–21. 28. Vowinkel T, Anthoni C, Wood KC, et al. CD40-CD40 ligand mediates the recruitment of leukocytes and platelets in the inflamed murine colon. Gastroenterology 2007;132:955–65. 29. Kayo S, Ikura Y, Suekane T et al. Close association between activated platelets and neutrophils in the active phase of ulcerative colitis in humans. Inflamm Bowel Dis 2006;12:727–35. 30. Harries AD, Beeching NJ, Rogerson SJ, Nye FJ. The platelet count as a simple measure to distinguish inflammatory bowel disease from infective diarrhoea. J Infect 1991;22:247–50. 31. Lam A, Borda IT, Inwood MJ, Thomson S. Coagulation studies in ulcerative colitis and Crohn’s disease. Gastroenterology 1975;68:245–51. 32. Talstad I, Rootwelt K, Gjone E. Thrombocytosis in ulcerative colitis and Crohn’s disease. Scand J Gastroenterol 1973;8:135–8. 33. Cabrera-Abreu JC, Davies P, Matek Z, Murphy MS. Performance of blood tests in diagnosis of inflammatory bowel disease in a specialist clinic. Arch Dis Child 2004;89:69–71. 34. Desai D, Faubion WA, Sandborn WJ. Review article: biological activity markers in inflammatory bowel disease. Aliment Pharmacol Ther 2007;25:247–55. 35. Vermeire S, Van Assche G, Rutgeerts P. Laboratory markers in IBD: useful, magic, or unnecessary toys? Gut 2006;55:426–31. 36. Shine B, Berghouse L, Jones JE, Landon J. C-reactive protein as an aid in the differentiation of functional and inflammatory bowel disorders. Clin Chim Acta 1985;148:105–9. 37. Sachar DB, Smith H, Chan S, Cohen LB, Lichtiger S, Messer J. Erythrocytic sedimentation rate as a measure of clinical activity in inflammatory bowel disease. J Clin Gastroenterol 1986;8:647–50. 38. Solem CA, Loftus EV, Jr., Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease. Inflamm Bowel Dis 2005;11:707–12. 39. Fagan EA, Dyck RF, Maton PN et al. Serum levels of C-reactive protein in Crohn’s disease and ulcerative colitis. Eur J Clin Invest 1982;12:351–9. 40. Saverymuttu SH, Hodgson HJ, Chadwick VS, Pepys MB. Differing acute phase responses in Crohn’s disease and ulcerative colitis. Gut 1986;27:809–13. 41. Poullis AP, Zar S, Sundaram KK et al. A new, highly sensitive assay for C-reactive protein can aid the differentiation of inflammatory bowel disorders from constipation- and diarrhoea-predominant functional bowel disorders. Eur J Gastroenterol Hepatol 2002;14:409–12. 42. Maudgal DP, Ang L, Patel S, Bland JM, Maxwell JD. Nutritional assessment in patients with chronic gastrointestinal symptoms: comparison of functional and organic disorders. Hum Nutr Clin Nutr 1985;39:203–12. 43. Kane W, Miller K, Sharp HL. Inflammatory bowel disease presenting as liver disease during childhood. J Pediatr 1980;97:775–8. 44. Gupta N, Cohen SA, Bostrom AG et al. Risk factors for initial surgery in pediatric patients with Crohn’s disease. Gastroenterology 2006;130:1069–77. 45. Ferrante M, Penninckx F, De Hertogh G et al. Protein-losing enteropathy in Crohn’s disease. Acta Gastroenterol Belg 2006;69:384–9.
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46. Semeao EJ, Jawad AF, Stouffer NO, Zemel BS, Piccoli DA, Stallings VA. Risk factors for low bone mineral density in children and young adults with Crohn’s disease. J Pediatr 1999;135:593–600. 47. Thomas DW, Sinatra FR. Screening laboratory tests for Crohn’s disease. West J Med 1989;150:163–4. 48. Mendes FD, Levy C, Enders FB, Loftus EV, Jr., Angulo P, Lindor KD. Abnormal hepatic biochemistries in patients with inflammatory bowel disease. Am J Gastroenterol 2007;102:344–50. 49. Broome U, Glaumann H, Hellers G, Nilsson B, Sorstad J, Hultcrantz R. Liver disease in ulcerative colitis: an epidemiological and follow up study in the county of Stockholm. Gut 1994;35:84–9. 50. Feldstein AE, Perrault J, El-Youssif M, Lindor KD, Freese DK, Angulo P. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology 2003;38:210–7. 51. Hyams JS. Extraintestinal manifestations of inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr 1994;19:17–21. 52. Wilschanski M, Chait P, Wade JA et al. Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis. Hepatology 1995;22:1415–22. 53. Ridder RM, Kreth HW, Kiss E, Grone HJ, Gordjani N. Membranous nephropathy associated with familial chronic ulcerative colitis in a 12-year-old girl. Pediatr Nephrol 2005;20:1349–51. 54. Siveke JT, Egert J, Sitter T et al. 5-ASA therapy and renal function in inflammatory bowel disease. Am J Gastroenterol 2005;100:501. 55. Van Staa TP, Travis S, Leufkens HG, Logan RF. 5-aminosalicylic acids and the risk of renal disease: a large British epidemiologic study. Gastroenterology 2004;126:1733–9. 56. Margetts PJ, Churchill DN, Alexopoulou I. Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine. J Clin Gastroenterol 2001;32:176–8. 57. De Broe ME, Stolear JC, Nouwen EJ, Elseviers MM. 5-Aminosalicylic acid (5-ASA) and chronic tubulointerstitial nephritis in patients with chronic inflammatory bowel disease: is there a link? Nephrol Dial Transplant 1997;12:1839–41. 58. Izzedine H, Simon J, Piette AM et al. Primary chronic interstitial nephritis in Crohn’s disease. Gastroenterology 2002;123:1436–40. 59. Canani RB, de Horatio LT, Terrin G et al. Combined use of noninvasive tests is useful in the initial diagnostic approach to a child with suspected inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2006;42:9–15. 60. Olives JP, Breton A, Hugot JP et al. Antineutrophil cytoplasmic antibodies in children with inflammatory bowel disease: prevalence and diagnostic value. J Pediatr Gastroenterol Nutr 1997;25:142–8. 61. Ruemmele FM, Targan SR, Levy G, Dubinsky M, Braun J, Seidman EG. Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease. Gastroenterology 1998;115:822–9. 62. Dubinsky MC, Johanson JF, Seidman EG, Ofman JJ. Suspected inflammatory bowel disease–the clinical and economic impact of competing diagnostic strategies. Am J Gastroenterol 2002;97:2333–42. 63. Hoffenberg EJ, Fidanza S, Sauaia A. Serologic testing for inflammatory bowel disease. J Pediatr 1999;134:447–52. 64. Gupta SK, Fitzgerald JF, Croffie JM, Pfefferkorn MD, Molleston JP, Corkins MR. Comparison of serological markers of inflammatory bowel disease with clinical diagnosis in children. Inflamm Bowel Dis 2004;10:240–4. 65. Zholudev A, Zurakowski D, Young W, Leichtner A, Bousvaros A. Serologic testing with ANCA, ASCA, and anti-OmpC in children and young adults with Crohn’s disease and ulcerative colitis: diagnostic value and correlation with disease phenotype. Am J Gastroenterol 2004;99:2235–41. 66. Elitsur Y, Lawrence Z, Tolaymat N. The diagnostic accuracy of serologic markers in children with IBD: the West Virginia experience. J Clin Gastroenterol 2005;39:670–3. 67. Khan K, Schwarzenberg SJ, Sharp H, Greenwood D, Weisdorf-Schindele S. Role of serology and routine laboratory tests in childhood inflammatory bowel disease. Inflamm Bowel Dis 2002;8:325–9. 68. Young Y, Abreu MT. Advances in the pathogenesis of inflammatory bowel disease. Curr Gastroenterol Rep 2006;8:470–7. 69. Papadakis KA, Yang H, Ippoliti A et al. Anti-flagellin (CBir1) phenotypic and genetic Crohn’s disease associations. Inflamm Bowel Dis 2007;13:524–30. 70. Targan SR, Landers CJ, Yang H et al. Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn’s disease. Gastroenterology 2005;128:2020–8. 71. Fuchizaki U, Machi T, Kaneko S. Clinical challenges and images in GI. Yersinia enterocolitica mesenteric adenitis and terminal ileitis. Gastroenterology 2006;131:1379, 1659.
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72. Tuohy AM, O’Gorman M, Byington C, Reid B, Jackson WD. Yersinia enterocolitis mimicking Crohn’s disease in a toddler. Pediatrics 1999;104:e36. 73. Meyer AM, Ramzan NN, Loftus EV, Jr., Heigh RI, Leighton JA. The diagnostic yield of stool pathogen studies during relapses of inflammatory bowel disease. J Clin Gastroenterol 2004;38:772–5. 74. Sands BE. Inflammatory bowel disease: past, present, and future. J Gastroenterol 2007;42:16–25. 75. Behr MA, Schurr E. Mycobacteria in Crohn’s disease: a persistent hypothesis. Inflamm Bowel Dis 2006;12:1000–4. 76. Chamberlin W, Ghobrial G, Chehtane M, Naser SA. Successful treatment of a Crohn’s disease patient infected with bacteremic Mycobacterium paratuberculosis. Am J Gastroenterol 2007;102:689–91. 77. Sechi LA, Gazouli M, Sieswerda LE et al. Relationship between Crohn’s disease, infection with Mycobacterium avium subspecies paratuberculosis and SLC11A1 gene polymorphisms in Sardinian patients. World J Gastroenterol 2006;12:7161–4. 78. Baldassarre ME, Altomare MA, Fanelli M et al. Does calprotectin represent a regulatory factor in host defense or a drug target in inflammatory disease? Endocr Metab Immune Disord Drug Targets 2007;7:1–5. 79. Bjerke K, Halstensen TS, Jahnsen F, Pulford K, Brandtzaeg P. Distribution of macrophages and granulocytes expressing L1 protein (calprotectin) in human Peyer’s patches compared with normal ileal lamina propria and mesenteric lymph nodes. Gut 1993;34:1357–63. 80. Roseth AG, Fagerhol MK, Aadland E, Schjonsby H. Assessment of the neutrophil dominating protein calprotectin in feces. A methodologic study. Scand J Gastroenterol 1992;27:793–8. 81. Steinbakk M, Naess-Andresen CF, Lingaas E, Dale I, Brandtzaeg P, Fagerhol MK. Antimicrobial actions of calcium binding leucocyte L1 protein, calprotectin. Lancet 1990;336:763–5. 82. Roseth AG, Schmidt PN, Fagerhol MK. Correlation between faecal excretion of indium-111-labelled granulocytes and calprotectin, a granulocyte marker protein, in patients with inflammatory bowel disease. Scand J Gastroenterol 1999;34:50–4. 83. Tibble J, Teahon K, Thjodleifsson B et al. A simple method for assessing intestinal inflammation in Crohn’s disease. Gut 2000;47:506–13. 84. Fagerberg UL, Loof L, Myrdal U, Hansson LO, Finkel Y. Colorectal inflammation is well predicted by fecal calprotectin in children with gastrointestinal symptoms. J Pediatr Gastroenterol Nutr 2005;40: 450–5. 85. Loftus EV, Jr. Objective measures of disease activity: alternatives to symptom indices. Rev Gastroenterol Disord 2007;7 Suppl 2:S8–S16. 86. Angriman I, Scarpa M, D’Inca R et al. Enzymes in feces: Useful markers of chronic inflammatory bowel disease. Clin Chim Acta 2007. 87. Tibble JA, Sigthorsson G, Foster R, Forgacs I, Bjarnason I. Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology 2002;123: 450–60. 88. Carroccio A, Iacono G, Cottone M et al. Diagnostic accuracy of fecal calprotectin assay in distinguishing organic causes of chronic diarrhea from irritable bowel syndrome: a prospective study in adults and children. Clin Chem 2003;49:861–7. 89. Bunn SK, Bisset WM, Main MJ, Golden BE. Fecal calprotectin as a measure of disease activity in childhood inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2001;32:171–7. 90. Sugi K, Saitoh O, Hirata I, Katsu K. Fecal lactoferrin as a marker for disease activity in inflammatory bowel disease: comparison with other neutrophil-derived proteins. Am J Gastroenterol 1996;91:927–34. 91. Buderus S, Boone J, Lyerly D, Lentze MJ. Fecal lactoferrin: a new parameter to monitor infliximab therapy. Dig Dis Sci 2004;49:1036–9. 92. Walker TR, Land ML, Kartashov A et al. Fecal lactoferrin is a sensitive and specific marker of disease activity in children and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007;44:414–22.
17 Radiologic Evaluation of Pediatric Inflammatory Bowel Disease Benedict C. Nwomeh∗ and Wallace V. Crandall
Introduction Radiologic imaging is a vital component of disease evaluation in the patient with inflammatory bowel disease (IBD). Imaging techniques are useful at initial presentation to help establish the diagnosis and to assess the location, extent, inflammatory activity, and severity of disease. These modalities are also very important for disease monitoring during and after treatment, in selecting appropriate treatment options, planning surgical strategies, and for assessing complications of disease and effects of therapeutic interventions. Despite ongoing advances in imaging technology, conventional plain radiographs and contrast studies such as the upper gastrointestinal series and the small bowel follow-through are still important tools in the evaluation of IBD. In recent years, cross-sectional imaging techniques such as ultrasound, computer tomography, and magnetic resonance imaging have added an extra dimension and a deeper perspective to our understanding of this disease. Advances in imaging technology have brought newer generation scanners that allow rapid acquisition of highresolution images of diseased bowel with three-dimensional rendering. Imaging techniques have also enhanced our understanding of the various extraintestinal disease manifestations. This chapter will discuss the current role of these various modalities in the clinical management of pediatric patients with Crohn disease (CD) and ulcerative colitis (UC) and review some of the emerging techniques that may yield more detail and improve on the accuracy of current methods.
Crohn Disease The hallmark of CD is segmental, transmural bowel involvement with a chronic relapsing course, and the propensity to affect any portion of the gastrointestinal tract. The disease may be limited to a single segment of bowel, commonly the terminal ileum. However, multiple segments may be affected, with intervening normal bowel, known as “skip lesions.” CD may be complicated by perianal disease, strictures, fistulas, and abscesses. This clinical pattern is closely mirrored by the radiologic findings. With several imaging modalities available, the clinical condition of the patient and the clinical question to be answered should determine which imaging techniques are employed. *Assistant Professor of Surgery, Division of Pediatric Surgery, The Ohio State University, Surgical Director, The Center for Pediatric and Adolescent IBD, Columbus Children’s Hospital, Columbus, OH 43205, Phone: 614-722-3972, Fax: 614-722-3903
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Imaging Techniques Plain Radiographs Abnormalities in plain abdominal radiographs consistent with IBD are present in two thirds of pediatric patients but these are non-specific findings such as mural thickening, dilatation and abnormal pattern of gas and feces [1]. As such the plain film has little role in the initial evaluation of the patient with CD. However, plain films remain the first line investigation in the patient with an acute abdomen, in whom dilated bowel loops and air-fluid levels indicate acute intestinal obstruction, and pneumoperitoneum signifies intestinal perforation. For example, toxic megacolon affecting patients with Crohn colitis usually manifests as dilated colon. Contrast Studies Despite the plethora of new imaging techniques, no radiologic test has replaced conventional contrast studies as the gold standard for the diagnosis of CD. Contrast studies allow direct mucosal assessment in the hand of the experienced radiologist. The upper gastrointestinal (UGI) series is an excellent modality in which contrast is administered by mouth (or through a gastric tube) for mucosal assessment of the stomach and duodenum. The small bowel follow through (SBFT) is performed as a continuation of the UGI examination. Additional contrast is administered or ingested, and the contrast is followed through the jejunum and ileum into the right colon. Fluoroscopic compression images of the small intestine, specifically the terminal ileum, are obtained. (Figure 17.1) A small bowel enteroclysis examination involves direct injection of contrast and methylcellulose via a nasojejunal catheter placed under fluoroscopic guidance. A double contrast view of the small intestine is obtained, providing better distension and superior mucosal detail. However, the SBFT is often chosen instead of the enteroclysis study because the latter is more unpleasant for the patient, involves a higher radiation dose, and is more difficult
Figure 17.1. Compression view of the right lower quadrant from SBFT demonstrates a long segment of narrowed, ulcerated and nodular appearing ileum giving the characteristic “cobblestone” appearance (arrows). Loop separation is caused by thickening of bowel walls and mesentery inflammation.
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to perform. The barium enema (BE), using a single or double contrast technique, may be used to evaluate the colon. If reflux across the ileocecal valve is obtained, it also may provide a double contrast view of the terminal ileum. The ability to visualize the terminal ileum is critical, as it is frequently affected in CD. However, given the common availability of endoscopic assessment, patient discomfort with BE, and the risk for complications such as toxic megacolon, BE has been largely replaced by colonoscopy. Early changes of CD include aphtous lesions, a coarse granular pattern, nodularity, and fold thickening, which may progress to deeper ulceration, cobblestoning, and fissuring. In the colon, ulceration occurs within a background of normal-appearing mucosa. Inflammatory edema produces mucosal elevations seen more commonly in the colon than the small bowel. In the patient with more severe CD, mucosal distortions and pseudopolyps may occur due to the elevation of submucosa at the margins of healing ulcers. As inflammation spreads in transmural and circumferential dimensions, the radiologic findings progress to strictures and shortening, with the most severe cases producing the characteristic “string sign.” In addition, bowel may be noted to adhere to adjacent loops or to other viscera and deep ulcers may extend to create fistula. The finding of discontinuous, patchy, and asymmetric colonic mucosal changes is a hallmark of CD. Contrast studies are limited in their ability to image extraluminal extension of disease or extraintestinal manifestations. Only indirect assessment of bowel wall thickening or mesenteric involvement can be made. Mesenteric inflammation, thickening, and fibrosis may cause separation and shortening of bowel loops. Mesenteric lymphadenopathy may appear as extraluminal masses indenting the bowel wall. Computed Tomography Computed tomography (CT) is the most widely used cross-sectional imaging modality in patients with CD. Its major role in children with CD is in the evaluation of disease extent and in assessing for complications. CT enteroclysis has been shown to be more accurate than SBFT in the diagnosis of CD, but neither is able to detect the early mucosal changes of CD [2]. Changes readily detected by CT include bowel wall thickening, luminal narrowing, and mesenteric involvement. Mesenteric findings include thickening due to fibrofatty infiltration, lymphadenopathy, and fatty encroachment of the affected loop of bowel. Patients with known CD, who present with new symptoms suspicious for complications or a deteriorating clinical course, are best imaged with CT to assess for progressive disease or the onset of complications such as obstruction, fistulae, abscesses, or malignant change. (Figure 17.2) Extraintestinal manifestations of CD in the hepatobiliary, pancreatic, urinary, and musculoskeletal systems are also readily assessed by CT. Specific CT findings of complications and extraintestinal manifestations of CD are discussed below. The sensitivity of CT scan in patients with CD is increased by optimal opacification and distension of the bowel by administering oral contrast at an age and weight appropriate dose, or by the enteroclysis technique. Bowel wall thickening greater than 3 mm in pediatric patients is generally considered abnormal [3]. Magnetic Resonance Imaging Magnetic resonance imaging (MRI) offers unique advantages to the pediatric patient because, in addition to being non-invasive, it avoids exposure to ionizing radiation. In selected cases, MRI can replace or complement CT because its excellent soft tissue contrast and three-dimensional capabilities are ideal properties for imaging the bowel [4]. In the past, MRI was often limited by motion artifacts but this problem has been largely overcome by the recent introduction of respirationsuspended sequences. Other technological advances, including improved coils, fat suppression,
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Figure 17.2. Oral and intravenous contrast enhanced CT image of the pelvis. A thickened loop of small bowel containing intraluminal contrast (white arrow) marginates an intra-abdominal abscess containing fluid and air (arrowhead). An enhancing fistulous tract is seen extending to the base of the abscess cavity (open arrow).
use of oral agents and intravenous gadolinium, powerful gradient systems, and ultrafast pulse sequences have led to overall improvement in gastrointestinal imaging. Optimal image quality depends greatly on adequate luminal distension with contrast medium. Without enteric contrast, MRI has produced inconsistent results in children with CD [5, 6]. The method of enteric contrast administration has proved to be a critical factor because oral ingestion (magnetic resonance follow-through), while patient-friendly, produces inadequate luminal distension, downgrades the image quality, and may limit the ability to detect early or minimal disease. The alternative method, known as magnetic resonance enteroclysis (MRE), requires duodenal intubation to permit volume challenge, which causes reflex bowel atony and produces superb contrast for evaluating luminal, transmural, and extramural changes. By combining the advantages of enteroclysis with threedimensional cross-sectional imaging, MRE has been touted as the only imaging modality that can provide comprehensive diagnostic information on small bowel CD [4]. Routine use of MRE in children has not been widely adopted because of the need to insert a duodenal tube fluoroscopically, entailing exposure to ionizing radiation and need for intravenous sedation. However, orally administered polyethylene glycol (PEG) may sufficiently distend the bowel for optimal MRI evaluation in pediatric patients. In a study comparing PEG-MRI with endoscopy and histology among 75 children with suspected CD, increased wall thickness and parietal contrast enhancement correlated highly with endoscopic scores (r = 0.94, p < 0.0001) and histologic scores (r = 0.95, p < 0.0001) among the 26 patients with a final diagnosis of CD [7]. The diagnostic sensitivity and specificity of PEG-MRI was 84% and 100%, respectively. Despite these promising results, further studies will be needed to confirm the utility of MRI in the evaluation of intestinal CD in pediatric patients. We currently use MRI mostly for the evaluation of complex perianal disease, as discussed below. Ultrasound The lack of ionizing radiation and noninvasive nature of US make it an ideal method of evaluation in children. In addition, for routine US imaging, bowel cleansing is not required, nor is
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enteric or intravenous contrast. However, because it is operator dependent, its role in patients with CD is generally limited to the evaluation of complications, particularly abscesses, and extraintestinal disease manifestations. It is rarely used for primary diagnosis. Affected bowel segments demonstrate wall thickening, lack of peristalsis, and poor stratification of the different layers. (Figure 17.3a) [8]. Similar to adults, US findings in children with CD show good correlation with endoscopy [9]. The most promising use of US may be in the ongoing evaluation of disease activity as well as response to treatment. In children, the sonographic value of bowel wall thickening as an index of increased disease activity has been demonstrated [10, 11]. With moderate-severe disease, the predictive value of increased bowel wall thickening greater than 2.5 mm in the ileum as an index of active disease was 88% (82% for colon >3 mm) [10]. Assessment of disease severity can also be enhanced by measuring the vessel density in the affected bowel segment using color Doppler US. (Figure 17.3b) [12]. When incorporated into a clinical protocol, US may reduce
(a)
(b)
Figure 17.3. (a) Longitudinal ultrasound of the right lower quadrant demonstrates a segmental region of thickened, hypoechoic small bowel (arrows). (b) Transverse Doppler image demonstrates hyperemia of bowel wall (arrow).
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the need for contrast studies [10, 13]. In expert hands, US has been used to assess fistulae and strictures, and also monitor postoperative disease recurrence [14]. There are a number of limitations to the use of US in CD. Although the assessment of terminal ileal disease with US is quite good, the proximal small bowel and distal portions of the colon are poorly imaged. In addition, superficial lesions as seen in early disease can be missed in both children and adults [9].
Ulcerative Colitis Ulcerative colitis is a chronic, idiopathic, inflammatory disease of the rectal and colonic mucosa that is characterized by mucosal inflammation, edema, and ulceration. Several distinguishing features permit clinical and radiological distinction from CD. As a rule, UC nearly always affects the rectum and extends proximally to involve a variable length of colon in a contiguous fashion. Other than the occasional “backwash ileitis” of the terminal ileum, the small bowel is not affected. On rare occasions, variants with transmural involvement or without rectal inflammation also occur. Radiologic features of UC are quite distinct, although in the majority of cases, diagnosis is dependent on clinical presentation, laboratory tests and findings on colonoscopy and biopsy.
Imaging Techniques Plain Radiographs The non-specific finding of mucosal edema occasionally noted on plain films is rarely helpful for diagnosis. However, in the patient presenting acutely with symptoms of toxic megacolon, the plain film shows marked colon dilatation and is adequate for monitoring response to treatment and the potential onset of bowel perforation. Contrast Enema Given the availability of colonoscopy and its ability to obtain tissue for histologic assessment, as well as the discomfort of BE, contrast studies of the colon are less commonly performed than in the past. However, if needed, it can be used for confirming the diagnosis, evaluating extent and severity of disease, and detecting complications. The earliest change seen on the air-contrast study is a fine granular pattern of the colonic mucosa, which may be associated with blunting and broadening of the haustral folds due to mucosal edema. As the disease progresses, mucosal irregularity increases (Figure 17.4). Subsequently, ulcers appear and begin to extend deeper, undermining the submucosa and forming flask-shaped or “collar-button” ulcers. Extensive mucosal ulceration may leave islands of residual inflamed mucosa that are recognized as “inflammatory pseudopolyps.” In contrast to CD, these changes are contiguous, circumferential, and symmetric with no skip lesions. With long-standing disease, the colonic wall becomes rigid, shortened, and narrow due to fibrosis of the submucosa, giving the appearance of the “lead pipe” colon. A contrast enema should be administered with extreme caution in the patient with an acute presentation. A physical examination to exclude peritoneal signs and a plain film to rule out toxic megacolon and free air should be performed prior to a BE, as any of these findings would be a contraindication. Computed Tomography CT may be useful in differentiating UC from CD, and it has the advantage of being able to visualize bowel wall as well as adjacent structures [15]. Adequate preparation for the CT
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Figure 17.4. Image (ACBE –UC). Anterior image of the transverse colon from ACBE demonstrating granular mucosa with early ulcerations seen in profile (arrows) and en face (arrowheads).
examination is important. When optimal colonic imaging is desired, oral contrast should be given sufficient time to opacify the entire small bowel and colon, and if necessary additional rectal contrast should be administered. Early mucosal changes are difficult to detect on CT, but in chronic disease bowel wall thickening and luminal narrowing is readily seen [16]. However, these rather non-specific findings overlap with those of other colitides including Crohn colitis [15, 17]. Characteristic CT features in UC include a symmetric, contiguous wall thickening involving the rectum and extending proximally in a contiguous manner. Small bowel changes and skip lesions are absent. Thickening of the mesentery or mesenteric lymphadenopathy are rare, but proliferation of perirectal fat can occur.
Magnetic Resonance Imaging Characteristic findings of MRI in the active stage of UC include loss of haustral markings, thickening, and contrast enhancement of the colonic wall [18, 19]. As with CT, these findings overlap those of CD and the few pediatric studies available reveal inconsistencies in the ability of MRI to differentiate UC from CD [5, 6]. At present, MRI seems more promising for characterizing small bowel disease and offers little advantages over CT in the evaluation of colonic IBD.
Ultrasound As previously noted, US has the advantages of being cheap, noninvasive, and lacking in ionizing radiation, but its principal finding of increased bowel wall thickness is nonspecific and cannot distinguish between UC and CD. In addition, early mucosal changes are not detected with US and the difficulty in visualizing the rectosigmoid limits its ability to evaluate the true extent of the disease. In the few pediatric studies, there appears to be a consensus that the appropriate role of US is in the monitoring of disease activity and assessing response to treatment [10, 20, 21]. With moderate-severe disease, the predictive value of increased bowel wall thickening greater than 3 mm in the colon as an index of active disease was 82% [10].
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Indeterminate Colitis Patients with IBD whose clinical, endoscopic, pathologic, and radiologic presentation cannot easily be differentiated into CD or UC are assigned the diagnosis of indeterminate colitis (IC). Indeterminate colitis appear to be more common in children compared to adults, with a prevalence rate of nearly 30% recently reported in a cohort of 250 children with IBD [22]. Careful radiologic evaluation may play a significant role in subsequent reclassification of patients with IC. The distinction between CD and UC may be important in selecting appropriate treatment and in determining prognosis. Demonstration of small bowel inflammation, skip lesions, and mesenteric extension usually indicates CD, particularly in the absence of colonic disease. Patients classified as IC usually have normal small bowel imaging on the SBFT and CT. As noted previously, newer techniques such as US, radionuclide scans, and MRE may demonstrate small bowel disease, particularly in the distal ileum. The most promising technique may be the MRE when optimal luminal distension is achieved with biphasic contrast in addition to intravenous gadolinium enhancement [2]. When extensive colonic disease is present, the finding of terminal ileal inflammation may be misleading because some patients with UC may have “backwash ileitis.” Although the colon is usually accessible for endoscopic evaluation, cross-sectional imaging with CT or MRI may demonstrate transmural involvement, extension into mesenteric fat, fistulae, or abscesses, which may prompt a more definitive reclassification as CD. Using US to differentiate between CD and UC has so far proved unreliable in children, although it may be useful for monitoring disease activity [9, 11, 23].
Other Radiologic Modalities in IBD White Blood Cell Scan Radionuclide-labeled autologous white blood cells (WBC) reinjected intravenously are taken up by inflamed tissues and can then be detected by a gamma camera scan (Figure 17.5). Within a few minutes of injection, the labeled WBC marginates in inflamed bowel and usually increases in intensity over a period of 2–4 hours. The WBC scan is a helpful diagnostic tool for the detection of inflammation and abscesses. Soon after it was introduced, the 111 In-labeled WBC scan was shown to be highly sensitive in patients with IBD [24]. Subsequently, Technetium TC 99m Hexamethyl propylene amine oxime (99m Tc HMPAO) labeled WBC scan was adopted because of ready availability, longer shelf life, lower radiation dose, and superior image resolution [25]. Most pediatric studies indicate that a positive WBC scan is highly predictive of IBD. However, false negative studies can occur in very early disease or in patients who are in remission due to recent steroid treatment [25–27]. Negative scans have also been observed in children with proximal small bowel disease. Localization of tracer activity can be a useful aid in differentiating children with CD from those with UC. Uptake localized to the small bowel or a more widespread but discontinuous bowel activity correlates highly with CD whereas in UC the characteristic finding is a continuous pattern of uptake involving the rectum with a variable proximal extension in the colon [25, 28–30]. The WBC scan can also be a reliable indicator of disease activity. A “scan score” calculated by comparing uptake of tracer in affected bowel segments with iliac crest bone marrow activity correlated much better with clinical disease activity than did the erythrocyte sedimentation rate [31]. In the follow-up of patients with known IBD, a negative scan indicates remission and may prompt changes in treatment [25]. The WBC scan may be useful in several areas of clinical decision-making in children with known IBD. A positive WBC scan can identify ileal inflammation when ileoscopy is not feasible [32]. The finding of small bowel activity or skip areas of
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Figure 17.5. 3D volume rendered image from a Tc-HMPAO WBC scan of the abdomen demonstrates intense focal activity in the right lower quadrant (arrow) compatible with the diagnosis of active inflammatory bowel disease of the distal small bowel.
colonic involvement could help to establish the diagnosis of CD in patients previously assigned the diagnosis of indeterminate colitis [25]. In cases of luminal narrowing, a positive WBC scan may help distinguish active inflammation from fibrosis. The WBC scan is attractive for children because it is associated with much less radiation exposure than contrast studies. However, scintigraphy has several limitations including false positive studies in the presence of gastrointestinal bleeding and inability to define anatomic detail including strictures and fistulae [25, 26]. It is also time-consuming, and drawing sufficient blood for labeling can be a challenge in younger children.
Positron Emission Tomography Positron emission tomography (PET) is a functional imaging technique that has been applied to the detection of inflamed areas of bowel. The high metabolic activity of inflamed tissue results in the uptake of the glucose analog, fluoro-2-deoxy-D-glucose (FDG), which has been radiolabeled with a positron-emitting isotope such as fluorine-18 (F-18). It is transported into cells at a rate proportional to the glycolytic activity of the cell. Within an hour of the intravenous injection of F-18 labeled FDG, the scan is performed, with a total image acquisition time of less than a half hour. PET scanning detects inflamed bowel in children with a reported accuracy similar to the WBC scan [33, 34]. As compared to the WBC scan, PET is faster and does not require blood to be drawn. However, PET scans depend on equipment and expertise that may not be generally accessible. Given the limited availability and the paucity of pediatric studies, PET has a minimal role in the evaluation of pediatric IBD at the present time.
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Evaluation of Complications Perianal Disease Perianal disease occurs in over one-third of patients with CD but is not associated with UC. Diagnosis of external manifestations such as skin tags, fissures, ulcerations, and simple perianal abscesses, requires only a careful inspection and digital rectal examination as appropriate. Additional information on complex abscesses, fistulae, and strictures can be obtained by performing an examination under anesthesia (EUA) with procto-sigmoidoscopy and with imaging studies. Anatomic classification of perianal disease is enhanced by use of modern imaging techniques especially MRI and endoscopic ultrasound (EUS) [35–37]. Anal fistulography has been largely abandoned because of patient discomfort, poor accuracy, and inability to visualize the anal sphincter anatomy [38, 39]. CT is also unreliable in assessing perianal fistulae due to its poor intrinsic contrast resolution that limits its ability to define the anatomy of the levator muscle [40, 41]. Because CT entails exposure to ionizing radiation, it is also disadvantageous in children. Both MRI and EUS appear to be highly accurate in demonstrating anal sphincter anatomy and in illustrating the relationship of abscesses and fistulae to the levators [35–37, 42–44]. Detailed and accurate demonstration of the anatomic relationships has significant implications for the surgical management of perianal disease [35, 45]. In patients with recurrent fistula-in-ano following initial operative intervention, subsequent surgery guided by MRI reduced further recurrence by 75% [46]. Similarly, among a group of patients undergoing infliximab therapy for fistula-in-ano, EUS was accurate in identifying a subset of patients who could discontinue treatment without recurrence of fistula drainage [47]. Both MRI and EUS have also been used to accurately define the perineal body and demonstrate anovaginal and rectovaginal fistulae [48–50]. While reports present conflicting accounts of the superiority of one technique over the other, the most accurate assessment of perianal disease has been obtained when any two out of the three techniques (EUA, MRI, and EUS) were combined [51]. However, the method chosen should take into account both the cost and the equipment and expertise available at individual institutions [52].
Enteric Fistula and Intraabdominal Abscesses The incidence of enteric fistula and intraabdominal abscess in children with CD is approximately 10% each, with a cumulative incidence of up to 30% each in adult patients [53–55]. Intraabdominal abscesses are commonly evaluated with CT or US, and both modalities are also very effective in providing image-guidance for percutaneous drainage of abscesses (Figure 17.2). [56–58]. Abscesses frequently develop in the abdominal wall, peritoneal cavity, retroperitoneum or iliopsoas, and subphrenic region [55]. Abscesses occurring between loops of bowel (interloop abscesses) are common. In half of patients, the abscess cavity occurs near an anastomosis following surgical resection. Radiologic demonstration of enteric fistula can be challenging. Fistula usually arises from the extension of primary small bowel or colonic disease into adjacent mesentery, nearby bowel, skin, or the viscera of the genitourinary system. Fistula tracts can also extend into solid organs, muscle, or spine. Most commonly, fistulae arise from the terminal ileum and penetrate into the cecum or adjacent small bowel (Figure 17.6a and b). These communications are difficult to define with standard contrast imaging due to overlap of bony structures and contrast filled bowel, or because tissue edema prevents outlining of the fistulous tract with contrast. Enteroclysis is more sensitive
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(a)
(b)
Figure 17.6. (a) An overhead radiograph of the abdomen from a SBFT demonstrates narrowed segment of diseased small bowel from which arise multiple fistulae (arrows). Contrast is seen in the rectum consistent with enterocolic fistulae formation. (b) Image (SBFT – TI fistula). Coned view of the terminal ileum from SBFT demonstrates multiple fistulous tracts arising from the terminal ileum and extending to the cecum (arrows).
for demonstrating fistula than the SBFT examination. CT is more useful for demonstrating fistula tracks, although it is only possible to determine whether a tract is patent when it has been opacified by contrast. The CT is also an excellent modality for evaluating fistulae with concomitant abscesses. Other cross-sectional imaging modalities such as the MRI and US may also be useful in imaging enteric fistulae. MR is vastly superior for detecting enteric fistulae and intraabdominal abscesses
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Figure 17.7. Coronal T2 – weighted fat suppressed image of the pelvis demonstrates T2 bright linear fistulous tract arising from the right side of the rectum at the level of the levator musculature (arrow). T2 bright inflammatory changes are seen to extend deep into the pelvis along the obterator internus muscle (arrowhead).
compared to enteroclysis, and it appears to be at least as sensitive as CT scan (Figure 17.7) [59, 60]. Although US has also been shown to be comparable to enteroclysis in detecting fistulae, there is insufficient experience with this technique to recommend its routine use at the present time [8]. One of the more dramatic manifestations of enteric fistula is involvement of the genitourinary tract. Most commonly, communication develops between the terminal ileum and the bladder, but may extend to involve the ureters, uterus, and vagina [61]. Bladder fistulae occur more frequently in males who do not have the protective shield of the uterus. Clinically, bladder fistulae present with pneumaturia and recurrent urinary tract infections. Bladder and vaginal fistulae are often difficult to visualize with conventional cystography or BE. The most sensitive imaging technique for bladder fistulae is CT with adequate oral contrast. The finding of air within the bladder in the absence of recent instrumentation is diagnostic of either a fistula or infection with a gas-forming organism. If the primary aim of the CT study is to detect fistulae, intravenous contrast should not be given so that any contrast material subsequently noted in the bladder or vagina confirms the diagnosis [61, 62]. Bowel Obstruction and Perforation The radiologic hallmark of bowel obstruction is dilatation of proximal bowel with paucity of gas distally. Air-fluid levels may also be noted in proximal bowel. If contrast examination is performed, contrast progression to distal bowel is reduced according to the degree of the obstruction. It is important to distinguish between partial obstruction where initial nonoperative treatment may be appropriate and complete obstruction, where surgical intervention is often required. CT is helpful in evaluating the severity of intramural disease and any associated abscesses. The diagnosis of intestinal perforation is made when free extraperitoneal gas is detected by either plain film or CT. The radiologic signs of bowel obstruction or perforation in patients with Crohn disease are similar to the findings in other patients, and further details will be found in most general radiology textbooks.
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Toxic Megacolon Toxic megacolon is a complication more frequently seen with UC, but may also occur in patients with severe CD. The clinical scenario is a patient with IBD presenting with an acute abdomen and signs of sepsis. Occasionally, toxic megacolon is the initial presentation of the patient with UC. The diagnosis should be made on a plain radiograph. Marked colonic dilatation with absent haustral pattern is seen, with the threshold for diagnosis depending on the child’s age. In adolescents, the threshold is a colonic diameter >5 cm. Following initial medical treatment, serial films are obtained to monitor for progression and evidence of perforation. Colon contrast studies should be avoided as they increase the risk of perforation.
Extraintestinal Disease Although IBD predominantly affects the gastrointestinal system, it is associated with a large number of extraintestinal manifestations that can significantly contribute to morbidity and affect the overall quality of life. Most commonly affected, as a direct pathophysiologic consequence of the disease, are the skin, eyes, and musculoskeletal and hepatobiliary systems. Ultimately, almost every organ system may be affected by either the secondary systemic effects of the disease or the adverse effects of treatment. Radiologic assessment of some of these systemic disorders is an important part of the comprehensive assessment of the patient with IBD. In addition to the brief account given below, detailed description of these systemic manifestations, including radiologic evaluation, will be found in the appropriate chapters in this book.
Hepatobiliary Disease Gallstones There is an overall increased incidence of gallstones in patients with IBD, but the association is far stronger with CD than UC. The best modality for detecting gallstones is US, although CT may be indicated in some situations. Primary Sclerosing Cholangitis Primary sclerosing cholangitis (PSC) is characterized by inflammatory fibrosis of the intra- and extrahepatic biliary ducts with progression to stricture, cholestasis, and cirrhosis (Figure 17.8). In contrast to gallstones, PSC is more strongly associated with UC than CD. Although endoscopic retrograde cholangiopancreatography (ERCP) has high sensitivity for detecting early biliary changes, in children this procedure may require general anesthesia and depends on equipment and technical expertise that is not available to some pediatric centers. Magnetic resonance cholangiopancreatography (MRCP) is an alternative noninvasive method that produces similar cholangiographic images without exposure to ionizing radiation. However, due to lower sensitivity for detecting changes of PSC, ERCP should be considered when MRCP is negative but strong clinical suspicion persists [63].
Bone and Joint Disease Osteopenia Osteopenia and osteoporosis are well known complications of chronic IBD with several potential mechanisms including cytokines activation, malnutrition, malabsorption, delayed puberty,
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Figure 17.8. MRCP maximum intensity projection (MIP) image of the biliary tree demonstrates common duct dilation (arrow) with patent left and right hepatic ducts.
and treatment with corticosteroids [64, 65]. Reduced bone mineral density (BMD) causes skeletal fragility and increases the propensity for fractures in children with CD [66]. The most common method for the detection of osteopenia is the dual-energy X-ray absorptiometry (DEXA) scan. The BMD measured by DEXA scan of the lumbar spine, femoral neck, and radius is expressed as Z-scores, defined as the standard deviation of the measured BMD in relation to the mean for the child’s age and sex. Presently, consensus is lacking on the normal ranges of Z-scores in children. In addition, when growth failure has occurred, correct assessment of BMD may require interpretation in terms of bone age or height age, rather than chronological age [67, 68]. The cost, limited availability, and difficult interpretation are some of the disadvantages to the use of DEXA in children [69]. Unfortunately, alternative means of measuring BMD in children either have low sensitivity (quantitative ultrasound) or entail a higher radiation dose (quantitative computer tomography) [69, 70].
Future Trends Emerging technological developments may soon alter the landscape for radiographic imaging of IBD. With advances in hardware and software leading to improved image resolution, crosssectional imaging techniques may replace conventional contrast studies as the gold standard for small bowel evaluation in CD. The most promising modality is the MRE combined with enteral contrast volume challenge [4]. MRI will likely also play an increasing role in the differentiation of CD from UC, the follow-up of patients with indeterminate colitis, and the evaluation of disease activity and postoperative complications [19]. Increased use of pelvic MRI may also lead to the development of a pediatric perianal disease index, similar to one already described in adult patients with CD [71]. The now familiar technique of US may be put into increasing use as radiologists, and possibly gastroenterologists, begin to maximize its potential in the monitoring of disease activity and postoperative recurrence [8, 72].
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One of the most exciting developments in the diagnostic assessment of IBD is the threedimensional MRI and CT colonography, the so-called virtual endoscopy [73, 74]. Acknowledgments We would like to thank Drs. D. Gregory Bates and Jane Balint for their expert review and suggestions, and to thank Dr. Bates for contributing the images for this chapter. References 1. Taylor, G.A., et al., Plain abdominal radiographs in children with inflammatory bowel disease. Pediatr Radiol, 1986. 16(3): 206–9. 2. Furukawa, A., et al., Cross-sectional imaging in Crohn disease. Radiographics, 2004. 24(3): 689–702. 3. Jabra, A.A., E.K. Fishman, and G.A. Taylor, Crohn disease in the pediatric patient: CT evaluation. Radiology, 1991. 179(2): 495–8. 4. Gourtsoyiannis, N.C., N. Papanikolaou, and A. Karantanas, Magnetic resonance imaging evaluation of small intestinal Crohn disease. Best Pract Res Clin Gastroenterol, 2006. 20(1): 137–56. 5. Durno, C.A., et al., Magnetic resonance imaging to distinguish the type and severity of pediatric inflammatory bowel diseases. J Pediatr Gastroenterol Nutr, 2000. 30(2): 170–4. 6. Darbari, A., et al., Gadolinium-enhanced magnetic resonance imaging: a useful radiological tool in diagnosing pediatric IBD. Inflamm Bowel Dis, 2004. 10(2): 67–72. 7. Laghi, A., et al., Contrast enhanced magnetic resonance imaging of the terminal ileum in children with Crohn disease. Gut, 2003. 52(3): 393–7. 8. Maconi, G., et al., Bowel ultrasound in Crohn disease. Best Pract Res Clin Gastroenterol, 2006. 20(1): 93–112. 9. Faure, C., et al., Ultrasonographic assessment of inflammatory bowel disease in children: comparison with ileocolonoscopy. J Pediatr, 1997. 130(1): 147–51. 10. Bremner, A.R., et al., Sonographic evaluation of inflammatory bowel disease: a prospective, blinded, comparative study. Pediatr Radiol, 2006. 36(9): 947–953. 11. Haber, H.P., et al., Bowel wall thickness measured by ultrasound as a marker of Crohn disease activity in children. Lancet, 2000. 355(9211): 1239–40. 12. Spalinger, J., et al., Doppler US in patients with crohn disease: vessel density in the diseased bowel reflects disease activity. Radiology, 2000. 217(3): 787–91. 13. Bremner, A.R., et al., Ultrasound scanning may reduce the need for barium radiology in the assessment of small-bowel Crohn disease. Acta Paediatr, 2004. 93(4): 479–81. 14. Gasche, C., Transabdominal bowel sonography in clinical decision-making, in Advanced therapy of inflammatory bowel disease, T.M. Mayless and S.B. Hanauer, Editors. 2001, B.C. Decker: Hamilton, ON. 55–62. 15. Horton, K.M., F.M. Corl, and E.K. Fishman, CT evaluation of the colon: inflammatory disease. Radiographics, 2000. 20(2): 399–18. 16. Jabra, A., E. Fishman, and G. Taylor, CT findings in inflammatory bowel disease in children. Am J Roentgenol, 1994. 162(4): 975–9. 17. Philpotts, L.E., et al., Colitis: use of CT findings in differential diagnosis. Radiology, 1994. 190(2): 445–9. 18. Nozue, T., et al., Assessment of disease activity and extent by magnetic resonance imaging in ulcerative colitis. Pediatr Int, 2000. 42(3): 285–8. 19. Maccioni, F., M.C. Colaiacomo, and S. Parlanti, Ulcerative colitis: value of MR imaging. Abdom Imaging, 2005. 30(5): 584–92. 20. Maconi, G., et al., Ultrasonography in the evaluation of extension, activity, and follow-up of ulcerative colitis. Scand J Gastroenterol, 1999. 34(11): 1103–7. 21. Ruess, L., et al., Inflammatory bowel disease in children and young adults: correlation of sonographic and clinical parameters during treatment. AJR Am J Roentgenol, 2000. 175(1): 79–84. 22. Carvalho, R.S., et al., Indeterminate colitis: a significant subgroup of pediatric IBD. Inflamm Bowel Dis, 2006. 12(4): 258–62. 23. Miao, Y.M., et al., Ultrasound and magnetic resonance imaging assessmentof active bowel segments in Crohn disease. Clin Radiol, 2002. 57(10): 913–8.
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24. Segal, A.W., et al., Indium-111 tagged leucocytes in the diagnosis of inflammatory bowel disease. Lancet, 1981. 2(8240): 230–2. 25. Del Rosario, M.A., et al., Clinical applications of technetium Tc 99m hexamethyl propylene amine oxime leukocyte scan in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr, 1999. 28(1): 63–70. 26. Charron, M., C. Di Lorenzo, and S. Kocoshis, Are 99mTc leukocyte scintigraphy and SBFT studies useful in children suspected of having inflammatory bowel disease? Am J Gastroenterol, 2000. 95(5): 1208–12. 27. Fitzgerald, P.G., et al., The use of indium 111 leukocyte scans in children with inflammatory bowel disease. J Pediatr Surg, 1992. 27(10): 1298–300. 28. Charron, M., J.F. del Rosario, and S. Kocoshis, Use of technetium-tagged white blood cells in patients with Crohn disease and ulcerative colitis: is differential diagnosis possible? Pediatr Radiol, 1998. 28(11): 871–7. 29. Alberini, J.L., et al., Technetium-99m HMPAO-labeled leukocyte imaging compared with endoscopy, ultrasonography, and contrast radiology in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr, 2001. 32(3): 278–86. 30. Charron, M., J. Fernando del Rosario, and S. Kocoshis, Distribution of acute bowel inflammation determined by technetium-labeled white blood cells in children with inflammatory bowel disease. Inflamm Bowel Dis, 1998. 4(2): 84–8. 31. Bhargava, S.A., S.R. Orenstein, and M. Charron, Technetium-99m hexamethylpropyleneamine-oximelabeled leukocyte scintigraphy in inflammatory bowel disease in children. J Pediatr, 1994. 125(2): 213–7. 32. Charron, M., F. Del Rosario, and S. Kocoshis, Assessment of terminal ileal and colonic inflammation in Crohn disease with 99mTc-WBC. Acta Paediatr, 1999. 88(2): 193–8. 33. Skehan, S.J., et al., 18F-fluorodeoxyglucose positron tomography in diagnosis of paediatric inflammatory bowel disease. Lancet, 1999. 354(9181): 836–7. 34. Lemberg, D.A., et al., Positron emission tomography in the investigation of pediatric inflammatory bowel disease. Inflamm Bowel Dis, 2005. 11(8): 733–8. 35. Morris, J., J.A. Spencer, and N.S. Ambrose, MR imaging classification of perianal fistulas and its implications for patient management. Radiographics, 2000. 20(3): 623–35; discussion 635–7. 36. deSouza, N.M., et al., High resolution magnetic resonance imaging of the anal sphincter using a dedicated endoanal coil. Comparison of magnetic resonance imaging with surgical findings. Dis Colon Rectum, 1996. 39(8): 926–34. 37. Buchanan, G.N., et al., Clinical examination, endosonography, and MR imaging in preoperative assessment of fistula in ano: comparison with outcome-based reference standard. Radiology, 2004. 233(3): 674–81. 38. Kuijpers, H.C. and T. Schulpen, Fistulography for fistula-in-ano. Is it useful? Dis Colon Rectum, 1985. 28(2): 103–4. 39. Pomerri, F., et al., [Radiologic diagnosis of anal fistulae with radio-opaque markers]. Radiol Med (Torino), 1988. 75(6): 632–7. 40. Schratter-Sehn, A.U., et al., Endoscopic ultrasonography versus computed tomography in the differential diagnosis of perianorectal complications in Crohn disease. Endoscopy, 1993. 25(9): 582–6. 41. Bartram, C. and G. Buchanan, Imaging anal fistula. Radiol Clin North Am, 2003. 41(2): 443–57. 42. Hussain, S.M., et al., Fistula in ano: endoanal sonography versus endoanal MR imaging in classification. Radiology, 1996. 200(2): 475–81. 43. West, R.L., et al., Prospective comparison of hydrogen peroxide-enhanced three-dimensional endoanal ultrasonography and endoanal magnetic resonance imaging of perianal fistulas. Dis Colon Rectum, 2003. 46(10): 1407–15. 44. Laniado, M., et al., Perianal complications of Crohn disease: MR imaging findings. Eur Radiol, 1997. 7(7): 1035–42. 45. Buchanan, G.N., et al., Potential clinical implications of direction of a trans-sphincteric anal fistula track. Br J Surg, 2003. 90(10): 1250–5. 46. Buchanan, G., et al., Effect of MRI on clinical outcome of recurrent fistula-in-ano. Lancet, 2002. 360(9346): 1661–2.
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47. Schwartz, D.A., et al., Use of endoscopic ultrasound to guide combination medical and surgical therapy for patients with Crohn perianal fistulas. Inflamm Bowel Dis, 2005. 11(8): 727–32. 48. Stewart, L.K., J. McGee, and S.R. Wilson, Transperineal and transvaginal sonography of perianal inflammatory disease. AJR Am J Roentgenol, 2001. 177(3): 627–32. 49. Stoker, J., et al., Anovaginal and rectovaginal fistulas: endoluminal sonography versus endoluminal MR imaging. AJR Am J Roentgenol, 2002. 178(3): 737–41. 50. Dwarkasing, S., et al., Anovaginal fistulas: evaluation with endoanal MR imaging. Radiology, 2004. 231(1): 123–8. 51. Schwartz, D.A., et al., A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn perianal fistulas. Gastroenterology, 2001. 121(5): 1064–72. 52. Schwartz, D.A., J.H. Pemberton, and W.J. Sandborn, Diagnosis and treatment of perianal fistulas in Crohn disease. Ann Intern Med, 2001. 135(10): 906–18. 53. Gupta, N., et al., Risk factors for initial surgery in pediatric patients with Crohn disease. Gastroenterology, 2006. 130(4): 1069–77. 54. Michelassi, F., et al., Incidence, diagnosis, and treatment of enteric and colorectal fistulae in patients with Crohn disease. Ann Surg, 1993. 218(5): 660–6. 55. Yamaguchi, A., et al., The clinical characteristics and outcome of intraabdominal abscess in Crohn disease. J Gastroenterol, 2004. 39(5): 441–8. 56. Gervais, D.A., et al., Percutaneous abscess drainage in Crohn disease: technical success and short- and long-term outcomes during 14 years. Radiology, 2002. 222(3): 645–51. 57. Jawhari, A., et al., Intra-abdominal and pelvic abscess in Crohn disease: results of noninvasive and surgical management. Br J Surg, 1998. 85(3): 367–71. 58. Sahai, A., et al., Percutaneous drainage of intra-abdominal abscesses in Crohn disease: short and long-term outcome. Am J Gastroenterol, 1997. 92(2): 275–8. 59. Low, R.N., et al., Crohn disease evaluation: comparison of contrast-enhanced MR imaging and singlephase helical CT scanning. J Magn Reson Imaging, 2000. 11(2): 127–35. 60. Rieber, A., et al., MRI in the diagnosis of small bowel disease: use of positive and negative oral contrast media in combination with enteroclysis. Eur Radiol, 2000. 10(9): 1377–82. 61. Simoneaux, S. and L. Patrick, Genitourinary complications of Crohn disease in pediatric patients. Am J Roentgenol, 1997. 169(1): 197–199. 62. Gore, R.M., CT of inflammatory bowel disease. Radiol Clin North Am, 1989. 27(4): 717–29. 63. Ferrara, C., et al., Magnetic resonance cholangiopancreatography in primary sclerosing cholangitis in children. Pediatr Radiol, 2002. 32(6): 413–7. 64. Semeao, E.J., et al., Risk factors for low bone mineral density in children and young adults with Crohn disease. J Pediatr, 1999. 135(5): 593–600. 65. Gokhale, R., et al., Bone mineral density assessment in children with inflammatory bowel disease. Gastroenterology, 1998. 114(5): 902–11. 66. Semeao, E.J., et al., Vertebral compression fractures in pediatric patients with Crohn disease. Gastroenterology, 1997. 112(5): 1710–3. 67. Herzog, D., et al., Interpretation of bone mineral density values in pediatric Crohn disease. Inflamm Bowel Dis, 1998. 4(4): 261–7. 68. Ahmed, S.F., et al., Bone mineral assessment by dual energy X-ray absorptiometry in children with inflammatory bowel disease: evaluation by age or bone area. J Pediatr Gastroenterol Nutr, 2004. 38(3): 276–80. 69. van Rijn, R.R., et al., Bone densitometry in children: a critical appraisal. Eur Radiol, 2003. 13(4): 700–10. 70. Levine, A., et al., Use of quantitative ultrasound to assess osteopenia in children with Crohn disease. J Pediatr Gastroenterol Nutr, 2002. 35(2): 169–72. 71. Van Assche, G., et al., Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn disease. Am J Gastroenterol, 2003. 98(2): 332–9. 72. Canani, R.B., et al., Combined use of noninvasive tests is useful in the initial diagnostic approach to a child with suspected inflammatory bowel disease. J Pediatr Gastroenterol Nutr, 2006. 42(1): 9–15. 73. Guilhon de Araujo Sant’Anna, A.M., et al., Wireless capsule endoscopy for obscure small-bowel disorders: final results of the first pediatric controlled trial. Clin Gastroenterol Hepatol, 2005. 3(3): 264–70. 74. Haykir, R., et al., Three-dimensional MR and axial CT colonography versus conventional colonoscopy for detection of colon pathologies. World J Gastroenterol, 2006. 12(15): 2345–50.
18 Endoscopic Modalities in Pediatric Inflammatory Bowel Disease Krishnappa Venkatesh and Mike Thomson*
Introduction Safe, informative, and effective endoscopy performed in a child-friendly situation with the minimum of distress to child and parent alike is a sine qua non of a unit adhering to best-practice in the care of children and adolescents with inflammatory bowel disease. The care of children and adolescents differs in important ways from that of adults. This is reflected in the emphasis placed on various aspects of endoscopy especially ileocolonoscopy, such as the frequent use of general anesthesia, the number and location of mucosal biopsies, and the routine inclusion of ileal intubation during a complete examination. The question of who should conduct the procedure continues to receive attention among pediatric gastroenterologists. It is generally accepted that a pediatrician, preferably with experience in pediatric gastroenterology, should be involved in the care of the child or adolescent and, ideally, should carry out the procedure. There can be few more satisfying experiences in medicine than making a clinical judgment and diagnosis in a child, confirming the nature and extent of the disease oneself by endoscopy, treating appropriately, and then visually demonstrating the success of such endeavors to child and parent by a follow-up procedure. Endoscopy plays an important role in the initial diagnosis of inflammatory bowel disease (IBD), differentiation of IBD into Crohn disease (CD) and ulcerative colitis (UC), assessment of disease extent, monitoring of response to therapy, surveillance of cancer, and to perform endo-therapeutic procedures such as stricture dilation [1].
Endoscopy – Background History The evolution of endoscopy in the diagnostic armamentarium was, initially a slow process. Rigid esophagoscopes and sigmoidoscopes were introduced in the late 19th century and semi-flexible scopes in the 1930s. They remained the only endoscopes in use until the 1960s. This was partly because of the lack of understanding about inflammatory bowel disease, which was for a long time thought to be a disease mainly confined to the recto-sigmoid region. However the invention of fiber optics in the 1950s heralded a new era leading to the development of the first
*Centre for Pediatric Gastroenterology, Sheffield Children’s NHS Foundation Trust, Phone: 44 –11-4-2717673, E-mail:
[email protected]
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flexible sigmoidoscope in 1963 and colonoscope in 1966. This made it possible to visualize, take biopsies and perform endo-therapeutic procedures and reach the duodenum and ileo-colon. The next major breakthrough was the arrival of video-chip technology in the 1980s. This allowed digital images to be displayed on a monitor and further to be stored, analyzed and transmitted as necessary. Further advances have seen the development of Sonde enteroscopy [2] limited by lack of therapeutic potential, and then push enteroscopy, allowing the therapeutic endoscopist access up to 70–100 cm small bowel beyond the pylorus. Intra-operative endoscopy appeared to be the only means available to access the whole of the small bowel at the turn of the century until the development of wireless capsule endoscopy (WCE). This technological breakthrough allowed the direct visualization of the entire small bowel without the need of external wires, fiberoptic bundles or cables but as yet is limited to diagnostic input alone. Double balloon enteroscopy (DBE) is a more recent modality, which enables high-resolution endoscopic imaging of the entire small bowel, with the advantage over WCE of potential for mucosal biopsies and interventional endo-therapy.
Patient Preparation Ideally, both the child and the parents should be offered a preparatory visit to the endoscopy unit to answer questions and defuse any potential concerns and anxieties regarding the procedure and admission. Children with greater knowledge of the procedure exhibit less distress and report less anxiety toward the procedure [3]. Younger children undoubtedly benefit from pre-admission visits and the involvement of a play therapist to enable some understanding of what is to take place and why [4–6]. Diagrams may help in explanations to older children. Preparatory videotapes are also useful for informing the patient and parent regarding what to expect. Units can benefit from devising a sample videotape specific to their own facility. A reduction in anticipatory anxiety may even reduce the amount of intravenous sedation required [7]. A child-friendly decorated endoscopy room with age-appropriate videotapes and familiar faces is important at this time of high stress. Parents may stay to watch the procedure in some units when intravenous sedation is provided. Most anesthesiologists would object to having parents present during administration of a general anesthetic, beyond the initial induction. Improved medical compliance and belief in the treatment are potential advantageous consequences of allowing parents to directly view the initial disease and its remission at follow-up ileocolonoscopy [8]. Young children often request photographs or a videotape of the ileocolonoscopy, and older adolescents may view the procedure themselves. A full screening is important to identify potential sedation or anesthetic risks. Although there is little correlation of mildly deranged peripheral coagulation indices with hemorrhage after mucosal biopsies, more pronounced bleeding diatheses may require forethought and appropriate blood product backup [9]. Properly informed consent should be obtained with an information sheet detailing potential complications and their incidence, and a separate consent should be signed in the event of research biopsies being requested. Guidelines concerning antibiotic prophylaxis in children with lesions susceptible to endocarditis or in the immunocompromised child are available in the literature [10]. A low rate of bacteremia owing to bacterial translocation across the bowel wall has been demonstrated following pediatric ileocolonoscopy [11]. A combination of intravenous or intramuscular ampicillin (50 mg/kg, maximum 2 g) and gentamicin (2 mg/kg, maximum 120 mg) 30 minutes before and 6 hours after the ileocolonoscopy is generally recommended. Vancomycin (20 mg/kg slow intravenous infusion 1 hour before) can be substituted for ampicillin in those with documented penicillin allergy.
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Bowel Preparation Poor bowel preparation is a major factor that may prevent or impede successful ileocolonoscopy. Although administration of regimens is not always easy, modern protocols can be remarkably effective in clearing the colon and ileum. Until 5 or 6 years ago, large volumes of oral electrolyte lavage solutions were used with variable success, coupled with the significant disadvantages of nasogastric administration and potential for fluid-electrolyte shifts in smaller children and infants. In one study, 40 ml/kg/h resulted in clear fecal effluent after a mean of 2.6 hours [12]. Subsequently, more favorable results and compliance were reported with low-volume oral agents and enemas, along with decreased oral intake [13–16]. Use of sodium phosphate preparations was associated with a transient rise in mean serum sodium and phosphate, but with no change in serum calcium [14, 15]. Refinements were made to these oral and enema regimens as newer preparations, which were more acceptable to children, became available; low-volume non-absorbable polyethylene glycol preparations are becoming increasingly popular in pediatric units and are well tolerated, with no observable electrolytic disturbance [17, 18]. Table 18.1 outlines several low-volume regimens that have been used successfully in children. The regimen employed in our unit, shown in Table 18.2, combines the beneficial effects of oral low-volume administration with the backup of an enema 1 to 2 hours beforehand if no clear fecal effluent is observed [19]. No clinically significant fluid shifts or electrolyte imbalances have been observed in over 2,000 colonoscopies over a 5-year period in our unit. The benefit of an intravenous antispasmodic agent administered directly before the ileocolonoscopy has recently been demonstrated [20]. Hyoscyamine 0.5 mg was given in this study of adults. An alternative could be hyoscine 20 mg administered intravenously. The use of such an agent given just prior to colonoscopy is determined by personal preference. Their use may facilitate ease of luminal visualization, but it also may increase the compliance of the colon, theoretically allowing a greater chance of loop formation. They are certainly of benefit in spastic colonic situations. It should be remembered that they work only for a short period of time, however, perhaps as short as 5 minutes and they may be re-administered in certain situations, such as when one needs to relax a haustral fold if a polyp is just beyond and obscured by it, or occasionally when one needs to relax a spastic ileocecal valve.
Table 18.1. Successful recent low-volume regimens for the preparation of the bowel for colonoscopy. Study Gremse et al. 1996 [15] Da Silva et al. 1997 [14] Pinfield et al. 1999 [18] Dahshan et al. 1999 [17]
Regimen Oral sodium phosphate (45 ml/1.7m2 ) 6 p.m. and 6 a.m. for a.m. procedure Oral sodium phosphate (22.5 ml if <30 kg, 45 ml if >30 kg) p.m. and 5 a.m. for a.m. procedure Sodium picosulphate with magnesium citrate (2.5g <2yrs, 5g 2–5yrs, 10g >5yrs per dose) 24 and 18 hrs pre procedure Magnesium citrate and X-prep
Diet
Success rate
Clear liquid 24 hrs
18/19
Clear liquid after first dose
10/14
Clear liquid for 24 hrs
32/32(3 vomited)
Clear liquid for 48 hrs
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Table 18.2. Bowel preparation for children undergoing colonoscopy. Clear fluids for preceding 24 hours (12 hours for infants receiving no solid intake) 5pm Senokot 1–2 mg/kg (max 30mg) Sodium picosulphate 2.5g if <1year 5g if 1–4 years 10g if >4 years 6am Repeat sodium picosulphate dose 1 hour before procedure Phosphate enema (1/2 if <1 year)
Monitoring and Sedation “Sedation and analgesia” comprise a continuum of states ranging from minimal sedation (anxiolysis) through general anesthesia. Moderate sedation is a medically controlled state of depressed consciousness that allows protective reflexes to be maintained and retains the patient ability to maintain the airway independently and continuously. Deep sedation is a medically controlled state of depressed consciousness or unconsciousness from which the patient is not easily aroused and accompanied by a partial or complete loss of protective reflexes with inability to maintain a patent airway. General anesthesia is a controlled state of unconsciousness accompanied by a loss of protective reflexes [21, 22]. The aims of adequate sedation include patient safety, anxiolysis, analgesia, amnesia as well as adequate endoscopic examination, time and cost efficiency [23]. Debate has surrounded the relative merits and safety of sedation and general anesthesia for upper gastrointestinal endoscopy and ileocolonoscopy in children for several years [24–26]. The risks of general anesthesia include those associated with intubation and administration of an anesthetic, which can be minimized by proper preparation and good intubation technique. However, the benefits include complete amnesia and total avoidance of pain to the patient and as well as freeing the endoscopist from managing airway, monitoring vital signs and recovering the patient [23]. Intravenous sedation (IV-S) usually consists of a narcotic (meperidine or fentanyl) and a benzodiazepine (diazepam or midazolam), the former for analgesia and the latter for anxiolysis and amnesia. Ketamine and midazolam has been used with reportedly lesser side effects [27]. Table 18.3 lists some of the commonly used sedation regimens with the reversal agents. IV-S has been argued to be safe, effective and less costly in comparison to general anesthesia with successful sedation achieved in more than 95% of elective procedures [28, 29]. However careful monitoring of IV-S through out the procedure is important [30, 31]. In spite of the advantages of IV-S pediatric gastrointestinal endoscopy has moved towards general anesthesia since it is now acknowledged that to get the requisite cooperation, and therefore a properly conducted procedure with minimum distress to the child, deep sedation is usually necessary. It is further recognized that there are attendant safety issues of airway maintenance in this situation, and at the very least,
Table 18.3. Sedation and reversal medications commonly employed in pediatric endoscopy. Midazolam: Intravenous (IV) initial dose 0.05–0.1 mg/kg, then titrate to max 0.3 mg/kg or 10 mg whichever lower [21], 0.75 mg/kg or 15 mg whichever lower Fentanyl: IV initial dose 0.5–1.0 g/kg, then titrate to max 5g/kg [48] Meperidine/Pethidine: IV initial dose 0.5 mg/kg, then titrate to max 2 mg/kg or 75 mg whichever lower [120] Flumazenil: IV 0.02 mg/kg (max 0.2 mg) and repeat every minute to max of 0.05 mg/kg or max 1mg [48] Naloxone: IV 0.1 mg/kg (max 2 mg) and repeat every 2–3 min to max 10 mg [48]
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a specific individual with appropriate advanced pediatric life support skills should be responsible for the child’s cardio-respiratory welfare during such a procedure. The vast majority of pediatric gastrointestinal endoscopy under the age of 8 years in the United Kingdom, for instance, now occurs under general anesthesia. When a child is sedated, resuscitation equipment should be easily accessible, and one or more people trained in pediatric advanced life support should be responsible for maintaining the airway and monitoring respiration, heart rate, blood pressure, and oxygen saturation [21, 32]. Sedation of younger children can be aided by environmental comforts such as a soothing voice or dimmed lights [33]. In all age groups, it is often necessary to use deep sedation because of the pain that can be associated with this procedure [34]. With deep sedation, it is clear that the risks are significant, including hypotension, respiratory compromise, and even respiratory arrest. Recent studies examining the safety of general anesthesia for day-case ileocolonoscopy in children refute claims that there may be more risk of perforation because the operator cannot judge the degree of discomfort as a marker of impending traction injury [35, 36]. There is indeed a lack of evidence to support the contention that there is a higher complication rate with a general anesthetic than with sedation [37]. In fact, the airway is protected in a more effective and safer manner than with sedation, especially in upper endoscopy, with an improved operator satisfaction [38]. Pre-procedural medication with a benzodiazepine have been found to be useful in reducing patient anxiety and improve patient and parent acceptance of the procedure without any adverse effects [39].
Endoscopic Techniques in Inflammatory Bowel Disease Upper Gastrointestinal Endoscopy While it is generally accepted that ileocolonoscopy and biopsy has a central role in the initial diagnosis and differentiation of inflammatory bowel disease [40], it is now widely accepted that esophagogastroduodenoscopy (EGD) also has a definitive place in the initial diagnostic work up [41, 42]. Upper gastrointestinal involvement was long thought be relatively uncommon [43, 44] hence EGD was not routinely performed. Presence of upper gastrointestinal symptoms have been commonly considered as an indication to endoscopy [45]. Typically described upper gastrointestinal symptoms include dysphagia, pain when eating, nausea and/or vomiting, and aphthous lesions of the mouth. Diagnosis was often based on radiological changes [46] and EGD was reserved for those patients who had upper GI symptoms and or uncertain diagnosis. However, several studies have shown a higher incidence of microscopic mucosal disease in the upper GI tract [45, 47–51] then previously thought even in the absence of any upper GI symptoms [42, 52]. Cameron et al. [48] in a prospective study described histological abnormalities on gastroduodenal biopsies in 71% of patients with CD. Histological abnormalities including granulomas are seen even when the gross appearance of the tissue is normal [41, 45, 51–53]. Therefore it is important to take biopsies from several sites in the upper gastrointestinal tract even if they appear normal endoscopically. Esophageal disease in CD (Figure 18.1) can vary from small erosions to transmural involvement resulting in perforation and fistulization into adjacent organs [54]. Granulomas are reported in 20–39% of esophageal biopsies in patients with CD [55, 56]. Other findings include erythema, ulceration, polypoid lesions, pseudomembranous formations, strictures and mucosal bridges [55, 57–60]. Endoscopic findings in the stomach and duodenum include linear and serpigenous ulcers, diffuse superficial ulcers, aphthous lesions, nodularity, cobblestone appearance, rigidity of the GI wall and narrowing of the lumen [61].
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Figure 18.1. Crohn disease of the oesophagus showing discrete ulcers.
Focal enhanced gastritis as an important feature of CD was first described by Schmitz-Moorman, et al. [62] (Figure 18.2). Further several studies confirmed this finding with a positive predictive value of 71–94% [48, 50, 63, 64]. Parente et al. [64] found focal antral gastritis more frequently in Helicobacter pylori negative adults with CD then in those with UC or in non inflammatory bowel conditions. Also they reported focal antral gastritis to be specific in 84% of patients with CD. While the presence of focal enhanced gastritis is suggestive of Crohn disease it is not pathognomonic of the condition. The presence of non-caseating granuloma is characteristic of CD. Granulomas are found in 7–68% of patients with CD in the upper GI tract [41, 45, 55, 61, 62] and often help in making a definitive diagnosis when none are found at other sites. Non-caseating granuloma in the upper gastrointestinal tract tends to occur in the superficial mucosa then in the muscularis or the serosal layers in comparison to ileal Crohn. Ulcerative colitis conventionally was thought to involve only the colon and possibly ileum (backwash ileitis). However it is increasingly recognized that features of inflammation in the upper GI tract [42, 50, 51, 65, 66] are seen in UC. Ruuska et al. [51] in a prospective study reported either macroscopic or histological upper gastrointestinal lesions in 75% of patients with UC. Abdullah et al. [41] also reported an incidence of 70% of histological abnormalities in the upper GI tract in patients with UC. Tobin et al. [50] in a controlled blinded study described esophagitis in 72% and 50% of patients with CD and UC, respectively; while gastritis occured in 92% of CD and 69% of UC.
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Figure 18.2. Focal enhanced gastritis in Crohn disease.
Ileocolonoscopy Equipment Most modern units employ adult and pediatric video-colonoscopes, and the general technical specifications for the pediatric instruments differ little between manufacturers (Table 18.4). When and in whom to use a pediatric colonoscope is mainly a matter of personal preference. We use personal judgment based on age and/or body weight. In general terms, the lower limit for the adult colonoscope is 3 to 4 years of age and/or 12 to 15 kg. The extra stiffness of the adult versions diminishes the likelihood of forming sigmoid loops, but extra care must then be taken, especially in younger children and with general anesthesia, not to advance against undue resistance, to avoid the unlikely complication of colonic perforation. The larger diameter of the adult colonoscopes can also lead to problems of maneuverability within the smaller colonic lumen of a young child. The variable stiffness colonoscope (see Table 18.4) may negotiate some of these problems. A control dial on the upper shaft of this small-diameter colonoscope (Olympus XCF-240AL/I) allows an increase in the stiffness of the insertion tube when passing through the sigmoid and transverse colon to avoid looping [67]. More recently, magnifying colonoscopes have been developed, and their value in combination with dye spray or chromoscopy in various gastrointestinal diseases has been described [68]. For instance, the decrease in the number of cryptal openings in ulcerative colitis can be observed and correlated to disease activity [69], but this does not substitute for histologic assessment.
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Table 18.4. Technical specifications of various pediatric colonoscopes. Parameter
Fujinon (EC-410 MP15)
Olympus (PCF 240L/I)
Olympus Variable Stiffness (CF 240AL/I)
Pentax (EC-3440PK)
Angle of Vision Depth of Field Distal End Insertion Tube Channel Angle Up/Down Angle Right/Left Working length
140° 6–100 mm 11 mm 11.1 mm 2.8 mm 180°/180° 160°/160° 1520 mm
140° 4–100 mm 11.3 mm 11.3 mm 3.2 mm 180°/180° 160°/160° 1330 mm (I) 1680 mm (L)
140° 3–100 mm 12.2 mm 12.0 mm 3.2 mm 180°/180° 160°/160° 1330 mm (I) 1680 mm (L)
140° 6–100 mm 11.5 mm 11.4 mm 3.8 mm 180°/180° 160°/160° 1500 mm
For insufflation, there may be some advantage awarded by the use of carbon dioxide in place of air because it is more rapidly absorbed, leading to less patient discomfort and, theoretically, less risk of perforation [70, 71].
Ileocolonoscopy Basic Technique Getting Started and Patient Positioning The patient is usually positioned in the left lateral knee to chest position, although some operators prefer the right lateral position, citing easier sigmoid negotiation. Certainly, if the procedure is not subsequently allowing easy access to the splenic flexure, then patient repositioning from one side to the supine and then to the other side may be advantageous. In general, frequent turning of the patient is conducive to easier ileocolonoscopy as a whole and is to be advocated. An assistant stands on the operator’s left to administer any abdominal pressure that may subsequently be deemed necessary to control, or try to prevent, loop formation in the sigmoid or transverse colon. Practical Tips in Ileocolonoscopy One important “trick” in learning ileocolonoscopy is to grasp the concept of the lumen and the positions of a clock face. For instance, if the lumen is at 9 o’clock, then to enter this requires anticlockwise rotation combined with upward deflection of the scope tip from the “neutral” position of 12 o’clock. Similarly, a combination of upward deflection of the tip with clockwise rotation of the colonoscope will allow entry of the lumen, suggested by a dark crescent, if seen at anywhere clockwise from 12 o’clock to 6 o’clock. Obviously, one may equally use downward tip deflection combined with the opposite rotatory control to that with upward tip deflection, and the execution and teaching of this concept are at personal discretion. With either approach, this is the most important maneuver that can be learned to assist in three-dimensional spatial orientation in the colon. Prolonged “side viewing” of the bowel wall as it slides by should be avoided. Generally, the only place where, very temporarily, the lumen should be out of view is the occasional difficult negotiation of the splenic flexure. The patient’s position may be changed throughout the procedure to facilitate removal of loops and to allow a better view of the lumen because the gravity-dependent material in the colonic lumen changes position. Relatively minimal insufflation of air is desirable in the sigmoid colon because excess air may increase the chance of sigmoid loop formation.
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In handling the colonoscope, it is good practice to have a flat unimpeded surface on which to place the remainder of the colonoscope that is not yet inserted; this is particularly important since any resistance encountered by the operator to forward advancement of the colonoscope can be attributed to colonic obstruction or loop formation within the child’s colon. Hence, relatively quickly, the trainee can acquire a realization of the normal expected resistance to scope advancement. This, in turn, allows understanding of the likelihood of loop formation, without any external resistance to scope advancement, causing confusion with regard to the behavior of the colonoscope within the patient. Generally, in ileocolonoscopy, gentle scope advancement with clear lumen visualization is desirable, and, usually, only the forefinger and thumb will be required to advance the colonoscope. If greater pressure is required, then the operator is not performing an optimum procedure, and loop formation is likely to have occurred. Rectal Intubation Prior to any colonoscopy, it is considered good practice to perform an anal and then a rectal digital examination, the latter to avoid missing, by colonoscopy, very low-lying rectal polyps (although, where possible, retroflexion of the colonoscope in the rectum should occur prior to removal of the instrument to avoid missing lesions close to the anal margin). Adequate water-soluble lubrication, avoiding the tip of the instrument, allows easy passage into the rectum, which can occur with or without digital guidance from the operator’s index finger. Posterior positioning of the tip and air insufflation will allow visualization of the rectal mucosa and the three semilunar folds, or valves of Houston, occurring on alternating sides of the lumen. Subsequently, direct visualization of the bowel lumen is mandatory, except in some circumstances at the splenic flexure. If, at any point, a maneuver results in loss of visualization of the lumen, then reversal of what the operator has just done will often return the lumen to view; if not, the gentle scope retraction combined with minor tip deflections using the wheels and minor rotation of the scope in both directions will usually result in reorientation in the lumen. Obviously, if luminal contents are blocking the view, then lens cleaning will help. Sigmoid and Descending Colon Gentle torquing of the shaft clockwise and anticlockwise combined with upward or downward tip deflection and scope advancement is ideal for negotiating the sigmoid colon- the so-called “torque-steering” technique. The initial sigmoid fold or valve can usually be passed by 90 to 120 of anticlockwise torsion. The different loops encountered in the sigmoid are demonstrated in Figure 18.3. A so-called N loop may be overcome by trans-abdominal pressure by an assistant on the apex of the loop pushing toward the feet (see Figure 18.3a). This often allows a so-called loop to form, which can usually be tolerated as the instrument advances toward the splenic flexure (see Figure 18.3b). Reducing an loop is accomplished by initial clockwise rotation and then slow removal of the colonoscope, keeping the lumen in the centre of the field of vision. This may not be possible until the transverse (or even ascending) colon has been entered, in which case, hooking the tip of the scope over the splenic flexure may assist it. Paradoxical movement of the tip forward may be observed as the instrument is withdrawn and the bowel “concertinas” over the colonoscope. Abdominal pressure in the left iliac fossa may be helpful. The sigmoid and descending colons are relatively featureless, with less haustral folds than more proximally in the colon. Splenic Flexure and Transverse Colon Non-looped colonoscope length used at his point might be 40 cm in older children and even 20 to 25 cm in those under the age of 3 to 4 years. This is valuable in determining whether a loop is
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Figure 18.3. Diagram of colonoscope sigmoid loops that may form. a) an N loop in the sigmoid colon; b) an loop in the sigmoid colon; c) a loop in a redundant transverse colon.
present. At the splenic flexure, the spleen may then be seen as a dark blue transmural discoloration. When negotiating the splenic flexure, the most successful combination of tip maneuvers is that of clockwise, right, and up followed by anticlockwise after passing the flexure. Occasionally, placing the patient in the right decubitus position may assist. The transverse colon is recognized by the triangular haustral folds and is usually easily passed (Figure 18.4). Supine or right decubitus positioning may ease this. A loop in the shape of a “U” may occur in a dependent transverse colon, which is supported by abdominal pressure. The more difficult loop may occur in a redundant transverse colon (Figure 18.3c). In addition, a good bit of advice is to apply gentle suction as the tip is advanced again in an attempt to concertina a potentially long dependent transverse colon over the colonoscope, thus maintaining a relatively short colonoscope and, hence, good control and maneuverability. Hepatic Flexure and Ascending Colon Non-looped colonoscope length used at this point might be 60 cm in older children and even 40 cm in those under the age of 3 to 4 years. This is valuable in determining whether a loop is present. The hepatic flexure is also recognized by the dark, usually blue, discoloration seen through the bowel wall, and positional change to the supine or right decubitus may again facilitate identification of the lumen. The combination of right, up, and clockwise followed by anticlockwise rotation and suction down into the ascending colon once around the sharply angled hepatic flexure is usually the most effective maneuver, but various combinations, including position change and scope withdrawal, may be required. Another tip is to remember that it is easy to be too far advanced into the vault of the hepatic flexure, leading to advance into a blind end, and often slight withdrawal of the instrument may reveal the fact that one is trying to negotiate this blind-ended area. The
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Figure 18.4. Normal triangular appearance of transverse colon.
two or three sharp folds then observed may then be most successfully negotiated by tip deflection using both up/down and left/right wheels with minimal advancement of the scope. This is most easily performed in the supine patient position, however. Once the hepatic flexure is negotiated, the transverse colonic loop may be reduced with anticlockwise or clockwise rotation followed by withdrawal of the colonoscope and suction. Loop withdrawal is essentially informed guesswork initially. Studies with the colon map guider, based on using a colonoscope with an inbuilt electromagnetic loop that allows accurate real-time colonoscope three-dimensional positioning by detection using an external positioning device and displayed on a screen next to the patient, have shown that even expert colonoscopists get the type of loop present wrong in half of the cases [72–74]. Once one starts to remove the loop, using rotation only initially, a tip is to gently start to remove the colonoscope and try to determine whether within-patient resistance is increasing or whether the colonoscope is trying to push your hand away from the patient as the loop unfolds. Usually, trying clockwise or anticlockwise combined with instrument withdrawal will, with experience, allow early determination of which rotation direction is likely to be successful in “delooping” the colonoscope. It is best to try to maintain good luminal vision during this procedure, but, not infrequently, the lumen is lost; however, if this loop removal technique is effective, it is then not unusual to find oneself then looking at the appendiceal orifice and hence the cecum because the scope will have naturally traveled down the ascending colon. It is important to remember that the ascending colon, which in children is of variable length, may be as short as 5 cm in some younger patients.
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Cecum Three useful ways to ensure that one has reached the cecum are as follows: 1. Observing the colonoscopic illumination in the right iliac fossa (using the specific high-intensity light transillumination application available with some colonoscopes is not usually necessary in children, excepting with some obese adolescents, for whom it can be helpful when applied in a dark environment). 2. Digitally indenting the abdominal wall over the right iliac fossa and observing the corresponding effect on the colonic wall with the colonoscope. 3. Identifying the triradiate fold, appendiceal orifice, and (especially if gas bubbles or ileal effluent are being excreted from it) the typical two lips–like appearance of the ileocecal valve. A good maxim is that if there is any doubt in the operator’s mind about having reached the cecum, then one is usually at the hepatic or even splenic flexure. Only about 80 cm of scope from the anus is needed when all loops are removed in an adult, and in smaller children, only 40 to 60 cm may be needed. This assumes normal anatomy of the ascending colon and cecum. Obviously, cecal strictures can confuse the picture. Ileal Intubation and its Importance The ileocecal valve is present approximately 1 to 4 cm distal to the appendiceal orifice opening into a smooth asymmetric fold and opens perpendicular to the axis of the colon. Figure 18.5 show the steps of the easiest technique for ileal intubation. Removal of any colonic loops is important to allow for a responsive scope with no paradoxical movement. Figures 18.5b and 18.6 show the valve maneuvered to the 6 o’clock position, usually after clockwise rotation of the scope and wheel-tip deflection to maintain a centred cecal view. Anticlockwise rotation can also be used but is less efficient. If too much gas is present, then the cecum may be “tented,” and this should be suctioned prior to an ileal intubation attempt. Figures 18.5c and 18.7 show the insertion of the biopsy forceps such that just the tip or the first few millimeters are visibly exposed beyond the end of the scope. The scope is then inserted just beyond the fold (using the downward deflecting wheel with the scope as above already in the 6 o’clock position), and the tip is inclined downward so that the forceps gently press into the wall. Slight left inclination may be required at this point to open the valve like a pair of lips on slight withdrawal of the scope (Figure 18.5c). Once the valve is opened, the scope may be passed into the ileum with further downward deflection. Often this is facilitated by small right and left deflections with an assistant pressing on the abdomen over the transverse colon to support a dependent transverse and also prevent loop formation. In the absence of ileocecal valve strictures, and with practice, this technique will allow an ileal intubation rate of 100%. Perforation of the cecum or ileum with this technique is a theoretical concern raised by some observers unfamiliar with this technique, but this has not occurred in our experience of over 5,000 ileocolonoscopies and is extremely unlikely. An alternative technique is “blind” intubation of the ileocecal valve. This involves the same positioning of the valve at 6 or 9 o’clock and then slowly withdrawing the scope back from just beyond the valve’s fold while insufflating with air and deflecting the scope tip downward. The disadvantage of this technique is that it is not under direct vision. Ileum The ileal mucosa will have the typical velvet-like appearance of small bowel (Figure 18.8), with the presence of smoother raised areas, which are Peyer patches, and, occasionally, lymphonodular hyperplasia of varying degrees (Figure 18.9). Villi are more easily seen if the lumen is flooded
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Figure 18.5. a) Identification of cecum with triradiate fold, appendicele orifice and ileocecal valve; b) Ileocecal valve at 6 o’clock position; c) Forceps opening up ileocecal valve with downward defection of colonoscope tip.
Figure 18.6. Ileocecal valve at 6 o’clock.
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Figure 18.7. Ileocecal entry using forceps.
with water. The ileal surface is shown in greater relief with a spray of standard blue or black ink (methylene blue in a 1:20 dilution may also be used); this is also useful in showing the detail of sessile polyps in the colon. Deeper intubation of the ileum by either technique is similar to duodenal negotiation during upper gastrointestinal endoscopy, and up to 40 cm of ileum can be observed. It is pertinent here to discuss the diagnostic need for entering the ileum in children suspected of inflammatory bowel disease. Williams and colleagues, in 1982 [75], reported their experience of total ileocolonoscopy in children in which the terminal ileum was examined in 63 patients. In 6 children, ileitis detected by ileocolonoscopy was the sole finding of Crohn disease, which was previously unrecognized by radiologic contrast studies. Lipson and colleagues compared ileoscopy and barium studies, with an endoscopy specificity of 0.96 for diagnosis of Crohn disease in the terminal ileum [76]. In 14 of 46 children, ileoscopy revealed diagnosis, which would otherwise have been missed. This study also made clear that the endoscopic appearances could be completely normal, yet the diagnosis of Crohn disease could be made histologically by the presence of granulomata. Also, a pronounced lymphoid hyperplasia pattern was present radiologically in 24% of children and would have been a source of error in two cases had contrast radiographs been relied on to make the diagnosis without ileoscopy. More recently, Deere and colleagues showed that sigmoid, colonic, and rectal biopsies confirm the diagnosis of inflammatory bowel disease in only 60% of cases, and diagnosis based on morphologic criteria was possible in only 85% of cases when the cecum was reached without ileal intubation [77]. Geboes and colleagues assessed 300 patients, including adolescents and children, and found endoscopic
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Figure 18.8. Normal appearance of terminal ileum.
and histologic ileal lesions in 123 and 125, respectively, of whom no colonic disease was present in 44 [78]. Ileal biopsies were essential for the diagnosis in 15 patients and contributory in 53. There are, of course, other reasons apart from the principal one, that is, diagnosis of chronic inflammatory bowel disease, for entering the ileum in children. For instance, ileoscopy will facilitate diagnoses of other causes of ileitis such as infection with tuberculosis or Yersinia [79]. In addition, therapeutic dilation of short terminal ileal strictures by per endoscopic balloon catheter may be attempted. Endoscope Withdrawal A more careful inspection of the colon is necessary on withdrawal of the scope, especially for the presence of polyps, which may have remained hidden behind a haustral fold during the initial insertion of the scope. Biopsies should be taken from all areas, including normallooking mucosa to allow for accurate histological diagnosis. Biopsy technique is similar to esophagogastroduodenoscopy, with the exception that many colonoscopic biopsy forceps have a central barb, allowing more than one biopsy to be taken each time the forceps are passed. Lastly, before removing the scope from the anus, a retroflexion maneuver obtained by maximum upward and right or left tip deflection and slight advancement of the scope into the rectal vault, followed by rotation clockwise and anticlockwise through 180° completes the examination. This is necessary to observe the ano-rectal junction and distal rectum. Distal ulcers, inflammation, or even polyps can be missed if this is not done.
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Figure 18.9. Lymphonodular hyperplasia of the terminal ileum.
Dilation of Strictures Through-the-scope balloon dilators are appropriate for ileocolonic dilation, employing the same concept and method as for upper gastrointestinal strictures, employing radiologic screening control. Long-term symptomatic relief can be afforded in some carefully selected patients, including adolescents in reported studies [80, 81]. Pressures of 35 to 50 psi in balloons of 12 to 18 mm are available. Theoretically, as for neoplastic or diverticulitis-associated strictures in adults, stent placement could be used as a last resort in inflammatory bowel disease–type strictures, but there are no reported cases of this occurring in childhood as yet.
Complications of Ileocolonoscopy Complications, excluding those due to sedation, are summarized in Table 18.5. Complications are more common following therapeutic procedures. The literature to date reveals over 3,000 colonoscopies under 20 years of age reported, with 5 perforations — 4 post-polypectomy and 1 in a patient with severe ulcerative colitis. Ten procedure-related minor complications are noted, including four small post-polypectomy hemorrhages, three cases of post procedure abdominal pain with spontaneous resolution, one common peroneal nerve palsy secondary to peri-procedure positioning, and two with a post-procedure fever for more than 24 hours [35, 36, 40, 82–86]. This equates to a complication rate owing to the procedure itself of approximately 0.3% and, without
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Table 18.5. Procedure-related and post-procedure complications in paediatric colonoscopy. Diagnostic Procedure-Related Vasovagal reactions Hemorrhage Perforation – traction serosal; direct transmural Pancreatitis Splenic trauma Therapeutic Procedure-Related Perforation Hemorrhage Thermal injury – transmural Post-Procedure Distension and discomfort (less if CO2 insufflation used) Delayed evidence of perforation or hemorrhage
polypectomy, of about 0.05%. This is in keeping with the British definition of “minimal” risk and the American definition of “minor risk over minimal” [87]. A single case of a child with serosal surface tears owing to a rigid colonoscope and a large sigmoid loop was reported in 1974 [88]. Flexible pediatric colonoscopes or the new variablestiffness colonoscopes may prevent this nowadays. The merits of conservative therapy of selected cases of colonic perforation have been discussed [89], and it would seem reasonable to adopt conservative management, for instance, in the case of silent asymptomatic perforations and those with localized peritonitis without signs of sepsis who continue to improve clinically without intervention [90]. In one study in adults, only 3 of 21 patients were managed non-surgically, and there was no difference in the morbidity or mortality between primary repair and resection and anastomosis [91]. In another, conservative management was successful in 13 of 48 patients, and 12 of the 13 were post-polypectomy perforations [92]. In contradistinction to adults, bacteremia has not been detected in children after ileocolonoscopy [12]. In addition, modern cleaning machines seem to largely prevent the glutaraldehyde-associated colitis reported in the past [93]. Splenic rupture is rarely seen and will present with hypovolemia and shoulder tip or abdominal pain within 24 hours of the ileocolonoscopy [94]. Similarly, direct trauma to the tail of the pancreas is the proposed mechanism of injury in the rare case of pancreatitis reported [95]. Because of the rarity of complications in pediatrics, most pediatric endoscopists, when presented with such a clinical situation, will be unfamiliar with the etiology of the symptoms, and colleagues’ opinions should often be sought [96].
Endoscopic Findings in Inflammatory Bowel Disease It is important to recognize the normal appearance of the bowel macroscopically and histologically. The colonic mucosa when seen through an endoscope appears glistening salmon-pink in color with a visible network of branching vessels seen beneath the mucosa. The smoothness of the mucosal surface is the hallmark of a healthy colon and there is a lack of contact bleeding, friability or exudates [97]. Microscopically the mucosa appears flat with normal crypt density, undistorted crypt architecture, intact surface epithelium, normal mucin content and without any neutrophil infiltration [98]. The earliest changes seen in UC are the presence of diffuse erythema and dull appearance of the vascular architecture consequent to the vascular congestion and edema. The engorged mucosa leads to contact bleeding and friability when touched with an endoscope. Progressively minute ulcers appear which coalesce to form large ulcers within a background of diffuse
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Figure 18.10. Pseudopolyps in ulcerative colitis.
colonic inflammation [98]. The colonic mucosa is involved in a continuous fashion from the rectum extending further up the colon. Long standing UC leads to development of pseudopolyps (Figure 18.10). Earliest changes in CD are the development of focal ulcers (aphthous lesions). These ulcers gradually enlarge and become deeper leading to development of linear (Figure 18.11) and transverse ulcers. Characteristically the ulcers are focal with normal intervening mucosa, the so-called skip lesions (Figure 18.12). More severe disease can cause nodularity giving the typical cobblestone appearance (Figure 18.13), strictures (Figure 18.14) and stenosis. Terminal ileum is the most common site to be involved in CD (Figure 18.15) hence, as has been stressed earlier; it is imperative that every attempt should be made to reach the terminal ileum at colonoscopy.
Follow-up and Surveillance Ileocolonoscopy It is the practice in many units to perform a follow-up ileocolonoscopy 2 to 3 months after the start of treatment in a newly diagnosed case of inflammatory bowel disease since Modigliani and colleagues showed that only 29% of adults with Crohn disease in clinical and biochemical remission actually achieved endoscopic remission [99]. This has a number of advantages. It allows the physician to observe the mucosal efficacy of the therapy because in many instances, such as steroid use in colitis, the clinical improvement of the patient may not be mirrored by the mucosal improvement, which is regarded by most as the most important meter of a successful
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Figure 18.11. Deep aphthous ulcer in Crohn disease.
treatment regimen [8]. Ileocecal trans-cutaneous Doppler ultrasonography may be of benefit as a noninvasive alternative to repeat ileocolonoscopy in this situation, as noted above. In addition, the activity of mucosal inflammation may determine the long-term risk for carcinogenesis in the bowel.
Enteroscopy Enteroscopy, now a standard endoscopic procedure in adult medicine and recently reviewed, [100] came of age because of the realization that the small bowel did indeed have specific pathology requiring not only diagnostic but also therapeutic expertise. Sonde-type, intra-operative-assisted push enteroscopy [101, 102, 103] and more recently non surgical push enteroscopy [104] has been described in children. Sonde enteroscopy has largely been abandoned in favor of push enteroscopy [105, 106], given the desire for therapeutic capability. The techniques of per oral push enteroscopy and laparoscopy-assisted enteroscopy continue to evolve, and have been superceded by double balloon enteroscopy (DBE) Instruments and Technique Although a pediatric colonoscope can be used for enteroscopy, specifically designed enteroscopes up to 230 cm in length are now available. The Olympus SIF Q140 (Olympus, Center Valley,
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Figure 18.12. Skip lesions in Crohn disease.
Pennsylvania, USA) has a diameter of 10.5 mm and is 250 cm long. A push enteroscope, like a colonoscope, allows four-way tip deflection to 160–180 degrees. An overtube, typically 60 to 100 cm in length with a soft Goretex tapered tip, stiffens the enteroscope within the stomach and upper duodenum limiting looping, thereby allowing deeper advancement into the small bowel [105]. A push enteroscope can be introduced 120–180 cm beyond the ligament of Treitz, and with laparoscopic assistance, even the terminal ileum can be reached, allowing lesions such as a Meckel’s diverticulum to be found [103]. Preparation for enteroscopy is the same as for upper gastrointestinal endoscopy, although the procedure may be substantially longer and more uncomfortable. Therefore, it is the practice at our unit to use general anesthesia even in adolescents. Patients are positioned left lateral or semi-prone. After normal examination of the esophagus and stomach, air is removed, and minimal insufflation of the stomach allows deeper penetration into the small bowel when not using an overtube. At 60–80 cm in older children and adolescents, the ligament of Treitz is found, and extreme tip deflection is needed to find the lumen. The first jejunal loop is more readily identified because it is straighter and travels down to the pelvis. If using an overtube, which has been threaded over the enteroscope prior to oral insertion, this is deployed down the esophagus and into the second part of the duodenum; pre-pyloric deployment will not aid in deeper small bowel penetration. Some exponents use fluoroscopy to aid in overtube tip positioning [100]. When advancing the overtube, the enteroscope needs to be pulled back with clockwise rotation to straighten it, similar to the maneuver used to achieve the shortened scope position during endoscopic retrograde cholangiopancreatography.
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Figure 18.13. Typical cobblestone appearance in Crohn disease.
A number of reports demonstrate the utility of push enteroscopy in adults. One of few studies in children, using push enteroscopy, investigated the possibility of Crohn disease in children with growth retardation [107].
Double Balloon Enteroscopy Double balloon endoscopy (DBE) is a recent development, which enables high-resolution endoscopic imaging of the entire small bowel. While push enteroscopy can aid in visualization of the proximal jejunum, DBE goes a step further making it possible to examine, take biopsies and perform therapeutic procedures such as hemostasis and balloon dilatation through out the entire small bowel. This potential for mucosal biopsies and interventional endo-therapy provides significant advantage over WCE [108–110] Instruments and Technique The DBE system (Fujinon; Fujinon Inc., Japan) consists of a high resolution video enteroscope (EN-450P5/20) with a flexible overtube. The video enteroscope has a working length of 200 cm and an outer diameter of 8.5 mm while the flexible overtube has a length of 140 cm and outer diameter of 12 mm. The enteroscope has a 2.2 mm forceps channel that enables routine biopsy as well as other common therapeutic interventions. The enteroscope as well as the overtube are fitted with a balloon each at the tip. The overtube and balloons are disposable. The balloons can be
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Figure 18.14. Colonic stricture in Crohn disease.
inflated and deflated with air from a pressure controlled pump system with maximum inflatable pressure of 45 mm (Figures 18.19 and 18.20). Both balloons are deflated at the start of the procedure. On reaching the duodenum the overtube balloon is inflated to fix and stabilize the overtube within the lumen. Subsequently the enteroscope is advanced as far as is possible. Then the enteroscope tip balloon is inflated and the overtube balloon is deflated. The overtube is now advanced to reach the enteroscope tip. The overtube is again inflated and both enteroscope and overtube are gently withdrawn together in order to “concertina” the small bowel over both. The whole procedure is repeated and each set of maneuvers can allow up to 40cm of small bowel to be examined, until the terminal ileum (TI) is reached. If the TI is not reached then the distal most region reached is “tattooed” in the submucosal plane with an endo-needle. The DBE can then be repeated via the trans-anal route and retrograde movement from the TI proximally up the ileum allowing full examination of the whole small bowel. On withdrawal in either procedure close examination of the mucosal surface occurs as with standard endoscopy, but lesions are dealt with as soon as found, whether this is on intubation or withdrawal. Bowel preparation is as for standard ileo-colonoscopy. The procedure is carried out under general anesthetic or deep sedation with the presence of an anesthetist. DBE has been extensively evaluated in adults with obscure GI bleeding and to a lesser extent in CD. Since CD can be confined to the small bowel alone DBE has a definite role in the evaluation of patients with suspected CD with negative ileocolonoscopy and radiological investigations. In a recent study comparing DBE to BMFT [111], DBE was able to detect early or faint lesions like aphtha, erosions and small ulcers which were not found by BMFT. Further, DBE was better in
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Figure 18.15. Terminal ileal Crohn disease.
differentiating open and healed ulcers thus helpful in evaluation of response to treatment in CD. However small strictures are difficult to detect with DBE since they may be mistaken for an intestinal band.
Endosonography Endoluminal ultrasonography of the rectum has been an established technique for years; however, more recently, an echocolonoscope has allowed combined examination of the mucosa and the bowel wall. This is a forward-viewing colonoscope with the transducer (7.5 MHz) situated in the rigid tip of the scope [112]. Alternatively, an ultrasound miniprobe can be introduced via the biopsy channel (7.5 or 12.5 MHz). A fluid interface is necessary for all endosonography, and this can be achieved either with a fluid-filled balloon or filling the relevant colonic segment with water. Because this may be time-consuming, it is easier to concentrate on the region of interest rather than attempt to examine the entire colon. In adult practice, staging of cancers is the major indication for endosonography. In children and adolescents, indications for this technique might include suspicion of early invasive cancer arising from an adenoma, assessment of the extent and depth of sessile polyps to guide reception technique, assessment of colonic strictures/fistulae/anastomoses, assessment of the extent and depth of inflammatory bowel disease, assessment of the extent and depth of vascular lesions, examination of rectal and colonic portal hypertension with varices, and suspicion of lymphoma. Inflammatory bowel disease appears as wall thickening and subsequent loss of the normal layer structure of the colon with progressive inflammation. Although theoretical differentiation
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between UC and CD is possible owing to the transmural nature of Crohn disease, it has been shown recently that active UC can have echo-texture changes extending into the submucosa and that these changes correlate with disease activity [113]. Surgical decisions were made in one study of patients with CD in which endoscopic ultrasonography was used to differentiate between superficial and transmural involvement [114]. An ileoanal pouch was undesirable when transmural disease was identified. Perirectal and pericolonic fistulae and abscesses have been seen using the rigid rectal ultrasound probe, and this is a potential application for endoscopic ultrasonography [115]. Catheter probe–assisted endoscopic ultrasonography in inflammatory bowel disease has advantages over an echocolonoscope, which may be technically difficult to use. One study recently showed that wall thickness was twice as great in active inflammatory bowel disease, but UC could not be differentiated from CD [116]. Loss of wall structure correlated with disease activity score in the CD group, and wall thickness correlated with disease activity in the ulcerative colitis group. Other parameters, such as superior mesenteric artery maximum flow velocity and increased Doppler ultrasonography–demonstrated mural blood flow are being examined as viable non-invasive substitutes for determination of post-treatment ileocecal CD activity, thus potentially avoiding the need for follow-up ileocolonoscopy, as some units advocate.
New Endo-diagnostic Methods High Magnification Chromoscopic Colonoscopy (HMCC) Recent improvements in technology have led to the development of a generation of endoscopes with the ability to magnify endoscopic images. The high magnification endoscope allows conventional video imaging with the facility to increase magnification instantaneously up to 100 times by a thumb activated lever. By pushing the lever downwards the magnified picture is obtained immediately and by reverting back to the normal position the image is returned to normal [117]. A topical dye like indigo carmine 0.2–2% is sprayed on the mucosa helping further to delineate the pathology. During HMCC, pit patterns are observed which are classified according to the modified Kudos’ criteria [118] and based on the pit patterns it is possible to predict the histology as well as take targeted biopsies. This technique has been extensively used in cancer surveillance in adults [119, 120]. Matsumato et al. [69] observed that presence or absence of network pattern(NWP) and crypt opening (CO) highly correlated with the severity of disease in UC both clinically and histologically. Fugiya et al. [121] devised a classification system based on minute findings. In a prospective study they compared HMCC with the established Matt’s criteria [122] and histopathological findings, and found that while colonoscopy correlated well with histopathology and correctly identified normal and clearly defined abnormal mucosa it was insufficient for the assessment of minute mucosal changes that reflect smoldering histopathological changes. HMCC on the other hand not only helped to recognize distinctive features in such mucosa predicting the severity of the disease state it also helped in predicting relapses in those who were in a quiescent state. Further, in another prospective study, Sugano et al. [123] have found HMCC effective in the evaluation of minute mucosal changes in patients with UC in remission. HMCC has also been evaluated in cancer surveillance in UC [124] and has been shown to assist in taking targeted biopsies. Confocal Laser Endomicroscopy Confocal laser endomicroscopy(CLE) is an exciting new technology developed in the last 5 years. It is an adaptation of light microscopy, whereby a low power laser illumination is focused to a single point in a microscopic field of view. Light emanating from that specific point is focused
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to a pinhole detector. Light emanating from outside the focally illuminated spot is not focused to the pinhole and, therefore, is geometrically rejected from detection. The beam path is scanned in a raster pattern and measurements of light returning to the detector from successive points are digitized to produce two-dimensional images. Each such image thus is an optical section representing one focal plane within the specimen [125–127]. The components of the laser confocal endomicroscope are based on the integration of a confocal laser microscope mounted in the tip of a conventional colonoscope (EC3870K; Pentax, Tokyo, Japan), which enables confocal microscopy in addition to standard videoendoscopy. The diameter of the distal tip and insertion tube is 12.8 mm. The distal tip contains an air and water jet nozzle, two light guides, a 2.8 mm working channel and an auxiliary water jet channel. The water jet channel is used for the topical application of the contrast agent. During CLE, an argon ion laser delivers an excitation wavelength of 488 nm with a maximum laser output of < 1 mw at the surface mucosa. Confocal images can then be collected at a scan rate of 0.8 frames / second (1024 × 1024 pixels) or 1.6 frames / second (1024 × 512 pixels). The optical slice thickness is 7 um with a lateral resolution of 0.7 um and z-axis range of 0–250 um below the surface layer. Sodium fluorescein is given intravenously at the time of the procedure as a contrast agent. Thus it is possible to get cellular and sub-cellular microscopic images at the time of endoscopic procedure. The advantages of using CLE are that as it is less invasive, there are potentially significant time, histopathological, materials, man-power and consequent financial savings to institutions conducting pediatric endoscopic services. There is no doubt that this new technique will be useful in taking targeted biopsies in patients with IBD and reduce the need to take biopsies.
Summary Pediatric endoscopy differ significantly from their adult parallels in nearly every aspect, including patient and parent management and preparation, selection criteria for sedation and general anesthetic, bowel preparation, expected diagnoses, instrument selection, imperative for terminal ileal intubation, and requirement for biopsies from macroscopically normal mucosa. The chapter has highlighted the importance of endoscopy in general and ileocolonoscopy in particular in the diagnostic and therapeutic management of IBD. Also the role of other advanced diagnostic techniques like DBE has been discussed, while wireless capsule endoscopy is discussed in a separate chapter. Endoscopy is a necessary and important investigation in the various stages of management of inflammatory bowel disease from diagnosis to surveillance of cancer. There is no dispute in the use of ileocolonoscopy in the initial assessment of patients with IBD. Recent data has shown that upper GI endoscopy also has an important role in the initial diagnosis and differentiation of IBD and hence is recommended as a part of initial investigation of all cases presenting with symptoms suggestive of IBD. Other endoscopic investigative modalities like WCE, DBE, HMCC, Confocal endomicroscopy and endosonography aid in further management of IBD. Apart from diagnosis endoscopy also has an important role in the therapeutic management of IBD. References 1. ASGE guideline: endoscopy in the diagnosis and treatment of inflammatory bowel disease. Gastrointest Endosc. 2006; 63:558–65. 2. Fouch P, Sawyer R, Sanowski RA. Push–enteroscopy for diagnosis of patients with gastrointestinal bleeding of obscure origin. Gastrointest Endosc. 1990; 36:337–41. 3. Claar RL, Walker LS, Barnard JA. Children’s knowledge, anticipatory anxiety, procedural distress, and recall of esophagogastroduodenoscopy. J Pediatr Gastroenterol Nutr. 2002; 34:68–72. 4. Acharya S. Assessing the need for pre-admission visits. Pediatr Nurs. 1992; 4:20–3.
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5. Glasper A, Stradling P. Preparing children for admission. Pediatr Nurs. 1989; 85:18–20. 6. Whiting M. Play and surgical patients. Pediatr Nurs. 1993; 5:11–3. 7. Mahajan L, Wyllie R, Steffen R et al. The effects of a psychological preparation program on anxiety in children and adolescents undergoing gastrointestinal endoscopy. J Pediatr Gastroenterol Nutr. 1998; 27:161–5. 8. Williams C, Nicholls S. Endoscopic features of chronic inflammatory bowel disease in childhood. In: Baillieère’s Clinical Gastroenterology. 8 ed. Walker-Smith M. 1994; 121–31. 9. Ewe K. Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci. 1981; 26:388–93. 10. Rey J, Axon A, Budzynska A, et al. Guidelines of the European Society of Gastrointestinal Endoscopy (E.S.G.E.). Antibiotic prophylaxis for gastrointestinal endoscopy. Endosc. 1998; 30:318–24. 11. El-Baba M, Tolia V, Lin C, et al. Absence of bacteremia after gastrointestinal procedures in children. Gastrointest Endosc. 1996; 44:378–82. 12. Sondheimer J, Sokol RJ, Taylor SF, et al. Safety, efficacy and tolerance of intestinal lavage in pediatric patients undergoing diagnostic ileo-colonoscopy. J Pediatr. 1991; 119:148–52. 13. Abubakar K, Goggin N, Gormally S, et al. Preparing the bowel for ileo-colonoscopy. Arch Dis Child. 1995; 73:459–61. 14. da Silva M, Brairs G, Patrick M, et al. Ileo-colonoscopy preparation in children: safety, efficacy, and tolerance of high versus low-volume cleansing methods. J Pediatr Gastroenterol Nutr. 1997; 24:33–7. 15. Gremse D, Sacks A, Raines S. Comparison of oral sodium phosphate to polyethylene glycol-based solution for bowel preparation for ileo-colonoscopy in children. J Pediatr Gastroenterol Nutr. 1996; 23:586–90. 16. Trautwein A, Vinitski L, Peck S. Bowel preparation before ileo-colonoscopy in the pediatric patient: a randomized study. Gastroenterol Nurs. 1996; 19:137–9. 17. Dahshan A, Lin C, Peters J, et al. A randomized, prospective study to evaluate the efficacy and acceptance of three bowel preparations for ileo-colonoscopy in children. Am J Gastroenterol. 1999; 94:3497–501. 18. Pinfield A, Stringer M. Randomised trial of two pharmacological methods of bowel preparation for day case ileo-colonoscopy. Arch Dis Child. 1999; 80:181–3. 19. Chilton A, O’Sullivan M, Cox M, et al. A blinded, randomized comparison of a novel, low-dose, triple regimen with fleet phospho-soda: a study of colon cleanliness, speed and success of ileo-colonoscopy. Endosc. 2000; 32:37–41. 20. Marshall J, Patel M, Mahajan R, et al. Benefit of intravenous antispasmodic (hyoscyamine sulfate) as premedication for ileo-colonoscopy. Gastrointest Endosc. 1999; 49:720–6. 21. Committee on Drugs of the American Academy of Pediatrics: Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics. 1992; 89:1110–5. 22. Practice Guidelines for Sedation and Analgesia by Non-Anesthesiologists. Anesthesiology. 2002; 96:1004–17. 23. Nowicki MJ, Vaughn CA. Sedation and anesthesia in children for endoscopy. Techniques in Gastrointestinal Endoscopy. 2002; 4:225–30. 24. Hassall E. Should pediatric gastroenterologists be i.v. drug users? J Pediatr Gastroenterol Nutr. 1993; 16:370–2. 25. Tolia V, Peters J, Gilger M. Sedation for pediatric endoscopic procedures. J Pediatr Gastroenterol Nutr. 2000;30:477–85. 26. Murphy S. Sedation for invasive procedures in paediatrics. Arch Dis Child. 1997; 77:281–6. 27. Gilger MA, Spearman RS, Dietrich CL, et al. Safety and effectiveness of ketamine as a sedative agent for pediatric GI endoscopy. Gastrointest Endosc. 2004; 59:659–63. 28. Chuang, E, Wenner WJ, Piccoli DA, et al. Intravenous sedation in pediatric upper gastrointestinal endoscopy. Gastrointestinal Endosc. 1995; 42–2. 29. Squires R, Morriss F, Schluterman S, et al. Efficacy, safety and cost of intravenous sedation versus general anesthesia in children undergoing endoscopic procedures. Gastrointest Endosc. 1995; 41:99–104. 30. O’Connor KW, Jones S. Oxygen desaturation is common and is under-appreciated during elective endoscopic procedures. Gastrointest Endosc. 1990; 36:S2–4.
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31. Yaster M, Nicholson DG, Deshpande JK et al. Midazolam-Fentanyl intravenous sedation in children: case report of respiratory arrest. Pediatrics. 1990; 86:463–7. 32. Bendig D. Pulse oximetry and upper gastrointestinal endoscopy in infants and children. J Pediatr Gastroenterol Nutr. 1991; 12:39–43. 33. Gilger M. Conscious sedation for endoscopy in the pediatric patient. Gastroenterol Nursing. 1993; 16:75–9. 34. Israel D, McLain B, Hassall E. Successful pan-ileocolonoscopy and ileoscopy in children. J Pediatr Gastroenterol Nutr. 1994; 19:83–9. 35. Dillon M, Brown S, Casey W, et al. Ileo-colonoscopy under general anesthesia. Pediatrics. 1998; 102:381–3. 36. Stringer M, Pinfield A, Revell L, et al. A prospective audit of paediatric ileo-colonoscopy under general anaesthesia. Acta Paediatr. 1999; 88:199–202. 37. Hassall E. Who should perform pediatric endoscopic sedation? J Pediatr Gastroenterol Nutr. 1994; 18:114–7. 38. Lamireau T, Dubrueil M, Daconceicao M. Oxygen saturation during esophagogastroduodenoscopy in children: general anesthesia versus intravenous sedation. J Pediatr Gastroenterol Nutr. 1998; 27:172–5. 39. Liacouras, Mascarenhas CA, Poon M, et al. Placebo-controlled trial assessing the use of oral midazolam as a pre-medication to conscious sedation for pediatric endoscopy. Gastrointestinal Endoscopy. 1998; 47:455–60. 40. Hassall E, Barclay G. Ament ME. Colonoscopy in childhood. Pediatrics. 1984; 73:594–9. 41. Abdullah BA, Gupta SK, Croffie JM. The role of esophagogastroduodenoscopy in the initial evaluation of childhood inflammatory bowel disease: A 7-year study. J Pediatr Gastroenterol Nutr. 2002; 35:633–40. 42. Castellaneta SP, Afzal N, Srivistava A. Diagnostic role of upper gastrointestinal endoscopy in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2004;39:257–61. 43. Haggitt RC, Meisnner WA. Crohn disease of the upper gastrointestinal tract. Am J Clin Pathol. 1973; 59:613–22. 44. Griffiths AM, Alemayehu E, Sherman P, et al. Clinical features of gastroduodenal Crohn disease in adolescents. J Pediatr Gastroenterol Nutr. 1989; 8:66–71. 45. Lenaerts C, Roy CC, Vaillencourt M. High incidence of upper gastrointestinal tract involvement in children’s with Crohn disease. Pediatrics. 1989; 83:771–81. 46. Fielding JF, Toye DKM, Beton DC, et al. Crohn disease of the stomach and duodenum. Gut. 1970; 11:1001–6. 47. Cameron DJS. Upper and lower GI endoscopy in children and adolescents with Crohn disease: a prospective study. J Gastroenterol and Hepatol. 1991; 6:355–8. 48. Oberhuber G, Puspok A, Oesterreicher C, et al. Focally enhanced gastritis: a frequent type of gastritis in patients with Crohn disease. Gastroenterology. 1997; 112:698–706. 49. Oberhuber G, Hirch M, Stolte M. High incidence of upper gastrointestinal tract involvement in Crohn disaese. Virchow’s arch, 1998. 432:49–52. 50. Tobin JM, Sinha B, Ramani P, Upper gastrointestinal mucosal disease in Pediatric Crohn disease and ulcerative colitis: a blinded controlled study. J Pediatr Gastroenterol Nutr. 2001; 32:443–8. 51. Ruuska T, Vaajalathi P, Arajarvi P. Prospective evaluation of upper gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn disease. J Pediatr Gastroenterol Nutr. 1994; 19:181–6. 52. Mashako MN, Cezard J, Navarro J, et al. Crohn disease lesions in the upper gastrointestinal tract - correlation between clinical, radiological, endoscopic and histological features in adolescents and children. J Pediatr Gastroenterol Nutr. 1989; 8:442–6. 53. Kirschner BS. Gastroduodenal Crohn disease in childhood. J Pediatr Gastroenterol Nutr, 1989; 9: 138–40. 54. Huchzermeyer H, Paul F, Seifert E, et al. Endoscopic results in five patients with Crohn disease of the esophagus. Endoscopy. 1977; 8:75–81. 55. Ramaswamy K, Jacobson K, Jevon G, et al. Esophageal Crohn disease in children: a clinical spectrum. J Pediatr Gastroenterol Nutr. 2003; 36:454–8. 56. Rudolph I, Goldstein F, Di marino AJ, et al. Crohn disease of the esophagus: three cases and literature review. Can J Gastroenterol. 2001; 15:117–22.
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57. Walker RS, Breuer RI, Victor T. Crohn esophagitis: a unique cause of esophageal polyposis. Gastrointest Endosc. 1996; 43:511–5. 58. D’Haens G, Rutgeerts P, Geboes K, et al. The natural history of esophageal Crohn disease: Three patterns of evolution. Gastrointest Endosc. 1994; 40:296–300. 59. Geboes K, Janssens J, Rutgeerts P, et al. Crohn disease of the esophagus. J Clin Gastroenterol. 1986; 8:31–7. 60. Hanai H, Honda S, Sugimoto K, et al. Endoscopic therapy for multiple mucosal bridges in the esophagus of a patient with Crohn disease. Gastrointest Endosc. 1999; 50:715–7. 61. Rutgeerts P, Onette E, Vantrappen G, et al. Crohn disease of the stomach and the duodemun: A clinical study with emphasis on the value of endoscopy and endoscopic biopsies. Endoscopy. 1980; 12:288–94. 62. Schmitz-Moorman P, Malchow H, Pittner PM, et al. Endoscopic and biopsy study of the upper gastrointestinal tract in Crohn disease patients. Pathol Res Pract. 1985; 178:377–87. 63. Kundhal PS, Stormon MO, Zachos M, et al. Gastric antral biopsy in the differentiation of pediatric colitides. Am J Gastroenterol. 2003; 98:557–61. 64. Parente F, Cercino C, Bollini S, et al. Focal gastric inflammatory infiltrates in inflammatory bowel disease. Am J Gastroenterol. 2003; 95:705–11. 65. Kaufman SS, Vanderhoff J, Young R, et al. Gastroenteric inflammation in children with ulcerative colitis. Am J Gastroenterol. 1997; 92:1209–12. 66. Sasaki M, Okada K, Koyama S, et al. Ulcerative colitis complicated by gastroduodenal lesions. J Gastroenterol. 1996; 31:585–9. 67. Brooker J, Saunders B, Shah S, et al. A new variable stiffness colonoscope makes ileo-colonoscopy easier: a randomised controlled trial. Gut. 2000; 46:801–5. 68. Tada M, Kawai K. Research with the endoscope. New techniques using magnification and chromoscopy. Clin Gastroenterol. 1986; 15:417–37. 69. Matsumoto T, Kuroki F, Mizuno M, et al. Application of magnifying chromoscopy for the assessment of severity in patients with mild to moderate ulcerative colitis. Gastrointest Endosc. 1997; 46:400–5. 70. Hussein A, Bartram CN, Williams C, et al. Carbon dioxide insufflation for more comfortable ileocolonoscopy. Gastrointest Endosc. 1984; 30:68–70. 71. Stevenson G, Wilson J, Wilkinson J, et al. Pain following ileo-colonoscopy: elimination with carbon dioxide. Gastrointest Endosc. 1992; 38: 564–7. 72. Cirocco W, Rusin L. Fluoroscopy: A valuable ally during difficult ileo-colonoscopy. Surg Endosc. 1996; 10:1080–4. 73. Latt T, Nicholl R, Domizio P, et al. Rectal bleeding and polyps. Arch Dis Child. 1993; 69:144–7. 74. Williams C, Saunders B, Bell G, et al. Real-time magnetic three-dimensional imaging of flexible endoscopy. Gastrointest Endosc Clin N Am. 1997; 7:469–75. 75. Williams C, Laage N, Campbell C, et al. Total ileo-colonoscopy in children. Arch Dis Child. 1982; 57:49–53. 76. Lipson A, Bartram C, Williams CB, et al. Barium studies and ileoscopy compared in children with suspected Crohn disease. Clin Radiol. 1990; 41:5–8. 77. Deere H, Thomson M, Murch S, et al. Histological comparison of rectosigmoid and full colonoscopic biopsies in the assessment of inflammatory bowel disease in childhood. Gut. 1998; 42:A55. 78. Geboes K, Ectors N, D’Haens G, et al. Is ileoscopy with biopsy worthwhile in patients presenting with symptoms of inflammatory bowel disease? Am J Gastroenterol. 1998; 93:201–6. 79. Salvatore S, Thomson M. Crohn disease or intestinal tuberculosis? Inflamm Bowel Dis Monitor. 1999; 1:59–61. 80. Breysem Y, Janssons J, Coremans G, et al. Endoscopic balloon dilation of colonic and ileo-colonic Crohn strictures: long-term results. Gastrointest Endosc. 1992; 38:142–7. 81. Gevers A, Couckay H, Coremans G, et al. Efficacy and safety of hydrostatic balloon dilation of ileocolonic Crohn strictures. A prospective long-term analysis. Acta Gastroenterol Belg. 1994; 57:320–2. 82. Gans S, AM, Cristie D, et al. Pediatric endoscopy with flexible fiberscopes. J Pediatr Surg. 1975; 10:375–80. 83. Howdle PD, Littelwood JM, Firth J, et al. Routine ileo-colonoscopy service. Arch Dis Child. 1984; 59:790–3.
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84. de la Torre ML, Vargas Gomez MA, Mora Tiscarreno M, et al. Angiodysplasia of the colon in children. J Pediatr Surg. 1995; 30:72–5. 85. Habr Gama A. Pediatric ileo-colonoscopy. Dis Colon Rectum. 1979; 22:530–5. 86. Jalihal A, Mishra SP, Arvind A, et al. Colonoscopic polypectomy in children. J Pediatr Surg. 1992; 27:1220–2. 87. Nicholson R. Medical research with children: ethics law and practice. 1986. New York: Oxford University Press. 88. Livstone E, C.G., Troncale F, et al. Diastatic serosal lacerations: an unrecognized complication of ileo-colonoscopy. Gastroenterology. 1974; 67:1245–7. 89. Ho H, Burchell S, Morris P, et al. Colon perforation, bilateral pneumothoraces, pneumopericardium, pneumomediastinum, and subcutaneous emphysema complicating endoscopic polypectomy: anatomic and management considerations. Am. Surg. 1996; 62:770–4. 90. Damore L, Rantis P, Vernava A, et al. Colonoscopic perforations. Etiology, diagnosis, and management. Dis Colon Rectum. 1996; 39:1308–14. 91. Gedebou T, Wong R, Rappaport W, et al. Clinical presentation and management of iatrogenic colon perforations. Am J Surg. 1996; 172: 454–7. 92. Orsoni P, Berdah S., Verrier C, et al. Colonic perforation due to ileo-colonoscopy: a retrospective study of 48 cases. Endoscopy. 1997; 29:160–4. 93. Rozen P, Somjan G, Baratz M, et al. Endoscope-induced colitis: description. Probable cause by glutaraldehyde, and prevention. Gastrointest Endosc. 1994; 40:547–53. 94. Ong E, Bohlmer U, Wurbs D. Splenic injury as a complication of endoscopy: Two case reports and a literature review. Endoscopy. 1991; 23:302–4. 95. Thomas A, Mitre R. Acute pancreatitis as a complication of ileo-colonoscopy. J Clin Gastroenterol. 1994; 19:177–8. 96. Rothbaum R. Complications of pediatric endoscopy. Gastrointest Clin North Am. 1996; 6: 445–59. 97. Chutkun RK, Waye JD. Endoscopy in inflammatory bowel disease in Inflammatory bowel disease. Ed: Kirsner J. 2000. 98. Jenkins D, Balsitis M, Gallivan MF, et al. Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease. The British Society of Gastroenterology Initiative. J Clin Pathol. 1997; 50:93–105. 99. Modigliani R, Mary J, Simon J, et al. Clinical, biochemical, and endoscopic picture of attacks in Crohn disease: evolution on prednisolone. Gastroenterol. 1990; 98:811–8. 100. Lewis B. Enterosocopy. Giastrointest Endosc Clin N Am. 2000; 10:101–6. 101. Duggan C, Shamberger R, Antonioli D, et al. Intraoperative enteroscopy in the diagnosis of partial intestinal enteroscopy in infancy. Dig Dis Sci. 1995; 40:236–8. 102. Tada M, Misake F, Kawai K. Pediatric enteroscopy with a Sonde-type small intestine fiberscope (SSIF-type VI). Gastrointest Endosc. 1983; 29: 44–7. 103. Turck D, Bonnevalle M, Gottrand F, et al. Intraoperative endoscopic diagnosis of heterotopic gastric mucosa in the ileum causing recurrent acute intussusception. J Pediatr Gastroenterol Nutr. 1990; 11:275–8. 104. Darbari A, Kalloo AN, Cuffari C, et al. Diagnostic yield, safety, and efficacy of push enteroscopy in pediatrics. Gastrointest Endosc. 2006; 64:224–8. 105. Barkin J, Lewis B, Reiner D, et al. Diagnostic and therapeutic jejunoscopy with a new, longer enteroscope. Gastrointest Endosc. 1992; 38:55–8. 106. MacKenzie J. Push enteroscopy. Gastrointest Endosc Clin N Am. 1999; 9:29–36. 107. Perez-Cuadrado E, Macenalle, Iglesias J, et al. Usefulness of oral video push enteroscopy in Crohn disease. Endoscopy. 1997; 29: 745–47. 108. Yamamoto H, Sekine Y, Sato Y, et al. Total enteroscopy with a non surgical steerable double balloon method. Gastrointest Endosc. 2001; 53:216–20. 109. May A, Nachbar L, Wardek A, et al. Double balloon enteroscopy: preliminary experience with obscure gastrointestinal bleeding or chronic abdominal pain. Endoscopy. 2003; 35:985–91. 110. Yamamoto H, Sugano K. A new method of enteroscopy: the double balloon method. Can J Gastroenterol. 2003; 17:273–4. 111. Oshitani N, Yukawa T, Yamagami H, et al. Evaluation of deep small bowel involvement by double balloon enteroscopy in Crohn Disease. Am J Gastroenterol. 2006; 101:1484–9.
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112. Mallery S, Van Dam J. Interventional endoscopic ultrasonography: current status and future direction. J Clin Gastroenterol. 1999; 29:297–305. 113. Shimizu S, Tada M, Kawai K, et al. Value of endoscopic ultrasonography in the assessment of inflammatory bowel diseases. Endoscopy. 1992; 24:354–8. 114. Hildebrandt U, Kraus J, Ecker K, et al. Endosonographic differentiation of mucosal and transmucosal non-specific inflammatory bowel disease. Endoscopy. 1992; 24:359–63. 115. Tio T, Mulder C, Wijers O, et al. Endosonography of peri-anal and peri-colorectal fistula and/or abscess in Crohn disease. Gastrointest Endosc. 1990; 36:331–6. 116. Soweid A, Chak A, Katz J, et al. Catheter probe assisted endoluminal US in inflammatory bowel disease. Gastrointest Endosc. 1999; 50:41–6. 117. Togashi K, Konishi F. Magnification Chromo-colonoscopy. ANZ J Surg. 2006; 76:1101–5. 118. Kudo S. Endoscopic mucosal resection of flat and depressed types of early colorectal cancer. Endoscopy. 1993; 25:455–61. 119. Ohta A, Tominaga K, Sakai Y, et al. Efficacy of magnifying colonoscopy for the diagnosis of colorectal neoplasia: comparison with histopathological findings. Dig Endosc. 2004; 16:308–14. 120. Hurlstone DP, Fuji T, Lobo AJ, et al. Early detection of colorectal cancer using high-magnification chromoscopic colonoscopy. B. J. Surg. 2002; 89:272–82. 121. Fujiya M, Saitoh Y, Nomura M, et al. Minute findings by magnifying colonoscopy are useful for the evaluation of ulcerative colitis. Gastrointest Endosc. 2002. 56:535–42. 122. Matts SG. The value of rectal biopsy in the diagnosis of ulcerative colitis. Q J Med. 1961; 30:393–407. 123. Sugano S, Fujinuma S, Sakai Y, et al. Magnifying colonoscopy for the diagnosis of inflammatory changes in ulcerative colitis. Dig Endosc. 2006; 18:173–180. 124. Matsumoto T, Nakamura S, Jo Y, et al. Chromoscopy might improve diagnostic accuracy in cancer surveillance for ulcerative colitis. Am J Gastroenterol. 2003; 98:1827–33. 125. Delaney PM, Harris MR. Fibroptics in confocal microscopy, in Handbook of biological confocal microscopy. Ed: Pawley JB. 1995; 515–23. 126. Kiesslich R, Goetz M, Vieth M. et al. Confocal Laser Endomicroscopy. Gastrointest Endosc Clin N Am. 2005; 15:715–31. 127. Polglase AL, McLaren W, Skinner SA, et al. A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract. Gastrointest Endosc. 2005; 62:686–95.
19 The Pathology of Chronic Inflammatory Bowel Disease Pierre Russo∗
Introduction Chronic inflammatory bowel disease (IBD) typically refers to two major entities, ulcerative colitis (UC) and Crohn disease (CD). However, the differential diagnosis of colitis and enteritis in pediatrics encompasses numerous disorders (Table 19.1), including self-limited entities related to infections or medication, or those due to immunodeficiency states. Endoscopic biopsies and surgical specimens are obtained most frequently in those entities without an identifiable pathogen or which follow a prolonged clinical course, when the possibility of chronic inflammatory bowel disease is raised, or in the course of therapy and management of complications. Although the pathology of UC and CD, historically derived from the examination of resected specimens, has been amply documented, the current extensive use of endoscopy and biopsy, improvements in the sensitivity of diagnostic imaging, the use of serologic testing, and the implementation of these diagnostic modalities earlier in the course of disease has produced observations which have blurred traditional distinctions. The purpose of this chapter is to outline and illustrate the pathologic manifestations and differentiating features of UC and CD, as well as discuss newer observations, based mainly upon endoscopic biopsies, which are “atypical” and challenge classical distinction between the two.
Major Histologic Features Noted in Mucosal Specimens Active Colitis Active colitis refers to the presence of neutrophils either in the lamina propria, in crypt epithelium (cryptitis) or within the lumen, forming small abscesses (crypt abscesses). Neutrophils confined to the lumen of mucosal vessels are not considered part of the process of active colitis. A predominantly neutrophilic infiltrate without significant architectural changes is generally a feature of diseases with a self-limiting course, such as infections and drug reactions. Neutrophils in these cases are frequently confined to the superficial portion of the mucosa, and may be associated with small erosions or ulcers (Figure 19.1).
∗
Chief, Anatomic Pathology, Department of Pathology, The Children’s Hospital of Philadelphia, 34th Street & Civic Center Boulevard, Philadelphia, PA, 19104, Phone: 215-590-1733, E-mail:
[email protected]
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Table 19.1. Differential diagnosis of colitis in infancy and childhood. Allergic Vascular Neuromuscular Immunodeficiencies (congenital and acquired) Infectious Pseudomembranous or antibiotic associated Chronic idiopathic
Treatment related
Eosinophilic colitis Necrotizing enterocolitis Henoch-Schönlein purpura Hemolytic uremic syndrome Hirschsprung’s disease Chronic pseudo-obstruction Bacterial, parasitic, viral Ulcerative colitis Crohn’s disease Lymphocytic colitis Collagenous colitis Autoimmune enterocolitis Diversion colitis Neutropenic colitis Pouchitis Graft versus host disease Fibrosing colonopathy
Adapted and modified from [Seidman, 1995 #5234]
Focal Active Colitis Focal active colitis (FAC) is observed in acute self-limited colitis and can be an early manifestation of idiopathic inflammatory bowel disease. In a recent report of 29 pediatric patients with FAC,
Figure 19.1. Active colitis in a 3 year-old due to Salmonella. There is a superficial, mild inflammatory infiltrate with small crypt microabscesses without significant crypt architectural changes, associated with superficial hemorrhages. Hematoxylin-eosin (H+E), ×100.
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8 developed Crohn disease, whereas the other patients had either infectious colitis or remained idiopathic [1]. However, FAC must be distinguished from iatrogenic changes. Non-disease Related Alterations Non-disease related alterations in the colonic mucosa may be induced by certain enemas used in bowel preparation or by the procedure itself. For example, soap suds enemas may result in hyperemia and edema of the bowel, especially noted on endoscopy [2]. Oral sodium phosphate solutions (oral FleetTM ) may cause aphthoid-like erosions endoscopically similar to Crohn disease [3]. Histologic features are generally mild, consisting of erosions or neutrophilic infiltrates in the epithelium overlying mucosal lymphoid aggregates; mucin depletion and increased cell proliferation can also be noted in the crypts [3–5]. In contrast, disease-related FAC is characterized by a more florid and basally-situated cryptitis. Hydrogen peroxide enemas have been associated with acute hemorrhagic colitis and with “pseudolipomatosis”, resulting from artificial introduction of gas into the mucosa [2]. Hypertonic saline, FleetTM and bisacodyl enemas can cause mucin depletion, focal disruption of surface epithelium, mild acute inflammation and edema, which usually resolve within one week [6]. Cleansing solutions used to disinfect endoscopes may produce adherent mucosal plaques, mucosal vacuolar changes, congestion and hemorrhage [7]. Eosinophilic Colitis Eosinophilic colitis refers to a patchy or diffuse infiltrate dominated by eosinophils, usually with infiltration of the crypt or surface epithelium. Wide variations in the number of eosinophils in the normal colonic mucosa are due to differences in specimen site (greater numbers of eosinophils in the cecum as opposed to the rectum), age and geography [8, 9]. In infants, the main consideration is milk allergy; parasitic infection and chronic inflammatory bowel disease are also possibilities. Chronic Colitis The features of chronic colitis are based on the recognition of architectural changes in the mucosa, such as a “villiform” aspect of the surface epithelium, crypt destruction and atrophy, and shortening of the crypts with irregular branching and loss of their regular outline. Shortening of the crypts is most often due to the presence of a basally-situated chronic inflammatory infiltrate (basal plasmacytosis) which separates the base of the crypts from the muscularis mucosae (Figure 19.2). The presence of an increased mononuclear inflammatory cell infiltrate, usually an integral part of the process, is the least useful histologic parameter given the wide range in numbers of lymphocytes and plasma cells in normal specimens. Though considered a hallmark of chronic idiopathic inflammatory bowel disease, histologic features of chronicity may also be seen in other settings in pediatrics, such as immunodeficiency disorders, metabolic diseases such as glycogen storage disease type Ib, or result from mucosal injury due to ischemia or Hirschsprung’s disease. Chronic active colitis Chronic active colitis refers to the presence of a neutrophilic infiltrate superimposed on the above changes, and is usually seen during exacerbations of IBD.
Pathologic Features of Ulcerative Colitis and Crohn Disease The pathologic characteristics of UC and CD and the main features that distinguish the two diseases are, in most respects, similar in children and adults, and are outlined in Table 19.2. Features helpful in differentiating these two entities in mucosal biopsies are outlined in Table 19.3.
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Figure 19.2. Active chronic colitis features crypt architectural changes characterized by irregular branching, increased inter-cryptal distance and by shortening of the crypts, due to the presence of an inflammatory infiltrate in the deep mucosa separating the base of the crypts from the muscularis mucosa (basal plasmacytosis). In addition, there is goblet cell depletion and a micro-abscess. H+E, ×100.
Table 19.2. Distinguishing features of ulcerative colitis and crohn’s disease. Ulcerative colitis Macroscopic Rectal involvement Distribution Terminal ileum Serosa Bowel wall Mucosa Pseudopolyps Strictures Fistulas Involvement of gut proximal to colon Microscopic Inflammation Lymphoid hyperplasia Crypt abscesses Mucus depletion Deeply situated sarcoid-like granulomas Fissures and sinuses Villous surface transformation Submucosal fibrosis Neuromatous hyperplasia
Crohn’s Disease
Yes a Diffuse a “backwash” ileitis Usually normal Normal thickness Hemorrhagic Frequent No No No b
Variable Segmental or diffuse Often thickened and stenosed “creeping fat” Frequently thickened Cobblestone and ulcers linear Less common Common Common Common
Confined to mucosa and superficial submucosa Infrequent Extensive Frequent No
Transmural common Focal Infrequent Yes
No Common Rare Rare
Yes Infrequent Common Common
(a) treatment may create the appearance of rectal sparing and discontinuous involvement (b) see text
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Table 19.3. Distinguishing features of ulcerative colitis and crohn disease in biopsies Ulcerative colitis Distribution of inflammation Rectal involvement Proximal > distal colonic involvement Crypt abscesses Villous surface appearance Pyloric metaplasia Mucin depletion Granulomas
Diffuse Yes a No a Diffuse Common Infrequent Frequent Superficial; foreign body
Crohn’s disease Frequently focal Variable Frequent Variable, often focal Occasional Typical Infrequent Deep; sarcoid-like
(a) see text
Ulcerative Colitis Ulcerative colitis is classically defined as diffuse chronic mucosal inflammation limited to the colon, which invariably affects the rectum, and extends proximally in a symmetric uninterrupted pattern to involve part or all of the large intestine. The mucosa characteristically exhibits a diffuse hemorrhagic appearance (Figure 19.3). Microscopically, ulcerative colitis is characterized by inflammation limited to the mucosa and superficial submucosa (Figure 19.4); deeper layers of the bowel are only exceptionally involved, as in toxic megacolon. Infiltration of the mucosa by neutrophils, with cryptitis, epithelial degeneration, goblet cell depletion and crypt abscesses are characteristic though relatively non-specific microscopic features of active UC. Chronicity, as previously defined, is characterized by crypt architectural changes such as irregular branching and
Figure 19.3. Ulcerative colitis. Specimen from a total colectomy reveals a diffusely hemorrhagic granular mucosa from the rectum (on the left) to the ascending colon (on the left). The process is macroscopically continuous, without “skip” areas. Uninvolved appendix with a small amount of terminal ileum is also present.
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Figure 19.4. Histologic section from the specimen in Figure 19.3. is characterized by a diffuse inflammatory process limited to the mucosa and superficial portion of the submucosa. The colonic wall is of normal thickness.
atrophy, usually accompanied by a mononuclear inflammatory infiltrate. Increased crypt epithelial turnover in UC results in goblet cell depletion and Paneth cell metaplasia, less frequently observed in CD. The latter must be interpreted with caution in pediatric cases, as Paneth cells can be present in the distal colon in normal young children. Crypt abscesses are not specific, but when diffuse are suggestive of UC, whereas they tend to be more isolated in Crohn disease [10]. Rupture of crypt abscesses into the lamina propria or erosions may result in collections of histiocytes which may simulate but should be distinguished from true granulomas (Figure 19.5). Pseudopolyps Pseudopolyps, more commonly found in UC than CD, are discrete areas resulting from surviving islands of mucosa or heaped-up granulation tissue. The latter are more accurately referred to as “inflammatory polyps”. Occasionally, regenerating mucosa within such an inflammatory polyp may form irregular, dilated glands, which bear a marked resemblance to retention or “juvenile” polyps [10]. In contrast to adenomas, pseudopolyps have a short stalk and are generally smoothsurfaced (Figure 19.6). Extensive arborization and fusion of the polyps may result in mucosal bridging. Colonic Malignancy Colonic malignancy is a significant complication in ulcerative colitis patients. Duration of disease and pancolitis are well recognized as risk factors for the development of malignancy, with the risk of cancer increasing over that of the general population by 1% each year after 10 years of disease [11, 12]. Unfortunately, there is a paucity of prospective data describing long term inflammatory bowel disease with early onset ulcerative colitis and ultimate cancer risk in pediatric patients. Other less well characterized risk factors include concomitant sclerosing cholangitis, an
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Figure 19.5. Crypt microabscess with rupture resulting in a histiocytic reaction around the base of a crypt in a colonic biopsy from an 8 year-old girl with ulcerative colitis. H+E ×200.
Figure 19.6. Inflammatory “pseudopolyps” in a patient with ulcerative colitis. The base of the polyps are broad, and the polyps consist of heaped-up regenerating mucosa with an inflammatory infiltrate.
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(b)
Figure 19.7. Dysplasia in 16 year-old boy with 10-year history of ulcerative colitis. A) plaque-like lesions present in the colon. B) Histologic section through area of dysplasia in crypt and surface epithelium shows piled-up enterocytes with hyperchromatic nuclei and loss of polarity.
excluded, defunctionalized or bypassed segment and depressed red blood cell folate levels [12]. Children who develop colitis before the age of 10 years should undergo colonoscopy screening during their adolescence, and dysplasia and adenocarcinoma have been documented in adolescents and young adults with long-standing colitis [13]. Dysplasia in colitics is generally plaque-like or nodular, frequently referred to as the DALM (dysplasia-associated lesion or mass) lesion [14] (Figure 19.7). Epithelial dysplasia generally precedes carcinoma; therefore yearly surveillance colonoscopy is recommended. Since reliability and patient compliance of serial colonoscopy to detect dysplasia is not perfect, prophylactic colectomy should be considered in any individual who developed ulcerative colitis during childhood.
Crohn Disease In contrast to UC, CD features segmental intestinal involvement, with thickening of the bowel wall consequent to transmural inflammation and fibrosis, resulting in obstructive strictures, especially in the ileocecal area. The serosa is typically congested, with the presence of adhesions and fat wrapping, or “creeping fat”. Mucosal involvement can be patchy and discontinuous. Aphthous
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Figure 19.8. Crohn disease. Ileo-cecectomy specimen is characterized by a stricture in the area of the ileocecal valve. The mucosa has a “cobblestone” appearance, and the wall appears thickened with prominent and extensively adherent serosal fat. Contrast with Figure 19.3.
ulcers overlying lymphoid tissue are among the earliest lesions observed endoscopically, but are non-specific and may be seen in other conditions. Uneven involvement of the mucosa results in a typical “cobblestone” appearance (Figure 19.8). Transmural involvement in resected specimens and the presence of granulomas are the major histologic features which distinguish CD from UC and other colitides. Transmural disease in CD usually results from submucosal edema, fibrosis and inflammation, typically in the form of lymphoid aggregates, also involving the muscle layers and the serosa (Figure 19.9). Intramural abscesses are also noted, with fistulae, perforations and adhesions, which can involve multiple loops of bowel and form a mass. Lymphangiectasia, neural hyperplasia and vascular changes are frequently observed in CD and are almost never seen in UC. Granulomas Granulomas are virtually diagnostic of CD when they are well-formed, non-necrotic, basally situated and remote from areas of active inflammation (Figure 19.10). Their presence in biopsies may predate radiologic evidence of disease, and prolonged follow-up is necessary when they are observed in the absence of grossly evident disease [15]. The likelihood of finding granulomas is clearly a function of the diligence with which they are sought, increasing with the number of biopsies and sections examined [16]. Granulomas appear to be more frequently observed in the pediatric age group. One large study in Germany found them in 26% of biopsy specimens from 42% of patients, twice as commonly as in adults [17]. Comparison of initial biopsies of children with and without rectosigmoid granulomas showed similar age of onset of disease in the two groups, though those with granulomas tended to have more extensive disease and perianal complications [18]. Shepherd and colleagues observed granulomas more frequently in their younger patients and those with a shorter clinical course, with an increased prevalence in the more distal portion of the gastrointestinal tract [19]. In a recent study at The Children’s Hospital of Philadelphia, granulomas were identified in 61% of pediatric CD patients undergoing upper and lower endoscopy and were more frequent in untreated patients (De Matos, accepted, J. Pedi GI Nutr). In nearly half of those patients, granulomas were present in the upper GI tract, in the
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Figure 19.9. Crohn disease. Low power microscopic section demonstrates transmural involvement. Inflammation, in the form of lymphoid aggregates, extends through the muscularis propria into thickened serosal fat. Contrast with Figure 19.4. H+E, ×10.
Figure 19.10. Crohn disease, terminal ileum. A well-formed, non-necrotic granuloma is present in the superficial submucosa, away from any ruptured crypt. Contrast with Figure 19.5. H+E, ×100.
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Table 19.4. Differential diagnosis of granulomas in colon specimens. Crohn disease Infections Salmonella (microgranulomas) Campylobacter (microgranulomas) Mycobacteria (tuberculosis and avium-intracellulare) Yersinia Brucellosis Tularemia Schistosomiasis Fungal infections Mucin and foreign body granulomas Chronic granulomatous disease Pneumatosis intestinalis Malakoplakia Sarcoidosis
terminal ileum, or both, but not in the colon, emphasizing the need for extracolonic biopsies in these patients. Granulomas can also be seen, however, in a number of other conditions (Table 19.4). The granulomas seen in tuberculous infections of the gastrointestinal tract are typically multiple, large and have caseous necrosis [20]. Those associated with yersiniosis are also necrotic, and frequently present in mesenteric lymph nodes [21]. Chronic granulomatous disease (CGD) can occasionally present with colitis similar to CD [22]. Numerous necrotizing granulomas may be observed; in non-inflamed or quiescent cases, collections of pigmented macrophages may be noted in the mucosa (Figure 19.11). In doubtful cases, the diagnosis of CGD can be established by the nitroblue tetrazolium (NBT) test [23].
Figure 19.11. Chronic granulomatous disease. Colon biopsy from a 5-year old boy reveals numerous granulomas throughout the mucosa and submucosa. H+E ×100.
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Distinguishing Acute Self-limited Colitis from Early Inflammatory Bowel Disease Distinguishing acute self-limited colitis (ASLC) from early inflammatory bowel disease relies primarily on stool cultures and duration of diarrhea, as patients without an identifiable pathogen or in whom diarrhea lasts more than several weeks are more likely to have IBD. However, microbiologic investigations can reveal a colitis-causing pathogen such as Salmonella, Campylobacter and Yersinia in up to 15% of patients with IBD [24]. In adults, biopsies have been found useful in distinguishing even early IBD from acute self-limited colitis or ileitis, as these may appear similar to the endoscopist. However, initial colonic or rectal biopsies from 10% to 34% of pediatric patients ultimately shown to have UC lacked architectural distortion or other histologic features of chronic colitis [25–30]. This is seen particularly in younger patients (< 10 years), and may be due to shorter duration of symptoms or longer progression to chronicity in children [31] (Figure 19.12A and B). A primarily crypt-directed inflammation with numerous crypt abscesses suggests UC whereas in infectious colitis the inflammation is superficial, largely in the lamina propria and assumes a more “non-specific” appearance [32]. Further, crypt architectural distortion, basal lymphoplasmacytosis, and crypt Paneth cell metaplasia in left colonic biopsies are usual features of UC but rarely present in self-limited colitis [32–35]. (a)
(b)
Figure 19.12. Early IBD. A) Colonic biopsies from a 3-year old with several months’ history of abdominal pain and diarrhea shows mild inflammatory and crypt architectural changes. B) Colonic biopsies 6 months later reveal active chronic colitis with much more evident crypt architectural distorsion. H+E, ×100.
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Rectal Sparing and Patchiness Although ulcerative colitis is traditionally considered to be a diffuse process that begins in the rectum and extends proximally in a continuous fashion, a number of studies suggest that initial rectal biopsies in children with UC may not demonstrate mucosal architectural changes as consistently as in adults or may even be “normal” (rectal sparing) (Figure 19.13). An unequivocal diagnosis of IBD may be more difficult in these cases, as may be distinction between UC and CD. Faubion et al identified a 27% prevalence of rectal sparing in children with IBD and sclerosing cholangitis, suggesting the possibility that rectal sparing may be more common in this subset of patients [36]. Moreover, discontinuous involvement and rectal healing have been reported during the course of long-standing disease in adults, which likely results from treatment effect or natural variation in the course of disease and also reflects the current clinical practice of sampling multiple mucosal biopsies over time [37, 38]. Medical therapy can have a profound but variable effect on mucosal histology, ranging from decreased intensity of the inflammatory infiltrate to complete normalization of the mucosa, including discontinuity of mucosal disease in UC [39]. Quiescent colitis is characterized by mucosal atrophy and crypt architectural changes in the absence of the acute inflammation, ulceration and mucus depletion seen in the active phase (Figure 19.14). Hyperplasia of endocrine cells may be observed [40]. Regenerative features of epithelial cells must be distinguished from changes of dysplasia, in that the former is not characterized by an increase in the number of epithelial cells or N/C ratio, and the nuclear chromatin is finely distributed.
Figure 19.13. Rectal sparing in ulcerative colitis. Fifteen year-old female with several years history of ulcerative colitis which became refractory to medical therapy. The colectomy specimen reveals a diffuse colitis, much milder in the rectum than proximally.
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Figure 19.14. “Quiescent” colitis. Rectal biopsy in an 11-year old boy with history of ulcerative colitis while on therapy. Mild crypt architectural changes are present without active inflammation. H+E ×100.
Backwash Ileitis “Backwash ileitis” refers to an abnormal radiologic or endoscopic appearance of the terminal ileum, usually in patients with an ulcerative pancolitis, originally thought to result from reflux of inflamed colonic contents into the terminal ileum. Strict morphologic criteria for this diagnosis, though not defined, seem to rest primarily upon a combination of length of involvement of the ileum (usually <10 cm), a normal ileocecal valve without radiologic and/or endoscopic signs of transmural disease or stenosis, and mild mucosal inflammation without granulomas. In a study by Heuschen, 22% of patients with pancolitis had evidence of backwash at colectomy, whereas none of those with left sided colitis had evidence of backwash [41]. However, ileitis in UC may also represent primary ileal disease [42]. Recently, Haskell and colleagues found a 17% (34 of 200 patients) prevalence of inflammation in the terminal ileum of ileocolectomy specimens from patients with ulcerative colitis [43]. These changes were generally mild, consisting of villous atrophy, increased mononuclear cells in the lamina propria, and scattered crypt abscesses. Of these 34 patients, 32 had pancolitis, but in two patients colonic inflammation was subtotal or left sided. Furthermore, in the absence of granulomas, differentiating “backwash ileitis” from CD of the ileum can be problematic. Pyloric gland metaplasia has been suggested as a useful differentiating feature, if present [44]. “Backwash ileitis” is not believed to be a contraindication to the use of the ileum as a pouch nor to predispose to pouchitis after ileo-anal anastomosis [45]. The prevalence of backwash ileitis, defined as mild mixed inflammatory infiltrate of the lamina propria without crypt distorsion, atrophy or epithelial changes and contiguous to active inflammation in the colon, did not increase the risk of pouch failure in one pediatric study [42].
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Upper GI Tract Involvement in UC Disease of the upper intestinal tract in CD is well-documented and present in 30% of patients, in whom it may cause functional abnormalities such as delayed gastric emptying [46–49]. Endoscopic biopsies of the upper GI tract in children with IBD have revealed esophagitis, duodenal ulcers and villous atrophy, with a comparable prevalence in both CD and UC in some prospective studies [50, 51]. Upper GI tract disease with extensive duodenal involvement has been reported to occur concomitant with or many years after a well-established diagnosis of UC [52]. Whether upper GI tract disease reflects aberrant anatomic expression of UC, misdiagnosed CD or a co-existing illness is still debatable. In one study by Kundhal et al, granulomas were present on antral biopsy in five of 39 children with a diagnosis of ulcerative or intermediate colitis (14%), thus changing the diagnosis to CD [53]. On the other hand, conditions such as reflux esophagitis and Helicobacter pylori-associated gastritis are common, and may be coincidental in patients with UC [54], to which must be added the confounding effects of long-standing use of medications such as corticosteroids. Recent studies have reported that focally enhanced gastrititis, defined as a perifoveolar or periglandular mononuclear or neutrophilic inifiltrate around gastric crypts, is significantly more common in CD than in UC in patients without H. pylori. [53, 54] (Figure 19.15). In a retrospective study of 238 children with UGI biopsies, focal gastritis was present in 65% of patients with CD and in 20.8% of patients with UC, compared to 2.3% of controls without IBD and one of 39 with H. pylori [55]. Pascasio reviewed 438 consecutive biopsies in children with gastritis looking for histologic markers for CD such as granulomas, and focal glandulitis [56]. Of 58 patients diagnosed as having CD by colonic biopsy and other standard criteria, 34 (77%) were predicted to have CD by gastric biopsy alone. Eosinophils were a significant component in many of the inflammatory foci. In their experience, none of the focal glandulitis biopsies had a history of UC.
Figure 19.15. Focal gastritis. Antral biopsy in a 14 year-old boy with IBD reveals a clustering of neutrophils and mononuclear inflammatory cells around several glands, in a background of diffuse mild chronic inflammation. H+E, ×200.
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Periappendiceal Inflammation in Ulcerative Colitis Ulcerative colitis is classically regarded as a diffuse disease beginning in the rectum and extending proximally in a continuous fashion without skip areas. However, several recent studies have documented discontinuous mucosal disease, or “skip” areas, in patients with ulcerative colitis: cecal involvement (cecal patch) separated by normal mucosa from distal colitis in 15% to 86% of patients undergoing surgery [57–61], and appendiceal involvement [62, 63]. D’Haens et al found that 75% of patients had periappendiceal involvement at the time of diagnosis of distal UC, where inflammation was limited to the left side of the colon [61]. Yang et al. reported that involvement at the appendiceal orifice is not a consequence of therapy for extensive UC, but rather a distinctive “skip” lesion in patients with distal UC [64]. Only one pediatric study examined appendices from resected intestinal specimens of patients with IBD who failed medical therapy and found that all the patients in the study (17 UC, 24 CD) had appendiceal involvement [65]. Appendiceal inflammation is typically superficial, and can be differentiated from the transmural inflammation of typical acute appendicitis. Fulminant and Indeterminate Colitis Severe fulminant colitis, also referred to as toxic megacolon, is a medical and surgical emergency, which, although reported to occur in up to 5% of all ulcerative colitis patients, is relatively uncommon in pediatric patients. Toxic megacolon usually occurs in the presence of severe pancolitis and results in profound dilatation of the colon secondary to severe intestinal inflammation which results in disturbed intestinal motility. Under these conditions, disrupted mucosal integrity may allow entry of bacteria to submucosal tissues which may lead to necrosis, perforation and peritonitis. The use of antidiarrheal agents, a recent barium enema, or colonoscopy have been implicated [66]. Histopathologic examination of these cases at presentation may not always adequately distinguish between UC and CD [67]. Deep linear ulcers and fissuring with a “cobblestone” mucosa is commonly observed in these cases (Figure 19.16). Identification of small bowel involvement (other than “backwash ileitis”), deep lymphoid aggregates away from areas of mucosal ulceration and epithelioid granulomas are useful indicators in making a diagnosis of CD [67]. As originally used by Price [68], the term “colitis indeterminate” was applied to cases presenting as fulminant colitis with overlapping features of UC and CD. More recently it has been used to describe any case of IBD in which a definite diagnosis may not be established, which may occur in 5% of cases according to a large multicenter European study involving mostly adults [69]. Silverberg et al, in a report of the Working Party of the 2005 World Congress of Gastroenterology, have suggested that the diagnosis of “indeterminate colitis” be made only after colectomy, and that a term “colonic IBD type unclassified (IBDU)” be used instead in patients who have not undergone colectomy [70]. In children, a diagnosis of IC has been assigned to those cases in which the disease is limited to the colon, and when distinction between UC and CD cannot be made on the basis of combined clinical, laboratory, radiologic, endoscopic and histologic data. One-fifth of cases of IBD in children less than five years of age were classified as IC in a recent study [71]. After a median follow-up of 7 years, 5 of 19 cases initially assigned to the IC group were re-classified as either CD or UC [71]. Similar findings were reported in a series including older children in Sweden [72]. Long-term follow-up studies of mostly adult patients initially classified with IC suggest that an eventual diagnosis of either UC or CD can be obtained in most [73], but not all patients [74]. Confirmation of a diagnosis of CD has become more important with the creation of ileal pouch reservoirs, which have a poor outcome in CD [75]. The outcome of ileal pouch procedures in patients remaining with a diagnosis of IC is controversial, some studies reporting a higher rate of complications [75–77], others suggesting no difference in outcome between patients with IC and UC [78, 79].
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(a)
(b)
Figure 19.16. Fulminant colitis. A) Total colectomy specimen from a seventeen year-old boy shows a granular diffusely hemorrhagic mucosa, predominantly towards the proximal portion of the colon (left side of the photograph). B) Low power histologic section.
Pouchitis In UC patients who undergo ileal pouch anal anastomosis (IPAA), the ileal mucosa commonly undergoes histologic modifications to a colon-like appearance resulting from changes in bacterial population, short-chain fatty acid and bile salt concentrations [80, 81]. Morphological similarity to an inflamed colon is reinforced by the detection of a mucin histochemical profile similar to that of colonic epithelium and by an inflammatory immunoprofile like that seen in ulcerative colitis [82–84]. At endoscopic examination, pouchitis may be mild, with mucosal hyperemia and edema, to severe, with ulcers, hemorrhage and pseudomembrane formation [85–87]. Histologic examination of mucosal biopsy specimens obtained from these pouches typically demonstrate partial to complete villous blunting with crypt hyperplasia and increased mononuclear inflammatory cells and eosinophils in the lamina propria (Figure 19.17). Areas of pyloric gland metaplasia of crypt epithelium may be present. Active inflammation, usually focal, is characterized by neutrophils in the lamina propria, cryptitis, crypt abscesses and, in severe cases, erosions or ulcers. Granulomas of the mucin or foreign body type may also be identified [82, 84]. A minority of patients develop
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Figure 19.17. Pouchitis. Biopsy from the neo-rectum in an 18 year-old female following an ileo-anal pull-through reveals active chronic inflammation of the ileal mucosa with crypt loss and distorsion.
inflammation of the ileal limb proximal to the pouch, strictures (typically in the proximal pouch) and fistulas, and even extraintestinal disease which can mimic CD. Furthermore, histologic evaluation of removed pouches may document deep or transmural inflammation [83, 88]. In addition, ischemic changes secondary to vascular compromise and pouch mucosal prolapse may occur, such as crypt hyperplasia, extension of smooth-muscle fibres from the muscularis mucosae into the lamina propria and superficial erosions with fibrinoinflammatory exudate. In view of the previous discussion, a diagnosis of CD should be considered only when review of the prior colectomy specimen reveals unequivocal features of CD, such as non-mucin granulomas, or when unequivocal CD develops in parts of the gastrointestinal tract distant from the pouch. References 1. Xin, W., P.I. Brown and J.K. Greenson, The clinical significance of focal active colitis in pediatric patients. Am J Surg Pathol, 2003. 27(8): 1134–8. 2. Withers, G.D. and R.B. Scott, Drug-induced bowel injury, in Pediatric Gastrointestinal Disease, W.W.A., et al., Editors. 2000, B C Decker: Hamilton, Ontario. pp. 788–795. 3. Zwas, F.R., N.W. Cirillo, H.B. el-Serag, et al., Colonic mucosal abnormalities associated with oral sodium phosphate solution. Gastrointest Endosc, 1996. 43(5): 463–6. 4. Driman, D.K. and H.G. Preiksaitis, Colorectal inflammation and increased cell proliferation associated with oral sodium phosphate bowel preparation solution. Hum Pathol, 1998. 29(9): 972–8. 5. Watts, D.A., A.M. Lessells, I.D. Penman, et al., Endoscopic and histologic features of sodium phosphate bowel preparation-induced colonic ulceration: case report and review. Gastrointest Endosc, 2002. 55(4): 584–7. 6. Leriche, M., G. Devroede, G. Sanchez, et al., Changes in the rectal mucosa induced by hypertonic enemas. Dis Colon Rectum, 1978. 21(4): 227–36. 7. Jonas, G., A. Mahoney, J. Murray, et al., Chemical colitis due to endoscope cleaning solutions: a mimic of pseudomembranous colitis. Gastroenterology, 1988. 95(5): 1403–8.
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8. Lowichik, A. and A.G. Weinberg, A quantitative evaluation of mucosal eosinophils in the pediatric gastrointestinal tract. Mod Pathol, 1996. 9: 110–114. 9. Pascal, R.R., T.L. Gramlich, K.M. Parker, et al., Geographic variations in eosinophil concentration in normal colonic mucosa. Mod Pathol, 1997. 10(4): 363–5. 10. Riddell, R.H., Pathology of idiopathic inflammatory bowel disease, in Inflammatory Bowel Disease, J.B. Kirsner and R.G. Shorter, Editors. 1995, Williams and Wilkins: Baltimore. pp. 517–554. 11. Griffiths, A.M. and P.M. Sherman, Colonoscopic surveillance for cancer in ulcerative colitis: a critical review. J Pediatr Gastroenterol Nutr, 1997. 24(2): 202–210. 12. Ekbom, A., C. Helmick, M. Zack, et al., Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med, 1990. 323(18): 1228–1233. 13. Markowitz, J., M. McKinley, E. Kahn, et al., Endoscopic screening for dysplasia and mucosal aneuploidy in adolescents and young adults with childhood onset colitis. Am J Gastroenterol, 1997. 92(11): 2001–6. 14. Blackstone, M.O., R.H. Riddell, B.H. Rogers, et al., Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: an indication for colectomy. Gastroenterology, 1981. 80(2): 366–74. 15. Keller, K.M., S.W. Bender, H. Kirchmann, et al., Diagnostic significance of epithelioid granulomas in Crohn disease in children. Multicenter Paediatric Crohn Disease Study Group. J Pediatr Gastroenterol Nutr, 1990. 10(1): 27–32. 16. Schmitz-Moormann, P., P.M. Pittner and M. Sangmeister, Probability of detecting a granuloma in a colorectal biopsy of Crohn disease. Pathol Res Pract, 1984. 178(3): 227–9. 17. Schmitz-Moormann, P. and M. Schag, Histology of the lower intestinal tract in Crohn disease of children and adolescents. Multicentric Paediatric Crohn Disease Study. Pathol Res Pract, 1990. 186(4): 479–84. 18. Markowitz, J., E. Kahn and F. Daum, Prognostic significance of epithelioid granulomas found in rectosigmoid biopsies at the initial presentation of pediatric Crohn disease. J Pediatr Gastroenterol Nutr, 1989. 9(2): 182–6. 19. Shepherd, N.A., Granulomas in the diagnosis of intestinal Crohn disease: a myth exploded? Histopathology, 2002. 41(2): 166–8. 20. Pulimood, A.B., B.S. Ramakrishna, G. Kurian, et al., Endoscopic mucosal biopsies are useful in distinguishing granulomatous colitis due to Crohn disease from tuberculosis. Gut, 1999. 45(4): 537–41. 21. El-Maraghi, N.R. and N.S. Mair, The histopathology of enteric infection with Yersinia pseudotuberculosis. Am J Clin Pathol, 1979. 71(6): 631–9. 22. Isaacs, D., V.M. Wright, D.G. Shaw, et al., Chronic granulomatous disease mimicking Crohn disease. J Pediatr Gastroenterol Nutr, 1985. 4(3): 498–501. 23. Schappi, M.G., V.V. Smith, D. Goldblatt, et al., Colitis in chronic granulomatous disease. Arch Dis Child, 2001. 84(2): 147–51. 24. Schumacher, G., First attack of inflammatory bowel disease and infectious colitis. A clinical, histological and microbiological study with special reference to early diagnosis. Scand J Gastroenterol Suppl, 1993. 198: 1–24. 25. Konuma, Y., M. Tanaka, H. Saito, et al., A study of the histological criteria for ulcerative colitis: retrospective evaluation of multiple colonic biopsies. J Gastroenterol, 1995. 30(2): 189–94. 26. Glickman, J.N., A. Bousvaros, F.A. Farraye, et al., Pediatric patients with untreated ulcerative colitis may present initially with unusual morphologic findings. Am J Surg Pathol, 2004. 28(2): 190–7. 27. Escher, J.C., K.F. Ten, K. Lichtenbelt, et al., Value of rectosigmoidoscopy with biopsies for diagnosis of inflammatory bowel disease in children. Inflamm Bowel Dis, 2002. 8(1): 16–22. 28. Markowitz, J., E. Kahn, K. Grancher, et al., Atypical rectosigmoid histology in children with newly diagnosed ulcerative colitis. Am J Gastroenterol, 1993. 88(12): 2034–7. 29. Robert, M.E., M. Skacel, T. Ullman, et al., Patterns of colonic involvement at initial presentation in ulcerative colitis: a retrospective study of 46 newly diagnosed cases. Am J Clin Pathol, 2004. 122(1): 94–9. 30. Washington, K., J.K. Greenson, E. Montgomery, et al., Histopathology of ulcerative colitis in initial rectal biopsy in children. Am J Surg Pathol, 2002. 26(11): 1441–9. 31. Robert, M.E., L. Tang, L.M. Hao, et al., Patterns of inflammation in mucosal biopsies of ulcerative colitis: perceived differences in pediatric populations are limited to children younger than 10 years. Am J Surg Pathol, 2004. 28(2): 183–9.
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32. Jenkins, D., M. Balsitis, S. Gallivan, et al., Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease. The British Society of Gastroenterology Initiative. J Clin Pathol, 1997. 50(2): 93–105. 33. Nostrant, T., N. Kumar and H. Appelman, Histopathology diffentiates acute self-limited colitis from ulcerative colitis. Gastroenterology, 1987. 92: 318–328. 34. Dundas, S.A., J. Dutton and P. Skipworth, Reliability of rectal biopsy in distinguishing between chronic inflammatory bowel disease and acute self-limiting colitis. Histopathology, 1997. 31(1): 60–6. 35. Tanaka, M., R.H. Riddell, H. Saito, et al., Morphologic criteria applicable to biopsy specimens for effective distinction of inflammatory bowel disease from other forms of colitis and of Crohn disease from ulcerative colitis. Scand J Gastroenterol, 1999. 34(1): 55–67. 36. Faubion, W.A., Jr., E.V. Loftus, W.J. Sandborn, et al., Pediatric “PSC-IBD”: a descriptive report of associated inflammatory bowel disease among pediatric patients with psc. J Pediatr Gastroenterol Nutr, 2001. 33(3): 296–300. 37. Kim, B., J.L. Barnett, C.G. Kleer, et al., Endoscopic and histological patchiness in treated ulcerative colitis. Am J Gastroenterol, 1999. 94(11): 3258–62. 38. Kleer, C.G. and H.D. Appelman, Ulcerative colitis: patterns of involvement in colorectal biopsies and changes with time. Am J Surg Pathol, 1998. 22(8): 983–9. 39. Geboes, K. and I. Dalle, Influence of treatment on morphological features of mucosal inflammation. Gut, 2002. 50(Suppl 3): III37–42. 40. Gledhill, A., M.E. Enticott and S. Howe, Variation in the argyrophil cell population of the rectum in ulcerative colitis and adenocarcinoma. J Pathol, 1986. 149(4): 287–91. 41. Heuschen, U.A., U. Hinz, E.H. Allemeyer, et al., Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis. Gastroenterology, 2001. 120(4): 841–7. 42. Alexander, F., S. Sarigol, J. Difiore, et al., Fate of the pouch in 151 pediatric patients after ileal pouch anal anastomosis. J Pediatr Surg, 2003. 38(1): 78–82. 43. Haskell, H., C.W. Andrews, Jr., S.I. Reddy, et al., Pathologic features and clinical significance of “backwash” ileitis in ulcerative colitis. Am J Surg Pathol., 2005. 29(11): 1472–81. 44. Koukoulis, G.K., Y. Ke, J.D. Henley, et al., Detection of pyloric metaplasia may improve the biopsy diagnosis of Crohn ileitis. J Clin Gastroenterol, 2002. 34(2): 141–3. 45. Gustavsson, S., L.H. Weiland and K.A. Kelly, Relationship of backwash ileitis to ileal pouchitis after ileal pouch-anal anastomosis. Dis Colon Rectum, 1987. 30(1): 25–8. 46. Gryboski, J.D., J. Burger, R. McCallum, et al., Gastric emptying in childhood inflammatory bowel disease: nutritional and pathologic correlates. Am J Gastroenterol, 1992. 87(9): 1148–53. 47. Kaufman, S.S., J.A. Vanderhoof, R. Young, et al., Gastroenteric inflammation in children with ulcerative colitis. Am J Gastroenterol, 1997. 92(7): 1209–12. 48. Lenaerts, C., C.C. Roy, M. Vaillancourt, et al., High incidence of upper gastrointestinal tract involvement in children with Crohn disease. Pediatrics, 1989. 83(5): 777–781. 49. Wright, C.L. and R.H. Riddell, Histology of the stomach and duodenum in Crohn disease. Am J Surg Pathol, 1998. 22(4): 383–90. 50. Tobin, J.M., B. Sinha, P. Ramani, et al., Upper gastrointestinal mucosal disease in pediatric Crohn disease and ulcerative colitis: a blinded, controlled study. J Pediatr Gastroenterol Nutr, 2001. 32(4): 443–8. 51. Abdullah, B.A., S.K. Gupta, J.M. Croffie, et al., The role of esophagogastroduodenoscopy in the initial evaluation of childhood inflammatory bowel disease: a 7-year study. J Pediatr Gastroenterol Nutr, 2002. 35(5): 636–40. 52. Valdez, R., H.D. Appelman, M.P. Bronner, et al., Diffuse duodenitis associated with ulcerative colitis. Am J Surg Pathol, 2000. 24(10): 1407–13. 53. Kundhal, P.S., M.O. Stormon, M. Zachos, et al., Gastral antral biopsy in the differentiation of pediatric colitides. Am J Gastroenterol, 2003. 98(3): 557–61. 54. Parente, F., C. Cucino, S. Bollani, et al., Focal gastric inflammatory infiltrates in inflammatory bowel diseases: prevalence, immunohistochemical characteristics, and diagnostic role. Am J Gastroenterol, 2000. 95(3): 705–11. 55. Sharif, F., M. McDermott, M. Dillon, et al., Focally enhanced gastritis in children with Crohn disease and ulcerative colitis. Am J Gastroenterol, 2002. 97(6): 1415–20.
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56. Pascasio, J.M., S. Hammond and S.J. Qualman, Recognition of Crohn disease on incidental gastric biopsy in childhood. Pediatr Dev Pathol, 2003. 6(3): 209–14. Epub 2003 Mar 28. 57. Goldblum, J.R. and H.D. Appelman, Appendiceal involvement in ulcerative colitis. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc., 1992; Vol. 5(6), pp. 607–10. 58. Groisman, G.M., J. George and N. Harpaz, Ulcerative appendicitis in universal and nonuniversal ulcerative colitis. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc., 1994; Vol. 7(3), pp. 322–5. 59. Kroft, S.H., S.J. Stryker and M.S. Rao, Appendiceal involvement as a skip lesion in ulcerative colitis. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc., 1994; Vol. 7(9), pp. 912–4. 60. Perry, W.B., F.G. Opelka, D. Smith, et al., Discontinuous appendiceal involvement in ulcerative colitis: pathology and clinical correlation. Journal of gastrointestinal surgery: official journal of the Society for Surgery of the Alimentary Tract., 1999; Vol. 3(2), pp. 141–4. 61. D’Haens, G., K. Geboes, M. Peeters, et al., Patchy cecal inflammation associated with distal ulcerative colitis: a prospective endoscopic study. Am J Gastroenterol, 1997. 92(8): 1275–9. 62. Okawa, K., T. Aoki, K. Sano, et al., Ulcerative colitis with skip lesions at the mouth of the appendix: a clinical study. Am J Gastroenterol, 1998. 93(12): 2405–10. 63. Matsumoto, T., S. Nakamura, M. Shimizu, et al., Significance of appendiceal involvement in patients with ulcerative colitis. Gastrointest Endosc, 2002. 55(2): 180–5. 64. Yang, S.K., H.Y. Jung, G.H. Kang, et al., Appendiceal orifice inflammation as a skip lesion in ulcerative colitis: an analysis in relation to medical therapy and disease extent. Gastrointestinal endoscopy., 1999; Vol. 49(6), pp. 743–7. 65. Kahn, E., J. Markowitz and F. Daum, The appendix in inflammatory bowel disease in children. Mod Pathol, 1992. 5(4): 380–3. 66. Fazio, V.W., Toxic megacolon in ulcerative colitis and Crohn colitis. Clin Gastroenterol, 1980. 9(2): 389–407. 67. Swan, N.C., J.G. Geoghegan, D.P. O’Donoghue, et al., Fulminant colitis in inflammatory bowel disease: detailed pathologic and clinical analysis. Dis Colon Rectum, 1998. 41(12): 1511–5. 68. Price, A.B., Overlap in the spectrum of non-specific inflammatory bowel disease–‘colitis indeterminate’. J Clin Pathol, 1978. 31(6): 567–77. 69. Shivananda, S., J. Lennard-Jones, R. Logan, et al., Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut, 1996. 39(5): 690–7. 70. Silverberg, M.S., J. Satsangi, T. Ahmad, et al., Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol, 2005. 19(Suppl A): 5–36. 71. Mamula, P., G.W. Telega, J.E. Markowitz, et al., Inflammatory bowel disease in children 5 years of age and younger. Am J Gastroenterol, 2002. 97(8): 2005–10. 72. Lindberg, E., B. Lindquist, L. Holmquist, et al., Inflammatory bowel disease in children and adolescents in Sweden, 1984–1995. J Pediatr Gastroenterol Nutr, 2000. 30(3): 259–64. 73. Meucci, G., A. Bortoli, F.A. Riccioli, et al., Frequency and clinical evolution of indeterminate colitis: a retrospective multi-centre study in northern Italy. GSMII (Gruppo di Studio per le Malattie Infiammatorie Intestinali). Eur J Gastroenterol Hepatol, 1999. 11(8): 909–13. 74. Wells, A.D., I. McMillan, A.B. Price, et al., Natural history of indeterminate colitis. Br J Surg, 1991. 78(2): 179–81. 75. Marcello, P.W., D.J. Schoetz, Jr., P.L. Roberts, et al., Evolutionary changes in the pathologic diagnosis after the ileoanal pouch procedure. Dis Colon Rectum, 1997. 40(3): 263–9. 76. Atkinson, K.G., D.A. Owen and G. Wankling, Restorative proctocolectomy and indeterminate colitis. Am J Surg, 1994. 167(5): 516–8. 77. Koltun, W.A., D.J. Schoetz, Jr., P.L. Roberts, et al., Indeterminate colitis predisposes to perineal complications after ileal pouch-anal anastomosis. Dis Colon Rectum, 1991. 34(10): 857–60. 78. Yu, C.S., J.H. Pemberton and D. Larson, Ileal pouch-anal anastomosis in patients with indeterminate colitis: long-term results. Dis Colon Rectum, 2000. 43(11): 1487–96.
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20 Video Capsule Endoscopy in Pediatric Inflammatory Bowel Disease Marc Girardin∗ and Ernest G. Seidman∗∗
Introduction Traditionally, colonoscopy and biopsies along with radiological studies using contrast have served as the imaging “gold standard” for the evaluation of pediatric patients with suspected or known inflammatory bowel disease (IBD), as in adults [1]. Imaging techniques are obligatory at initial presentation to establish the diagnosis and to assess the location, extent, inflammatory activity, and severity of disease. In 1989 we reported on the utility of an esophagogastroduodenoscopy (EGD) with biopsies in order to ascertain the presence of findings suggestive of Crohn disease in the upper gastrointestinal tract [2]. This is now part of the diagnostic guidelines of the IBD Working Group of the European Society for Pediatric Gastroenterology Hepatology and Nutrition [3]. Other imaging techniques employed in IBD are extensively discussed elsewhere in this book by Drs Nwomeh and Crandall. These include trans-abdominal (US) and endoscopic ultrasound (EUS), enterography by computed tomography (CTE) or magnetic resonance imaging (MRE), as well as nuclear scans and positron emission tomography. Despite these techniques, complete assessment of the small bowel has remained a challenge. Push enteroscopy [4] can certainly access more of the proximal jejunum than EGD. However this technique only affords visualization of the proximal jejunum and is a relatively invasive procedure in young children. Although intra-operative enteroscopy can afford visualization of the entire small bowel, it is even more invasive, necessitating a laparotomy or laparoscopy. Potential complications that may ensue include prolonged ileus, obstruction, perforation, or fistula formation. Double-balloon or push-pull enteroscopy is a novel technique that can achieve diagnostic, as well as therapeutic, enteroscopy for the entire bowel, without requiring surgery [5]. However, this procedure requires a long period of manipulation, and no experience in pediatric patients has been reported to date. Thus, the small bowel has been a relatively inaccessible “black box” for pediatric endoscopy specialists.
*Research Fellow, McGill Center for IBD, Division of Gastroenterology, Faculty of Medicine, McGill University, E-mail:
[email protected] **Director, McGill IBD Center, MGH Campus, C10.145, 1650 Cedar Avenue, Montreal, QC, CANADA H3G 1A4, E-mail:
[email protected]
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That all changed rather dramatically with the recent development of videocapsule endoscopy (CE). This innovative technique has revolutionized enteroscopy, providing for the first time a non-invasive method for the complete endoscopic evaluation of the small bowel mucosa [6, 7]. The extremely short focal length of the lens (1 mm) permits incredibly precise imaging of the intestinal mucosa as the capsule transits along the lumen, without requiring insufflation of air. The astounding resolution of the lens (0.1 mm) yields extraordinarily detailed, high-quality images of the mucosa and offers the ability to visualize normal villi, easily identifying focal areas of villous edema or atrophy (Figure 20.1). A recent meta-analysis has shown that CE is better able to identify small bowel lesions consistent with Crohn disease compared to traditional radiological methods [8]. The goals of this review are to provide an update on the clinical utility of CE for IBD in the pediatric age group, as well as information on the practical applications of CE in children.
(a)
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Figure 20.1. Normal mucosal findings (A) in the mid small bowel as seen by wireless capsule endoscopy in a child suspected of Crohn disease. The astonishing resolution of the capsule’s lens (0.1 mm) affords visualization of the normal villi and mucosal blood vessels. In contrast, subtle inflammatory changes of the small bowel mucosa that were not visualized radiologically can readily be seen focally by capsule endoscopy. There include (B) areas of mucosal nodularity with focal villous atrophy as well as white tipped villi, signifying inflammatory edema, as well as superficial linear ulcerations (C).Whereas these lesions detected by capsule endoscopy are typical of Crohn disease, they may be caused by other etiologies, including the use of medications such as non-steroidal anti-inflammatory drugs.
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Potential Uses of Capsule Endoscopy for Inflammatory Bowel Disease The diagnosis of IBD entails the documentation of the extent as well as severity of the chronic inflammation affecting one or more segments of the gastrointestinal tract, as well as the exclusion of other etiologies. The gastroenterologist must take into consideration the patient’s history, physical findings, as well as the radiological, endoscopic and histological findings. There is no single test that is pathognomonic for ulcerative colitis (UC) or Crohn disease (CD). Bowel imaging techniques, whether endoscopic or radiological, are employed to support the diagnosis. The combination of ileocolonoscopy and EGD with multiple biopsies can usually differentiate between UC and CD, based on the distribution and pattern of mucosal inflammation [1, 3]. Endoscopic procedures provide invaluable information regarding the anatomic extent and severity of the mucosal inflammation. However, the vast majority of the small bowel is inaccessible to standard endoscopy or even enteroscopy. Over the past few years, several studies have established the utility of CE to evaluate the small bowel in patients with IBD [9]. The potential uses of CE in established or known IBD are summarized in Table 20.1, and discussed below. Diagnostic Utility in Suspected Crohn Disease No gold standard test exists for the diagnosis of small bowel CD. Contrast small bowel radiography (SBR) and endoscopy (EGD and ileo-colonoscopy) have been the recommended methods for evaluating known or suspected small bowel CD [1, 3]. However, SBR has relatively low sensitivity for early and superficial lesions of CD in the small bowel [8]. Ileoscopy, when achieved, generally only affords examination of the terminal ileum. Push enteroscopy can be employed to examine the proximal regions of the small bowel that cannot be examined by EGD. However, it too has a rather limited range. A recent consensus statement suggested that CE is a far more promising tool for the evaluation of the small bowel in IBD [9]. In the early clinical reports that assessed the diagnostic accuracy of CE in suspected CD, most patients studied had chronic symptoms such as abdominal pain and or diarrhea, with weight loss or supportive laboratory evidence of IBD such as elevated markers of inflammation (Erythrocyte sedimentation rate, C-reactive protein) and or iron deficiency anemia. In addition, prior traditional investigations including EGD, ileo-colonoscopy and SBR were generally negative or non-diagnostic in these initial studies [9]. The data [9, 11] collectively suggest that CE is superior to SBR and standard endoscopic approaches for the diagnosis of such cases of “obscure” CD limited to the small bowel. More recently, prospective comparative studies have evaluated the utility of CE for the diagnosis of CD, again showing that it surpasses other imaging modalities. A recent meta-analysis focused on 11 prospective comparative studies comparing CE to other modalities for the diagnosis of established or suspected non-stricturing CD [8]. CE was compared to multiple diagnostic modalities (ileoscopy, push enteroscopy, and small bowel radiography, including SBFT and enteroclysis, CT enterography, and small bowel MRI) in a total of 228 patients. The yield for CE was significantly higher compared to barium small bowel radiography (63% and 23%, respectively). Similarly, the yield for CE versus ileoscopy was 61% and 46%, while that for CE versus CT was 69% and 30%, respectively. Subset analysis of patients with established, but not suspected CD showed that CE Table 20.1. Potential indications for capsule endoscopy in inflammatory bowel disease. 1. Diagnosis of suspected small bowel Crohn’s disease. 2. Determination of the extent and severity of small bowel disease in established Crohn’s disease.* 3. Evaluation of the presence of small bowel lesions in patients with colonic inflammatory bowel disease (ulcerative or indeterminate colitis). 4. Evaluation of mucosal healing of small bowel Crohn’s disease after treatment. 5. Assessment of post-operative recurrence of small bowel Crohn’s disease. *Particularly in cases of small bowel Crohn’s disease with symptoms potentially attributable to functional bowel disease.
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had a higher yield compared to the other modalities. Prospective studies are underway to obtain further data for the latter category of patients. Ongoing issues include the lack of standardization between studies in terms of inclusion and exclusion criteria, as well as the widely variable capsule reading experience varied between studies. Overall however, CE appears to be more sensitive for small bowel CD than other traditional imaging modalities. Moreover, a normal CE examination (Figure 20.1A) has a very high negative predictive value, essentially ruling out small bowel CD. Newer techniques for small bowel imaging such as CT enterography (CTE) and MR enterography (MRE) are capable of evaluating bowel wall thickness and enhancement, supporting the diagnosis of CD [12, 13]. These techniques may also be useful because in addition to evaluating the intestinal wall, they can also detect the presence of extraintestinal abnormalities, such as abscess formation. Also, CTE and MRE have been shown to correlate with disease activity [12, 13], whereas no studies have yet addressed that issue using CE. A recent study compared CE with MRE in 36 adults with known or suspected small bowel CD [14]. Among the 18 patients with known CD, CE detected inflammatory lesions in the proximal and mid small bowel (jejunum and ileum) in 12, compared to only one with MRI (p = 0.016). There was no significant difference in sensitivity between the two studies for disease of the terminal ileum. The authors suggested that CE is better to assess the severity and extent of small bowel inflammation. Another study compared to MRE and CE in 27 patients with established and 25 with suspected CD [15]. Among those with established CD, the yield for CE was 93% compared to 79% with MRE. In those with suspected CD, CE was more sensitive and specific (92%/100% vs. 77%/80%, respectively). Additional prospective studies will be required to definitively understand the roles of CE vs CTE or MRE in the diagnostic algorithm for known and suspected CD. The current recommendation based on available data [16] is shown in Figure 20.2. An economic analysis comparing CE to the
Figure 20.2. Algorithm for the approach to suspected small bowel Crohn disease (CD). The absence of any mucosal lesions demonstrated by a complete assessment of the small bowel by capsule endoscopy essentially excludes active CD of the small bowel. Patients with symptoms suggestive of or known to have a stenosis should either undergo a patency capsule exam or evaluation by CTE or MRE prior to capsule endoscopy. From: Seidman EG, et al. Inflamm Bowel Dis 1393): 331:7, 2007 Mar with permission. Notes: Abbreviations: CD = small bowel Crohn disease; CTE = CT enterography; MRE= MR enterography; SB = Small bowel; SBFT = Small bowel follow through.
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traditional modalities for diagnosing CD [17] concluded that CE was a less costly strategy if its diagnostic yield was 64% or greater, based on average diagnostic yields in the literature of 70% for CE and 54% for SBFT and colonoscopy/ileoscopy. The authors suggested that CE may also be less costly as a first-line test in this situation.
Detection of Post-operative Recurrence Capsule endoscopy may also be used to determine the presence of early post-operative recurrence of CD. One prospective comparison of CE and ileocolonoscopy within six months of surgery was carried out in 32 adult CD patients, 21 (68%) of whom had recurrent disease [18]. While CE was able to identify more proximal disease in more than two-thirds of patients, ileocolonoscopy was more sensitive overall (90% vs. 62%). In view of the non-invasive nature of CE compared to ileocolonoscopy, it may be considered as an alternative approach in this clinical situation in the pediatric age group.
Indeterminate Colitis Indeterminate Colitis (IC) may be defined as a chronic inflammatory bowel disease limited to the colon, without clear endoscopic or pathologic features diagnostic for either CD or UC. A few pilot studies [19–21] found that CE led to a change in diagnosis in 29–40% of patients. The study [20] comparing CE and IBD serologic testing in 31 IC patients found equal sensitivity (61%). However, CE was more sensitive than ASCA or Omp-C in diagnosing small bowel CD. The author’s conclusion was that CE is superior to IBD serological markers in identifying small bowel CD in IC patients [20]. Another recent preliminary study looked at the usefulness of CE in IC, Crohn colitis or suspected CD, all with normal SBR [22]. Capsule endoscopy was positive for lesions suggestive of small bowel CD in 16 of 22 patients (73%). The yield was high for those with IC (70%). Overall, CE shows promise as a diagnostic tool for CD in patients with IC. However, larger prospective studies are needed to confirm the usefulness of CE in IC.
Experience in Pediatric Inflammatory Bowel Disease Capsule endoscopy has been approved as safe and beneficial test in the pediatric population [7, 9]. Limited data have been reported to date on the use of CE in the diagnosis of IBD in children. One trial studied 12 adolescent patients with a clinical suspicion of CD despite negative EGD and colonoscopy [23]. Ileoscopy, achieved in 50% of the patients, was normal in all. Lesions suggestive of CD were identified by CE in 7/12 (58%) cases. In the only comparative and prospective, self-controlled pediatric trial reported to date, 30 patients from 10 to 18 years of age were evaluated for obscure small bowel disease [9]. Lesions consistent with a diagnosis of CD was found only by CE in 10/20 (50%) patients suspected of CD, while the diagnosis was formally ruled out in 8 patients. Two remaining cases were found to have eosinophilic gastroenteropathy, for an overall diagnostic yield of 60%. Preliminary reports suggest that CE is potentially useful in the evaluation of possible CD among young patients presenting with a protein-losing enteropathy [24] and/or growth failure [25], when other studies are negative.
Specificity of Capsule Findings No gold standard test exists for CD. The diagnosis is based on a compilation of clinical, endoscopic, histological, radiological and biochemical findings. Furthermore, a study in adults suggested that up to 13% of normal, asymptomatic individuals can have mucosal breaks and other minor lesions
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of the small bowel detected by CE [26]. Therefore, CE findings of mucosal lesions of the small bowel are alone not sufficient for a diagnosis of CD. Other causes to be considered include celiac disease, infectious, ischemic, autoimmune as well as immunodeficiency-related, allergic and drug-induced etiologies. Non-steroidal anti-inflammatory drug (NSAID) induced enteropathy is common and should be excluded, as it remains uncertain whether the lesions detected by CE in NSAID enteropathy can be reliably distinguished from those due to CD. The chronicity of the lesions may assist in the differential diagnosis of CD and NSAID induced enteropathy [27]. A standard terminology system has been developed along with a CE scoring index for CD, but these tools have not been universally adopted nor yet validated in pediatric patients [28]. Hopefully, such a standardized scoring system will be utilized by clinical investigators carrying out CE so that the data from future trials are standardized and comparable. It is also be important to develop a system for classifying the extent and severity of inflammatory lesions seen on CE in normal individuals, and to develop reliable criteria for the diagnosis of CD by CE.
Practical Issues in Pediatric Patients Capsule Retention The major contraindication to CE is the presence of a known or suspected gastrointestinal tract obstruction and/or small bowel strictures, because of the risk of capsule retention [29]. The incidence of capsule retention varies widely between reports, from 0.75% to 5% [16]. Most episodes of capsule retention are caused by NSAID, CD, or radiation induced enteropathy. In adults, tumors are more often implicated as a cause of capsule retention than in pediatrics. Most cases of retention are transitory and remain asymptomatic. However, it may rarely cause symptomatic small bowel obstruction and require endoscopic surgical removal. To minimize the risk of capsule retention in the small bowel, a careful history should be taken regarding obstructive symptoms. Patients with CD are at a particular risk for stricture formation, and this risk increases with duration and severity of small bowel disease. The rate of capsule retention in patients with suspected CD appears to be quite low. In 3 reports with a total of 51 patients with suspected CD, no instances of a retained capsule were encountered [30–32]. However, these studies were all conducted in adult patients. In the one pediatric prospective trial of CE for suspected CD however, capsule retention was seen in 10% (2/20) of cases, despite normal SBR [9]. In both cases, the capsule passed the unsuspected inflammatory stenosis subsequent to treatment with oral corticosteroids. The rate of capsule retention in patients with known CD is substantially higher, in the range of 4–7%[19, 33]. An example is shown in Figure 20.3. Several studies have shown that the patency capsule is useful to screen for the risk of capsule retention in patients suspected of having a stricture or obstruction [34, 35]. The newer Agile Patency Capsule (Given Imaging Inc) has been used in Europe, and was recently FDA approved in the United States for use in patients with suspected small bowel obstruction or known stricture [36, 37]. It is identical in size to the conventional imaging capsule, but rather than being inert, it is designed to dissolve spontaneously in the small bowel lumen. Its body is comprised of lactose with barium, a radiofrequency identification (RFID) tag, and two side timer plugs with exposed windows. It remains intact for a minimum of 30 hours, and then begins to disintegrate. The system includes an RFID patency scanning device that can detect the RFID tag. If the patient witnesses excretion of the patency capsule intact or the scanner does not detect the RFID tag at or prior to 30 hours, it is safe to proceed with the conventional CE. If the patency scanner is contraindicated (such as in the case of a pacemaker or implanted cardiac defibrillator) fluoroscopy may be employed to check for the presence of the patency capsule or RFID tag. Although there have been rare cases of abdominal pain associated with the patency capsule, as well as occasional episodes of temporary intestinal occlusion [38], it is generally safe. In the unlikely event that a
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Figure 20.3. Capsule endoscopy image of an ulcerated stricture in an adolescent patient with known Crohn disease. The patient had ongoing anemia and elevated markers of inflammation, despite a normal ileocolonoscopy and a barium small bowel follow through. The ulcerated stenosis of the mid small bowel was readily seen only by capsule endoscopy. The patient presented with symptoms of partial bowel obstruction within 24 hours of ingesting the capsule. All symptoms and radiological signs of bowel obstruction cleared promptly with intravenous corticosteroids, and the capsule was expelled shortly thereafter.
capsule is retained and induces symptoms, one can use double balloon enteroscopy to dilate the stenosis and retrieve the capsule without resorting to surgery. Preparations and Prokinetics The quality of the preparation is logically critical to adequate visualization of the small bowel mucosa. Yet, the ideal preparation for CE in the setting of IBD remains unknown. There are no large multicenter randomized comparative studies, nor a validated scale with which to grade the utility of various preparations [39]. Various trials have examined the use of oral sodium phosphate based or polyethylene glycol (PEG) based preparations, without reaching a firm conclusion [39]. One published prospective, randomized and blinded study in 80 patients looked at a 2L PEG solution versus clear liquids only [40]. The PEG solution enhanced the quality of images and improved the diagnostic yield. Most of the other studies were not randomized and preparation quality assessments were not standardized. Taken together, they do suggest that preparations may improve the quality of CE visualization. Whether or not they definitely improve the diagnostic yield or clinical outcome remains unknown. In general, only about 85% of CE studies obtain images of the complete small bowel, including the terminal ileum and or cecum. Studies have thus examined the use of prokinetics agents to
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improve transit times and completeness of the small bowel evaluation [41]. In general, prokinetic agents may shorten gastric and/or small bowel transit times, but the ideal regimen remains controversial. Ultimately, the roles of bowel preparations and prokinetics need to be determined in larger randomized studies. In our experience, CE in children does not routinely require a bowel preparation or the use of a prokinetic agent. However, one should routinely ascertain if there is any history suggestive of gastroparesis or if medications are being used which may interfere with gastric emptying. We do employ a PEG preparation (2L) for older adolescents, as in adults. Patients should be fasting for a minimum of 8 hours prior to the test. We allow patients to drink clear fluids 1–2 h after the study has begun and to eat a light meal about 2 h after ingesting the capsule. Endoscopic Placement of the Capsule Younger children, particularly those under the age of 9, are generally unable to swallow the capsule, which measures 26.4 mm in length and 11 mm in diameter. This problem is not limited
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(b)
Figure 20.4. Methods of “front loading” the capsule endoscope onto a gastroscope: A) using a Roth net, and B) employing the US Endoscopy device. From: Keuchel M, Dirks MH, Seidman E G: Swallowing and motility disorders, pacemakers & obesity, in: Keuchel M, Hagenmüller F, Fleischer D (eds): Atlas of Video Capsule Endoscopy. Wurzburg, Germany, Springer, 2006, 24–9 (with permission).
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to children, and may be encountered in older patients as well. To prevent the loss of a capsule (the battery is activated upon its removal from the package), we recommend that patients practice by swallowing similar sized candies. If a parent has any doubt as to their ability to swallow the capsule, it is worthwhile having the child demonstrate that they are indeed capable of swallowing a similar sized vitamin tablet or jelly bean, prior to undergoing CE. For patients unable or unwilling to swallow the capsule, CE can be safely performed by introducing the capsule into the proximal duodenum endoscopically, under direct vision. This can be accomplished by “front loading” the capsule on a gastroscope (Figure 20.4) holding it in place using a foreign body retrieval net or a polyp retriever snare [7, 42, 43]. Although the Roth net is more secure than using a snare, it may be difficult to open the net and release the capsule into the small lumen of the duodenum in young children. When using a snare, it is advisable to place a rubber band (such as a variceal ligator) around the waist of the capsule in order to secure the grip and prevent it from slipping off (Figure 20.4). A specific capsule delivery device (Figure 20.4) has been developed (US Endoscopy) which affords the secure delivery of the capsule into the duodenum [43]. As with the Roth net however, it may be difficult to launch the capsule into the duodenum in young children. The same technique can be used in patients with severe gastroparesis. Age and Size Limitations Aside from swallowing issues, the capsule endoscope may be too large to cross the esophageal sphincters or pass through the pylorus and/or ileocecal valve. In our experience, the child’s size is more relevant than age. The capsule has been successfully inserted into the stomach via direct vision in children as young as 2.5 or in those who weighed as little as 12 kg [44, 45]. Other Precautions and Considerations in Pediatric Patients We advise the routine use of endotracheal intubation in order to protect the child’s airway, particularly for patients incapable of independently swallowing the capsule, or in those with neurological impairment.
Conclusions In summary, the advent of CE has revolutionized the field of small bowel enteroscopy. It has certainly led to improvements in the diagnosis and evaluation of small bowel diseases, including IBD, in a non-invasive manner and without exposing patients to radiation. Studies thus far suggest that CE does play a role in the evaluation of patients with small bowel CD and appears to be superior to other imaging modalities. Larger, prospective randomized controlled trials are still needed to further understand its role in the evaluation of pediatric IBD and how it should be used in conjunction with other modalities, such as CT and MR cross-sectional imaging. Further research is also needed to determine the ideal bowel preparation that will lead to a more complete exam and to optimize diagnostic yield. References 1. Seidman EG. Role of endoscopy in pediatric inflammatory bowel disease. Gastrointest Endosc Clinics N Am 2001; 11:641–57. 2. Lenaerts C, Roy CC, Vaillancourt M, Weber AM, Morin CL, Seidman E. High incidence of upper GI tract involvement in children with Crohn disease. Pediatrics 1989; 83:777–781. 3. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis–the Porto criteria. IBD Working Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition J Pediatr Gastroenterol Nutr 2005; 41:1–7.
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4. Waye JD. Small-bowel endoscopy. Endoscopy 2003; 35:15–21. 5. Yamamoto H, Kita H, Sunada K, et al. Clinical outcomes of double-balloon endoscopy for the diagnosis and treatment of small-intestinal diseases. Clin Gastroenterol Hepatol 2004; 2:1010–1016. 6. Iddan G, Meron G, Glukhovsky A, et al. Wireless capsule endoscopy. Nature 2000; 405: 417. 7. Seidman EG, Sant’Anna AM, Dirks MH. Potential applications of wireless capsule endoscopy in the pediatric age group. Gastrointest Endosc Clin N Am 2004; 14:207–218. 8. Triester SL, Leighton JA, Leontiadis GI, et al. A meta-analysis of capsule endoscopy (CE) compared to other modalities in patients with non-stricturing small bowel Crohn disease. Am J Gastroenterol 2006; 101:954–964. 9. Guilhon de Araujo Sant’Anna AM, Dubois J, Miron MJ, Seidman EG. Wireless capsule endoscopy for obscure small bowel disorders: final results of the first pediatric controlled trial. Clin Gastroenterol Hepatol 2005; 3:264–270. 10. Kornbluth A, Colombel JF, Leighton JA, et al. ICCE consensus for inflammatory bowel disease. Endoscopy 2005; 37:1051–4. 11. Seidman EG, Leighton JA Legnani P, Kornbluth A, Bjarnasson I. Capsule Endoscopy in Inflammatory Bowel Disease: ICCE 2006 Consensus. Endoscopy 2007 (in press). 12. Bodily KD, Fletcher JG, Solem CA, et al. Crohn Disease: mural attenuation and thickness at contrastenhanced CT Enterography–correlation with endoscopic and histologic findings of inflammation. Radiology 2006; 238:505–16. 13. Sempere GA, Martinez Sanjuan V, Medina Chulia E, et al. MRI evaluation of inflammatory activity in Crohn disease. Am J Roentgenol 2005; 184:1829–35. 14. Golder SK, Schreyer AG, Endlicher E, Feuerbach S, Scholmerich J, Kullmann F, Seitz J, Rogler G, Herfarth H. Comparison of capsule endoscopy and magnetic resonance (MR) enteroclysis in suspected small bowel disease. Int J Colorectal Dis 2006; 21:97–104. 15. Albert JG, Martiny F, Krummenerl A, et al. Diagnosis of small bowel Crohn disease: a prospective comparison of capsule endoscopy with magnetic resonance imaging and fluoroscopic enteroclysis. Gut. 2005; 54:1721–7. 16. Seidman EG, Legnani P, Leighton J. The role of capsule endoscopy in inflammatory bowel disease: where we are and where we are going. Inflamm Bowel Dis 2007 (in press). 17. Goldfarb NI, Pizzi LT, Fuhr JP Jr., et al. Diagnosing Crohn disease: an economic analysis comparing wireless capsule endoscopy with traditional diagnostic procedures. Dis Manag 2004; 7:292–304. 18. Bourreille A, Jarry M, D’Halluin PN, et al. Wireless capsule endoscopy versus ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn disease: a prospective study. Gut 2006; 55: 978–983. 19. Mow W, Lo SK, Targan SR, et al. Initial experience with wireless capsule enteroscopy in the diagnosis and management of inflammatory bowel disease. Clin Gastroenterol Hepatol 2004; 2:31–40. 20. Lo SK, Zaidel O, Tabibzadeh S, et al. Utility of wireless capsule enteroscopy (WCE) and IBD serology in re-classifying indeterminate colitis (IC). Gastroenterology 2003; 124:S1310. 21. Mascarenhas-Saraiva, M, Lopes LM. Wireless capsule endoscopy (WCE) is useful for diagnosis and monitoring of small bowel Crohn disease. Gastrointest Endosc 2003; 57:AB170. 22. Galter S, Gonzalez B, Nontfort D, et al. Usefulness of the capsule endoscopy in the study of the inflammatory bowel disease: preliminary results. Gastroenterology 2006; 130:A478. 23. Arguelles-Arias F, Caunedo A, Romero J, et al. The value of capsule endoscopy in pediatric patients with a suspicion of Crohn disease. Endoscopy 2004; 36:869–73. 24. Barkay O, Moshkowitz M, Reif S. Crohn disease diagnosed by wireless capsule endoscopy in adolescents with abdominal pain, protein-losing enteropathy, anemia and negative endoscopic and radiologic findings. Isr Med Assoc J 2005; 7:216–8. 25. Moy L, Levine J. The role of capsule endoscopy in the evaluation of patients with unexplained growth failure. Gastroenterology 2006; 130:A190. 26. Goldstein J, Eisen GM, Lewis B, et al. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol Hepatol 2005; 3:133–41. 27. Yousfi MM, De Petris G, Leighton JA, et al. Diaphragm disease after use of nonsteroidal antiinflammatory agents: first report of diagnosis with capsule endoscopy. J Clin Gastroenterol 2004; 38:686–91.
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28. Gralnek I, De Franchis R, Seidman E, Leighton J, Legnani P, Ephrath H, Lewis B. Development and validation of a capsule endoscopy scoring index for small bowel mucosal disease activity: The Lewis Score. Am J Gastoenterol 2006; 101:S466 29. Cave D, Legnani P, de Franchis R, et al. ICCE consensus for capsule retention. Endoscopy 2005; 37:1065–7. 30. Fireman Z, Mahajna E, Broide E, et al. Diagnosing small bowel Crohn disease with wireless capsule endoscopy. Gut 2003; 52:390–2. 31. Herrerias JM, Caunedo A, Rodriguez-Tellez M, et al. Capsule endoscopy in patients with suspected Crohn disease and negative endoscopy. Endoscopy 2003; 35:564–8. 32. Eliakim R, Fischer D, Suissa A, et al. Wireless capsule video endoscopy is a superior diagnostic tool in comparison to barium follow-through and computerized tomography in patients with suspected Crohn disease. Eur J Gastroenterol Hepatol 2003; 15:363–7. 33. Buchman AL, Miller FH, Wallin A, et al. Videocapsule endoscopy versus barium contrast studies for the diagnosis of Crohn disease recurrence involving the small intestine. Am J Gastroenterol 2004; 99:2171–77. 34. Voderholzer WA. The role of PillCam endoscopy in Crohn disease: the European experience. Gastrointest Endosc Clin N Am 2006;16:287–97. 35. Signorelli C, Rondonotti E, Villa F, et al. Use of the Given Patency System for the screening of patients at high risk for capsule retention. Dig Liver Dis 2006; 38:326–30. 36. Boivin ML, Lochs H, Voderholzer WA. Does passage of a patency capsule indicate small-bowel patency? A prospective clinical trial. Endoscopy 2005; 37:808–15. 37. Delvaux M, Ben Soussan E, Laurent V, et al. Clinical evaluation of the use of the M2A patency capsule system before a capsule endoscopy procedure, in patients with known or suspected intestinal stenosis. Endoscopy 2005; 37:801–7. 38. Gay G, Delvaux M, Laurent V, et al. Temporary intestinal occlusion induced by a “patency capsule” in a patient with Crohn disease. Endoscopy 2005; 37:174–7. 39. de Franchis R, Avgerinos A, Barkin J et al. ICCE consensus for bowel preparation and prokinetics. Endoscopy 2005; 37:1040–5. 40. Viazis N, Sgouros S, Papaxoinis K, et al. Bowel preparation increases the diagnostic yield of capsule endoscopy: a prospective, randomized, controlled study. Gastrointest Endosc 2004;60:534–8. 41. Villa F, Signorelli C, Rondonotti E, et al. Preparations and prokinetics. Gastrointest Endosc Clin N Am 2006; 16:211–20. 42. Barth BA, Donovan K, Fox VL. Endoscopic placement of the capsule endoscope in children. Gastrointest Endosc 2004; 60:818–21. 43. Keuchel M, Dirks MH, Seidman EG. Swallowing and motility disorders, pacemakers & obesity, in: Keuchel M, Hagenmüller F, Fleischer D (eds): Atlas of Video Capsule Endoscopy. Wurzburg, Germany, Springer, 2006, 24–9. 44. Kavin H, Berman J, Martin TL, et al. Successful wireless capsule endoscopy for a 2.5-year-old child: obscure gastrointestinal bleeding from mixed, juvenile, capillary hemangioma-angiomatosis of the jejunum. Pediatrics 2006; 117: 539–43. 45. Dirks MH, Costea F, Sant’Anna AMG, Peretti N, Seidman EG. Videocapsule endoscopy in pediatric Crohn disease: A 4-year experience. J Pediatr Gastroenterol Nutr 2006; 43: Suppl. 2, S26–7.
21 Bone Health Assessment in Pediatric Inflammatory Bowel Disease Meena Thayu, Edisio Semeao and Mary B. Leonard∗
Introduction Throughout childhood and adolescence, bone mineral accrual results in ethnic-, gender-, maturation-, and site- specific increases in bone dimensions and density. During the critical twoyear interval surrounding the time of peak height velocity, approximately 25% of skeletal mass is laid down, and 90 percent of peak bone mass is established by 18 years of age. [1] This rapid accumulation of bone mass correlates with the rate of growth and requires the coordinated actions of growth hormone, insulin-like growth factor-I (IGF-I) and sex steroids in the setting of adequate biomechanical loading and nutrition. Individuals with higher peak bone mass in early adulthood have a protective advantage against fracture when the inexorable decline in bone mass associated with older age or menopause occurs. Accordingly, the NIH Consensus Statement on Osteoporosis Prevention, Diagnosis and Therapy concluded “bone mass attained early in life is perhaps the most important determinant of life-long skeletal health.” [2] Furthermore, the Consensus Statement specifically called for research to determine the impact of chronic diseases and glucocorticoid therapy on bone accrual in children, and to determine the effects of bisphosphonates on the growing skeleton. Children and adolescents with inflammatory bowel disease (IBD) have multiple risk factors for impaired bone development, including poor growth, delayed maturation, malnutrition, decreased weight-bearing activity, chronic inflammation, and immunosuppressive therapies, such as glucocorticoids. The impact of these threats to bone health may be immediate, resulting in fragility fractures during childhood and adolescence, [3–5] or delayed, due to suboptimal peak bone mass accrual. [6] Recent years have seen numerous studies on the effects of IBD on bone accrual during childhood and adolescence; however, the short- and long-term implications for fracture risk in pediatric IBD have not been characterized. This chapter summarizes the normal changes in bone density and structure during growth, as well as the risk factors for poor bone accrual in childhood IBD. The classification of bone health in children and adolescents is discussed, as are the advantages and disadvantages of available technologies for the assessment of bone in children and adolescents. The difficulties in assessing and interpreting bone measures in pediatric IBD are underscored in a review of selected studies,
∗
Department of Pediatrics, The Children’s Hospital of Philadelphia, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, 3535 Market Street, Philadelphia, PA 19104-4399, Phone: 215-590-0874, Fax: 215-590-0874, E-mail:
[email protected]
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and an example is provided for a stepwise approach to identify discrete determinants of bone deficits in pediatric IBD. [7] Finally, potential therapies are considered.
Skeletal Modeling and Bone Accrual During Childhood Skeletal development is a complex process that is sensitive to the hormonal, mechanical, and nutritional milieu of the bone. The bones are continuously modified and renovated by the two processes of modeling and remodeling: both result in the replacement of old bone with new bone. Remodeling is the major process in adults and does not result in a change of the bone shape. Remodeling takes place in the basic bone multicellular units on the trabecular surface and within the cortical bone. Normally, bone resorption by osteoclasts is followed by bone formation by osteoblasts; teams of osteoclasts and osteoblasts are juxtaposed in the bone multicellular units and bone resorption and formation are tightly coupled. For example, treatment of post-menopausal women with bisphosphonates (an anti-resorptive agent) resulted in significant reductions in bone resorption within 6 weeks, followed by a reduction in bone formation in 3 months. [8, 9] Skeletal remodeling is vital to microdamage repair. However, after mid-adulthood, the amount of resorption exceeds formation, resulting in a negative bone balance. In contrast, modeling during growth and development results in new bone formed at a location different from the site of bone resorption; formation and resorption are not coupled within a bone multicellular unit. For example, a small study of bisphosphonate therapy in children reported significant reductions in bone resorption markers with no changes in formation markers. [10] Modeling results in an increase in bone diameter and modification of bone shape. Figure 21.1 summarizes the complex interplay of site-specific bone resorption and formation activities that
Figure 21.1. Bone formation (+) and resorption (–) during growth. Source: From: Baron R 2003 General Principles of Bone Biology. In: Favus M (ed.) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 5 ed. Lippincott Williams & Wilkins, Philadelphia, pp. 1–8.
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are necessary to achieve bone growth from length A to B. [11] Growth in the diameter of the cortical shaft is the result of bone formation at the outer (periosteal) surface and bone resorption at the inner (endosteal) surface. Simultaneously, the growth plate moves upward and the wider metaphysis is reshaped into a diaphysis by continuous resorption by osteoclasts beneath the periosteum.
Changes in Cortical and Trabecular Bone with Growth Cortical and trabecular bone do not respond in the same way to diseases, medications, or mechanical loading, and should be considered two functional entities. Trabecular volumetric bone mineral density (BMD), as measured by three-dimensional quantitative computed tomography (QCT), does not increase before puberty. [12, 13] During puberty, trabecular BMD increases significantly in healthy children due to increases in trabecular thickness. The increases in BMD is comparable in girls and boys, [14] but is significantly greater in black adolescents than in white adolescents. [15] Sex differences in cortical dimensions are established during puberty (Figure 21.2): [16] cortical width increases by periosteal bone formation in boys, and by less periosteal bone formation but more endocortical apposition in girls. Androgens stimulate periosteal apposition while estrogens inhibit periosteal apposition and stimulate endosteal apposition. These sex differences have important implications for bone strength; the greater periosteal dimensions in males result in greater bone strength. The long bones are tubular structures that are loaded mainly in bending. The resistance of long bones to bending (i.e. bone strength) is represented by the cross-sectional moment of inertia (CSMI) = /4 (Rp 4 – Re 4 ); Rp and Re indicate the periosteal and endosteal radius, respectively. [17] These power relationships indicate that small increases in Rp result in marked increases in bone bending strength. Because the patterns of modeling on the periosteal and endocortical envelopes during growth produce changes in cortical geometry that impact life-long fracture risk, [18, 19] the long term effects of chronic childhood diseases, such as IBD, likely depend on the stage of skeletal maturation at disease onset and the disease effects on the periosteal and endosteal surfaces. Children further from peak bone mass at Crohn disease onset may have irreversible deficits not seen in adult-onset Crohn disease.
Growth
Boys Puberty
Girls
Figure 21.2. Sex specific increases in cortical bone dimensions during growth and maturation. Source: Adapted from: Seeman E 2002 Pathogenesis of bone fragility in women and men. Lancet 359:1841–50.
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Biochemical Markers of Bone Metabolism Biochemical markers of bone metabolism are released into the circulation during the process of bone formation and resorption, providing information about the dynamic process of bone metabolism. Biomarkers of formation, such as bone-specific alkaline phosphatase (BSAP), are byproducts of osteoblast activity. Biomarkers of bone resorption are related to collagen degradation products, including pyridinium crosslinks and C-telopeptide of collagen cross-links (-CTX). In adults, biochemical markers of bone turnover correlate well with formation and resorption, as measured by bone biopsy, and are independent predictors of fracture risk. [20] Further, bone biomarkers can be used to monitor the effectiveness of bone therapies. [8] Because formation and resorption are tightly coupled in adults, drugs that increase bone formation (e.g. teriparatide) increase markers of formation and resorption, while drugs that inhibit resorption (e.g. bisphosphonates) decrease markers of formation and resorption. [21] In adults, bone metabolism is primarily due to remodeling. However, in children biomarkers of bone metabolism represent the aggregate turnover due to (1) endochondral bone formation (longitudinal growth of bone), (2) increase in bone circumference, and (3) bone remodeling. [22] The pubertal growth spurt is reflected by marked increases in bone biomarkers. [24] Therefore, use of bone biomarkers in children and adolescents requires consideration of gender, pubertal maturation and growth velocity; [23] and is most appropriately limited to short-term longitudinal studies to assess the impact of specific interventions. [22]
Potential Threats to Bone Health in Pediatric IBD Osteopenia has been well-documented in children and adults with IBD. [24–28] We, and others, have reported vertebral compression fractures with children with IBD, [3–5] and hip, spine, and forearm fracture rates are significantly increased in adults with Crohn disease. [29–34] The osteopenia in IBD is multifactorial; likely etiologies include growth failure, delayed maturation, anorexia, malabsorption, cytokine effects on bone cells, and glucocorticoid therapies. Malnutrition In addition to the to the usual symptoms of diarrhea, abdominal pain, weight loss, and anemia, children may exhibit growth failure years prior to disease diagnosis. [35, 36] Anorexia, malabsorption, and increased metabolic demands all contribute to poor growth. [37] Small bowel disease may impair absorption of iron, zinc, folate, and vitamin B12 . [37] Nutrients that may contribute to impaired bone acquisition in pediatric IBD include calcium, vitamin D, vitamin K and magnesium. [38] Multiple studies have reported that vitamin D deficiency frequently complicates pediatric IBD. [39–42] For example, Pappa, et al recently examined vitamin D levels in 130 children and young adults with IBD, 94 with Crohn disease and 36 with ulcerative colitis. The prevalence of vitamin D deficiency [serum 25 (OH) vitamin D concentration ≤ 15 ng/mL] was 34.6%, and the mean serum 25 (OH) vitamin D concentration was similar in patients with Crohn disease and ulcerative colitis, 52.6% lower among patients with dark skin complexion, 33.4% lower during the winter months (December 22 to March 21), and 31.5% higher among patients who were taking vitamin D supplements. Patients with Crohn disease and upper gastrointestinal tract involvement were more likely to be vitamin D deficient than those without it. A similar study reported that 45% of children with IBD had vitamin D levels less than 20 ng/mL. [39] Of note, none of these studies detected a relation between vitamin D levels and spine BMD, as measured by dual energy x-ray absorptiometry (DXA). [39–41]
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Decreased Muscle Mass and Biomechanical Loading of the Skeleton Bone adapts its strength in response to the magnitude and direction of the forces to which it is subjected. Mechanical forces on the skeleton arise primarily from muscle contraction. This capacity of bone to respond to mechanical loading with increased bone size and strength is greatest during growth, especially during adolescence. [43] Numerous studies have documented the beneficial effect of physical activity and biomechanical loading on bone geometry in healthy children. [44–49] These relationships dictate that studies of bone health in chronic childhood diseases consider the effects of alterations in muscle mass and strength. Weight-bearing physical activity and biomechanical loading of bone are critical determinants of bone mass in growing normal children [50]. The influence of skeletal loading on bone accretion is illustrated in two exercise trials in healthy children. An easily implemented school-based jumping intervention augmented cortical thickness in the femoral neck of healthy children. [51] A randomized clinical trial of physical activity and calcium supplementation in prepubertal children resulted in a significant, positive interaction between calcium supplements and physical activity in both cortical thickness and cortical area. [52] Burnham, et al. recently evaluated whole body lean and fat mass in children and young adults with Crohn disease, relative to height and pubertal maturation, compared with healthy controls. [53] While Crohn disease was associated with significant deficits in lean mass, adjusted for height, age, race, and Tanner stage (p = 0.003); fat mass was not decreased (mean fat mass-forheight z-score = −0.04 ± 0.86). Within the controls, fat mass-for-height was positively associated with lean mass-for-height (r = 0.41, p < 0.0001); this association was absent in Crohn disease. Therefore, Crohn disease subjects exhibited significant deficits in lean mass with preserved fat mass, consistent with inflammatory cachexia. Harpavat, et al. recently reported that none of the subjects in a small series of children with IBD were participating in weight bearing physical activities. [54] To our knowledge, no studies have compared physical activity patterns in children with IBD and healthy controls. Nonetheless, the reports of decreased lean mass in pediatric IBD suggest that decreased biomechanical loading of the skeleton may contribute to impaired bone accrual in this disorder. Glucocorticoid Induced Osteopenia Glucocorticoids are widely used in the treatment of IBD and impact bone formation and resorption. Decreased bone formation is the primary mechanism for bone loss in glucocorticoid-induced osteopenia. [55] Mesenchymal stem cells, which also give rise to adipocytes, myoblasts and chondrocytes, differentiate into osteoblasts. Glucocorticoids shift the cellular differentiation away from osteoblasts and towards adipocytes, and prevent the termination differentiation of osteoblasts. [56] Osteoblast numbers are decreased further by glucocorticoid-induced increases in osteoblast apoptosis. [57] In addition, glucocorticoids inhibit osteoblast production of bone matrix components. [58] Finally, glucocorticoids suppress the synthesis of IGF-1, an agent that enhances bone formation. [59] The cellular response to glucocorticoids also includes an early phase of increased bone resorption, probably a result of the increased expression of receptor activator of nuclear factor--B ligand (RANKL) and decreased osteoprotegerin (OPG) – increased RANKL and decreased OPG both promote osteoclastogenesis, as detailed below. [60] However, typically a more chronic state of decreased bone resorption develops, due to loss of cell signaling to osteoclast progenitors. [61] Patients treated with glucocorticoids have an underlying disease which frequently also carries a risk of osteoporosis. Therefore, the independent effects of glucocorticoids on bone turnover and bone structure during growth are not readily apparent from observational clinical studies. However, recent animal models demonstrate that glucocorticoid administration during growth resulted in decreased bone formation, decreased bone resorption, reductions in the age dependent
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increases in trabecular thickness, and reductions in linear growth and accrual of cortical thickness in the femur. [62, 63] These deficits were associated with decreased bone strength in the vertebrae and femur in mechanical testing. [62, 63] Of note, it is unclear if the reductions in femoral cortical thickness were proportionate to the significant reductions in bone length. That is, did the bones have normal cortical thickness and strength relative to the shorter length? Inflammation and Bone Loss Cellular inflammatory pathways in Crohn disease activate the protean transcriptional regulatory factor nuclear factor-B with increased production of a variety of cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor- (TNF-). [64] Three groups of cytokines are particularly important in bone physiology: IL-6, TNF- and lL-1. [60] RANKL stimulates osteoclast differentiation and activation, and inhibits osteoclast apoptosis. In contrast, OPG acts as a decoy receptor for RANKL and acts as an inhibitor of bone resorption. TNF-, IL-1 and IL-6 exert their osteoclastogenic effects through increased RANKL, as well as through other autocrine and paracrine pathways independent of RANKL. [65–67] The effects of TNF- on bone formation are strikingly similar to the effects of glucocorticoids. TNF- inhibits osteoblast differentiation, inhibits osteoblast synthesis of collagen, and promotes osteoblast apoptosis. [68]
Assessment of Bone Status in Children and Adolescents Classification of Bone Health and Relation to Fracture Risk DXA is widely accepted as a quantitative measurement technique for assessing skeletal status. In elderly adults, DXA BMD is a sufficiently robust predictor of osteoporotic fractures that it can be used to define the disease. The World Health Organization criteria for the diagnosis of osteoporosis in adults is based on a T-score, the comparison of a measured BMD result with the average BMD of young adults at the time of peak bone mass. [69] A T-score ≤ −2.5 SD below the mean peak bone mass is used for the diagnosis of osteoporosis, and a T-score ≤ −2.5 SD with a history of a low-impact fracture is classified as severe osteoporosis. While the T-score is a standard component of DXA BMD results, it is clearly inappropriate to assess skeletal health in children through comparison with peak adult bone mass. Rather, children are assessed relative to age or body size, expressed as a Z-score. In adults, low impact fractures are defined as fractures that occur after a fall from standing height or less. This definition is often difficult to apply to fractures in children that occur during play or sports activities. Despite the growing body of published normative data utilizing DXA in children, there are no evidence-based guidelines for the definition of osteoporosis in children. Fractures occur commonly in otherwise healthy children with a peak incidence during early adolescence around the time of the pubertal growth spurt. [70] Faulkner, et al recently reported that peak gains in bone area preceded peak gains in bone mineral content (BMC) in a longitudinal sample of boys and girls, supporting the theory that the dissociation between skeletal expansion and skeletal mineralization results in a period of relative bone weakness. [70] This may be due to increased calcium demands during maximal skeletal growth. Khosla, et al. recently reported that forearm (the most common site) fracture rates have increased significantly in males and females over the last 30 years; the peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8 and 11 years in girls. [70] Possible explanations include changing patterns of physical activity or decreased bone acquisition due to poor calcium intake. Several studies have compared the DXA BMD of normal children and adolescents with forearm fractures to that of age-matched controls without fractures. Most, [72–76], but not all [77, 78] found that mean DXA BMD was significantly lower in children with forearm fractures
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than in controls. One study reported that 69% of fractures in healthy children were due to lowenergy falls at home; [77] illustrating the difficulties defining low-energy fractures in children. Studies using QCT or metacarpal morphometry to characterize cortical geometry showed that decreased cortical thickness was associated with significantly increased fracture risk. [76, 79] Finally, television, computer, and video viewing had a dose-dependent association with wrist and forearm fractures. [80] A recent prospective cohort study in over 6200 children in the United Kingdom reported that a weak inverse relationship between whole body (less head) BMD at 9.9 years of age and subsequent fracture risk [odds ratio (OR) per SD decrease = 1.12; 95% CI, 1.02–1.25]. [81] The association between fracture risk and BMD was much stronger when adjusted for bone and body size; fracture risk was inversely related to BMC adjusted for bone area, height, and weight (OR = 1.89; 95% CI, 1.18–3.04). These data suggest that low DXA BMD can be a contributing factor for pediatric fracture in healthy children; however, bone geometry and non-skeletal factors such as sports participation, body size, and sedentary activities contribute to fracture risk. Importantly, the relationships between DXA BMD, bone geometry and fracture risk in children with chronic diseases, such as IBD, may be different that those observed in healthy children. Limitations of DXA in Children and Adolescents DXA is, by far, the most commonly employed method for the assessment of bone health in children. However, DXA has several limitations that are pronounced in the assessment of children (Table 21.1). A recent study highlights the importance of these limitations [82]: among children referred for enrollment in a childhood osteoporosis protocol based on low DXA spine BMD, 80% had at least one error in interpretation of the DXA scan. Ultimately, only 26% retained the diagnosis of low BMD. The significant limitation of DXA is the reliance on measurement of areal rather than volumetric BMD. DXA provides an estimate of bone mineral density expressed as grams per anatomical region (e.g., individual vertebrae, whole body, or hip). Dividing the BMC within the defined anatomical region (g) by the projected area of the bone (cm2 ) then derives “areal-BMD” (g/cm2 ). This BMD is not a measure of volumetric density (g/cm3 ) because it provides no information about Table 21.1. Limitations of DXA techniques in infants and children. Scan Acquisition Scan Analysis
Reference Data [86, 87, 92–103]
Interpretation
• Fan beam results in magnification error with apparent differences in bone area and BMC as body size varies [155] • Difficult to define landmarks and region of interest in the immature hip [156] • Software developed to improve bone detection in the infant and child result in significantly different results for BMC and body composition [105, 157, 158] • Limited data in young children • Analysis methods not standardized • Variable hardware and software across published reference data sets • Some are not gender-specific [104] • Some presented relative to age, others relative to height, Tanner stage, and weight • Underestimates volumetric density in children with short stature [159, 160] • Unable to distinguish between changes in bone dimensions and density • Unable to distinguish between cortical and trabecular bone
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the depth of bone. Bones of larger width and height also tend to be thicker. Since bone thickness is not factored into DXA estimates of BMD, reliance on areal-BMD inherently underestimates the bone density of short people. Despite identical volumetric bone density, the child with smaller bones appears to have a mineralization disorder (decreased areal-BMD). This is clearly an important artifact in children with chronic diseases, such as IBD, that are associated with growth delay and short stature. [83] The confounding effect of skeletal geometry on DXA measures is now well recognized and multiple analytic strategies have been proposed to express DXA bone mass in a form that is less sensitive to differences in skeletal size. [84–88] The technique developed by Carter, et al. is based on the observation that vertebral BMC scaled proportionate to the projected bone area to the 1.5 power. [84] Therefore, vertebral volume is estimated as (area)15 and bone mineral apparent density (BMAD) is defined as BMC/(area)15 . Kroger et al proposed an alternative estimate of vertebral volume: the lumbar body is assumed to have a cylindrical shape and volume of the cylinder is calculated as ()(radius2 )(height), which is equivalent to ()((width/2)2 )(area/width). [89, 90] This approach was validated by comparison with magnetic resonance (MR) measures of vertebral dimensions in 32 adults; [85] DXA-derived volumetric BMD correlated moderately well with BMD based on MR-derived estimates of vertebral volume (R = 0.665). Although these methods provide estimates of vertebral volume, the BMC includes the bone content of the superimposed cortical spinous processes. A recent study by Wren, et al sought to evaluate the usefulness of DXA spine correction factors based on published geometric formula and anthropometric parameters, compared with three-dimensional QCT. [91] Subject height, weight, body mass index, skeletal age, and Tanner stage were assessed in 84 healthy children. Two geometric calculations based on DXA spine results were used to estimate volumetric BMD: (1) BMAD, and (2) areal BMD/bone height. Linear regression was used to compare DXA-BMC vs. QCT-BMC and CT volumetric BMD vs. DXA areal BMD, BMAD and (areal BMD/bone height). DXA and QCT BMC were highly correlated (r2 = 0.94). However, DXA areal BMD correlated more strongly with CT Vol (r2 = 0.68) than with CT density (r2 = 0.39), illustrating the confounding effect of bone size on DXA areal BMD results. The use of DXA correction factors only slightly improved the density correlations [r2 = 0.49 for BMAD; r2 = 0.55 for (areal BMD/bone height)]. The correlations between QCT volumetric BMD and DXA estimates were particularly poor for subjects in Tanner stages 1–3 [r2 = 0.02 for areal BMD; r2 = 0.13 for BMAD; r2 = 0.27 for (areal BMD/bone height)]. In contrast, multiple regression accounting for the anthropometric and developmental parameters greatly improved the agreement between the DXA and CT densities (r2 = 0.91). These results suggest that DXA BMC is a more accurate and reliable measure than DXA BMD for assessing bone acquisition, particularly for prepubertal children and those in the early stages of sexual development. Use of DXA BMD would be reasonable if adjustments for body size, pubertal status, and skeletal maturity are made, but these additional assessments add significant complexity to research studies, and to clinical interpretation. An additional shortcoming of DXA is that the integrated measure of bone mass in a given projected area does not allow distinction between cortical and trabecular bone. DXA-based measures provide no information on bone architecture, and are limited in their usefulness to differentiate the spectrum of bone accrual during growth. Comparisons to appropriate pediatric reference data are essential to describe accurately the clinical impact of childhood disease on bone development, to monitor changes in bone mineralization, and to identify patients for treatment protocols. Multiple sources of pediatric DXA reference data are now available for the calculation of DXA z-scores. These include varied approaches, such as gender-specific centile curves, age- and height- specific means and standard deviations, Tanner- and weight-specific percentiles, age-, sex-, weight- and height- adjusted curves, and z-score prediction models. [86, 87, 92–103] Differences in reference data have a
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significant impact on the diagnosis of osteopenia in children with chronic disease. [104] For example, use of reference data that are not gender-specific results in significantly greater misclassification of males as osteopenia. [104] In addition, use of published pediatric reference ranges has been complicated by differences in scanner manufacturers, and frequent changes in hardware and software technology, including fan-beam technology, low density software analysis modes and specialized pediatric software. These technical changes result in clinically significant alterations in DXA results [105]. Further effort is needed to develop adequate reference data and validate classification schemes of bone health in children. Peripheral Quantitative Computed Tomography A three-dimensional structural analysis of trabecular architecture and cortical bone dimensions can be obtained by computed tomography (CT). This technique offers an opportunity to overcome these limitations and advance our understanding of bone mineralization in children. CT provides an image unobscured by overlying structures. [106] The CT attenuation of different bone tissues provides quantitative information, referred to as quantitative CT (QCT). In contrast to DXA, this technique describes authentic volumetric BMD, accurately measures bone dimensions, and distinguishes between cortical and trabecular bone. In order to minimize radiation exposure, special high–resolution scanners were developed for the peripheral skeleton (pQCT), specifically, the radius or tibia. The distal site is largely trabecular bone, while the mid-shaft is almost entirely cortical bone. The volume of each component is calculated from the scan thickness and crosssectional area, and the density by attenuation of the x-ray beam. Bone strength can also be estimated by pQCT from the total bone area, and cortical thickness and density. [107] For example, QCT studies of bone mineral accretion and bone strength demonstrated gender, maturation, and ethnic-specific patterns of development of bone strength during childhood and adolescence. [108]
Clinical Studies of Bone Health in Pediatric IBD Numerous studies have reported decreased DXA BMD in children with IBD. [40] However, as detailed above, DXA studies are frequently confounded by disease effects of growth. For example, two recent studies reported that DXA BMD for age z-scores were significantly correlated with height for age z-scores in children with IBD. [40, 109] Furthermore, expression of DXA results as BMAD (an estimate of volumetric BMD) eliminated the correlation with height z-scores. [109] Another study addressed the confounding effect of short stature by expressing the spine DXA results as percent predicted BMC for bone area for age and gender in 73 children with Crohn disease or ulcerative colitis. [110] The percent predicted bone area for age and gender was decreased in IBD, compared with controls, consistent with shorter stature. While the median BMD for age and gender z-score was significantly decreased in IBD (mean z-score in spine = –1.6, in whole body = –0.9), the percent predicated BMC for bone area, age, and gender was normal. The authors concluded that children with IBD have small bones for age due to growth retardation, but adequate bone mass relative to bone size. Finally, Herzog, et al reported that BMD z-scores were less than –2.0 in 44% of children when expressed relative to chronologic age, but were less than –2.0 in only 26–30% when expressed relative to bone age of height age. [111] The above studies illustrate the varied approaches used to adjust for the confounding effects of poor growth. We recently reported that whole body BMC relative to height predicted cortical bone CSMI (an estimate of bone strength, as described above) as measured by QCT. [88] Therefore, we assessed whole body BMC, lean mass and fat mass (as measured by DXA) relative to height in 104 children and young adults with established Crohn disease, and 233 healthy controls, 4 to 26 years of age. The studies demonstrated significant bone and muscle deficits. [7, 54] Individuals with Crohn disease had significantly lower height-for-age, body mass index (BMI) -for-age, and whole
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Table 21.2. Hierarchical models of whole body BMC Z-scores in crohn disease [7]. Models
Males Z (95% CI)
1) 2) 3) 4)
Age, Race Height, Age, Race Height, Age, Race, Tanner Height, Age, Race, Tanner, Lean Mass
–1.16 –0.63 –0.50 –0.19
(–1.51, (–0.95, (–0.85, (–0.43,
–0.82) –0.30) –0.15) 0.06)
Females p < 0.001 < 0.001 0.006 0.13
Z (95% CI) –0.61 –0.44 –0.35 –0.05
(–0.95, (–0.81, (–0.72, (–0.34,
p
–0.27) 0.001 –0.06) 0.02 0.02) 0.06 0.25) > 0.2
body lean mass-for-height z scores than healthy controls (all p<0.001). Ninety percent of Crohn disease subjects had been treated with glucocorticoids. The cumulative exposure averaged 7,900 mg over 15.2 months, resulting in an average dose of 0.50 mg/kg/day. Table 21.2 summarizes four sequential models in males and females. The least adjusted models assessed whole body BMC in Crohn disease, compared with controls, adjusted for age and race, and revealed substantial deficits. Assessment of BMC without consideration of the decreased skeletal size for age in subjects with Crohn disease group may overestimate bone deficits. Accordingly, the second model was also adjusted for height. Figure 21.3 demonstrates that the marked BMC deficits relative to age (A) are less pronounced when assessed relative to height (B). Adjustment for height attenuated the Crohn disease effect in the multivariate regression model; however, significant BMC deficits persisted in males and females with Crohn disease, compared with controls. In order to determine if delayed pubertal maturation for age contributed to the decreased BMC in Crohn disease, the third model in Table 21.2 included Tanner stage. Adjustment for delayed pubertal maturation did not appreciably change the estimate of BMC deficits in Crohn disease. The fourth and final model, adjusted for lean mass, eliminated significant BMC deficits in Crohn disease. None of the glucocorticoid measures were significantly correlated with BMC-for-height z scores. However, height z score was negatively and significantly associated with duration of glucocorticoid therapy (r = –0.24, p = 0.02), and cumulative (mg/kg) glucocorticoids (r = –0.36, p < 0.001). Parenteral nutrition, isolated upper tract disease, hypoalbuminemia, nasogastric feeding, and decreased BMI z-scores were associated with decreased BMC-for-height z-scores. Over ninety percent of the children and young adults in the prior study had a history of glucocorticoid exposure; therefore, it was not possible to distinguish between disease and glucocorticoid effects on bone. The impact of the underlying IBD process is best assessed in subjects with newly-diagnosed disease. The largest study of DXA BMD in newly diagnosed subjects was A.
B.
Figure 21.3. Distribution of whole body BMC relative to age (A) and relative to height (B) in children and young adults with Crohn Disease, compared with healthy controls. Source: From Burnham JM, Shults J, Semeao E, Foster B, Zemel BS, Stallings VA, Leonard MB 2004 Whole body BMC in pediatric Crohn disease: independent effects of altered growth, maturation, and body composition. J Bone Miner Res 19 [12]:1961–8.
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reported by Gupta, et al; [112] however, the study was complicated by the observation that BMD was markedly decreased in controls, compared with the DXA reference database. Overall, DXA spine BMD was comparable in the 41 children with ulcerative colitis and the controls, while results were significantly lower in the 82 subjects with Crohn disease. Sylvester recently examined DXA BMD and bone biomarkers in 23 children with newly diagnosed Crohn disease. [113] Although BMD z-scores did not differ between Crohn disease subjects and controls in this small sample, bone biomarkers were significantly lower in Crohn disease. This may be due to reduced bone remodeling, or reduced growth velocity. Importantly, activated T-cells produced greater concentrations of interferon-, which may contribute to lower bone turnover. Another small series in 18 children with newly diagnosed Crohn disease demonstrated that BMD was below the 16th percentile for age in 28% of subjects. [55] Delayed pubertal development correlated with lower BMD z-scores, which may represent the confounding effect of poor growth. Walther, et al. recently compared lumbar spine BMAD z-scores in 34 steroid-naïve and 53 steroid-treated children with IBD in order to obtain information about the influence of nonsteroidal factors. [109] Overall, 56 had Crohn disease and 30 had ulcerative colitis. Reference data were obtained in 52 controls. The mean BMAD z-scores in the subjects with Crohn disease were –0.76 + 1.25 in females and –0.79 + 0.92 in males. The mean BMAD z-scores in the subjects with Ulcerative Colitis were –0.30 + 0.75 in females and –1.08 + 1.23 in males. Among the steroid-naïve subjects, the duration of treatment ranged from 0 to 8 years; the majority (approximately 80%) were within the first five weeks of therapy. Among the steroid treated subjects, the cumulative steroid exposure averaged 4,600 mg (range 0.05 to 25,000 mg) over a treatment duration of several days to 7.6 years. The mean BMAD z-scores were comparable in steroid-naïve (–0.74 + 1.08) and steroid-treated (–0.66 + 1.08) subjects. The 19 subjects that had been treated with calcium and/or vitamin D supplements were all within the steroid-treated group. The study is limited by the small number of controls, and the lack of data on disease activity between the steroid-naïve and steroid-treated groups. Nonetheless, these data indicate bone deficits in the absence of steroid therapy. The studies listed above were all based on DXA estimates of BMC and BMD, and did not distinguish between cortical and trabecular bone. A recent study examining metacarpal thickness in 26 children with IBD suggested cortical osteopenia in this small sample. [114] To our knowledge, no published studies have reported QCT results in children or adults with IBD. Finally, only one study has addressed the impact of childhood IBD on peak bone mass. Bernstein, et al. assessed spine, proximal femur, and whole body BMD in 780 premenopausal adult women (age < 45 yr) that were diagnosed with IBD prior to 20 years of age. [115] The mean BMD T-scores were normal in the spine (–0.14 + 1.05), femoral neck (–0.15 + 1.04) and whole body (0.09 + 1.04) and results did not differ between the 12 subjects with disease onset before puberty, and the 58 subjects with disease onset after puberty.
Potential Therapies for Bone Health in Pediatric IBD Physical Activity Physical activity is an important determinant of bone mass accretion during growth; simple loading exercises promote bone accretion in healthy children. Resistance exercise prevents bone loss in adult transplant recipients. [116] Therefore, weight-bearing physical activity should be encouraged in children and adolescents in an effort to positively affect bone acquisition. Vitamins and Minerals Multiple prospective randomized double-blind intervention trials have documented that calcium supplementation promotes bone accretion in normal children and adolescents [117–122].
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Accordingly, the National Academy of Science Food and Nutrition Board, and the National Institutes of Health Consensus Panel on Calcium Intake increased calcium intake standards for adolescents to 1300 and 1500 mg/day, respectively [123, 124]. These recommendations reflect the need for increasing calcium intake with age in order to accommodate the calcium needs for the rapidly growing skeleton, especially during the years of the adolescent growth spurt. A national dietary intake survey showed that calcium intake of children declines in all ethnic groups at the ages when calcium requirements increase [125]. Subjects with Crohn disease involving the small bowel are at increased risk for calcium oxalate kidney stones. Normally dietary calcium binds with oxalate in the gut to form a complex that is poorly absorbed. In small bowel disease, fat malabsorption results in increased binding of fatty acids with calcium to form insoluble soaps, thereby increasing the soluble oxalate for absorption. [126] Calcium supplements result in decreased urinary oxalate without increasing urinary calcium above normal; therefore, calcium is recommended to prevent enteric hyperoxaluria. [127] To our knowledge, no calcium balance studies or calcium supplementation trials have been conducted in children with chronic illness. Vitamin D is essential for the maintenance of adequate calcium levels for bone mineralization and all pediatric IBD patients are at risk for Vitamin D deficiency, especially during the winter months. In 1997, the Institute of Medicine concluded that the Adequate Intake of vitamin D in children and young adults in 200 IU per day. [124] However, in the years following the Institute of Medicine report, a series of publications have argued that 200 IU is not adequate in healthy children and adults. [128–135] The optimal dose many even exceed the “tolerable upper limit” of 2000 IU/day. [136, 137] A recent study of the serum 25(OH)D response to oral cholecalciferol reported that each additional 100 IU of cholecalciferol resulted in a 0.7 ng/ml increase in serum 25(OH)D over a 2 to 3 month period, then plateaued. [130] Weaver, et al reported that 863 IU/day would be required in healthy adolescent girls, on average to achieve a serum 25(OH)D of 32 ng/ml. [132] Based on these data, on multiple observations of significant vitamin D deficiency in our subjects with Crohn disease, on reports that 1,000 IU is routinely used in adults with osteoporosis, [137] and on practice guidelines advocating 800 IU/day in adults with Crohn disease, [138] there is an urgent need for studies to identify the optimal vitamin D supplementation doses in pediatric IBD. It is prudent to measure serum 25-hydroxyvitamin D levels, especially in subjects at northern latitudes in the winter months. Bisphosphonates The beneficial effects of bisphosphonates in adults with post-menopausal osteoporosis and corticosteroid-induced osteoporosis are well-recognized. However, concerns regarding the impact on the structure of the modeling skeleton initially tempered enthusiasm for these medications in children. Bisphosphonate therapy results in distinctive radiographic metaphyseal bands in children; the significance of these bands is unclear. Pamidronate proved effective in uncontrolled observational studies of children with osteogenesis imperfecta; bone density and size increased and the incidence of fractures decreased [139–141]. The treatment did not alter fracture healing, growth rate, or growth plate appearances. A recent report of osteopetrosis in a child treated with a cumulative pamidronate dose approximately seven fold greater than recommended raised concerns regarding the safety of this treatment in growing children [142, 143]. Similar complications have not been observed in children on lower doses [144]. Recent years have seen a rapid increase in the number of case series and case reports describing bisphosphonate therapy in children with disparate chronic diseases, [145–153] The two largest studies conducted in children with chronic inflammatory conditions are summarized in Table 21.3. Both of these studies demonstrated significant improvements in DXA BMD; however, only one was a randomized trial. [10] The trial had many important limitations. First, the study population included 22 children with highly disparate conditions, including juvenile arthritis,
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Table 21.3. Bisphosphonate studies in children and adolescents with chronic inflammatory disease. Study / Subjects
Intervention / Outcome
Comments and Results
• Serum alkaline phosphatase levels decreased Bianchi, et al. [161] Design: 12 month case-series by 16.5 + 10.8%. Chronic Rheum • Oral alendronate • Urinary excretion of NTX decreased by 17 + Disorder and ↓ spine Weight ≤ 20 kg: 5 mg q day 16.5%. BMD N = 39a , age 5–18 Weight > 20 kg: 10 mg q day • Instructed to ↑ calcium to RDA • Mean spine areal-BMD Z-scores (adjusted for sex, age, body surface area) increased Outcome: from a mean of –2.7 at baseline to –1.9 at • DXA spine areal-BMD 6 months (p < 0.01 compared with baseline) and to –1.05 at 12 months (p < 0.001 compared with baseline). • Baseline height z-score significantly greater in placebo group (–0.2 vs. –2.0). • 18 completed study. Rudge, et al. [10] Design: 12 month RCT • Significant ↓ in bone resorption markers in Chronic • Oral alendronate vs. alendronate group (p < 0.01) Glucocorticoids placebo1–2 mg/kg weekly • Lumbar spine: significant ↑ in BMAD in N = 22b , age 4–17 No calcium supplements • Rx Vit D if level < 20 ng/mL alendronate group (p = 0.013) compared with baseline, but not in placebo group (p = 0.16) Outcome: • DXA of spine & femur shaft • Femur mid-shaft: marginal ↑ in CSMI in alendronate group (p = 0.08) compared with baseline, but not in placebo group (p = 0.18) a) 16 juvenile arthritis, 11 systemic lupus erythematosis (SLE), 6 dermatomyositis, 2 Behcet’s syndrome, 2 Wegener’s granulomatosis, 2 undefined. b) 7 juvenile arthritis, 6 SLE, 4 dermatomyositis, 2 IBD, 1 renal transplant, 1 autoimmune anemia, and 1 cystic fibrosis
lupus, dermatomyositis, inflammatory bowel disease, renal transplantation, autoimmune anemia, and cystic fibrosis; only 18 completed the protocol. Second, baseline height z-scores and subject age differed significantly between the intervention and placebo group. Third, the spine and femur BMD was assessed using DXA and was likely confounded by bone size. These data highlight the growing use of bisphosphonates in children, and the need for controlled trials using three dimensional imaging techniques. Insufficient data are available on the long term effects of bisphosphonates to recommend its routine use in pediatric IBD, especially in patients at risk for low bone turnover due to cytokine effects. [113, 154] However, future studies may demonstrate an important role for this treatment in patients requiring long-term glucocorticoid therapy.
Summary In conclusion, children with IBD are at risk for impaired bone mineral accrual. However, studies employing QCT and bone histomorphometry are needed to fully appreciate the magnitude of bone disease in pediatric IBD, as well as the implications for lifetime fracture risk and targeted therapies. Currently, the prevention of bone disease is best accomplished by providing adequate calcium and vitamin D supplementation, and encouraging physical activity. Prospective trials of therapeutic agents need to be performed to assess efficacy and safety in the developing skeleton.
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116. Mitchell MJ, Baz MA, Fulton MN, Lisor CF, Braith RW 2003 Resistance training prevents vertebral osteoporosis in lung transplant recipients. Transplantation 76(3):557–62. 117. Cadogan J, Eastell R, Jones N, Barker ME 1997 Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial. Bmj 315(7118):1255–60. 118. Chan GM, Hoffman K, McMurry M 1995 Effects of dairy products on bone and body composition in pubertal girls. J Pediatr 126(4):551–6. 119. Johnston CC, Jr., Miller JZ, Slemenda CW, Reister TK, Hui S, Christian JC, Peacock M 1992 Calcium supplementation and increases in bone mineral density in children. N Engl J Med 327(2):82–7. 120. Lee WT, Leung SS, Wang SH, Xu YC, Zeng WP, Lau J, Oppenheimer SJ, Cheng JC 1994 Doubleblind, controlled calcium supplementation and bone mineral accretion in children accustomed to a low-calcium diet. Am J Clin Nutr 60(5):744–50. 121. Lloyd T, Andon MB, Rollings N, Martel JK, Landis JR, Demers LM, Eggli DF, Kieselhorst K, Kulin HE 1992 Calcium supplementation and bone mineral density in adolescent children. N Engl J Med 327:82–87. 122. Bonjour JP, Carrie AL, Ferrari S, Clavien H, Slosman D, Theintz G, Rizzoli R 1997 Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial. J Clin Invest 99(6):1287–94. 123. NIH 1994 NIH Consensus Development Panel on Optimal Calcium Intake. JAMA 272:1942–1948. 124. 1997 Food and Nutrition Board, Institute of Medicine: Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. National Academy Press, Washington, DC. 125. Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL 1994 Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988–91. Adv Data (258):1–28. 126. Stauffer JQ 1977 Hyperoxaluria and intestinal disease. The role of steatorrhea and dietary calcium in regulating intestinal oxalate absorption. Am J Dig Dis 22(10):921–8. 127. Worcester EM 2002 Stones from bowel disease. Endocrinol Metab Clin North Am 31(4):979–99. 128. Heaney RP 2003 Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr 78(5):912–9. 129. Heaney RP 2004 Functional indices of vitamin D status and ramifications of vitamin D deficiency. Am J Clin Nutr 80(6 Suppl):1706S–9S. 130. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ 2003 Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77(1):204–10. 131. Armas LA, Hollis BW, Heaney RP 2004 Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 89(11):5387–91. 132. Weaver CM, Fleet JC 2004 Vitamin D requirements: current and future. Am J Clin Nutr 80(6 Suppl):1735S–9S. 133. Calvo MS, Whiting SJ, Barton CN 2004 Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr 80(6 Suppl):1710S–6S. 134. Calvo MS, Whiting SJ 2003 Prevalence of vitamin D insufficiency in Canada and the United States: importance to health status and efficacy of current food fortification and dietary supplement use. Nutr Rev 61(3):107–13. 135. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR 2002 Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone 30(5):771–7. 136. Vieth R 1999 Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 69(5):842–56. 137. Heaney RP 2000 Vitamin D: how much do we need, and how much is too much? Osteoporos Int 11(7):553–5. 138. Valentine JF, Sninsky CA 1999 Prevention and treatment of osteoporosis in patients with inflammatory bowel disease. Am J Gastroenterol 94(4):878–83. 139. Rauch F, Plotkin H, Zeitlin L, Glorieux FH 2003 Bone mass, size, and density in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate therapy. J Bone Miner Res 18(4):610–4.
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140. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R 1998 Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 339(14):947–52. 141. Glorieux FH 2000 Bisphosphonate therapy for severe osteogenesis imperfecta. J Pediatr Endocrinol Metab 13(2 Suppl):989–92. 142. Marini JC 2003 Do bisphosphonates make children’s bones better or brittle? N Engl J Med 349(5): 423–6. 143. Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S 2003 Bisphosphonate-induced osteopetrosis. N Engl J Med 349(5):457–63. 144. Glorieux FH, Rauch F, Shapiro JR 2003 Bisphosphonates in children with bone diseases. N Engl J Med 349(21):2068–71; author reply 2068–71. 145. Steelman J, Zeitler P 2003 Treatment of symptomatic pediatric osteoporosis with cyclic single-day intravenous pamidronate infusions. J Pediatr 142(4):417–23. 146. Gandrud LM, Cheung JC, Daniels MW, Bachrach LK 2003 Low-dose intravenous pamidronate reduces fractures in childhood osteoporosis. J Pediatr Endocrinol Metab 16(6):887–92. 147. Cimaz R, Gattorno M, Sormani MP, Falcini F, Zulian F, Lepore L, Bardare M, Chiesa S, Corona F, Dubini A, Lenhardt A, Martini G, Masi L, Bianchi ML 2002 Changes in markers of bone turnover and inflammatory variables during alendronate therapy in pediatric patients with rheumatic diseases. J Rheumatol 29(8):1786–92. 148. Acott PD, Wong JA, Lang BA, Crocker JF 2005 Pamidronate treatment of pediatric fracture patients on chronic steroid therapy. Pediatr Nephrol 20(3):368–73. 149. Stewart WA, Acott PD, Salisbury SR, Lang BA 2003 Bone mineral density in juvenile dermatomyositis: assessment using dual x-ray absorptiometry. Arthritis Rheum 48(8):2294–8. 150. Rodd C 2001 Bisphosphonates in dialysis and transplantation patients: efficacy and safety issues. Perit Dial Int 21(3 Suppl):S256–60. 151. Klein GL, Wimalawansa SJ, Kulkarni G, Sherrard DJ, Sanford AP, Herndon DN 2005 The efficacy of acute administration of pamidronate on the conservation of bone mass following severe burn injury in children: a double-blind, randomized, controlled study. Osteoporos Int 16(6):631–5. 152. Ringuier B, Leboucher B, Leblanc M, Troussier F, Duveau E, Audran M, Ginies JL 2004 Effect of oral biphosphonates in patients with cystic fibrosis and low bone mineral density. Arch Pediatr 11(12):1445–9. 153. Hawker GA, Ridout R, Harris VA, Chase CC, Fielding LJ, Biggar WD 2005 Alendronate in the treatment of low bone mass in steroid-treated boys with Duchennes muscular dystrophy. Arch Phys Med Rehabil 86(2):284–8. 154. Gordon CM 2006 Bone loss in children with Crohn disease: Evidence of “osteoimmune” alterations. J Pediatr 148(4):429–32. 155. Cole JH, Scerpella TA, van der Meulen MC 2005 Fan-beam densitometry of the growing skeleton: are we measuring what we think we are? J Clin Densitom 8(1):57–64. 156. McKay HA, Petit MA, Bailey DA, Wallace WM, Schutz RW, Khan KM 2000 Analysis of proximal femur DXA scans in growing children: comparisons of different protocols for cross-sectional 8-month and 7-year longitudinal data. J Bone Miner Res 15(6):1181–8. 157. Shypailo RJ, Ellis KJ 2005 Bone assessment in children: comparison of fan-beam DXA analysis. J Clin Densitom 8(4):445–53. 158. Koo WW, Hammami M, Shypailo RJ, Ellis KJ 2004 Bone and body composition measurements of small subjects: discrepancies from software for fan-beam dual energy X-ray absorptiometry. J Am Coll Nutr 23(6):647–50. 159. Katzman DK, Bachrach LK, Carter DR, Marcus R 1991 Clinical and anthropometric correlates of bone mineral acquisition in healthy adolescent girls. J Clin Endocrinol Metab 73(6):1332–9. 160. Prentice A, Parsons TJ, Cole TJ 1994 Uncritical use of bone mineral density in absorptiometry may lead to size-related artifacts in the identification of bone mineral determinants. Am J Clin Nutr 60(6):837–42. 161. Bianchi ML, Cimaz R, Bardare M, Zulian F, Lepore L, Boncompagni A, Galbiati E, Corona F, Luisetto G, Giuntini D, Picco P, Brandi ML, Falcini F 2000 Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children: a prospective multicenter study. Arthritis Rheum 43(9):1960–6.
22 Assessment of Growth and Nutritional Status in Pediatric Inflammatory Bowel Disease Babette Zemel∗
Introduction Growth failure and poor nutritional status are common in children with IBD, and can occur before the presentation of other symptoms, particularly among children with Crohn disease [1–5]. Inadequate energy intake can be a major cause of nutrition-related growth failure in children with IBD, but nutrient deficiencies can also contribute to nutrition-related growth failure. Disease severity and treatment regimens, such as glucocorticoid use, also influence growth status. Growth status is a good indicator of overall well-being and nutritional status in children [6], but additional factors, such as genetic potential and timing of sexual maturation also affect growth status. Thus, clinical assessment of growth and nutritional status requires consideration of current and previous growth status, skeletal and sexual maturation, genetic potential for growth, biochemical indicators of micronutrient status, and evaluation of dietary intake. The assessment of growth and nutritional status has two components. The first involves the data acquisition or measurement, such as obtaining height and weight information. The second component is the determination of status, which is the interpretation of the measurement in relation to an appropriate reference. For example, knowing that a child has a height measurement of 145 centimeters has little meaning until height status is determined by comparing the measurement to a growth chart to show that the height is at the 3rd percentile for age and gender. The height status must further be interpreted in light of the genetic and biological potential for growth as assessed by factors such as mid-parental height, ethnicity, skeletal age and sexual maturation.
Medical History and Laboratory Evaluation The standard pediatric medical evaluation contains some elements of nutritional assessment. In particular, the medical history should contain a nutritional history including review of a “typical” day’s food intake, past dietary history, use of energy, vitamin, or mineral supplements, and ∗ 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, 3535 Market Street, Room 1560, Philadelphia, PA 19104–4399, Phone: 215-590-1669, Fax: 215-590-0604, E-mail:
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uncommon food practices (such as pica, vegan diet, etc). The Dietary Reference Intakes [7–12] can be used as a guide for assessing dietary quality. However, children with IBD may have increased nutrient requirements (due to inflammation, stool losses, low body stores of nutrients, increased nutrient metabolism [13]) that might not be reflected in the dietary recommendations for healthy children and adolescents. The medical history should include a growth chart review to evaluate past growth patterns, including pubertal history. The physical examination should include current weight, height, mid-arm circumference, a triceps skinfold measurement, mid-parental height, and assessment of pubertal maturation. Details of the recommended methods, equipment, and reference standards are given below. Laboratory evaluation should be based on the outcome of the history and physical examination for each individual patient. Body mass index (weight-for-height [2]) and upper arm anthropometry provide a good indication of energy and protein malnutrition. Further assessment of the adequacy of energy and protein intake can be determined by serum albumin and prealbumin; albumin levels reflect the last month (half-life ∼18 to 20 days) and prealbumin levels reflect the last week (half-life ∼2 to 3 days) of nutrient intake. Iron status can be screened by a complete blood count (hemoglobin, hematocrit, red cell indices) assessment. Other iron studies (serum iron, total ironbinding capacity, transferrin, ferritin) should be obtained as indicated. Plasma zinc is not an ideal indicator of zinc status since it is a poor reflection of total body zinc stores [14]. A low plasma zinc level suggests zinc deficiency, but zinc stores may be depleted in the presence of a normal plasma zinc level. Vitamin D is another nutrient of concern and hypovitaminosis D has been documented in children with Crohn disease [15]. Additional laboratory tests may include serum calcium, phosphorus, and alkaline phosphatase. Bone mineral content or bone density (dual-energy x-ray absorptiometry) is used to identify poor bone mineral accrual in children, and history of fracture or bone pain is also an indicator of bone abnormalities. Skeletal age determination is important for diagnosing delayed bone age, and for determining the potential for catch-up growth.
Anthropometry The anthropometric examination is a rapid, inexpensive, noninvasive means of determining both short- and long-term growth and nutritional status. Although the measurements are relatively simple, they require properly designed and regularly calibrated equipment and trained personnel to perform the measurements. This is especially important for monitoring changes in the health and nutritional status of the child over time, since measurement errors can have a profound effect on growth velocity. Several measures are included in the assessment since each one provides unique information and contributes to the global picture of nutritional status. Measurement results are compared to appropriate reference standards in order to evaluate growth and nutritional status and monitor changes in status over time. The Measurement of Growth Since the presentation of IBD occurs in childhood and adolescence, the assessment of growth status consists of measurement of weight and height. They should both be measured at each office visit, so that current body mass index (weight/height [2]) can be calculated. For children with disabilities or severe scoliosis, alternative linear growth measures such as length, upper arm length or lower leg length are recommended as described elsewhere [16].
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Weight Weight is a key measure in the assessment of both growth and nutritional status. As a measure of overall body mass, it is an indicator of growth. It is also an excellent short- term measure of nutritional status because it can change rapidly. Weight status can be determined by comparison with age and gender appropriate weight charts. However, determination of underweight and overweight requires a measurement of height since children of the same weight who differ in height can have vastly different “relative weights”. For children two to twenty years of age, body mass index is the preferred measure of relative weight. Weight should be measured on a digital electronic or beam balance scale to the nearest 0.1 kg. The scale should be checked weekly with known calibration weights to assure proper functioning. The scale should be set to zero prior to each measurement to be sure that there is no drift in the functioning of the equipment. Shoes and heavy clothing should be removed, and pockets emptied for the measurement of weight. Height Height is a cumulative measure of a child’s nutritional history. Deficits in height can represent previous nutritional insults, or current growth failure. Height measurements over time can be used to assess current growth failure or catch-up growth. Height should be measured with a wall-mounted stadiometer with a smoothly gliding headboard that is firmly perpendicular to the wall. Digital stadiometers should be calibrated daily with a fixed calibration rod to assure proper functioning. As an alternative, a carefully positioned wallmounted tape measure can be used, provided the markings are readable and a head paddle is available that will fit at a 90-degree angle to the wall. Height measurements should be accurate to 0.1 cm. Stadiometers and wall-mounted tape measures should be situated where the floor is level and the child can be positioned with the back of their heels parallel to their back. To assure accurate height measurements, shoes and interfering hair adornments must be removed. The child should be positioned with the heels, buttocks, and back of the head against the stadiometer [17]. The arms should be extended and relaxed, and the heels as close together as is comfortable for the child. The head should be positioned so that the Frankfort plane is parallel to the floor. The Frankfort plane is an imaginary line that extends from the lower margin of the orbit to the upper margin of the auditory meatus (Figure 22.1). Consistent positioning of the head will significantly reduce measurement error, especially for longitudinal follow-up of growth status and calculation of growth velocity. Poor posture also contributes to measurement error. This can be avoided by instructing the child to stand as straight as possible and to inhale deeply and hold their breath momentarily as the height measurement is obtained. For older children an alternate technique involves a “stretched” height measurement whereby the anthropometrist glides the palm of their hand along the spine in an upward sweeping motion and applies upward pressure to the mastoid processes to encourage fully erect posture. Because of the measurement error, height measurement should be taken in triplicate and the mean recorded. Genetic potential for growth can be estimated if the heights of both biological parents are available. These should be recorded on the growth chart and the mid-parent height computed (the average height of the mother and father). Tables with the values to adjust a child’s height based on mid-parent height are age and gender-specific, so periodic re-evaluation of genetic potential for growth is warranted [18]. Growth Velocity Growth velocity is calculated as the change in height (or weight) divided by the time between measurements. For children who are not fully mature, growth velocity is an excellent indicator of
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Figure 22.1. The Frankfurt plane extends from the auditory meatus to the lower border of the orbit. For proper measurement of height the Frankfurt plane should be parallel to the floor as shown in the figure.
current nutritional status and well-being. Growth velocity varies with age, gender, maturational status and season, so these factors must be considered in interpreting velocity measures. There are several reasons why growth velocity measurements should be used cautiously. The accuracy of the growth velocity measurement is sensitive to the accuracy and precision of the measurements on which it is based. Because growth velocity is derived from two measurements, each with their own measurement error, the measurement error associated with the velocity is even greater than that of a single measurement. Thus, as shown by Voss et al. [19], a height measurement of a 5-year-old child at the 3rd percentile for age has a 95% confidence interval that spans the 2nd to the 4th percentile. In contrast, a 12-month height velocity for that child has a 95% confidence interval ranging from the 8th to the 52nd percentile. Growth velocity should be calculated over a six or twelve month interval depending on the velocity reference standards to be used. Assessment of growth velocity over a longer or shorter interval than that used in the standards may overestimate or underestimate the true velocity, in part due to seasonal fluctuations in growth velocity and other growth spurts. Anthropometric Indicators of Nutritional Status Anthropometric indicators of nutritional status primarily reflect energy and protein status. The most commonly used indicator is body mass index, an overall indicator of relative weight that is sensitive to overnutrition and undernutrition. Additional indicators, based on upper arm anthropometry
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(mid-upper arm circumference and the triceps skinfold thickness), provide estimates of lean and fat tissues at sites known to be sensitive to nutrition and health. Body Mass Index An optimal relative weight measure is one that is an index of weight independent of height. In adults, body mass index is a simple relative weight measure that has a zero correlation with height and does not vary significantly by gender. Therefore, among adults, the nutritional classification scheme is based on ranges of BMI as shown in Table 22.1. For children, body mass index varies significantly with age and gender, so it is critical to compare body mass index values to the Centers for Disease (CDC) charts. For children, a classification scheme based on body mass index has not been well-defined, except for classification of overweight and obesity as shown in Table 22.1. It is important to note that these definitions are intended as screening classification, requiring further medical evaluation to more accurately assess nutritional status and related health concerns [20]. Upper Arm Anthropometry Mid–upper arm circumference is a good measure of short term nutritional status. It is a summary measure of muscle, fat, and bone on the arm, and is an easily accessible measurement site requiring simple equipment. A nonstretchable flexible measuring tape should be used with measurements accurate to 0.1 cm. The measurement of the midpoint is taken with the arm flexed at 90° and the palm facing upward (Figure 22.2). The midpoint of the upper arm is located midway between the tip of acromion process and the olecranon [17]. The midpoint should be marked with a washable ink pen. Prior to measurement of arm circumference, the arm should be extended to a fully relaxed position (gently shaking the arm usually assures that it is relaxed). The circumference measurement should be taken over the marked midpoint with the tape perpendicular to the long axis of the arm (Figure 22.3). Good measurement technique involves checking to be sure there is no pinching or gaping of the tape as it encircles the arm. The triceps skinfold thickness is taken at the same location as the mid-upper arm circumference over the triceps muscle on the back of the upper arm [17]. It is a measure of subcutaneous fat stores, serving as an overall indicator of energy stores. It correlates well with total body fat measured by other techniques. Spring-loaded skinfold calipers are needed to measure skinfold thickness accurately. Holtain skinfold calipers are scaled to 0.2 mm and Lange calipers are scaled to 0.5 mm. To measure the triceps skinfold thickness, the child should be upright with their arm hanging down in a relaxed position. The fold of fat and skin is lifted away from the underlying triceps muscle at the level marked previously for the mid-upper arm circumference measurement. While continuously holding the skinfold in position, the calipers are placed on the skin next to the fingers lifting up the fold and released so that they exert a constant pressure on the subcutaneous fat fold. The reading should be taken 4 seconds after releasing the caliper’s handles. Table 22.1. Nutritional status classification of relative weight status based on the body mass index for children [28, 29] and adults [30, 31]. Pediatric Ranges Undetermined < 85th Percentile 85th to 95th Percentile Greater than 95th Percentile
Adult Ranges
Nutritional Status Classification
Less than 18.5 kg/m2 18.5 to 25 kg/m2 25 to 30 kg/m2 Greater than 30 kg/m2
Undernourished Healthy Weight Overweight Obese
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Figure 22.2. Mid Upper Arm Circumference is taken at the mid-point of the upper arm. The flexible tape measure should be positioned perpendicular to the long axis of the arm so that there is no pinching or gaping.
Figure 22.3. The triceps skinfold thickness is taken at the same location as the mid-upper arm circumference using skinfold calipers.
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Calculation of Upper Arm Fat Area and Upper Arm Muscle Area The mid-upper arm circumference and triceps skinfold thickness can be combined to calculate upper arm fat area and upper arm muscle area. These measures correlate well with total body stores of fat and muscle. However, unlike total body measures of fat and muscle, reference data from the National Health and Nutrition Examination Survey for these measures are available for upper arm fat area and muscle area so that they can be used in the clinical setting. The formulas for calculating upper arm fat area and upper arm muscle area are as follows: Upper Arm Area = Armcirc2 /4 × Arm Muscle Area mm2 = [Armcirc − (triceps × 2 /4 × Arm Fat Area mm2 = Arm Area − Arm Muscle Area, Note: arm circumference can be converted from cm to mm by multiplying by 10, and = 3.14 Use of Reference Data Appropriate use and interpretation of reference data is critical in the anthropometric assessment of growth and nutritional status. Anthropometric measures change with age and differ by sex, and the rates of change also vary by age. Therefore, comparison of a child’s measurements with age and sex specific reference ranges is a powerful index of their status. For example, it’s not possible to determine if a weight of 25 kg is a healthy weight for a child unless compared to the age and sex-specific reference percentiles for weight. Similarly, a child may gain weight between visits, but failure to maintain their weight percentile is a potential indicator of inadequate energy intake to sustain normal growth. For screening purposes, the 5th percentile of reference data is often referred to as a cut-off point for growth failure or failure-to-thrive. By definition, five percent of the reference population had values below the 5th percentile, so it is important to recognize that values below this cut point are not necessarily abnormal. For children who are at risk for nutritional complications, the 5th percentile may be too low a threshold. The 25th percentile may be a more appropriate point for further nutritional evaluation or intervention to prevent nutritional complications. For children whose status is above the 25th percentile, failure to maintain percentile rank may also represent declining growth and nutritional status. Ideal reference data should be based on a large, representative sample of children from a well-nourished population, with appropriate characterization of the variability in the population. Table 22.2. lists the recommended reference data for anthropometric measures of growth and nutritional status.
Table 22.2. Recommended reference data for the assessment of growth and nutritional status Measure Height Weight Body Mass Index Growth Velocity Upper Arm Anthropometry Skeletal Maturation Sexual Maturation
Reference Data Source CDC Growth Charts [32] CDC Growth Charts [32] CDC Growth Charts [32], Interantional Obesity Task Force Standards [33] Incremental Growth Charts [34], Height Velocity Standards [35] Norms for upper limb fat and muscle [36, 37] Greulich and Pyle Atlas [21] Tanner Whitehouse III Method [22] National Health and Nutrition Examination Survey [26, 27, 38]
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Skeletal Maturation Skeletal maturation provides an excellent index of the biological maturation of the child. Figure 22.4 depicts the hand-wrist x-rays of two healthy boys, one who is 10 years of age and the other who is 14 years of age, illustrating the differences in the size and shape of the epiphyses. Delayed skeletal maturation can occur for a variety of reasons, including chronic undernutrition. The maturation of the epiphyses of the hand and wrist as seen on a hand-wrist radiograph is compared to an atlas or standard of typical stages of development in healthy children in order to assign a “bone age”. In the United States, the Greulich and Pyle Atlas [21] is most commonly used and elsewhere, the Tanner-Whitehouse III [22] system is used. The Greulich and Pyle Atlas was based on a longitudinal sample of Caucasian well-off children participating in the Brush Foundation study between 1931 and 1942 in Cleveland, Ohio. The atlas depicts a series of handwrist radiographs illustrating the typical bone development of children at various ages: from birth to 18 years in girls, and from birth to 19 years in boys. The standard deviation in months for each bone age is also given and a bone age that is more than two standard deviations above or below expected is considered to be clinically significant. The Tanner-Whitehouse III method is more commonly used outside the U.S. [27]. This method assigns a unique score to 13 bones of the hand and wrist (the radius, the ulna; the first, third, and fifth metacarpal; and the proximal, middle, and distal phalanx). The composite score is then used to calculate the bone age. The reference ranges for bone ages are based on large international (mainly European) studies conducted between the 1950s to the 1990s. The authors provide reference ranges (3rd to the 97th percentile) for boys and girls in order to assess advanced or delayed skeletal maturation. The Tanner-Whitehouse III method has the advantage of assigning scores to individual bones rather than the entire hand-wrist as in the Greulich and Pyle system, and is thereby more flexible for children with mosaic maturation of the bones in the hand-wrist.
10 Year Old Male
14 Year Old Male
Figure 22.4. Hand-Wrist Radiographs showing different levels of skeletal maturation of the radius and ulna, carpal bones, metacarpals and phalanges.
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Sexual Maturation Delayed sexual matuation is common in children with IBD, and is characteristic of children with poor growth. Delayed sexual maturation may manifest as delayed onset or delayed progression through the stages of sexual development. Sexual maturation is assessed by classification of breast development in girls, genital development in boys, and pubic hair development in both boys and girls into the five stages described by Tanner [23]. Self-assessment using line drawings and written descriptions [24] of Tanner stages has been validated in children with Crohn disease [25] and are shown in Figure 22.5a and b. For proper use of the self-assessment questionnaire, children should be encouraged to read the descriptions carefully and view themselves in a mirror in order to most accurately select their stage of development. Parents may assist with the self-assessment. When Tanner stage is assessed by physical exam, testes size is measured by palpation and compared to an orchidometer. The ranges of testes size corresponding to Tanner’s stages of genital development in boys are shown in Table 22.3. Sexual maturation is also characterized by menarche, the onset of menses in girls and by spermarche, the onset of nocturnal emmissions in boys. The age at menarche and the onset and progression through Tanner stages are variable in healthy children. Recent descriptions of these maturational events in children from the U.S. National Health Examination Survey have demonstrated ethnic differences in the timing of onset and progression through the stages of sexual maturation [26, 27].
Figure 22.5a. Self-Assessment Questionnaire for Assessment of the Tanner Stages of Sexual Maturation – Girls, by permission of Naomi M. Morris
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Figure 22.5b. Self-Assessment Questionnaire for Assessment of the Tanner Stages of Sexual Maturation – Boys, by permission of Naomi M. Morris
Table 22.3. Categorization of tanner stage of sexual maturation based on testes size. Tanner Stage
Testes Size
1 2 3 4 5
=3 cc 4 to 6 cc 8 to 10 cc 12 to 15 cc >15 cc
Summary Growth and nutritional assessment are indicators of the overall well-being of children and adolescents with IBD. Laboratory information has limited utility in determining nutritional status but is useful for identifying deficiencies for some nutrients such as iron. The anthropometric exam provides important information about short and long-term nutritional status, but requires attention to detail to obtain accurate and precise measures. Comparison with well-designed reference data is key to determining growth and nutritional status and monitoring changes over time. Delayed skeletal and sexual maturation, and assessment of genetic potential for growth provide a context for interpreting growth and nutritional status. References 1. Bousvaros A, Sylvester F, Kugathasan S, et al. Challenges in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2006;12(9):885–913. 2. O’Sullivan M, O’Morain C. Nutrition in inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2006;20(3):561–73.
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3. Paerregaard A, Uldall Urne F. Anthropometry at the time of diagnosis in Danish children with inflammatory bowel disease. Acta Paediatr 2005;94(11):1682–3. 4. Newby EA, Sawczenko A, Thomas AG, et al. Interventions for growth failure in childhood Crohn disease. Cochrane Database Syst Rev 2005(3):CD003873. 5. Sentongo TA, Semeao EJ, Piccoli DA, et al. Growth, body composition, and nutritional status in children and adolescents with Crohn disease. J Pediatr Gastroenterol Nutr 2000;31(1):33–40. 6. Zemel BS, Riley EM, Stallings VA. Evaluation of methodology for nutritional assessment in children: anthropometry, body composition, and energy expenditure. Ann Rev Nutr 1997;17:211–35. 7. IOM (Institute of Medicine). 1997. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Food and Nutrition Board. Washington, DC: National Academy Press. 8. IOM (Institute of Medicine). 2002. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (macronutrients). Report of the Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Food and Nutrition Board. Washington, DC: National Academy Press. 9. IOM (Institute of Medicine). 2000. Dietary reference intakes vitamin C, vitamin E, selenium, and carotenoids. Report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Food and Nutrition Board. Washington, DC: National Academy Press. 10. Institute of Medicine (U.S.). Panel on Dietary Reference Intakes for Electrolytes and Water. Dietary reference intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC: National Academies Press; 2004. 11. Institute of Medicine (U.S.). Panel on Micronutrients. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc : a report of the Panel on Micronutrients and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Washington, DC: National Academy Press; 2002. 12. Institute of Medicine (U.S.). Standing Committee on the Scientific Evaluation of Dietary Reference Intakes., Institute of Medicine (U.S.). Panel on Folate Other B Vitamins and Choline., Institute of Medicine (U.S.). Subcommittee on Upper Reference Levels of Nutrients. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B b6 s, folate, vitamin B b12 s, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998. 13. Kleinman RE, Baldassano RN, Caplan A, et al. Nutrition support for pediatric patients with inflammatory bowel disease: a clinical report of the North American Society for Pediatric Gastroenterology, Hepatology And Nutrition. J Pediatr Gastroenterol Nutr 2004;39(1):15–27. 14. Wood RJ. Assessment of marginal zinc status in humans. J Nutr 2000;130(5S Suppl):1350S–4S. 15. Sentongo TA, Semaeo EJ, Stettler N, et al. Vitamin D status in children, adolescents, and young adults with Crohn disease. Am J Clin Nutr 2002;76(5):1077–81. 16. Zemel B, Stallings V. Alternative measures for assessing linear growth. In: Ulijaszek S, Johnston F, Preece M, eds. Cambridge Encyclopedia of Human Growth. Cambridge: Cambridge University Press; 1998:74–5. 17. Lohman TG, Roche AF, Martorell R. Anthropometric standardization reference manual. Champaign, IL: Human Kinetics Books; 1988. 18. Himes JH, Roche AF, Thissen D, et al. Parent-specific adjustments for evaluation of recumbent length and stature of children. Pediatrics 1985;75(2):304–13. 19. Voss LD, Wilkin TJ, Bailey BJ, et al. The reliability of height and height velocity in the assessment of growth (the Wessex Growth Study). Arch Dis Child 1991;66(7):833–7. 20. Flegal KM, Tabak CJ, Ogden CL. Overweight in children: definitions and interpretation. Health Educ Res 2006;21(6):755–60. 21. Greulich W, Pyle S. Radiographic Atlas of Skeletal Development of the Hand and Wrist: Stanford University Press; 1950. 22. Tanner J, Healy M, Goldstein H, et al. Assessment of Skeletal Maturity and Prediction of Adult Height (TW3) Method. London: W.B. Saunders; 2001. 23. Tanner JM. Growth at Adolescence. 2nd ed. Oxford: Blackwell Scientific Publication; 1962.
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24. Morris NM, Udry JR. Validation of a self-administered instrument to assess stage of adolescent development. J Youth and Adolesc 1980;9:271–80. 25. Schall JI, Semeao EJ, Stallings VA, et al. Self-assessment of sexual maturity status in children with Crohn disease. J Pediatr 2002;141(2):223–9. 26. Sun SS, Schubert CM, Liang R, et al. Is sexual maturity occurring earlier among U.S. children? J Adolesc Health 2005;37(5):345–55. 27. Sun SS, Schubert CM, Chumlea WC, et al. National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics 2002;110(5):911–9. 28. Ogden CL, Flegal KM, Carroll MD, et al. Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 2002;288(14):1728–32. 29. Barlow SE, Dietz WH. Obesity evaluation and treatment: Expert Committee recommendations. The Maternal and Child Health Bureau, Health Resources and Services Administration and the Department of Health and Human Services. Pediatrics 1998;102(3):E29. 30. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006;295(13):1549–55. 31. Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 2004;291(23):2847–50. 32. Ogden CL, Kuczmarski RJ, Flegal KM, et al. Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics 2002;109(1):45–60. 33. Cole TJ, Bellizzi MC, Flegal KM, et al. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 2000;320(7244):1240–3. 34. Baumgartner RN, Roche AF, Himes JH. Incremental growth tables: supplementary to previously published charts. Am J Clin Nutr 1986;43(5):711–22. 35. Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;107(3):317–29. 36. Frisancho A. New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr 1981;34:2450–45. 37. Frisancho A. Anthropometric standards for the assessment of growth and nutritional status. Ann Arbor, MI: University of Michigan Press; 1990. 38. Chumlea WC, Schubert CM, Roche AF, et al. Age at menarche and racial comparisons in US girls. Pediatrics 2003;111(1):110–3.
Section 4 Medical Therapy
23 Pharmacogenetics in Inflammatory Bowel Disease Marla C. Dubinsky∗
Introduction As the arsenal of IBD therapies becomes more powerful, choosing a therapy that is appropriate for an individual patient requires an understanding of the goals of IBD therapy. Maximizing the efficacy of IBD-directed therapies while minimizing their toxicity remains the principal objective in developing management strategies for IBD patients. Unfortunately, for most therapeutic agents and the majority of diseases, it is not currently possible to identify patients most likely to benefit from therapy on the basis of their genetic profile, nor is it possible to identify those individuals at risk of a severe adverse reaction. However, the introduction of pharmacogenetics in the management of IBD patients has helped clinicians achieve these objectives targeted at patients receiving either 6-Mercaptopurine (6-MP) or azathioprine (AZA), both members of the thiopurine family. This research strategy involved studying the Thiopurine S-methyltransferase (TPMT) drug-metabolizing enzyme which influences the concentration of drug reaching its target (pharmacokinetics). Pharmacogenetics is the study of the role of inheritance in individual variation in drug response – with inadequate therapeutic response at one end of the spectrum and adverse drug reactions at the other. Currently, most IBD patients are treated as if they are homogenous. However patients would certainly benefit from being stratified into those that will or will not have a benefit from a therapy and further divided into those that will or will not have a toxic response to a therapy. Moreover, patients could be directed to an alternate therapy that would be more beneficial or they could avoid toxicities by being aware that the available therapeutics offer little to no benefit. The recognition and understanding of the factors influencing therapeutic response has the potential to allow clinicians and the pharmaceutical industry the ability to individualize dosing and administration regimens to maximize benefit and avoid toxicity.
A Historical Perspective of TPMT Pharmacogenetics TPMT serves as a model of pharmacogenetic research such that TPMT was highlighted by the United States Food and Drug Administration (FDA) as one of the two ‘valid biomarkers’ for pharmacogenetics and pharmacogenomics in the 2003 FDA ‘Draft Guidance
*Assistant Professor of Pediatrics, David Geffen School of Medicine, UCLA, Director Pediatric IBD Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, Tel.: 310-423-7100, E-mail:
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%of subjects/0.5 units of activity
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Figure 23.1. Frequency distribution histogram of level of RBC TPMT enzyme activity in blood samples from 298 randomly selected Caucasian blood donors.
for Pharmacogenomic Data Submission’ [1]. TPMT is a cytosolic drug-metabolizing enzyme that catalyses the S-methylation of 6-MP and AZA [2, 3]. Thiopurines have a relatively narrow therapeutic index, with the potential for life-threatening drug-induced toxicity, primarily myelosuppression [4–6]. The notion that inherited genetic variability may play an important role in drug responsiveness in patients receiving thiopurines first arose when Weinshilboum noted striking differences in the way patients responded to standard therapeutic doses. He described large inherited variations in human tissue TPMT enzyme activity [7]. Levels of TPMT activity in the RBC reflect relative levels of that enzyme in the kidney, liver and lymphocyte [8–11]. Population based studies have demonstrated that TPMT activity is inherited as an autosomal co dominant trait. The frequency distribution of the TPMT polymorphisms reveals that 1 in 300 (0.3%) individuals have low to absent enzyme activity (homozygous TPMTL ), 11% have intermediate (heterozygous TPMTH /TPMTL ) and 89% have normal to high levels of activity (homozygous/wild type TPMTH ) [7]. Subsequently the human TPMT gene was cloned [12–14] and to date a total of 21 TPMT genetic polymorphisms have been identified. [15]. TPMT*3A, a double mutant, (A719G and G460A) is the most common allelic variant and predominates in Caucasians (frequency 5%) (Figure 23.2). Each mutation however,
Human TPMT Polymorphisms TPMT*1 (wild type)
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TPMT*3A G460A
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Figure 23.2. Common TPMT Mutant Alleles. Wild type (TPMT1) is the most common and associated with normal TPMT enzyme activity.
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TPMT*3B (G460A) and TPMT*3C (A710G), can occur independently. Although mutant allele frequencies may be similar among different ethnicities, the prevalent mutant alleles do differ such that TPMT*3C is most common among African-Americans [16]. TPMT *3C is also the prevalent mutant allele in East Asia (2%) [17]. The degree of reduction in TPMT activity and immunoreactive protein varies based on the mutant allele present in an individual [14]. The presence of TPMT*3A and *3B result in a virtual lack of TPMT enzyme activity and protein in the tissues of subjects who carry these alleles and, as a result, patients homozygous for these alleles can suffer severe, life-threatening myelosuppression when treated with standard doses of thiopurines, that is, they are ‘overdosed’ on standard doses [4, 5, 18]. TPMT*2, is also associated with a decrease in TPMT enzyme activity yet not to the same extent as TPMT*3A and *3B. [14, 15, 19, 20].
Pharmacology of Thiopurines 6-MP and AZA are often used interchangeably in the treatment of IBD. Once absorbed, AZA is rapidly converted via a non-enzymatic process to 6-MP and S-methyl-4-nitro-5-thioimidazole. AZA is 55% of 6-MP by molecular weight and 88% of AZA is converted to 6-MP such that a conversion factor of 2.08 must be taken into account when calculating equivalent doses of 6-MP and AZA. 6-MP (or AZA converted to 6-MP) undergoes a complex biotransformation to its inactive and active metabolites via competing catabolic and anabolic metabolic pathways (Figure 23.3). 6-MP undergoes extensive “first pass” catabolism by xanthine oxidase (XO), which is present in both the intestinal mucosa and liver limiting the systemic bioavailability of thiopurines. 6-MP also serves as a substrate for the thiopurine methyltransferase (TPMT) enzyme, which methylates 6-MP to the inactive methylated-mercaptopurine metabolite (6-MeMP). Like XO, TPMT may be present in the intestinal mucosa and may also contribute to the pre-systemic catabolism of 6-MP. The hypoxanthine phosphoribosyl transferase (HPRT) enzyme is paramount to the initiation of the anabolic transformation of 6-MP to its active metabolites. The intracellular activation of 6-MP yields the first active intermediate metabolite, thioinosine monophosphate (TiMP), which is then rapidly converted to the thioguanine nucleotides (6-TGN). The cytotoxic and AZATHIOPRINE
6-TU
XO
TPMT
6-MP
6-MMP HPRT
6-TIMP IMPDH
6-TXMP GMPS
6-TGMP KINASE
6-TGDP KINASE
6-TGTP
Figure 23.3. Thiopurine metabolism. Oral azathioprine (AZA) is rapidly converted to 6-MP by a nonenzymatic process [19]. Initial 6-MP transformations occur along competing catabolic (XO: xanthine oxidase; TPMT: thiopurine methyltransferase) and anabolic (HPRT: hypoxanthine phosphoribosyltransferase) enzymatic pathways. Once formed, 6-thiosine 5’-monophosphate (6-TImP) may be transformed into 6-thioguanine nucleotides (6-TGN) by the rate limiting inosine monophosphate dehydrogenase (IMPDH) or methylated into 6-methyl-mercaptopurine nucleotides (6-MMP).
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immunosuppressive effects of thiopurines, were, until recently, presumed to be primarily mediated via the incorporation of 6-TGN into cellular nucleic acids ultimately resulting in inhibition of lymphocyte proliferation. Recent advances in the understanding of the mechanism of action of thiopurines, however, suggests that the 6-thioguanine triphosphate (6-thio-GTP) nucleotide, may play an important role in the process of signaling lymphocyte apoptosis by inhibiting Rac1 activation in T cells [21]. The triphosphate metabolite appears to correlate most with clinical efficacy of thiopurines [22]. Further research is needed to examine the role of 6-thio-GTP in patients with IBD. The major enzymatic process that competes with the intracellular activation pathway is the thiol methylation of TiMP by TPMT. Although these methylated metabolites (Me-TiMP or 6-MMPR) have been shown in vitro to inhibit denovo purine synthesis, in vivo evidence is lacking as to their role in the mechanism of action of thiopurines [6]. TPMT methylation competes with the activation pathway and influences the relative proportion of intracellular active 6-TGN produced by a given individual. This inverse relationship between TPMT and 6-TGN has important implications in both the efficacy and toxicity of thiopurines. Patients with intermediate or absent TPMT activity can produce significantly higher concentrations of 6-TGN. The negative correlation between TPMT and 6-TGN was first reported in the treatment of childhood leukemia [4] and has since been confirmed among pediatric IBD patients [23]. Physicians should also pay particular attention to potential drug interactions such that the inhibition of recombinant human TPMT has been demonstrated in vitro and has been reported in vivo with both 6-MP and olsalazine [24, 25]. Thus caution should be taken when co-administering 5-ASA’s and thiopurines as TPMT inhibition may increase the risk of developing myelosuppression. A recent study demonstrated that after 5-ASA withdrawal the mean 6-TGN levels significantly decreased without significant changes in TPMT activity or blood counts suggesting an alternate mechanism to TPMT inhibition [26]. This effect may be additive in patients already genetically determined to produce lower levels of the TPMT enzyme such that diligent blood count monitoring is necessary.
The Clinical Application of TPMT Pharmacogenetics As explained above, TPMT methylates thiopurine metabolites at the expense of the formation of 6-TGN. However, patients with less than normal TPMT expression and activity can produce significantly higher concentrations of 6-TGN. This inverse relationship between TPMT and 6-TGN has important implications in both the efficacy and toxicity of thiopurines. The association between TPMT and myelosuppression in IBD patients was published by Colombel et al who reported that 27% of IBD patients experienced leukopenia and/or thrombocytopenia attributable to abnormal TPMT activity [27]. Moreover, TPMT deficiency (homozygote mutant) accounted for 10% of the cases and the median time to onset of bone marrow suppression was 1 month, whilst 17% of cases were TPMT heterozygotes. In this study only 32% of cases of myelosupression were secondary to lower TPMT activity. Thus patients should be regularly monitored with complete blood counts and secondary causes such as concomitant medications or concurrent viral illness should be considered. The a priori knowledge of an individual’s TPMT activity can identify those patients prone to early leukopenic events when treated with standard doses of thiopurines as a result of intermediate TPMT levels. Moreover, the 1 in 300 individuals at risk for potentially life-threatening complications can be rapidly identified and alternate immunomodulators can be administered. Intermediate TPMT activity is not a contraindication for thiopurine use and typically these patients can safely receive thiopurines at lower doses (30–50% of standard dose) and dose escalation can be successful while patients are monitored closely with regular blood counts and 6-TGN concentrations [28, 29]. For the majority of thiopurine recipients, clinicians can safely administer what is considered an optimal starting dose of 6-MP (1–1.5 mg/kg/day) and AZA
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(2.0–2.5 mg/kg/day) as a result of normal to high TPMT activity. Whether it be empiric or TPMT based dosing, patients require regular blood count and liver chemistry monitoring throughout the duration of thiopurine therapy. It remains unknown as to the safety implications of having high TPMT activity. Elevated levels of 6-MMP have been shown to be associated with an increase frequency of hepatotoxicity as defined by elevations in transaminases > 2x normal [23, 30]. Given that TPMT results in the formation of 6-MMP, it could be hypothesized that patients with high TPMT produce potentially hepatotoxic levels of 6-MMP and the first pass catabolism of the drug in the liver by higher than normal TPMT activity may lead to the accumulation of higher levels of 6-MMP. Liver enzyme elevations typically normalize in a timely manner in response to dose reduction as a result of a decrease in 6-MMP levels. Not all patients experience an elevation in transaminases in association with high 6-MMP levels and few merit a significant dose reduction, however these patients should be closely monitored.
Pharmacokinetics: The Role of Metabolite Monitoring The importance of metabolite monitoring and TPMT activity was first brought to our attention through the research initiated in childhood acute lymphoblastoid leukemia (ALL) [4]. Initial studies in IBD were conducted in the pediatric age group and reported that 6-TGN was shown to be significantly and independently associated with therapeutic response [23, 31]. This study demonstrated that significantly higher median 6-TGN levels were observed at points of clinical response (312) vs. non-response (199). Further analysis revealed that the best probability of treatment response was not significantly increased until 6-TGN levels were greater than 235 and the odds ratio (OR) of a therapeutic response for a 6-TG level higher than a cutoff of 235 was 5.0 as compared to when the levels were below this cut-point. A certain percentage of patients did achieve a therapeutic response with levels < 235, however, this response rate was almost less than ½ the proportion of patients (78%) achieving therapeutic response when levels were >235. Sub therapeutic dosing, or based on these studies, perhaps more appropriately sub therapeutic 6-TGN levels, is the most common reason why patients are not responding to thiopurines. Cuffari et al demonstrated that most patients, initially not responding to low dose thiopurine therapy that underwent dose escalation responded well once they achieved 6-TGN levels > 250 [32]. A recent meta-analysis reported that patients with 6-TGN levels above the threshold value were more likely to be in remission (62%) than those below the threshold value (36%) (pooled odds ratio, 3.3; 95% confidence interval, 1.7–6.3; P < .001) [33]. Metabolite monitoring is most informative in helping clinicians classify therapeutic failures. Non-compliance and under dosing remain the most common reasons for therapeutic failure and can be identified by measuring 6-MP metabolite levels. When both 6-TGN and 6-MMP levels are undetectable, there is a high likelihood that the patient is not adhering to therapy. However, a subgroup of patients continues to fail therapy despite dose escalation and receiving standard or even higher than standard doses of thiopurines. These patients can be divided into 2 distinct subgroups and are defined biochemically by their metabolite profiles. The most common subgroup is composed of patients “resistant” to thiopurines and biochemically characterized by the persistence of sub-therapeutic 6-TGN (< 235) and the preferential shunting towards excessive potentially hepatotoxic 6-MMP levels upon 6-MP/AZA dose escalation [30]. Individuals unmask this metabolic profile when they are challenged with higher doses of the drug. There is a small group of “refractory” patients who, despite therapeutic (> 235) and often potentially toxic 6-TGN (>450) levels, are unable to benefit from the immunosuppressive properties of these therapies. The identification of these 2 subgroups early on the course of therapy can significantly improve patient outcomes by moving patients quickly to alternate immunomodulator therapy.
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Conclusion Genetic inheritance plays a significant role in determining inter-individual variability of drug response. The goal is for patients to be treated as individuals, with a therapeutic plan that identifies a patient’s specific needs. Pharmacogenetics does look promising as a tool to achieve this goal of truly individualized drug therapy. TPMT remains a key example of the translational potential of pharmacogenetics in the treatment of IBD. [34, 35]. It appears that in the future pharmacogenetic studies will broaden its scope to include not only drug metabolism (pharmacokinetics) but also studies on drug targets (pharmacodynamics) [35]. Whole-genome approaches may improve the ability to characterize patient populations and better predict prognosis and drug response. References 1. US Department of Health and Human Services Food and Drug Administratio. Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research & Center for Devices and Radiological Health, 2003. 2. Remy CN. J Biol Chem 1963:238;1078–1084. 3. Lennard L. Eur J Clin Pharmacol 1992:43;329–339. 4. Lennard L, Van Loon JA, Weinshilboum RM. Clin Pharmacol Ther 1989:46;149–154 5. Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM. J Pediatr 1991:119;985–989. 6. Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RM. Clin Pharmacol Ther 1987:41;18–25 7. Weinshilboum RM, Sladek SL. Am J Human Genet 1980:32;651–662. 8. Van Loon JA, Weinshilboum RM. Biochem Genet 1982:20;637–658. 9. Woodson LC, Dunnette JH, Weinshilboum RM. J Pharmacol Exp Ther 1982:222;174–181. 10. Szumlanski CL, Honchel R, Scott MC, Weinshilboum RM. Pharmacogenetics 1992:2;148–159. 11. Coulthard SA, Howell C, Robson J, Hall AG. Blood 1998:92;2856–2862. 12. Honchel R, Aksoy I, Szumlanski C, Wood TC, Otterness DM, Wieben ED et al. Mol Pharmacol 1993:43;878–887. 13. Szumlanski C, Otterness D, Her C, Lee D, Brandriff B, Kelsell D et al. DNA Cell Biol 1996:15;17–30. 14. Tai H-L, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF et al. Am J Hum Genet 1996:58;694–702. 15. Salavaggione OE, Wang L, Wiepert M, Yee VC, Weinshilboum RM. Pharmacogenetics Genomics 2005:15;801–815. 16. Hon YY. Fessing MY. Pui CH. Relling MV. Krynetski EY. Evans WE. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet 1999:8;371–376. 17. Lee FJ, Kalow W. Thiopurine S methyltransferase activity in a Chinese population. Clin Pharmacol Ther 1993:54;28–33. 18. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Lancet 1990:336;225–229. 19. Tai H-L, Fessing MY, Bonten EJ, Yanishevsky Y, d’Azzo A, Krynetski EY et al. Pharmacogenetics 1999:9;641–650. 20. Wang L, Sullivan W, Toft D, Weinshilboum R. Pharmacogenetics 2003:13;555–564. 21. Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, Lehr HA, Wirtz S, Becker C, Atreya R, Mudter J, Hildner K, Bartsch B, Holtmann M, Blumberg R, Walczak H, Iven H, Galle PR, Ahmadian MR, Neurath MF. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003:111;1133–45. 22. Neurath MF, Kiesslich R, Teichgraber U, Fischer C, Hofmann U, Eichelbaum M, Galle PR, Schwab M. 6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn’s disease. Clin Gastroenterol & Hepatol 2005:3;1007–14 23. Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Theoret Y, Seidman EG. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000:118;705–7 24. Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmac 1995:39;456–9.
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25. Lewis LD, Benin A, Szumlanski CL, Otterness DM, Lennard L, Weinshilboum RM, Nierenberg DW. Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction. Clin Pharmacol & Ther 1997:464–475. 26. Dewitt O, Vanheuverzwyn R, Desager JP, Horsmans Y. Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn’s disease. Aliment Pharmacol Ther 2002:16;79–85. 27. Colombel JF, Ferrari N, Debuysere H, Marteau P, Gendre JP, Bonaz B, Soule JC, Modigliani R, Touze Y, Catala P, Libersa C, Broly F. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000:118;1025–1030. 28. Regueiro M, Mardini H. Determination of thiopurine methyltransferase genotype or phenotype optimizes initial dosing of azathioprine for the treatment of Crohn’s disease. J Clin Gastroenterol 2002:35;240–244. 29. Campbell S, Kingstone K, Ghosh S. Relevance of thiopurine methyltransferase activity in inflammatory bowel disease patients maintained on low dose azathioprine. Aliment Pharmacol Ther 2002:16;389–398. 30. Dubinsky MC, Hassard PV, Seidman EG, Kam LY, Abreu MT, Targan SR, Vasiliauskas EA. Preliminary Evidence Suggests That 6-MP Metabolite Profiles Provide a Biochemical Explanation for 6-MP Resistance in Patients with Inflammatory Bowel Disease. Gastroenterology 2002:122;904–915. 31. Cuffari C, Théorêt Y, Latour S, Seidman EG. 6-mercaptopurine metabolism in Crohn’s disease: correlation with efficacy and toxicity. Gut 1996:39;401–406. 32. Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001:48;642–646. 33. Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology 2006:130;47–53. 34. Weinshilboum R. New Engl J Med 2003:348;529–537. 35. Weinshilboum R, Wang L. Nat Rev Drug Disc 2004b:3;739–748.
24 5-Aminosalicylate Therapy M. Susan Moyer∗
Introduction Aminosalicylates (5-aminosalicylates, 5-aminosalicylic acid, 5-ASA, mesalamine, mesalazine) are widely used medications as first-line therapy in mild to moderate inflammatory bowel disease, particularly ulcerative colitis [1, 2]. Although the exact mechanism(s) of action remains unclear, they appear to have a number of important anti-inflammatory and immunomodulatory effects. The first drug in this class, sulfasalazine, was originally developed for the treatment of rheumatoid arthritis and is a combination of sulfapyridine, a sulfa antibiotic, and 5-aminosalicylic acid (5-ASA), a compound with anti-inflammatory properties. The discovery of the medication’s efficacy in the treatment of inflammatory bowel disease eventually led to elucidation of its pharmacokinetics [3]. The azo bond in the prodrug is cleaved by bacteria in the colon releasing 5-ASA, which has a topical therapeutic effect in the colon, and sulfapyridine, which is absorbed and contributes to the majority of the side effects associated with the drug. What has followed over the past two decades is the development of delivery systems for 5-ASA that allow release in the distal bowel without the potential confounding side effects of the antibiotic. Numerous clinical trials have supported the efficacy of these medications in the treatment of inflammatory bowel disease. Unfortunately there are very few studies in pediatric patients addressing either pharmacokinetic properties or efficacy. Therefore, the gastroenterologist treating children with inflammatory bowel disease must infer best practice from the adult literature [4]. Even in adults, a number of controversies remain in the clinical use of these medications including: the optimum dose and dosing interval for induction and maintenance of remission; the most appropriate preparation given the clinical setting; the overall efficacy in Crohn disease; the efficacy in preventing post-operative recurrence in Crohn disease; chemoprevention for colon cancer; and adherence [5, 6].
Pharmacokinetics Unless bound as a prodrug or combined with another delivery system, 5-ASA is readily absorbed from the stomach and proximal small bowel. Sulfasalazine, the first prodrug, delivered 5-ASA to the colon by combining it with sulfapyridine via an azo bond which was subsequently cleaved by bacteria in the colon. Unfortunately the dose-limiting side effects of the sulfa antibiotic were
*Cincinnati Children’s Hospital Medical Center, Division of GI, Hepatology & Nutrition, 3333 Burnet Avenue, ML-2010, Cincinnati, OH 45229, Phone: 513-636-4415, Fax: 513-636-7805, E-mail:
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problematic. Subsequent formulations have included other prodrugs, as well as pH-dependent and time-release preparations of mesalamine (Figure 24.1, Table 24.1). These drugs differ in the site in the gastrointestinal tract in which the active drug is released. (Figure 24.2). Balsalazide and olsalazine are prodrugs and have azo bonds that allow targeted release of the 5-ASA in the colon. The carrier molecule in balsalazide (Colazal® ; Salix Pharmaceuticals, Raleigh, NC) is 4-aminobenzoyl- alanine. In olsalazine (Dipentum® ; Celltech Pharmaceuticals, Rochester, NY), the azo bond connects two 5-ASA molecules. Virtually all of the active medication in these prodrugs is released in the colon. Delayed release of 5-ASA in the distal small bowel and colon has also been achieved by pH-dependent delivery systems. In these formulations, a coating of an acrylic-based resin, Eudragit, dissolves at a specific pH. The preparation available in the United States, Asacol® (Procter & Gamble Pharmaceuticals, Cincinnati, OH) is coated with Eudragit–S which releases the 5-ASA at a pH of 7 or higher, initiating release in the distal ileum. There are also preparations coated with Eudragit-L, which dissolves at a slightly lower pH of 6 and releases the drug in the mid-ileum (Table 24.1). These latter preparations are not available in the United States. Pentasa® (Shire US, Somerville, NJ) is formulated to allow the time-dependent release of 5-ASA. The active medication is incorporated into microgranules containing ethycellulose which dissolve when hydrated and release drug throughout the small intestine and colon. Finally, mesalamine can be delivered topically into the rectum as an enema (Rowasa® ; Solvay, Marietta, GA) or a suppository (Canasa® ; Scandipharm, Birmingham, AL). Release of 5-ASA more proximally can provide active drug to inflammation in the small bowel as well as the colon. This can also result in less active drug available in the distal colon as suggested in studies comparing balsalazide with a pH-dependent preparation [7]. Other variables that can impact pharmacokinetics are transit time and luminal pH. Rapid transit and a more acidic luminal pH in patients with active disease [8] can potentially result in suboptimal concentrations of 5-ASA in the colon. The actual clinical importance of these differences in pharmacokinetic characteristics is still unclear [9].
Prodrugs
Olsalazine (Dipentum®)
Sulfasalazine (Azulfidine®)
Balsalazide (Colazal®)
azo bond
mesalamine sulfapyridine 4-aminobenzol-β-alanine
Active drug (mesalamine)
Eudragit-S coated pH-dependent release (Asacol®)
Ethylcellulose coated microgranules time-dependent release (Pentasa®)
Figure 24.1. Formulations of oral 5-aminosalicylic acid.
MMX - double matrix system (lipophilic, hydrophilic) pH-dependent coating (Mesavance™)
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Table 24.1. Oral preparations of 5-aminosalicylic acid. Preparation
Delivery system
Prodrug Sulfasalazine (Azulfidine® ) Balsalazide (Colazal® ) Olsalazine (Dipentum® ) Active drug (mesalamine) Pentasa®
Asacol® Claversal® * Mesasal® * Salofalk® *
Formulation
Release
azo bond (sulfapyridine) azo bond (4-aminobenzoyl- alanine) azo bond (two 5-aminosalicylate molecules)
Tablet
colon
Capsule (powder)
colon
Capsule (powder)
colon
time-release (semipermeable ethyl cellulose membrane) pH-dependent (≥7) (Eudragit-S) pH-dependent (≥6) (Eudragit-L) pH-dependent (≥6) (Eudragit-L) pH-dependent (≥6) (Eudragit-L)
Capsule (granules)
small bowel, colon
Tablet
distal ileum, colon
Tablet
mid-ileum, colon
Tablet
mid-ileum, colon
Tablet
mid-ileum, colon
*not available in the United States
Once released, free 5-ASA is absorbed into the intestinal epithelium and undergoes metabolism to N-acetyl-5-ASA by N-acetyltransferase 1. This inactive metabolite is absorbed and secreted by the kidneys or excreted back into the lumen by a membrane-bound drug efflux pump, p-glycoproetien, and subsequently excreted in the feces. Any free ASA that is absorbed is metabolized in a similar manner in the liver. Therefore, the amount of active 5-ASA that reaches the systemic circulation is usually minimal.
Pentasa Asacol® Azulfidine® Colazal® Dipentum® Rowasa® Canasa® Duodenum
Jejunum
Ileum Proximal
Figure 24.2. Site of release of 5-amimosalicylic acid preparations.
Colon
Rectum Distal
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There have been five reported pharmacokinetic studies in the pediatric population: one with sulfasalazine [10], three with a pH-dependent delivery system [11–13] and one with a time-release formulation [14]. Daily doses of mesalamine ranged from 20–84 mg/kg and, in general, the pharmacokinetic profiles were similar to those reported in adults.
Mechanism of Action The precise mechanism(s) of action of 5-ASA in inflammatory bowel disease is unclear, although the primary therapeutic effect is thought to be directly on the mucosa itself (topical) rather than systemic [15]. These medications have both anti-inflammatory and immunomodulatory properties. One of the more important mechanistic effects is most likely inhibition of cyclo-oxygenase and 5-lipoxygenase which blocks the production and pro-inflammatory activity of prostaglandin E2 and leukotrienes. Other therapeutic effects may include (1) anti-oxidant and free radical scavenging properties (2) inhibition of antigen presentation, T-cell proliferation and antibody production by B cells, (3) inhibition of cellular function of natural killer cells, mast cells, neutrophils, mucosal lymphocytes and macrophages and (4) inhibition of expression and activation of adhesion molecules [15, 16]. 5-ASA has also been reported to inhibit the activation of nuclear factor-kappa B (NFB) [17]. This transcription factor plays a central role in orchestrating the expression of a number of inflammatory mediators including pro-inflammatory cytokines, chemokines, and adhesion molecules.
Indications and Efficacy Ulcerative Colitis The efficacy of sulfasalazine and the newer 5-ASA preparations for induction and maintenance of remission in ulcerative colitis is well-established and these medications remain the first-line therapy in treating mild-to-moderate ulcerative colitis [18]. The optimum dose for induction of remission has been controversial. Variability in study design, primary endpoints (response, remission), and definition of disease activity have made defining the optimum dose for active disease challenging. Doses of sulfasalazine over 3 g/day have shown better efficacy than lower doses but these higher doses tend to be associated with significantly more side effects [19]. A range of 5-ASA doses from 1.5–4.8 g/day has been shown to be effective in induction of remission in mild-to-moderate disease. In a recent systematic review of clinical trials of oral 5-ASA for induction of remission, 5-ASA was superior to placebo at all doses with regard to all measured outcomes and a dose-dependent trend was observed [20]. Clinical trials assessing varying doses of a pH-dependent preparation (Asacol® ) also support dose-related efficacy as well as a more rapid onset of action at higher doses [21]. In a randomized, double-blind, controlled trial comparing the efficacy of 2.4 and 4.8 g/day of Asacol® in moderately active ulcerative colitis (the ASCEND II trial), achieving the endpoint of overall improvement (complete remission or clinical response) was significantly more likely at the higher dose [22]. In a subgroup of patients with mild disease, there was no difference in efficacy between the two doses. Taken together, these data suggest that the optimum initial dose may be based on disease severity. Lower doses are therapeutic, and more cost effective, in inducing remission in mild disease. Current evidence supports the use of higher doses in moderately active ulcerative colitis. The optimum dose for maintenance of remission has also been difficult to infer from the literature. Early studies with sulfasalazine suggested a reduction of dose after remission was achieved, in part, to minimize side effects [23]. A dose-dependent effect of 5-ASA in maintenance of remission has not been consistently identified [24], however, there is a trend in clinical practice
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toward maintaining the dose that successfully induced remission, given the favorable side effect profile of the newer medications. Although there are theoretical benefits of one 5-ASA preparation over another based on site of release and location of disease in the colon, this has not been consistently demonstrated clinically. Preparations that are not released until they reach the colon may have some advantage in treating more distal disease [25], although the combination of an oral and rectal preparation has been shown to be as effective [26]. There has only been one published trial evaluating the efficacy of 5-ASA in pediatric patients with ulcerative colitis [27]. A multicenter, randomized, double-blind study comparing olsalazine (30 mg/kg/d) to sulfasalazine (60 mg/kg/d) for induction of remission in mild-to-moderate ulcerative colitis showed better efficacy of the sulfasalazine; however, the relatively low dose of the olsalazine, along with a smaller number of participants enrolled than anticipated, may have contributed to the result. The doses currently used in children with inflammatory bowel disease are variable but tend to fall into the range of 50–100 mg/kg/d of mesalamine equivalent [4, 8]. In children who do not swallow pills, the preparations used are limited to those in capsule form that can be opened and mixed with soft food (Colazal® , Pentasa® , Dipentum® ). Crohn Disease Efficacy of 5-ASA in inducing and maintaining remission in Crohn disease is less clear in adult studies. The National Cooperative Crohn Disease Study (NCCDS) did show a benefit of sulfasalazine over placebo in ileocolonic and colonic disease [29] and the newer 5-ASA preparations have been used as first-line therapy in mild-to-moderate active Crohn disease [30]. More recently, there has been increasing debate about the efficacy of these medications in patients with Crohn disease. A review of available studies in adults with Crohn disease suggested that sulfasalazine at a dose of 3–6 g/d was effective in inducing remission in 40–60% of patients, and higher (3.2–4.8 g/d), but not lower, doses of mesalamine could induce remission in 34–83% [5, 31]. A meta-analysis also supported the efficacy of mesalamine in maintenance of remission, although the effect was most pronounced in patients with ileitis and prolonged disease duration, and in the postsurgical setting [32]. The most recent systematic review of the efficacy of oral 5-ASA in Crohn disease, however, concluded that there was no evidence to suggest that 5-ASA preparations were superior to placebo in maintaining medically-induced remission [33]. An evidence-based consensus statement from the European Crohn and Colitis Organization also comments that the role of mesalamine in mild ileocecal Crohn disease is limited and debated the use of sulfasalazine in colonic Crohn disease given the frequent side effects [34]. This debate continues among gastroenterologists involved in the clinical care of these patients and many have not abandoned these medications for the treatment of mild-to-moderate ileocolonic or colonic Crohn disease. In general, if these medications are used in this setting, higher doses are more likely to be efficacious. 5-ASA preparations are used for induction and maintenance of remission in pediatric patients with Crohn disease, based on initial studies in adults and reports of cumulative experience in children [28]. The only published clinical trial of a time-release 5-ASA preparation in children with active small bowel Crohn disease suggested a beneficial effect on response at 8 weeks [35]. This was a small study of 14 children and the dose of 5-ASA was relatively low (50 mg/kg/d). The lack of rigorous pharmacokinetic studies and clinical trials in children makes decisions about the use of these drugs in pediatric patients with Crohn disease difficult. Extrapolation of systematic reviews and meta-analyses of the adult literature may not be advisable. Ideally, a large, multi-center trial with uniform dosing and well-defined primary endpoints would address this question. Until more definitive evidence is available in children, continued use in the setting of mild or mild-to-moderate ileal, ileocolonic or colonic Crohn disease may be reasonable. Doses
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recommended in the literature for Crohn disease in children are similar to those for ulcerative colitis (50–100 mg/kg/d) [4, 28]. Post-operative Recurrence in Crohn Disease Clinical relapse following surgical resection in Crohn disease is common. Both sulfasalazine and the newer mesalamine preparations have been studied to assess efficacy in preventing recurrence of disease in subjects who have undergone surgical resection. Once again, these studies are fairly heterogeneous and differ in clinical design including preparation used, dose, length of treatment postoperatively, and definition of relapse – histologic, endoscopic or clinical. Earlier studies examining the impact of sulfasalazine on recurrence showed that, overall, relapse rates decreased at one year; however, a meta-analysis of these studies found no benefit at three years postoperatvely [36]. The randomized, controlled trials of mesalamine preparations for maintenance of surgical remission have reported variable results. A meta-analysis of studies published through 1997 suggested that mesalamine decreases the risk of postoperative recurrence by approximately 13% [32]. The European Cooperative Crohn Disease Study published in 2000 showed a decrease in clinical recurrence in the mesalamine group but this only reached statistical significance in a subgroup of patients with isolated small bowel disease [37]. The subsequent randomized, controlled trials failed to demonstrate a significant decrease in the rate of clinical recurrence in subjects treated with mesalamine [38–40]. There have been no published trials in pediatric patients. The adult studies suggest that there may be some efficacy of 5-ASA in maintaining surgically-induced remission in Crohn disease; however, this effect appears to be modest at best. Chemoprevention of Colorectal Carcinoma There is increasing evidence that therapy with 5-ASA long-term can significantly decrease the risk of colon cancer in patients with ulcerative colitis. This was initially suggested in several epidemiologic cohort studies examining risk and protective factors related to colorectal cancer in the setting of inflammatory bowel disease. The impact was significant, with an adjusted odds ratio of 0.25–0.6 [41–43]. The effect was also more pronounced with higher doses, and mesalamine preparations were more protective than sulfasalazine. The adjusted odds ratio for mesalamine at doses >1.2 g/d was 0.09–0.24. One additional study reported conflicting results, but the sample size was small and the treatment of short duration (<4 years) [44]. Results of a recent systematic review of the existing observational studies supported a protective association between 5-aminosalicylates and colorectal cancer or the combined endpoint of colorectal cancer and dysplasia in patients with ulcerative colitis [45]. These studies are consistent with a reduction in the risk of colorectal cancer of between one third and one half in patients with inflammatory bowel disease who take 5-ASA on a regular basis. In those who consistently take > 1.2 g/d, there may be as much as a 72% reduction in the odds of dysplasia or colorectal cancer [42]. This protective effect may be related to therapeutic efficacy in controlling mucosal inflammation. The severity of colonic inflammation has been shown to be an important determinant of colorectal cancer risk in patients with ulcerative colitis [46]. However, there are a number of other plausible mechanisms for chemoprevention which may augment the anti-inflammatory effect. These agents are structurally similar to aspirin which has been shown, along with other nonsteroidal medications, to reduce the risk of developing colorectal cancer in general [47]. 5-ASA is an extremely potent antioxidant and free radical scavenger and exhibits anti-proliferative and pro-apoptotic effects [48]. This potential additional long-term benefit of 5-ASA in the management of colitis raises the potential benefit of continuing these medications, not only when used as primary therapy, but also when remission is maintained with other therapeutic agents such as immunomodulators. In addition, this information may provide an added incentive to patients to adhere to prescribed therapy, even when the disease is quiescent. In patients diagnosed during
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childhood who will potentially live with their disease for many decades, chemoprevention of colorectal cancer has particular relevance.
Safety and Side Effects Therapy with sulfasalazine is accompanied by fairly frequent side effects. The majority of these adverse events are related to the sulfapyridine moiety, specifically hypersensitivity reactions (fever, rash), agranulocytosis, and hemolysis (Table 24.2). In addition, sulfasalazine can cause oligospermia and contribute to folate deficiency. Supplementation with daily folic acid is recommended during treatment with sulfasalazine. The newer 5-ASA drugs are, in general, safe and well tolerated [49]. General side effects attributable to sulfasalazine and 5-ASA are listed in Table 24.2. The most common are headache, diarrhea, abdominal pain and nausea or dyspepsia. Rare but more serious adverse events include, alveolitis, nephritis and pancreatitis. Reports in the literature suggest that the risk of pancreatitis and interstitial nephritis is higher with mesalamine and the risk of blood dyscrasias and hepatitis is higher with sulfasalazine [49, 50]. There are infrequent reports of exacerbation of colitis on these drugs. Clinically, the gastrointestinal side effects, particularly diarrhea and abdominal pain, can present a challenge in differentiating an adverse medication reaction from underlying disease. A systematic review published by Loftus and colleagues showed no difference in side effects among the various 5-ASA compounds and the frequency of side effects was similar between mesalamine and placebo [51]. This study also reported more frequent side effects in patients treated with sulfasalazine compared to mesalamine therapy. The prevalence of adverse reactions to sulfasalazine often limits its use and the 5-ASA preparations may be preferred because they are better tolerated, although significantly more expensive. In patients treated with sulfasalazine who experience side effects, particularly hypersensitivity reactions, desensitization protocols have been reported [52]. Since the majority of these reactions are related to the sulfa moiety, switching to a different 5-ASA preparation is often successful and is the preferred option. In addition, patients who experience side effects on one particular 5-ASA compound may tolerate a different preparation as long as the sensitivity is not to mesalamine itself. In one published study, of 43 patients intolerant to sulfasalazine, 39 (91%) were able to tolerate at least one of the 5-ASA preparations (balsalazide, mesalamine, olsalazine). Of those 39 patients, 42% tolerated all three, 70% tolerated at least two and 18% tolerated one [53]. Adverse events and the safety profile of these medications in the published pediatric series is similar to those in adults [27, 28, 35, 54]. There are also scattered reports of pancreatitis, hepatitis, interstitial nephritis and pericarditis in children receiving these drugs. Although there are no evidence-based recommendations for monitoring these medications, periodic assessment of renal function is advisable. Table 24.2. Side effects of sulfasalazine and 5-aminosalicylates. 5-ASA and sulfasalazine Headache Abdominal pain Diarrhea Nausea Dyspepsia Rash* Fever* *Sulfasalazine > 5-ASA † 5-ASA > sulfasalazine
Sulfasalazine †
Nephritis Alveolitis Pancreatitis† Myopericarditis Hepatitis* Neutropenia*
Agranulocytosis Oligospermia Folate deficiency Hemolytic anemia
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Results of studies assessing safety in pregnancy have been variable. There have been some reports of increased incidence of congenital limb abnormalities, obstructive urinary abnormalities and low birth weight in infants born to women taking 5-ASA compounds during pregnancy [55, 56]. Other studies have found no adverse outcomes [57, 58]. Sulfasalazine and sulfapyridine cross the placenta and fetal concentrations approximate those in the mother. However, no increase in fetal complications or spontaneous abortion has been identified [49]. Supplementation with sufficient doses of folic acid is particularly important in pregnant women who continue sulfasalazine since this medication is a folic acid antagonist and folate deficiency tends to worsen during pregnancy. 5-ASA is found in negligible amounts in breast milk [59], although levels of the sulfapyridine moiety in sulfasalazine can be 40–60% of those in maternal serum. Based on a report of one breastfed infant who developed bloody diarrhea while the mother was taking sulfasalazine, and another infant who developed diarrhea while breastfed by a mother on a 5-ASA preparation, the Committee on Drugs of the American Academy of Pediatrics recommends using these medications with caution when breastfeeding [60]. Clinical monitoring for a change in stool consistency or the presence of blood is encouraged.
Adherence Adherence, or compliance over time, has been a particular problem with these medications in clinical practice. The rate of nonadherence in quiescent ulcerative colitis may be as high as 60% [61, 62]. These patients are at greater risk for relapse of their disease than those patients who take at least 80% of their medication. There is also increasing support for the role of these medications in cancer chemoprevention long-term if taken on a consistent basis. A number of factors contribute to nonadherence with these medications including side effects, number of pills and frequent dosing interval. In the initial clinical trials, the dosing interval for the newer 5-ASA preparations was three or four times a day. There has been a clinical trend toward dividing the daily dose twice a day to encourage compliance. A recent pilot feasibility study suggested that a daily dose of a 5-ASA preparation in patients with quiescent disease had similar short-term efficacy to traditional dosing and adherence was better [63]. In addition to the dosing interval, the number of pills patients may be required to take can be daunting. Higher doses of various 5-ASA preparations require that a patient take from 12 to 16 pills daily. Higher unit (per pill) doses are now available which may help with adherence. New delivery systems are also being developed which allow effective delivery of a larger once-a day dose [64, 65]. Although there are no publications related to adherence to 5-ASA regimens in pediatric patients with inflammatory bowel disease, nonadherence may be even more prevalent in this patient population, particularly adolescents.
Future Directions With the efficacy of 5-ASA established in the treatment of inflammatory bowel disease, particularly ulcerative colitis, investigative efforts have been directed toward developing preparations that are better tolerated and more conducive to adherence. The goal is a delivery system that provides equivalent or improved efficacy compared to current formulations but with fewer pills and less frequent dosing. Results of clinical trials of mesalamine pellets coated with Eudragit-L [66] and a new entericcoated form of mesalamine [67] have been published recently. The efficacy of these drugs is equivalent to that of Asacol® but, in general, they provide no specific advantage over the currently available medications. In the ASCEND II trial comparing 2 doses of Asacol (2.4 and 4.8 g/d), a
Chapter 24 5-Aminosalicylate Therapy placebo MMX 2.4 g/day MMX 4.8 g/day Asacol 800 mg TID
50
40
% remission
325
30
20
10 Placebo
MMX
Figure 24.3. Comparison of primary outcome (remission) of combined patient data from Study 301 and Study 302 after 8 weeks of therapy with MMX mesalamine.[65]
new investigational 800 mg tablet was used for the higher dosing regimen [22]. When available, this formulation would decrease the required number of pills by half. A new oral mesalamine formulation, MMX™ mesalamine (SPD 476; Mesavance™, Shire Pharmaceuticals, Wayne, PA), is a patented multi-matrix tablet that is designed to deliver mesalamine to the colon, particularly the distal colon. The tablet core contains microparticles of mesalamine in a lipophilic matrix which are then dispersed throughout a hydrophilic matrix. The core is coated with a pH-dependent gastric-acid resistant polymer which dissolves at a pH of seven or greater. The tablet begins to dissolve in the distal ileum and the double matrix then allows consistent and homogeneous release of the mesalamine throughout the colon [65]. A dose of 1.2 g three times a day was as effective as 5-ASA enemas (4 g/d) in inducing remission at 8 weeks in patients with active left-sided ulcerative colitis. Compliance was better with the oral preparation [64]. The results of two double-blind, placebo-controlled multicenter studies are shown in Figure 24.3. The primary endpoint for both trials was induction of remission at 8 weeks. Once-daily administration was as effective as twice-daily [65] and both 2.4 and 4.8 g once daily of the MMX mesalamine were as effective as Asacol 800 mg three times a day. These preliminary results are encouraging and could potentially have a significant impact on adherence. The tablet form will preclude use in children who cannot swallow pills.
References 1. Sandborn WJ. Treatment of ulcerative colitis with oral mesalamine: advances in drug formulation, efficacy expectations and dose response, compliance, and chemoprevention. Rev Gastroenterol Disord 2006;6:97–105. 2. Bergman R, Parkes M. Systematic review: the use of mesalazine in inflammatory bowel disease. Aliment Pharmacol Ther 2006;23:841–55. 3. Azad Khan AK, Piris J, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 1977;2:892–5. 4. Escher JC, Taminiau J, Nieuwenhuis E, et al.. Treatment of inflammatory bowel disease in childhood: Best available evidence. Inflamm Bowel Dis 2003;9:34–58. 5. Lim W-C, Hanauer SB. Controversies with aminosalicylates in inflammatory bowel disease. Rev Gastroenterol Disord 2004;4:104–17. 6. Indications for 5-aminosalicylate in inflammatory bowel disease: is the body of evidence complete? World J Gastroenterol 2006;12:6115–23.
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7. Levine DS, Riff DS, Pruitt R, et al. A randomized, double-blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active mild-to-moderate ulcerative colitis. Am J Gastroenterol 2002;97:1398–1407. 8. Fallingborg J, Christensen LA, Jacobsen BA, Rasmussen SN. Very low intraluminal colonic pH in patients with active ulcerative colitis. Dig Dis Sci 1993;38:1989–93. 9. Qureshi AY, Cohen RD. Mesalamine delivery systems: do they really make much difference? Adv Drug Deliv Rev 2005;57:281–302. 10. Goldstein PD, Alpers DH, Keating JP. Sulfapyridine metabolites in children with inflammatory bowel disease receiving sulfasalazine. J Pediatr 1979;95:638–40. 11. Klotz U. 5-aminosalicylic acid and chronic inflammatory bowel diseases in children. Klin Padiatr 1995;207:285–7. 12. Tolia V, Massoud N, Klotz U. Oral 5-aminosalicylic acid in children with colonic chronic inflammatory bowel disease: clinical and pharmacokinetic experience. J Pediatr Gastroenterol Nutr 1989;8:33–8. 13. Wiersma H, Escher JC, Dilger K, et al. Pharmacokinetics of mesalazine pellets in children with inflammatory bowel disease. Inflamm Bowel Dis 2004;10:626–31. 14. Christensen LA, Fallingborg J, Jacobsen BA, et al. Bioavailability of 5-aminosalicylic acid from slow release 5-aminosalicylic acid drug and sulfasalazine in normal children. Dig Dis Sci 1993;38:1831–6. 15. MacDermott RP. Progress in understanding the mechanism of action of 5-aminosalicylic acid. Am J Gastroenterol 2000;95:3343–5. 16. Nikolaus S, Folscn U, Schreiber S. Immunopharmacology of 5-aminosalicylic acid and of glucocorticoids in the therapy of inflammatory bowel disease. Hepatogastroenterology 2000;47:71–82. 17. Bantel H, Berg C, Vieth M, et al. Mesalazine inhibits activation of transcription factor NF-kappaB in inflamed mucosa of patients with ulcerative colitis. Am J Gastroenterol 2000;95:3452–7. 18. Kornbluth A, Sachar DB. Practice parameters committee of the American college of gastroenterology. Ulcerative colitis practice guidelines in adults (update). Am J Gastroenterol 2004;99:1371–85. 19. Margolin ML, Krumholz MP, Fiochios SE, Korelitz BI. Clinical trials in ulcerative colitis: II. Historical review. Am J Gastroenterol 1988;83:227–43. 20. Sutherland L, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2006;(2):CD000543. 21. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317:1625–9. 22. Hanauer SB, Sandborn WJ, Kornbluth A, et al. Delayed release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am J Gastroenterol 2005;100:2478–85. 23. Azad-Khan AK, Howes DT, Piris J, Truelove SC. Optimum dose of sulphasalazine for maintenance treatment of ulcerative colitis. Gut 1980;21:232–40. 24. Sutherland L, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cocahrane Database Syst Rec 2006;(2):CD000544. 25. Green JR, Lobo AJ, Holdsworth CD, et al. Balsalazide is more effective and better tolerated than mesalamine in treatment of acute ulcerative colitis. The Abacus Investigator Group. Gastroenterology 1998;114:15–22. 26. Safdi M. DeMicco M, Sninsky C, et al. A double-blind comparison of oral versus rectal mesalamine versus combination therapy in treatment of distal ulcerative colitis. Am J Gastroenterol 1997;92: 1867–71. 27. Ferry GD, Kirschner BS, Grand RJ, et al. Olsalazine versus sulfasalazine in mild to moderate childhood ulcerative colitis: results of the Pediatric Gastroenterology Collaborative Research Group Clinical Trial. J Pediatr Gastroenterol Nutr 1993;17:32–8. 28. D’Agata ID, Vanounou T, Seidman E. Mesalamine in pediatric inflammatory bowel disease: a 10-year experience. Inflamm Bowel Dis 1996;2:229–35. 29. Summers RW, Switz DM, Sessions JT Jr, et al. National cooperative crohn disease study: results of drug treatment. Gastroenterology 1979;77:847–69. 30. Hanauer SB, Sandborn W. Management of Crohn disease in adults. Am J Gastroenterol 2001;96:635–43. 31. Hanauer SB, Stromberg U. Oral Pentasa in the treatment of active Crohn disease: a meta-analysis of double-blind, placebo-controlled trials. Clin Gastroenterol Hepatol 2004;2:379–88.
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32. Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn disease: a meta-analysis adjusted for confounding variables. Gastroenterology 1997;113:1465–73. 33. Akobeng AK, Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn disease. Cochrane Database Syst Rev 2005;(1):CD003715. 34. Travis SPL, Stange EF, Lèmann M, et al. European evidence based consensus on the diagnosis and management of Crohn disease: current management. Gut 2006;55:16–35. 35. Griffiths A, Koletzko S, Sylvester F, et al.. Slow-release 5-aminosalicylic acid therapy in children with small intestinal Crohn disease. J Pediatr Gastroenterol Nutr 1993;17:186–92. 36. Achkar JP, Hanauer SB. Medical therapy to reduce postoperative Crohn disease recurrence. Am J Gastroenterol 2000;95:1139–46. 37. Lochs H, Mayer M, Fleig WE, et al. Prophylaxis of postoperative relapse in Crohn disease with mesalamine: European Cooperative Crohn Disease Study VI. Gastroenterology 2000;118:264–73. 38. Caprilli R, Cottone M, Tonelli F, et al. Two mesalazine regimens in the prevention of post-operative recurrence of Crohn disease: a pragmatic, double-blind, randomized controlled trial. Aliment Pharmacol Ther 2003;17:517–23. 39. Hanauer SB, Korelitz BI, Rutgeerts P, et al. Postooperative maintenance of Crohn disease remission with 6-mercaptopurine, mesalamine or placebo: a 2-year trial. Gastroenterology 2004;127:723–9. 40. Ardizzone S, Maconi G, Sampietro GM, et al. Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn disease. Gastroenterology 2004;127:730–40. 41. Eaden JA, Abrams K, Ekbom A, et al. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 2000;14:145–53. 42. Rubin DT, LoSavio A, Yadron N, et al. Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis. Clin Gastroenterol Hepatol 2006;4:1346–50. 43. Van Staa TP, Card T, Logan RF, Leufkens HGM. 5-aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiologic study. Gut 2005;54:1573–78. 44. Bernstein CN, Blanchard JF, Metge C, Yogendran M. Does the use of 5-aminosalicylates in inflammatory bowel disease prevent the development of colorectal cancer? Am J Gastroenterol 2003;98:2784–8. 45. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 2005;100:1345–53. 46. Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004;126:451–9. 47. Huls G, Koornstra JJ, Kleibeuker JH. Non-steroidal anti-inflammatory drugs and molecular carcinogenesis of colorectal carcinoma. Lancet 2003;362:230–2. 48. Bernstein CN, Eaden J, Steinhart AH, et al. Cancer prevention in inflammatory bowel disease and the chemoprophylactic potential of 5-aminosalicylic acid. Inflamm Bowel Dis 2002;8:356–61. 49. Baker DE, Kane S. The short- and long-term safety of 5-aminosalicylate products in the treatment of ulcerative colitis. Rev Gastroenterol Disord 2004;4:86–91. 50. Ransford RA, Langman MJS. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002;51:536–9. 51. Loftus EV, Kane SV, Bjorkman D. Systematic review: Short-term adverse effects of 5-aminosalicylic acid agents in the treatment of ulcerative colitis. Aliment Pharmacol Ther 2004;19:179–89. 52. Tolia V. Sulfasalazine desensitization in children and adolescents with chronic inflammatory bowel disease. Am J Gastroenterol 1992;87:1029–32. 53. Giaffer MH, O’Brien CJ, Holdsworth CD. Clinical tolerance to three 5-aminosalicylic acid releasing preparations in patients with inflammatory bowel disease intolerant to or allergic to sulphasalazine. Aliment Pharmacol Ther 1992;6:51–9. 54. Barden L, Lipson A, Pert P, et al. Mesalazine in childhood inflammatory bowel disease. Aliment Pharmacol Ther 1989;3:597–603. 55. Norgard B, Fomager K, Pedersen L. Birth outcome in women exposed to 5-ASA during pregnancy: a Danish cohort study. Gut 2003;52:243–7. 56. Norgard B, Puho E, Pedersen L, et al. Risk of congenital anomalies in children born to women with ulcerative colitis: a population-based, case-control study. Am J Gastroenterol 2003;98:2006–10. 57. Diav-Citrin O, Park YH, Veerasuntharam G, et al. The safety of mesalamine in human pregnancy: a prospective controlled cohort study. Gastroenterology 1998;114:23–8.
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58. Connell W, Miller A. Treating inflammatory bowel disease during pregnancy: risks and safety of drug therapy. Drug Saf 1999;21:311–23. 59. Klotz U, Harings-Kaim A. Negligible excretion of 5-aminosalicylic acid in breast milk. Lancet 1993;342:618–9. 60. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89. 61. Levy RL, Feld AD. Increasing patient adherence to gastrointestinal treatment and prevention regimens. Am J Gastroenterol 1999;94:1733–42. 62. Kane SV. Systematic review: adherence issues in the treatment of ulcerative colitis. Aliment Pharmacol Ther 2006;23:577–85. 63. Kane S, Huo D, Magnanti K. A pilot feasibility study of once daily versus conventional dosing mesalamine for maintenance of ulcerative colitis. Clin Gastroenterol Hepatol 2003;1:170–3. 64. Prantera C, Viscido A, Biancone L, et al. A new oral delivery system for 5-ASA: preliminary clinical findings for MMx. Inflamm Bowel Dis 2005;11:421–7. 65. Baker D. MMX.™ mesalamine. Rev Gastroenterol Disord 2006;6:146–52. 66. Marakhouski U, Fixa B, Holoman J, et al. A double-blind dose-escalating trial comparing novel mesalazine pellets with mesalazine tablets in active ulcerative colitis. Aliment Pharmacol Ther 2005;21:133–40. 67. Forbes A, Al-Damluji A, Ashworth S, et al. Multicentre randomized-controlled clinical trial of Ipocol, a new enteric-coated form of mesalazine, in comparison with Asacol in the treatment of ulcerative colitis. Aliment Pharmacol Ther 2005;21:1099–1104.
25 Antibiotic Therapy Douglas Jacobstein∗ and Howard Kader
Introduction Treatment of inflammatory bowel disease (IBD) with antibiotics has been used for several decades. Such utilization was initially intuitive and over the past couple of decades shown to be effective. There is a triad relationship believed to be involved in the pathogenesis of IBD that includes genetic susceptibility – environmental antigen – host immune response. Given the exposure to foreign bacteria as well as host bacteria colonization, studies have shown that certain aspects of bacteria will trigger an immune response that leads to intestinal mucosal inflammation and for reasons still not known, patients susceptible to developing IBD will lack the ability to turn off this immune system activation resulting in perpetual intestinal mucosal inflammation and clinical symptoms of IBD [1]. Additionally, Crohn patients with diverting ileostomies demonstrate a downstream decrease in disease activity with the fecal stream interrupted and recurrence when placed back into continuity [2]. A specific infectious agent has yet to be identified but more likely than not, it may not be any one organism but rather the process of the host’s immune reaction to that infectious stimulus that ultimately results in the development of IBD in the susceptible individual. Antibiotics therefore possess the ability to change the course of inflammatory bowel disease in a variety of ways including reducing luminal bacterial content, changing the microflora of the colon, reducing bacterial invasion of intestinal tissue, and limiting bacterial translocation [3]. Unfortunately, there are no randomized therapeutic antibiotic studies that have been performed in children with IBD to assess the efficacy and validity of their use. Most reported pediatric studies have at best mentioned that concurrent antibiotic use was permitted if already taking it during that specific study involving another medication intervention. Consequently, the pediatric gastroenterologist has to extrapolate from and rely on adult evidence-based medicine clinical trials (class I or II studies) regarding the role of antibiotic therapy in the treatment of IBD. The most frequently used maintenance antibiotics in management of adult IBD are metronidazole and ciprofloxacin. Ciprofloxacin has uniformly not been used in the treatment of children due to concerns regarding adverse bone growth effects noted in animal studies. To date no longterm ciprofloxacin studies in children have been published but short-term treatment of urinary tract infections and other infectious illness without adverse events can be found. Metronidazole has the Food and Drug Administration’s approval for the use in children for the treatment of infections and has been utilized in the chronic treatment of IBD.
*Division of Pediatric Gastroenterology, Sinai Hospital of Baltimore, 2411 W Belvedere Avenue, Suite 407,. Baltimore, MD, 21215–5217, Phone: 410-601-8661, Fax: 410-601-5389, E-mail:
[email protected]
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Antibiotic Use in Crohn Disease Based on adult IBD trials, metronidazole and ciprofloxacin have shown significance in the management of mild to moderate Crohn disease involving the distal small bowel as well as perianal disease related to enterocutaneous fistula(e) and perhaps delay in recurrence after ileal resection [4, 5].
Active Crohn Disease Several studies have been carried out over the last 30 years evaluating the use of antibiotics in active Crohn disease. In the only published efficacy study in children, Hildenbrand et al. evaluated the open label use of oral metronidazole 10–35 mg/kg in 20 children between the ages of 7–18 years with active Crohn disease. This group demonstrated improvement in clinical symptoms in 15/20 patients (12 improved, 3 moderately improved) who were followed for six months. Additionally, they reported that of 12 patients who were improved, 9 discontinued the medication after six months with return of symptoms in 7 patients within 11 months [6]. While pediatric studies are limited, several adult trials, both randomized and non-randomized, evaluating the use of antibiotics in active Crohn disease have been published. Ursing and Kamme described the use of metronidazole in 5 patients with Crohn disease and reported a response in 4 of them [7]. In the first double-blinded comparative study involving antibiotics, metronidazole was compared to sulfasalazine in active Crohn disease in seventy-eight patients. Patients were randomized to receive either metronidazole or sulfasalazine for 4 months and then crossed over to receive the alternate drug for an additional four months. The authors found that metronidazole was slightly more effective than sulfasalazine in treating active Crohn disease based on improvements in the Crohn Disease Activity Index [3]. Further double-blinded studies, including one performed by Sutherland et al. evaluated two doses of metronidazole (20 mg/kg and 10 mg/kg) with placebo. One hundred and five patients were randomized, and 56 completed the 16-week study. The authors found significant reductions in disease activity index scores and serum orosomucoid levels among the groups receiving metronidazole versus those who received placebo. The authors also found that patients with both large and small bowel disease responded better to therapy than those with isolated small bowel disease [8]. Few randomized trials have been published evaluating the use of ciprofloxacin as monotherapy in active Crohn disease. In a randomized study conducted by Colombel et al., 40 patients with mild to moderate active Crohn disease received either ciprofloxacin or mesalamine for 6 weeks. The authors found similar response rates (56% versus 55%) among patients who received ciprofloxacin versus those who received mesalamine as assessed by improvements in CDAI scores [9]. Ciprofloxacin was also compared to placebo in a study conducted by Arnold et al. The authors randomized 47 patients with active, resistant moderate Crohn disease to receive ciprofloxacin or placebo in combination with their previously prescribed conventional therapies and followed for six months. Significant decreases in CDAI were observed in the ciprofloxacintreated group, 187 to 112, versus 230 to 205 in the placebo-treated group [10]. Several studies conducted in adults have evaluated the use of combination therapy with ciprofloxacin and metronidazole in active Crohn disease. Response rates varied among the studies but all demonstrated improvements ranging from 45% to 90% in patients who used combined therapies with the best responses among those patients with colonic involvement [11–13]. Interestingly, in one of these studies, ciprofloxacin and metronidazole in combination were compared to methylprednisolone among 41 adult patients with active Crohn disease and similar reductions in symptoms and improvements in laboratory values (acute phase reactants, albumin, and hemoglobin) were seen in both groups [12].
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Perianal Disease Perianal Crohn disease including fistulae and abscesses occurs in almost 50% of patients with Crohn disease [14], and while a combination of surgical and medical treatment is preferred, antibiotics have shown some efficacy in several trials. Early reports by Ursing and Kamme noted improvements in perianal disease with the use of metronidazole [7]. In an uncontrolled trial, Allan and Cooke reported significant improvement in two patients with severe perianal disease after taking metronidazole [15]. In the first study evaluating the use of metronidazole for perianal disease only, Bernstein et al. placed 21 consecutive patients with perianal Crohn disease on metronidazole. The authors reported that all 21 had a dramatic reduction in drainage, erythema, and induration and complete healing in 10 of 18 patients maintained on the drug [16]. A followup study conducted by the same authors found continued efficacy of the drug in those patients maintained for longer periods of time including up to one year in 16 of 26 patients followed. The authors did however note that disease frequently returned when the drug dose was lowered, or the drug was discontinued [17]. Antibiotics have also been investigated in conjunction with other medications including azathioprine and infliximab in the treatment of perianal Crohn disease. Dejaco et al. evaluated 52 adult patients with perianal fistulas in an open-labeled trial using ciprofloxacin and/or metronidazole [18]. Patients who were on azathioprine were allowed to continue (17 patients), and an additional 14 patients received azathioprine after 8 weeks of antibiotic therapy. The authors found that 50% of patients had a clinical response to antibiotics at 8 weeks and 25% continued to respond at week 20. They also found that patients who received azathioprine and antibiotics were more likely to respond than those who received antibiotics alone. They concluded that antibiotics may therefore offer a bridge to immunosuppression as there was a good short-term response. In a more recent randomized, controlled trial, West et al. evaluated ciprofloxacin versus placebo in conjuction with infliximab among 24 patients with perianal Crohn disease [19]. Although statistical significance was not achieved, the authors noted a trend towards a better response among patients who received ciprofloxacin and infliximab versus placebo and infliximab at week 18 (73% versus 38%). Postoperative Recurrence of Crohn Disease A large proportion of patients with Crohn disease will require surgery at some point during the course of their disease, and a majority of these patients will eventually develop recurrence of disease requiring additional surgery [20, 21]. Previous studies have suggested that bacteria may play a role in the recurrence of disease as it occurs when the mucosa is re-exposed to luminal contents and bacteria [22]. Thus, antibiotics may have a beneficial role in the prevention of post-operative recurrence of Crohn disease. In a double-blind, placebo-controlled trial, Rutgeerts et al. evaluated the efficacy of metronidazole in the prevention of post-operative recurrence of Crohn disease following ileal resection [23]. Sixty adult patients were randomized to receive metronidazole or placebo for 3 months. While both groups demonstrated some endoscopic recurrence of disease at 3 months (75% placebo group versus 52% metronidazole group), the incidence of severe endoscopic disease recurrence was significantly reduced among the metronidazole-treated group (13% versus 43%). The authors also found a statistically reduced recurrence rate among the treated group at one year versus placebo although no differences were seen at 2 years and 3 years. A more recent study conducted with the use of ornidazole, a nitromidazole antibiotic with fewer side effects than metronidazole (not available in the United States), has also been performed [24]. Eighty patients were randomized to receive ornidazole or placebo for 1 year beginning a week after ileal resection. Ornidazole significantly reduced the clinical recurrence rate at 1 year (7.9% ornidazole group versus 37.5% placebo group), although no significant difference in clinical recurrence was
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seen at 24 and 36 months. The endoscopic recurrence rate at 12 months was also lower among those patients that received ornidazole compared with placebo. Both studies seem to indicate a reduction in post-operative recurrence among patients who receive antibiotics. Optimal dosing and the duration of therapy needed to prevent recurrence are still unclear and may require future studies.
Antibiotics in Ulcerative Colitis There are few evidence based studies demonstrating the utility of antibiotics in the treatment of ulcerative colitis aside from those involving colitis exacerbation secondary to Clostridium difficile superinfection, or due to toxic megacolon in which case treatment with antibiotics is employed until surgical resection can be performed. Dickinson et al. showed no significance in the use of vancomycin in patients with ulcerative colitis (UC) in 1985; Chapman et al. also showed no advantage of intravenous metronidazole in 1986, and Mantzaris et al. in 1997 showed no significance of ciprofloxacin use in mild-to-moderate active UC [25–27]. A subsequent study by Mantzaris et al. also showed no difference in response rates between patients with severe, acute colitis who were randomized to receive intravenous ciprofloxacin and hydrocortisone versus placebo and hydrocortisone [28]. Turunen et al. in a longer-term 6 months study of ciprofloxacin in active UC patients not doing well on steroids and mesalamine did demonstrate a lower treatment failure rate, 21% vs 44%, (p < 0.002) along with endoscopic and histologic improvement at 3 months, but not at 6 months. The authors also found that at 12 months, there was no longer a significant difference in response rates between the two groups [29]. Antibiotics were compared with sulfasalazine in a double blinded, controlled trial of patients with active, non-severe ulcerative colitis. Forty six patients were randomized to receive metronidazole or sulfasalazine for 28 days [30]. The authors found that only 6 of 23 patients in the metronidazole group improved versus 13 of 19 patients in the sulfasalazine group and concluded that metronidazole was ineffective in the treatment of active ulcerative colitis. Additional antibiotics including tobramycin, amoxicillin-clavulanic acid, amoxicillin, and tetracycline have also been studied in patients with active ulcerative colitis. Mixed results have been reported regarding the use of tobramycin. Burke et al. randomized 84 patients with acute relapse of their ulcerative colitis to receive tobramycin or placebo along with steroids for 7 days [31]. The authors found significant clinical improvements in the tobramycin group versus the placebo group after 3 to 4 weeks (74% versus 43%). Lobo et al. however reported that these response rates were short lived as they followed 81 of those previously followed 84 patients for 2 years and found no difference in relapse rates between groups. A second study by Mantzaris et al. showed no difference in response rates in patients with severe active ulcerative colitis who received intravenous tobramycin and metronidazole in conjunction with corticosteroids versus placebo and corticosteroids alone [32, 33]. More recently, Ohkusa et al. reported some success in the treatment of active ulcerative colitis with the use amoxicillin, tetracycline, and metronidazole [34]. In this randomized, controlled trial 20 patients with chronic, active ulcerative colitis were randomized to receive the above combination of antibiotics or placebo for two weeks. The antibiotics were selected based on their sensitivities towards Fusobacterium varium which has been proposed as a pathogenic factor in the development of UC. The authors reported significant improvements in endoscopic/histologic scores as well as clinical symptoms at 3 to 5 months and 12 to 14 months. They also reported a significantly higher remission rate among the treatment group versus those who received placebo. Finally, patients who present with fever and a colitis exacerbation admitted to the hospital may also be treated with triple antibiotics, ampicillin, gentamicin and metronidazole, until a bacterial superinfection triggering the disease exacerbation has been excluded at which point the antibiotics are stopped after negative stool cultures and negative blood cultures.
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Emerging Therapies More recently with the development of newer antimicrobials that have the majority of their action within the bowel lumen with minimal systemic absorption, researchers have started to study their effect in the management of IBD. Rifaximin (Xifaxan®) and Nitazoxanide (Alinia®) are the two most recent potential therapeutic candidates. Rifaximin comes in a tablet form to treat Escherichia coli related traveler’s diarrhea and also has effect against a broad spectrum of small bowel bacteria covering most gram-positive and gram-negative bacteria, both aerobes and anaerobes. Side effects are minimal, and headache, constipation, vomiting, abdominal cramp/pain. Ritaximin has no bowel absorption, but is not FDA approved for use in IBD or in children. There are limited adult randomized controlled studies or placebo-controlled studies involving rifaximin reported in the treatment of IBD. Campieri et al. in 2000 reported in abstract form only their results of a randomized postoperative recurrence prevention trial evaluating the efficacy of rifaximin 1.8 g/day for 12 weeks followed by probiotic VSL#3 of 6 g/day for another 9 months compared to mesalamine 4 g/day for 1 year after resection of disease bowel in 40 Crohn disease patients [35]. After 3 months there was a lower incidence of endoscopic recurrence in the rifaximin group 10% vs 40% which was maintained after 1 year: 20% vs 40%. Shafran and Johnson conducted and open-labeled study among 29 adult patients with mild to moderate Crohn disease [36]. Patients received rifaximin for 16 weeks. The authors reported 59% of patients had a significant reduction in disease activity scores at the end of 4 weeks and 78% had decreased their CDAI score by greater than 70 points at the end of 16 weeks. 59% of patients had achieved clinical remission by the end of the study, and the authors conclude that rifaximin may show some promise in the treatment of Crohn disease. Kornbluth et al. also reported some success in the treatment of mild to moderate, refractory Crohn disease with rifaximin daily at 2 doses (200 mg three times daily and 400 mg twice daily) [37]. Thirty patients were studied in an open-labeled, retrospective study. The authors found that 43% of patients with ileitis, 67% of patients with ileocolitis and 63% of patients with colitis improved, and they concluded that rifaximin may be effective in treating mild to moderate refractory Crohn disease. Rifaximin has also been evaluated in patients with ulcerative colitis. Gionchetti et al. in 1999 in their study of 28 moderate to severe ulcerative colitis patients showed no significant differences in outcome in patients not responding to intravenous methylprednisolone after 7–10 days with the additional use of 400 mg bid of rifaximin [38]. The authors did, however, note a reduction in stool frequency, rectal bleeding, and sigmoidoscopy scores among the rifaximin group. In abstract form in 2002 regarding an open-label study by Lukas et al. of mildly active ulcerative colitis patients, the authors reported a 30% reduction in disease activity after 1 month in their patients who used rifaximin as additional therapy [39]. Also, in left-sided ulcerative colitis relapsing on mesalamine, Guslandi et al. performed an open label study of 400 mg by mouth twice daily and with 2.4 g/day mesalamine, demonstrated that the addition of rifaximin resulted in 70% clinical remission [40]. An open label study for its use in ulcerative pouchitis demonstrated an 81% efficacy for a dose of 600–800 mg daily [41]. Another study involving chronic resistant ulcerative pouchitis by Gionchetti using rifaximin at 2 g/day along with ciprofloxacin 1g/day demonstrated an 89% remission [42]. Nitazoxanide comes in both tablet and suspension form making this ideal for pediatric use and has an FDA indication for parasitic infectious diarrhea (Cryptosporidium parvum and Giardia lamblia as well as helminthes and tapeworms). The drug is metabolized by the cytochrome P450 mechanism in the liver with bile, feces and urinary excretion. Its side effect profile is minimal with abdominal pain, diarrhea, headache and nausea reported and is similar to placebo. Some researchers have been studying its use to treat Clostridium difficile as well as in Crohn disease but published results are not available.
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Both drugs, rifaximin and nitazoxanide, have shown some promise as primary therapies in inflammatory bowel disease. More rigorous testing including randomized, controlled trials are necessary before the drugs are accepted as appropriate mainstream treatment, however. Additional Considerations When utilizing antibiotics in the acute or maintenance arm of therapy, careful consideration for which form of mesalamine treatment being used concurrently is necessary since medications such as olsalazine or sulfasalazine require the presence of bacteria to cleave their disulfide bond in order to permit action of the medication. Asacol requires a basic/neutral lumenal pH to be effective such that with stenotic disease and the potential of bacterial overgrowth with a more locally acidic lumenal pH, concurrent antimicrobial therapy theoretically may be beneficial. While generally well tolerated, antibiotics can lead to side effects that may require discontinuation and should be monitored closely. As previously mentioned, ciprofloxacin has been noted to cause arthropathies in immature animals, and long-term use is generally avoided among children. One pediatric study evaluated side effects associated with long-term metronidazole use. Duffy et al. reported on their experience among 13 pediatric Crohn disease patients who received metronidazole for 4 to 11 months [43]. They found that 85% (11 of 13) had peripheral neuropathies based on abnormal nerve conduction velocities or neurological examinations although only 6 of 11 were symptomatic. Complete resolution of the neuropathy occurred in 5 children, improvement occurred in 3 children and there was no change in one child.
Summary In summary, limited prospective studies investigating antibiotic use in pediatric inflammatory bowel disease are available. Based on available literature, some role for antibiotics including metronidazole and/or ciprofloxacin has been shown for acute exacerbations of Crohn disease and chronic penetrating Crohn disease. No available, objective evidence supports their use in acute ulcerative colitis. Additional prospective studies are needed to evaluate the role of newer antibiotics including rifamixin and nitazoxanide. References 1. Sartor RB. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am J Gastroenterol 1997;92:5S–11S. 2. Rutgeerts P, Goboes K, Peeters M, et al. Effect of faecal stream diversion on recurrence of Crohn disease in the neoterminal ileum. Lancet 1991;338:771–74. 3. Perencevich M and Burakoff R. Use of antibiotics in the treatment of inflammatory bowel disease. Inflamm Bowel Dis 2006;12:651–664. 4. Ursing B, Alm, T, Barany F, et al. Comparative study of metronidazole and sulfasalazine for active Crohn disease: the cooperative Crohn disease study in Sweden. Gastroenterology 1982;83:550–562. 5. Rutgeerts P, Hile M, Geboes K, et al. Controlled trial of metronidazole for prevention of Crohn recurrence after ileal resection. Gastroenterology 1995;108:1617–21. 6. Hildebrand H, Berg NO, Hoevels J, et al. Treatment of Crohn disease with metronidazole in childhood and adolescence. Gastroenterol Clin Biol 1980;4:19–25. 7. Ursing B and Kamme C. Metronidazole for Crohn disease. Lancet 1975;1:775–777. 8. Sutherland L, Singleton J, Sessions J, et al. Double-blind placebo controlled trial of metronidazole in Crohn disease. Gut 1991;32:1071–1075. 9. Colombel JF, Lemann M, Cassagnou M, et al. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn disease. Am J Gastroenterol 1999;94:674–678. 10. Arnold GL, Beaves MR, Pryjdun VO, et al. Preliminary study of ciprofloxacin in active Crohn disease. Inflamm Bowel Dis 2002;8:10–15.
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11. Greenbloom SL, Steinhart AH, Greenberg GR. Combination ciprofloxacin and metronidazole for active Crohn disease. Can J Gastroenterol 1998;12:53–56. 12. Prantera C, Zannoni F, Scribano ML, et al. An antibiotic regimen for the treatment of active Crohn disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol 1996;91:328–332. 13. Prantera C, Berto E, Scribano ML, et al. Use of antibiotics in the treatment of active Crohn disease: experience with metronidazole and ciprofloxacin. Ital J Gastroenterol Hepatol 1998;30:602–606. 14. Schwartz DA, Pemberton JH, Sandborn WJ. Diagnosis and treatment of perianal fistulas in Crohn disease. Ann Intern Med 2001;135:906–18. 15. Allan R and Cooke WT. Evaluation of metronidazole in the management of Crohn disease. Gut 1977;18:A422. 16. Bernstein LH, Frank MS, Brandt LJ, et al. Healing of perianal Crohn disease with metronidazole. Gastroenterology 1980;79:357–365. 17. Brandt LJ, Bernstein LH, Boley SJ, et al. Metronidazole therapy for perianal Crohn disease: a follow-up study. Gastroenterology 1982;83:383–387. 18. Dejaco C, Harrer M, Waldhoer T, et al. Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn disease. Aliment Pharmacol Ther 2003;18:1113–1120. 19. West RL, Van Der Woude CJ, Hansen BE, et al. Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn disease with infliximab: a double-blind placebo-controlled study. Aliment Pharmacol Ther 2004;20:1329–1336. 20. Baldassano RN, Han PD, Jeshion WC, et al. Pediatric Crohn disease: Risk factors for postoperative recurrence. Am J Gastroenterol 2001;96:2169–2176. 21. Penner RM, Madsen KL, Fedorak RN. Postoperative Crohn disease. Inflamm Bowel Dis 2005;11:765–777. 22. D’Haens GR, Geboes K, Peeters M, et al. Early lesions of recurrent Crohn disease caused by infusion of Intestinal contents in excluded ileum. Gastroenterology 1998;114:262–267. 23. Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn disease recurrence after ileal resection. Gastroenterology 1995;108:1617–1621. 24. Rutgeerts P, Van Assche G, Vermeire S, et al. Ornidazole for prophylaxis of postoperative Crohn disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2005;128:856–861. 25. Dickinson RJ, O’Connor HJ, Pinder I, et al. Double-blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut 1985;26:1380–84. 26. Chapman RW, Selby WS, Jewell DP. Controlled trial of intravenous metronidazole as adjunct to corticosteroids in severe ulcerative colitis. Gut 1986;27:1210–12. 27. Mantzaris GJ, Archavlis E, Christoforidis P, Kourtessas D, Amberiadis P, Florakis N, Petraki K, Spiliadi C, Triantafyllou G. A prospective randomized controlled trial of oral ciprofloxacin in acute ulcerative colitis. Am J Gastroenterol 1997;92:454–56. 28. Mantzaris GJ, Archavlis E, Christoforidis P, Kourtessas D, Amberiadis P, Florakis N, Petraki K, Spiliadi C, Triantafyllou G. A prospective randomized controlled trial of oral ciprofloxacin in acute ulcerative colitis. Am J Gastroenterol 1997;92:454–56. 29. Turunen UM, Farkkila MA, Hakala K, Seppala K, Sivonen A, Ogren M, Vuoristo M, Valtonen VV, Miettinen TA. Long-term treatment of ulcerative colitis with ciprofloxacin: A prospective, double-bind, placebo-controlled study. Gastroenterology 1998;115:1072–78. 30. Gilat T, Suissa A, Leichtman G, et al. A comparative study of metronidazole and sulfasalazine in active, not severe, ulcerative colitis. J Clin Gastroenterol 1987;9:415–417. 31. Burke DA, Axon AT, Clayden SA, et al. The efficacy of tobramycin in the treatment of ulcerative colitis. Aliment Pharmacol Ther 1990;4:123–129. 32. Lobo AJ, Burke DA, Sobala GM, et al. Oral tobramycin in ulcerative colitis: effect on maintenance of remission. Aliment Pharmacol Ther 1993;7:155–158. 33. Mantzaris GJ, Hatzis A, Kontogiannis P, et al. Intravenous tobramycin and metronidazole as an adjunct to corticosteroids in acute, severe ulcerative colitis. Am J Gastroenterol 1994;89:43–46. 34. Ohkusa T, Nomura T, Terai T, et al. Effectiveness of antibiotic combination therapy in patients with active ulcerative colitis: a randomized, controlled pilot trial with long-term follow-up. Scand J Gastroenterol 2005;40:1334–1342. 35. Shafran I and Johnson LK. An open-label evaluation of rifaximin in the treatment of active Crohn disease. Cur Med Res Opin 2005;21:1165–69.
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36. Kornbluth A, Hunt M, George J, et al. Efficacy and safety of rifaximin in the treatment of mild-moderate Crohn disease: results of an open-label pilot study. Gastroenterology 2005;128:A579. 37. Campieri M, Rizzello F, Venturi A, Poggioli G, Ugolini F, Helwig U, Amadini C, Romboli E, Gionchetti P. Combination of antibiotic and probiotic treatment is efficacious in prophylaxis of postoperative recurrence of Crohn disease: A randomized controlled study versus mesalazine. Gastroenterology 2000;118(suppl 1):A781. 38. Gionchetti P, Rizzello F, Ferrieri A, Venturi A, Brignola C, Ferretti M, Peruzzo S, Miglioli M, Campieri M. Rifaximin in patients with moderate to severe ulcerative colitis refractory to steroidtreatment: A double-blind, placebo-controlled trial. Dig Dis Sci 1999;44:1220–21. 39. Lukas M, Konecny M, Zboril V. Rifaximin in patients with mild to moderate activity of ulcerative colitis: An open label study. Gastroenterology 2002;122:A434. 40. Guslandi M, Giolla P, Testoni PA. Corticosteroid-sparing effect of Rifaximin, a nonabsorbable oral antibiotic, in active ulcerative colitis: preliminary clinical experience. Current Therapeutic Research 2004;65(3):292–96. 41. Kornbluth, A, Hunt M, George J, Rochester J, Fried-Boxt E, Legnani P. An open label pilot trial of Rifaximin in the treatment of patients with refractory pouchitis. Gastroenterology 2006; 130:A-658. 42. Gionchetti P, Rizzello F, Venturi A, Ugolini F, Rosi M, Brigidi P, Johansson R, Ferrieri A, Poggioli G, Campieri M. Antibiotic combination therapy in patients with chronic, treatment-resistant pouchitis. Aliment Pharmacol Ther 1999;13:713–18. 43. Duffy LF, Daum F, Fisher SE, et al. Peripheral neuropathy in Crohn disease patients treated with metronidazole. Gastroenterology 1985;88:681–84.
26 Nutritional Therapy Wael El Matary∗ and Mary Zachos∗∗
Introduction While similar in many respects, the inflammatory bowel diseases (IBD), can be classified based on certain distinctive endoscopic and histological characteristics. Clinical manifestations also vary between Crohn disease (CD) and ulcerative colitis (UC), including their impact on nutritional status. Therapeutic options aim to control the disease and prevent adverse outcomes [1]. In the treatment of IBD in children, nutrition and growth outcomes are critical indicators of overall well-being and therapeutic success. A history of weight loss or poor weight gain is a very common symptom at presentation particularly with Crohn and severe ulcerative colitis [2]. Linear growth impairment is reported even before the onset of intestinal symptoms in almost half of pediatric patients with Crohn disease [3]. Given the early age of onset, such impairment of growth is particularly problematic, with subsequent impact on onset of puberty, self-esteem and quality of life. In addition to a multitude of pharmacologic approaches to therapy, there is extensive evidence supporting the efficacy of nutritional therapy in Crohn disease. Despite the obvious advantages including the direct impact on growth, nutrition and the avoidance of adverse drug effects, nutritional therapy has not been as widely accepted in North America as other parts of the world [4]. Since linear growth and bone disease have been addressed in alternate chapters, this chapter will focus on nutritional deficiencies and the role of nutritional management in the treatment of IBD.
Nutritional Impairment in Pediatric Inflammatory Bowel Disease Several cohort studies have demonstrated weight loss, or poor weight gains at the time of initial diagnosis of CD. Griffiths, et al. reported 80% of the 386 children diagnosed with CD over a period of ten years had a history of weight loss [1]. Weight loss is seen less commonly, particularly through the course of established UC, but has been seen in up to 65% of children at diagnosis [2].
*Wael El Matary, MBBCH, MD, MRCP, Assistant Professor of Pediatrics, University of Alberta, Division of Gastroenterology – Department of Pediatrics, Stollery Children’s Hospital, #9222 Aberhart Centre 1, 11402 University Avenue NW, Edmonton, Alberta, T6G 2J3, Canada, Phone: 780-407-3339, Fax: 780-4073507, Email:
[email protected] **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, 555 University Avenue, Toronto, ON M5G 1X8, Canada, Phone: 416-813-8757, Fax: 416-813-6531, Email:
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The reasons for altered growth are likely multi-factorial, with decreased caloric intake being the most common [2,5–9]. Poor intake may be the consequence of anorexic effects of proinflammatory mediators or result from early satiety. Fear of pain or diarrhea in association with meals also limits caloric intake. Localization of disease in the small bowel may lead to disaccharide intolerance resulting in shorter gut transit times, pain and exacerbation of diarrhea. Malabsorption of food components and the diversion of calories to sites of gut inflammation may also lead to impaired weight gain and growth. Caloric Requirements in Children with Crohn Disease There is conflicting data from studies reporting resting energy expenditure (REE) in children with CD. In comparison to healthy controls, Azcue et al. [10] reported no difference in REE per unit of lean body mass in patients with CD, while Zoli et al. [11] found elevated REE in growing children with CD. Surprisingly, the latter study did not reveal any further increase in REE with relapse of disease, and suggested that energy may be “diverted” from growth to disease activity during relapse. It is imperative that children and adolescents consume a diet providing adequate protein with sufficient calories to support growth. The mean energy intake of patients with CD during relapse has been found to be up to 420 kcals per day lower than age matched controls [12]. In a study by Thomas et al. 71% of children consumed less energy with protein intake differing significantly compared to age matched controls [12]. While all of the studied patients with CD increased their caloric intakes when in remission, others have shown that despite being asymptomatic, the mean caloric intake of children and adolescents with CD was 82% of expected for height age [5]. Because of the difficulty ensuring adequate energy and nutrient requirements of children with inflammatory bowel disease, particularly during flares, active monitoring of nutritional status must be undertaken throughout childhood, but especially in adolescence. Where indicated, aggressive nutritional intervention should be initiated before puberty, whether disease is active or in remission, to correct the energy deficits and maximize growth potential. Dietary intakes of children and adolescents with IBD may be compromised in micronutrient content in addition to protein and energy. Specific micronutrient and vitamin deficiencies are encountered more commonly with Crohn disease than with ulcerative colitis. Hendricks et al. [6] compared a group of adolescents with CD and growth failure with a control group of adolescents with CD who were growing normally. Mean serum ferritin levels were significantly decreased in both groups and mean plasma zinc levels were borderline low in the growth failure group and low in the control group. Dietary zinc intake was below the Recommended Daily Allowance (RDA) in 88% of the group with growth failure and 44% of controls (64% combined) and less than 75% of the RDA in 41% of all adolescents with CD. Dietary iron intake was also below the RDA in 24% of all adolescents with CD, with one adolescent in the growth failure group consuming less than 75% of the RDA. One third of adolescents were consuming less than 75% of the RDA for calcium [6]. Other studies of micronutrient intakes in CD have found mean intakes of zinc, copper, iron, calcium, folic acid, vitamin C and vitamin D to be significantly (p<0.05) lower than age matched controls and RDAs [12]. Essential fatty acid status may also be altered, in association with low body mass index and disease activity [13]. Malabsorption of fat soluble vitamins can be an issue in patients with ileal disease [14, 15]. Vitamin D and vitamin K deficiencies may both contribute to the lowered bone mineral density (BMD) seen commonly in CD [16]. Whether or not to supplement a child’s diet should be considered on an individual basis, following dietary assessment, as firm recommendations for vitamin and mineral supplementation await future studies [17]. Kleinman and colleagues [18] have suggested that patients should be
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recommended a multivitamin/mineral to meet 100–150% of the RDA when dietary intake is less than expected. Elevated Body Mass Index in Inflammatory Bowel Disease Although most emphasis of the nutritional aspects of IBD is focused upon impaired nutritional status, the increasing rate of childhood obesity is also relevant in children presenting with acute IBD. Sondike and colleagues [19] reported this phenomenon in a group of 166 children from Wisconsin, USA. Sixteen (12%) of a group of newly diagnosed children with CD were overweight (BMI > 85%) or obese (BMI > 95%). This feature was also evident in the children diagnosed with UC: 17.6% of these 34 children were overweight or obese. Overweight status at presentation of IBD has previously been rarely reported. Only 3% of an adult cohort with CD was noted to be overweight [20].
General Management of Nutrition in Inflammatory Bowel Disease Following diagnosis of IBD, there are numerous ongoing aspects of nutritional management to address. Nutritional issues relating to therapy may arise. The commencement of steroids often leads to increased appetite and commonly alters fluid balance with initial fluid retention and weight gain that only partially reflects improvements in underlying nutritional status. Steroids are clearly linked with impaired bone mineralization, with enhanced resorption and decreased new bone formation [21], [22]. Adequacy of calcium and vitamin D intake must be reviewed regularly. Inhibition of linear growth and altered final height, due to suppression of insulin-like growth factor-1 (IGF-1), is also a feature of daily corticosteroid therapy [23]. Other medications may interfere with the absorption of specific micronutrients. Sulphasalazine may interfere with folate metabolism by reducing absorption, however, daily supplementation does not appear necessary [24]. In contrast, folate supplementation is required when the immunosuppressive drug methotrexate is used, as this drug acts to inhibit the conversion of folate to the active moiety tetrahydrofolate [25]. Questions related to nutrition and which foods to avoid are amongst the commonest raised by families both at diagnosis and in routine follow-up. The current consensus from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) is that diets of children with CD should be well balanced, based on the Food Guide Pyramid and follow dietary reference intakes [17]. Rigorous scientific study has not been performed and evidence to support the use of diets with specific carbohydrates or elimination of specific food groups is unavailable, despite isolated case reports of clinical efficacy [26]. A controlled study of a high fiber, low sugar diet compared with a low fiber, unrestricted sugar diet found no difference in the clinical course of adult patients in remission [27]. Low residue diets are also ineffective in the treatment of inflammation [28]. In the event of intestinal obstruction or transient abnormalities of digestion such as disaccharide intolerance in those with severe small bowel disease, short-term dietary restrictions may be required to alleviate symptoms [17, 29]. Effectiveness of Enteral Nutrition Therapy in Crohn Disease Elemental diets were first used in Crohn disease to provide preoperative nutritional support. Primary therapeutic efficacy was suspected in an uncontrolled study where patients awaiting surgery appeared to experience improvement in the clinical activity of their inflammatory bowel disease as well as in their nutritional status [30]. The first controlled study of adults with CD determined that an elemental diet was equally effective in the induction of remission as corticosteroids [31]. There is now a vast experience and literature supporting the use of enteral
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nutrition (EN) therapy in Crohn disease but the mechanism of action and ideal formulation are still being studied. There have been numerous open and comparative studies evaluating the use of EN with elemental formulae in adults [32–35] and children [36–38] with CD (Figures 26.1 a and b and 26.2 a and b). Individual studies comparing the effectiveness of EN for the induction of remission of Crohn disease have varied considerably in their results with remission rates ranging from 20 to 84%. This apparent discrepancy may stem from differences involving study populations (e.g. ages, disease activity), interventions (e.g. route of administration), outcome assessments (disease activity measures) and methodology (e.g. sample size, blinding, randomization). In three meta-analyses, one of which was recently updated to include the latest studies [39], investigating the use of EN in CD, steroids were found to be more effective in the induction of remission [39–41]. These analyses involved predominantly adult studies of varying quality. Incorporation of a recent well-conducted pediatric randomized controlled study [42], to the latest meta-analysis allowed for a sensitivity analysis of high quality studies based on the Jadad scale [43]. The two high quality studies had conflicting results, one favoring steroid therapy [44] and one favoring EN [42] though neither study demonstrated statistically significant differences. Combining these high quality studies in a subgroup analysis resulted in 34 patients treated with EN (both polymeric) and 35 treated with steroids. The OR was 1.18 (95% CI 0.37 to 3.70). The question of equivalent or superior efficacy of steroids to EN in children is also raised by Heuschkel et al. who combined in meta-analysis the data accrued in controlled trials conducted exclusively in children and adolescents [45]. They concluded that nutritional treatment and conventional corticosteroids are equally effective in a pediatric population, even if not in adults. However, to reach this conclusion, their NNT was 182 patients to detect a 20% difference in treatment effects. The actual number they had from 5 randomized controlled trials was only 147 children and hence, they included two non-randomized trials to reach the desired sample size. In summary, existing studies and meta-analyses suggests that the benefits of EN may differ between children and adults, and therefore other risks and benefits must be factored into the therapeutic decision pathway. Factors Affecting Response to Enteral Nutrition Formula Composition Polymeric Versus Elemental / Semi-elemental Diets. Nutritional therapy is classified by the nitrogen source derived from the amino acid or protein component of the formula. Elemental diets are created by mixing of single amino acids and are entirely antigen free. Oligopeptide or semi-elemental diets are made by protein hydrolysis and have a mean peptide chain length of four or five amino acids which is too short for antigen recognition or presentation. Polymeric diets
(a)
Figure 26.1 a. Illustrates superiority of corticosteroids over enteral nutrition by meta-analysis. [38]
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(b)
Figure 26.1 b. Illustrates equivalence of corticosteroids and enteral nutrition in subgroup analysis of high quality studies. [38]
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Figure 26.2 a. Illustrates non-significant trend favouring increased effectiveness of very low fat content enteral nutrition. [38]
(b)
Figure 26.2 b. Illustrates non-significant trend favouring increased effectiveness of very low % long chain trygliceride content enteral nutrition. [38]
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contain whole protein from sources such as milk, meat, egg or soy. They can be classified more simply as elemental (amino acid-based), semi-elemental (oligopeptide) and polymeric (whole protein) diets. Although elemental diets were used in the initial studies focusing upon the nutritional treatment of CD, subsequent studies in both children and adults have compared these elemental diets to polymeric diets [44, 46–48]. Comparisons between any combination of the different protein sources when combined in meta-analysis [39] have shown no significant difference in effectiveness. Similarly, one study comparing polymeric diets differing in glutamine-enrichment showed no difference in remission rates [49]. Fat Composition. In more recent years, several trials have been conducted to investigate the importance of fat composition [50–53], building on the hypothesis that the proportion or type of fat in an enteral feed could affect the production of pro- or anti-inflammatory mediators. Two trials, Leiper et al. [52] and Sakurai et al. [53], investigated the effect of low versus high long chain triglyceride (LCT) content, and differing amounts of medium chain triglycerides, respectively, in adult patients and showed no difference in effect. Another study by Bamba et al. [50] comparing diets of low (3.06 g/day), medium (16.56 g/day) or high fat (30.06 g/day) content showed higher remission rates in the lowest fat group. By intention to treat analysis, remission was achieved in 8 of 11 patients (72.7%) of the low fat group, 4 of 13 (30.8%) in the medium fat group and 2 of 12 (16.7%) of the high fat group. However, all of these studies were flawed by either small sample sizes, high dropout rates or unvalidated activity indices used to define remission. When studies evaluating fat composition were combined by meta-analysis [39], a non significant trend favoring very low fat and low LCT content has been demonstrated. However, these results should be interpreted with caution due to statistically significant heterogeneity and small size which may have lacked statistical power to show differences should they exist. In addition, subgroup analyses could not be performed based on the n6 or n9 fatty acid composition in the feeds due to significant heterogeneity. The possibility that fat composition influences immunomodulatory or anti-inflammatory effect in active Crohn disease warrants further exploration with larger trials. In summary, no specific formula composition of EN diets has been conclusively shown to influence induction of remission in active CD. Since polymeric formulae have the same clinical benefits, and better palatability, they may be associated with increased interest, tolerance and compliance of EN therapy, though this has not been shown. Due to the suspected contributing mechanisms of action and a trend favoring low fat diets (which are typically elemental) [39] many centers, including ours in Toronto, continue to utilize elemental diets administered via nasogastric tube for the majority of patients when nutritional therapy is favored over pharmacologic options. EN has been provided in an exclusive fashion in clinical studies to optimize the benefits. The question of whether supplementary EN could be considered instead of exclusive EN was explored in a randomized controlled pediatric trial by Johnson et al. [54]. This study showed that the combination of partial EN (50% of energy requirements) with normal diet lead to a substantially lower rate of remission compared to the use of exclusive EN (100% of energy requirements). Disease Related Factors Disease Duration. Several studies suggest higher efficacy of EN in children with newly diagnosed CD over those with established disease duration. A multi-centre North American study using a semi-elemental formula showed a remission rate of 83% in children newly-diagnosed with CD [55], compared to a response rate of 50% in children with previously diagnosed CD. An Australian retrospective study found 12 of 15 (80%) children with newly diagnosed CD entered remission, defined by PCDAI, compared to 7 of 12 (58%) children, who had been diagnosed with CD for a mean of 3.2 years [56]. The latter study also showed that although some children in this group
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did not enter remission, each had reductions in pediatric Crohn disease activity index (PCDAI) and each had nutritional improvements. Disease Location. As well as the impact of disease duration upon the success of EN in children, another potential factor is disease location. Several reports suggest increased efficacy when there is small bowel involvement [57, 58] and a trend towards earlier relapse in those with isolated colonic involvement [58]. Yet, Afzal et al. [59] demonstrated, in a prospective study of 65 children with acute intestinal CD treated with exclusive polymeric diet, that even the patients with disease limited to the colon had remission rates of 50%, albeit much lower than those with ileocolonic (82% remission rate) or ileal disease (91.7% remission rate). Thus, although remission rates are lowest in colonic disease, EN may still be considered. Duration of Therapy. Duration of exclusive EN has varied from four to eight weeks in most trials. The early effects of EN have been achieved over the first four weeks of therapy. Additional later effects in the fourth to eighth weeks of therapy may include further anti-inflammatory and nutritional benefits [56]. Additional Effects and Proof of Efficacy of Enteral Nutrition Mucosal Healing Small case series have demonstrated that the administration of EN leads to mucosal healing [47] and down-regulation of pro-inflammatory cytokines much more frequently than occurs with steroids [60, 61]. Fell et al. [47] initially showed mucosal healing in both the ileum (8 cases) and the colon (8 cases) of 29 children treated with a polymeric formula. These clinical and endoscopic improvements were associated with reductions in interleukin-1 (IL-1) mRNA and interferon- mRNA as well as an increase in transforming growth factor- (TGF-) mRNA [47]. Two recent pediatric studies have performed endoscopic assessments following EN therapy. A retrospective analysis reported greater endoscopic and histologic improvement in newly diagnosed pediatric patients treated with enteral nutrition, even though the clinical response rate with corticosteroid therapy was comparable. This study also suggested a longer duration of clinical remission following attainment of mucosal healing [62]. In a prospective study of 65 children, Afzal et al. [59] reported similar findings of endoscopic and histologic improvement in patients with ileal or ileo-colonic disease. Nutritional Status and Growth Improvement By detailed nutritional assessment, all body compartments improve with EN, even after just three weeks of enteral feeding [63]. Nutritional improvements do not correlate with the timing of inflammatory marker normalization, suggesting that these two clinical benefits of EN are independent [64, 65]. Nutritional status improves with EN as demonstrated in a pediatric study of 14 patients managed with EN. In addition to an increase in weight standard deviation scores after 8 and 16 weeks of therapy (p<0.05), IGF-1 and insulin-like growth factor binding protein 3 (IGF-BP3) both rose during therapy, indicating that alterations in the GH:IGF system can be rapidly improved with EN [63]. These changes in IGF-1 occur by seven days after initiation of EN [64]. Additional data pertaining to growth is provided by Papadopoulou et al. [66] who retrospectively compared growth in children treated with EN versus steroids. At one year the mean height standard deviation score for the steroid group was –0.13 compared with +0.85 for the enteral nutrition group (p<0.001).
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Quality of Life Improvement Despite the clear improvements in clinical status and mucosal healing, nutritional therapy is sometimes viewed as being difficult to administer successfully and to negatively affect quality of life (QOL). Gailhoustet et al. [67] explored this possibility in a subgroup of 30 children who had been managed with steroids or EN via nasogastric tube. A formal QOL questionnaire was not performed but patient responses did indicate some difficulties associated with the use of nasogastric tubes and family disruption. QOL has since been examined more formally by Afzal et al. [68] utilizing the validated IMPACT II questionnaire. Among the study population, 23 (88.5 %) of 26 children entered remission and 17 (65%) of them had histological improvements with EN. Twenty-four of the 26 children had improvements in their QOL scores during the period of nutritional therapy. The improvements in QOL were demonstrated across all measured domains, including the domain focusing upon treatments and interventions. Interestingly, the two children who did not have improved QOL ultimately required surgical intervention. Long Term Outcomes of Enteral Nutrition Use of Enteral Nutrition as Maintenance Therapy In general, once remission of active Crohn disease is established, maintenance of remission is a major challenge. In most studies of EN therapy, 60–70 % of patients experience a relapse within 12 months of completing therapy and resuming a normal diet [69]. The long-term outcomes of children whose first treatment had been EN was investigated in an uncontrolled retrospective analysis by pediatric gastroenterologists in England [58]. Among 79 patients newly diagnosed over a 7-year period, 44 (55%) chose to be treated with a six week course of enteral nutrition (73% via nasogastric tube) rather than with oral corticosteroids. Cumulative relapse rates were not reported, but median time to relapse was 54.4 weeks. These uncontrolled data suggest that some children experience a long asymptomatic interval after first treatment with enteral nutrition. However, data concerning the time to relapse in the steroid-treated group were not provided, so that the spectrum of long-term outcomes following nutritional versus pharmacologic treatment cannot be compared. After the successful induction of remission by EN in active CD, ongoing use of EN as maintenance therapy may be achieved by various methods including: regular overnight NG feeds [70]; oral supplements in addition to the ongoing usual diet [71, 72]; or by intermittent cycles alternating with normal diet [73]. In Canada, a common approach is the continuation of nocturnal nasogastric EN supplementation with liberal normal diet after establishment of remission on exclusive enteral feeds. This approach was associated with prolongation of remission and improved linear growth in children and adolescents [70]. The alternative is to maintain remission by intermittent bowel rest with nocturnal infusion of elemental feeds for one out of 4 months [73]. The beneficial effects of cyclical enteral nutrition on maintaining remission and promoting growth were demonstrated in a recent study comparing the outcome of alternate day oral administration of 0.3 mg/kg prednisone to cycles of exclusive enteral nutrition. After 18 months of follow-up, there was no significant difference in the proportion of patients maintaining remission. Nevertheless, the linear growth was significantly better in the group randomized to EN [74]. In other parts of the word including Europe, Japan and Australia, oral supplements in addition to normal diet are frequently employed to maintain remission. The evidence supporting this approach comes mainly from adult studies. Verma et al. [71] investigated the role of supplementing a normal diet with an elemental diet in long-term remission of Crohn disease. One group of 21 patients received oral nutritional supplements in addition to a normal diet compared to another group of 18 patients on a normal diet. Both groups were followed for 18 months. Ten patients (48%) of the first group maintained remission compared to 4 (22%) in the second group (p= 0.0003) [71]. A randomized controlled study from Japan reported similar results [72]. Maintenance of remission
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rates were compared between one group of patients receiving a therapy regimen in which 50% of the daily calorie requirement was provided by an elemental diet and the remaining 50% by a normal diet, while the comparison group received a 100% normal diet. The relapse rate in the half elemental diet group was significantly lower [34.6% vs. 64.0%; multivariate hazard ratio 0.40 (95% CI: 0.16–0.98)] than that in the 100% normal diet group after a mean follow-up of 11.9 months. Day et al. have provided supporting evidence for this approach in children [56]. Post-operative Effects While the efficacy of EN was fortuitously discovered during its use in the nutritional rehabilitation of patients pre-operatively, the effect of EN as prophylaxis against postoperative recurrence of CD has not been well-examined. Yamamoto et al. [75] investigated the impact of EN on clinical and endoscopic recurrence after resection for Crohn disease in 40 adult patients in a prospective, non-randomized, parallel, controlled study. The EN-treated group consisted of 20 patients who were given an elemental diet via nasogastric tube nightly and low fat foods were taken in the daytime. The parallel group of 20 patients had no nutritional therapy or food restriction. One of 20 (5%) in the EN group and 7 of 20 (35%) in the non-EN group developed clinical recurrence during 1-year follow-up (p=0.048). Endoscopic recurrence was evaluated at 6 and 12 months post-operatively. A significant difference (p= 0.027) in endoscopic recurrence between the EN group (30%) and the non-EN group (70%) was observed only at the 12-month post-operative assessment. Of note, clinical practice in Japan often employs concurrent mesalazine (Pentasa, 3 g/day) with EN therapy which all patients received in this study, but the potential confounding effect of compliance with the mesalazine on post-operative clinical and endoscopic recurrence of CD was not explored. Enteral Nutrition in Combination with Medical Therapy Thus far, there is minimal scientific evidence available on the role of EN with medical therapy particularly for the maintenance of remission. A steroid free algorithm of therapy would be an attractive therapeutic option particularly in children. One study exists on the combined use of EN in patients receiving infliximab [76]. This study suggested higher response rates to infliximab in patients receiving concurrent EN at 16 weeks, but confirmation by randomized controlled trial is necessary.
Adverse Effects of Enteral Nutrition There are very few adverse effects associated with the use of EN. Loose stools may be reported, particularly in those with predominantly colonic disease distribution. Nausea and constipation are less commonly reported [47]. A cross-sectional Japanese study in adults has reported a risk of selenium deficiency in patients with CD being treated with EN. Selenium concentrations were measured and compared in 29 patients with CD treated by EN, 24 patients with CD who were not being treated with EN and 21 healthy controls. Selenium levels were only decreased in CD patients receiving EN and were inversely correlated to the duration and daily dose of EN. Clinical manifestations of selenium deficiency were only found in one patient [77]. A European study examining the effect of exclusive EN on antioxidant concentrations in childhood CD reported conflicting results with respect to selenium. Mean selenium concentrations of the cohort increased significantly from 0.82 micromol/l to 1.14 micromol/l (p<0.001). There were however, significant reductions in mean concentrations of vitamin C and E [78]. Multiple factors including differences in age groups, disease activity, nutritional status and EN formulae may all impact on vitamin and anti-oxidant levels and the disparate results of the above studies. Further investigation of potential adverse effects at the micronutrient level is required.
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Severe adverse events related to EN are rare. There is one isolated case report of refeeding syndrome consequent to the use of EN in CD [79] and should be considered in children with severe CD especially with a recent history of rapid weight loss.
Mechanisms of Enteral Nutrition Postulated mechanisms of the effect of EN include the overall nutritional effects by correction of malnutrition and provision of important micronutrients to the diseased intestine, the concept of “bowel rest”, and immunological effects [80]. Formula Composition Due to the role of specific types of fat as modulators of inflammation [81] fat content of EN has been the focus of recent research. Omega-6 polyunsaturated fatty acids (n-6 PUFAs) are precursors of arachidonic acid, an important substrate for the production of pro-inflammatory eicosanoids. In contrast n-3 PUFAs, which are abundant in fish oils, inhibit arachidonic acid production, and inhibit protein kinase C activity needed for tumor necrosis factor (TNF) release from macrophages. Excess n-6 PUFAs would be expected to attenuate the effect of enteral nutrition in treating CD, whereas a relative increase in n-3 PUFAs might be beneficial. Whiting et al. [82] examined the hypothesis that a diet enriched in n-3 PUFAs would prevent or ameliorate disease in a well-characterized severe combined immunodeficiency (SCID) mouse model of chronic colitis that resembles CD [82]. Animals were fed either a standard diet or a diet enriched in n-3 PUFAs both before and following induction of colitis by injection of CD4+ CD45RBhigh T cells. In comparison to animals fed a standard diet, the n-3-fed animals had similar immune cell infiltration, but significantly reduced pathology scores, reduced neutrophil infiltration, and lower mucosal levels of pro-inflammatory cytokines (TNF-, IL-1, and IL-12) [82]. Improvement in intestinal barrier function was suggested by the preservation of the expression of epithelial tight junction protein ZO-1, a marker of intestinal permeability. These findings were interpreted as demonstrating that n-3 PUFAs reduce inflammation by reducing myeloid cell infiltration and activation, which in turn means lower levels of cytokines and less damage to the barrier. Numerous clinical trials examined the role of fat composition in the efficacy of EN [50–53] as detailed earlier. Overall, the trend for higher responses on low fat diet and the mechanistic plausibility are tantalizing but remain inconclusive. Furthermore, since polymeric formulae (usually high fat and more allergenic) have been shown to be as effective as elemental (usually low fat and hypoallergenic), the efficacy of EN is dependent on additional factors than fat content or “bowel rest”. Immunologic Effects Growing evidence implicates alternate mechanisms of efficacy of EN including direct antiinflammatory effects and alteration of the intestinal microflora leading to modification of host bacteria. Sanderson et al. [83] has provided an excellent review of the anti-inflammatory effects of EN. Four lines of evidence support this hypothesis including: direct effects on the inflamed intestine; changes in inflammatory markers preceding repletion of nutrition status; the existence of molecular pathways linking changes in luminal contents to the expression of class II major histocompatibility complex (MHC) genes in intestinal epithelium in animal studies; and direct effects on cytokine expression by intestinal epithelial cells. Studies investigating the effects of EN upon intestinal microflora are emerging and particularly exciting in light of the well-established role of microbes in disease pathogenesis [84]. Lionetti
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et al. [85] demonstrated that the enteric microflora is modified during and after a course of exclusive EN in a small group of 10 children managed with polymeric formula. Additional work by Eng et al. [86], using patterns of flora defined with polymerase chain reaction – denaturing gradient gel electorphoresis (PCR-DGGE) has shown similar alterations in bacterial populations within one week of starting EN and even after cessation of eight weeks of treatment. It is unclear whether such changes in the balance of the flora mediate epithelial events via cross-talk. These effects could be due to the pre-biotic properties of the formulae used in EN and deserve further study.
Conclusions Nutrition is an important component of the management of IBD in children and adolescents. Successful use of EN as a form of therapy, specifically for CD, requires a dedicated multidisciplinary team of nurses, dieticians, social workers and medical staff to support children and families during therapy. Pediatric gastroenterologists must consider EN in the therapeutic decision process since it yields all of the target outcomes of interest in the management of CD including alleviation of symptoms, mucosal healing, correction of nutritional deficiencies, optimization of growth, and normalization of quality of life, without adverse effects encountered with most pharmacologic therapy. Further work on the mechanism of efficacy of EN will likely shed light on the pathogenesis of IBD. A remaining challenge is the difficulty in maintaining remission as many patients do not welcome repeated restrictions on normal eating. Potential avenues of future study will likely include exploration of nutraceuticals and nutrients that have pharmacologic properties, such as the ability to induce immunomodulation, or, the development of designer formulae in alternative forms such as solid food in order to improve acceptance and palatability [80]. Alternatively, the combination of enteral and drug therapy with immunomodulators to maintain remission warrants further study. References 1. Griffiths, A., Inflammatory Bowel Disease; Chapter 41; Pediatric Gastrointestinal Disease. 3rd ed, ed. W.A.D.P.H.J.e. al. 2000, Hamilton: BC Decker. 2. Seidman, E., et al., Nutritional issues in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr, 1991. 12(4): 424–38. 3. Kanof, M.E., A.M. Lake, and T.M. Bayless, Decreased height velocity in children and adolescents before the diagnosis of Crohn disease. Gastroenterology, 1988. 95(6):1523–7. 4. Levine, A., et al., Consensus and controversy in the management of pediatric Crohn disease: an international survey. J Pediatr Gastroenterol Nutr, 2003. 36(4): 464–9. 5. Kelts, D.G., et al., Nutritional basis of growth failure in children and adolescents with Crohn disease. Gastroenterology, 1979. 76(4): 720–7. 6. Kirschner, B.S., et al., Reversal of growth retardation in Crohn disease with therapy emphasizing oral nutritional restitution. Gastroenterology, 1981. 80(1): 10–5. 7. Kirschner, B.S., O. Voinchet, and I.H. Rosenberg, Growth retardation in inflammatory bowel disease. Gastroenterology, 1978. 75(3): 504–11. 8. Motil, K.J., S.I. Altchuler, and R.J. Grand, Mineral balance during nutritional supplementation in adolescents with Crohn disease and growth failure. J Pediatr, 1985. 107(3): 473–9. 9. Motil, K.J., et al., The effect of disease, drug, and diet on whole body protein metabolism in adolescents with Crohn disease and growth failure. J Pediatr, 1982. 101(3): 345–51. 10. Azcue, M., et al., Energy expenditure and body composition in children with Crohn disease: effect of enteral nutrition and treatment with prednisolone. Gut, 1997. 41(2): 203–8. 11. Zoli, G., et al., Effect of oral elemental diet on nutritional status, intestinal permeability and disease activity in Crohn patients. Gastroenterology, 1996. 110(4): A1054.
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12. Thomas, A.G., F. Taylor, and V. Miller, Dietary intake and nutritional treatment in childhood Crohn disease. J Pediatr Gastroenterol Nutr, 1993. 17(1): 75–81. 13. Trebble, T.M., et al., Essential fatty acid status in paediatric Crohn disease: relationship with disease activity and nutritional status. Aliment Pharmacol Ther, 2003. 18(4): 433–42. 14. Driscoll, R.H., Jr., et al., Vitamin D deficiency and bone disease in patients with Crohn disease. Gastroenterology, 1982. 83(6): 1252–8. 15. Geerling, B.J., et al., Comprehensive nutritional status in patients with long-standing Crohn disease currently in remission. Am J Clin Nutr, 1998. 67(5): 919–26. 16. Schoon, E.J., et al., Low serum and bone vitamin K status in patients with longstanding Crohn disease: another pathogenetic factor of osteoporosis in Crohn disease? Gut, 2001. 48(4): 473–7. 17. Kleinman, R.E., et al., Nutrition support for pediatric patients with inflammatory bowel disease: a clinical report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr, 2004. 39(1): 15–27. 18. Kleinman, R.E., et al., Nutritional support for pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr, 1989. 8(1): 8–12. 19. Sondike, S., Weight status in pediatric IBD patients at the time of diagnosis: effects of the obesity epidemic. J Pediatr Gastroenterol Nutr, 2004. 39(Suppl 1): S317. 20. Blain, A., et al., Crohn disease clinical course and severity in obese patients. Clin Nutr, 2002. 21(1): 51–7. 21. Gokhale, R., et al., Bone mineral density assessment in children with inflammatory bowel disease. Gastroenterology, 1998. 114(5): 902–11. 22. Compston, J.E., Management of bone disease in patients on long term glucocorticoid therapy. Gut, 1999. 44(6): 770–2. 23. Hyams, J.S. and D.E. Carey, Corticosteroids and growth. J Pediatr, 1988. 113(2): 249–54. 24. Franklin, J.L. and H.H. Rosenberg, Impaired folic acid absorption in inflammatory bowel disease: effects of salicylazosulfapyridine (Azulfidine). Gastroenterology, 1973. 64(4): 517–25. 25. Feagan, B.G., et al., Methotrexate for the treatment of Crohn disease. The North American Crohn Study group investigators. N Engl J Med, 1995. 332(5): 292–7. 26. Fridge, J., The specific carbohydrate diet – a treatment for Crohn disease? J Pediatr Gastroenterol Nutr, 2004. 39(Suppl 1): S299. 27. Ritchie, J.K., et al., Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn disease. Br Med J (Clin Res Ed), 1987. 295(6597): 517–20. 28. Levenstein, S., et al., Low residue or normal diet in Crohn disease: a prospective controlled study in Italian patients. Gut, 1985. 26(10): 989–93. 29. Griffiths, A.M., Inflammatory bowel disease. Nutrition, 1998. 14(10): 788–91. 30. Voitk, A.J., et al., Experience with elemental diet in the treatment of inflammatory bowel disease. Is this primary therapy? Arch Surg, 1973. 107(2): 329–33. 31. O’Morain, C.A., A.W. Segal, and A.J. Levi, Elemental diet as primary treatment of acute Crohn disease: a controlled trial. Br Med J (Clin Res Ed), 1984. 288(6434): 1859–62. 32. Gorard, D.A., et al., Initial response and subsequent course of Crohn disease treated with elemental diet or prednisolone. Gut, 1993. 34(9): 1198–202. 33. Lindor, K.D., et al., A randomized prospective trial comparing a defined formula diet, corticosteroids, and a defined formula diet plus corticosteroids in active Crohn disease. Mayo Clin Proc, 1992. 67(4): 328–33. 34. Lochs, H., et al., Comparison of enteral nutrition and drug treatment in active Crohn disease. Results of the European Cooperative Crohn Disease Study. IV. Gastroenterology, 1991. 101(4): 881–8. 35. Malchow, H., et al., European cooperative Crohn disease study (ECCDS): results of drug treatment. Gastroenterology, 1984. 86(2): 249–66. 36. Sanderson, I.R., et al., Remission induced by an elemental diet in small bowel Crohn disease. Arch Dis Child, 1987. 62(2): 123–7. 37. Seidman, E.G., et al., Semi-elemental diet versus prednisone in pediatric Crohn disease. Gastroenterology, 1993. 104: A778. 38. Seidman, E.G., et al., Elemental diet versus prednisone as initial therapy in Crohn disease: early and long-term results. Gastroenterology, 1991. 100: 150A.
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39. Zachos, M., M. Tondeur, and A.M. Griffiths, Enteral nutritional therapy for induction of remission in Crohn disease. Cochrane Database Syst Rev, 2007. (1): CD000542. 40. Fernandez-Banares, F., et al., How effective is enteral nutrition in inducing clinical remission in active Crohn disease? A meta-analysis of the randomized clinical trials. J Parenter Enteral Nutr, 1995. 19: 1056–64. 41. Messori, A., et al., Defined-formula diets versus steroids in the treatment of active Crohn disease. A Meta-analysis. Scand J Gastroenterol, 1996. 31: 267–72. 42. Borrelli, O., et al., Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn disease: a randomized controlled open-label trial. Clin Gastroenterol Hepatol, 2006. 4(6): 744–53. 43. Jadad, A.R., et al., Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials, 1996. 17(1): 1–12. 44. Gonzalez-Huix, F., et al., Polymeric enteral diets as primary treatment of active Crohn disease: a prospective steroid controlled trial. Gut, 1993. 34(6): 778–82. 45. Heuschkel, R.B., et al., Enteral nutrition and corticosteroids in the treatment of acute Crohn disease in children. J Pediatr Gastroenterol Nutr, 2000. 31(1): 8–15. 46. Beattie, R.M., et al., Polymeric nutrition as the primary therapy in children with small bowel Crohn disease. Aliment Pharmacol Ther, 1994. 8(6): 609–15. 47. Fell, J.M.E., et al., Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn disease. Aliment Pharmacol Ther, 2000. 14: 281–9. 48. O’Sullivan, M.A. and C.A. O’Morain, Nutritional therapy in Crohn disease. Inflamm Bowel Dis, 1998. 4(1): 45–53. 49. Akobeng, A.K., et al., Double-blind randomized controlled trial of glutamine-enriched polymeric diet in the treatment of active Crohn disease. J Pediatr Gastroenterol Nutr, 2000. 30(1): 78–84. 50. Bamba, T., et al., Dietary fat attenuates the benefits of an elemental diet in active Crohn disease: a randomized, controlled trial. Eur J Gastroenterol Hepatol, 2003. 15(2): 151–7. 51. Gassull, M.A., et al., Fat composition may be a clue to explain the primary therapeutic effect of enteral nutrition in Crohn disease: results of a double blind randomised multicentre European trial. Gut, 2002. 51(2): 164–8. 52. Leiper, K., et al., A randomised controlled trial of high versus low long chain triglyceride whole protein feed in active Crohn disease. Gut, 2001. 49(6): 790–4. 53. Sakurai, T., et al., Short-term efficacy of enteral nutrition in the treatment of active Crohn disease: a randomized, controlled trial comparing nutrient formulas. J Parenter Enteral Nutr, 2002. 98–103. 54. Johnson, T., et al., Treatment of active Crohn disease in children using partial enteral nutrition with liquid formula: a randomised controlled trial. Gut, 2006. 55(3): 356–61. 55. Seidman, E., Relapse prevention/growth enhancement in pediatric Crohn disease: multicentre randomized controlled trial of intermittent enteral nutrition versus alternate day prednisone. J Pediatr Gastroenterol Nutr, 1996. 23: A344. 56. Day, A.S., et al., Exclusive enteral feeding as primary therapy for Crohn disease in Australian children and adolescents: a feasible and effective approach. J Gastroenterol Hepatol, 2006. 21(10): 1609–14. 57. Esaki, M., et al., Factors affecting recurrence in patients with Crohn disease under nutritional therapy. Dis Colon Rectum, 2006. 49(10 Suppl): S68–74. 58. Knight, C., et al., Long-term outcome of nutritional therapy in paediatric Crohn disease. Clin Nutr, 2005. 24(5): 775–9. 59. Afzal, N.A., et al., Colonic Crohn disease in children does not respond well to treatment with enteral nutrition if the ileum is not involved. Dig Dis Sci, 2005. 50(8): 1471–5. 60. Breese, E.J., et al., Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology, 1994. 106(6): 1455–66. 61. Breese, E.J., et al., The effect of treatment on lymphokine-secreting cells in the intestinal mucosa of children with Crohn disease. Aliment Pharmacol Ther, 1995. 9(5): 547–52. 62. Berni Canani, R., et al., Short- and long-term therapeutic efficacy of nutritional therapy and corticosteroids in paediatric Crohn disease. Dig Liver Dis, 2006. 38(6): 381–7. 63. Royall, D., et al., Total enteral nutrition support improves body composition of patients with active Crohn disease. JPEN J Parenter Enteral Nutr, 1995. 19(2): 95–9. 64. Bannerjee, K., et al., Anti-inflammatory and growth-stimulating effects precede nutritional restitution during enteral feeding in Crohn disease. J Pediatr Gastroenterol Nutr, 2004. 38(3): 270–5.
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65. Teahon, K., et al., Alterations in nutritional status and disease activity during treatment of Crohn disease with elemental diet. Scand J Gastroenterol, 1995. 30(1): 54–60. 66. Papadopoulou, A., et al., Remission following an elemental diet or prednisolone in Crohn disease. Acta Paediatr, 1995. 84(1): 79–83. 67. Gailhoustet, L., et al., Study of psychological repercussions of 2 modes of treatment of adolescents with Crohn disease. Arch Pediatr, 2002. 9(2): 110–6. 68. Afzal, N.A., et al., Improvement in quality of life of children with acute Crohn disease does not parallel mucosal healing after treatment with exclusive enteral nutrition. Aliment Pharmacol Ther, 2004. 20(2): 167–72. 69. Rigaud, D., et al., Controlled trial comparing two types of enteral nutrition in treatment of active Crohn disease: elemental versus polymeric diet. Gut, 1991. 32(12): 1492–7. 70. Wilschanski, M., et al., Supplementary enteral nutrition maintains remission in paediatric Crohn disease. Gut, 1996. 38(4): 543–8. 71. Verma, S., et al., Oral nutritional supplementation is effective in the maintenance of remission in Crohn disease. Dig Liver Dis, 2000. 32(9): 769–74. 72. Takagi, S., et al., Effectiveness of an ‘half elemental diet’ as maintenance therapy for Crohn disease: A randomized-controlled trial. Aliment Pharmacol Ther, 2006. 24(9): 1333–40. 73. Belli, D.C., et al., Chronic intermittent elemental diet improves growth failure in children with Crohn disease. Gastroenterology, 1988. 94(3): 603–10. 74. Seidman, E., Cyclical exclusive enteral nutrition versus alternative day prednisone in maintaining remission in pediatric Crohn disease. J Pediatr Gastroenterol Nutr, 1996. 23: A334. 75. Yamamoto, T., et al., Impact of long-term enteral nutrition on clinical and endoscopic recurrence after resection for Crohn disease: A prospective, non-randomized, parallel, controlled study. Aliment Pharmacol Ther, 2007. 25(1): 67–72. 76. Tanaka, T., et al., Effect of concurrent elemental diet on infliximab treatment for Crohn disease. J Gastroenterol Hepatol, 2006. 21(7): 1143–9. 77. Kuroki, F., T. Matsumoto, and M. Iida, Selenium is depleted in Crohn disease on enteral nutrition. Dig Dis, 2003. 21(3): 266–70. 78. Akobeng, A.K., et al., Effect of exclusive enteral nutritional treatment on plasma antioxidant concentrations in childhood Crohn disease. Clin Nutr, 2007. 26(1): 51–6. 79. Afzal, N.A., et al., Refeeding syndrome with enteral nutrition in children: a case report, literature review and clinical guidelines. Clin Nutr, 2002. 21(6): 515–20. 80. Ruemmele, F.M., et al., Nutrition as primary therapy in pediatric Crohn disease: fact or fantasy? J Pediatr, 2000. 136(3): 285–91. 81. Gorard, D.A., Enteral nutrition in Crohn disease: fat in the formula. European J Gastroenterol Hepatol, 2003. 15: 115–8. 82. Whiting, C.V., P.W. Bland, and J.F. Tarlton, Dietary n-3 polyunsaturated fatty acids reduce disease and colonic proinflammatory cytokines in a mouse model of colitis. Inflamm Bowel Dis, 2005. 11(4): 340–9. 83. Sanderson, I.R. and N.M. Croft, The anti-inflammatory effects of enteral nutrition. JPEN J Parenter Enteral Nutr, 2005. 29(Suppl 4): S134–8; discussion S138–40, S184–8. 84. Shanahan, F., Host-flora interactions in inflammatory bowel disease. Inflamm Bowel Dis, 2004. 10(Suppl 1): S16–24. 85. Lionetti, P., et al., Enteral nutrition and microflora in pediatric Crohn disease. JPEN J Parenter Enteral Nutr, 2005. 29(4 Suppl): S173–5; discussion S175–8, S184–8. 86. Eng WR, D.A., Leach S, et al., Exclusive enteral nutrition alters the intestinal microbiota of children with Crohn disease. Gastroenterology, 2005. 128: A511.
27 Probiotic Therapy David R. Mack∗
Introduction The term probiotic was first used to describe substances produced by a microorganism to promote the growth of another microorganism [1] but the definition has evolved to that espoused by the joint task force of the FAO/WHO, which is ‘live microorganisms that confer a health benefit when administered in adequate amounts’ [2]. Most microorganisms used as probiotics are bacteria that have been derived from human, animal and food sources. Most species of probiotics belong to the Lactobacillus and Bifidobacterium Genus but other bacterial strains within the Genus’ Enterococcus, Streptococcus and Escherichia have variously been used. The most common nonbacterial probiotic is the fungus Saccharomyces boulardii that is derived from the lychee fruit. Although not normally an inhabitant of the human intestinal tract as are some of the human and food derived bacterial strains, S. boulardii has gained consideration as a probiotic because it grows at normal body temperature and is intrinsically resistant to antibiotics. The use of probiotics has been proposed for providing benefits to human health for a long time but in recent years there has been increased interest for their use in a number of gastrointestinal conditions including inflammatory bowel disease [3]. In part, this has been the result of animal studies that have yielded provocative information regarding the importance of intestinal microbiota in stabilization and regeneration of the intestinal mucosa in the presence of inflammation [4] and that intestinal microbes can be involved in the development and chronicity of inflammation in various animal models of inflammatory bowel disease [5]. Probiotics are being ingested by patients with IBD sometimes through the advice of the physician but mostly self-prescribed as a form of alternative medicine [6, 7]. The interest in adults ingesting probiotics for their IBD has crossed over into probiotic usage in children and adolescents despite a significant lack of studies in younger aged IBD patients [8, 9]. Recent reports compared to even a few years ago would suggest increase in the use such that up to 50% of patients with IBD at least are trying probiotics if not taking them on a regular basis [7–11]. However, this must also be taken into the context of a 10-fold increase in information being published on medical journals cited by Medline in recent years available to the general public. As a measure of this increased information, a count of citations for a Medline search for probiotics and Crohn’s disease yields 9 citations prior to 2001 but 94 citations during the period from 2001 through 2005. Similarly, 14 citations are listed for ulcerative colitis and probiotics prior to 2001 but 137 from 2001 through 2005. The reasons
*Professor, Department of Pediatrics, University of Ottawa, Head, Pediatric Gastroenterology, Hepatology & Nutrition, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, CANADA K1H 8L1, Tel.: (613)-737-7600 ext 2516, Fax: (613)-738-4854, Email:
[email protected]
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people are using probiotics is most often related to worse disease severity, adverse side effects of traditional treatments and health beliefs [6–8]. Probiotics are available as single microbes or as blends of microbes and are generally combined with other prescription medicines. Although certain segments within healthcare provision have adopted probiotics for use in IBD without critical appraisal, it is important that we use the same principles as applied to pharmaceuticals in treating a disease condition as with probiotics for use in IBD. The aim of this chapter is to review the clinical trial data with respect to specific aspects of ulcerative colitis and Crohn’s disease care that is currently available.
Ulcerative Colitis Treatment of Active Inflammation Very small trials with approximately 10–35 participants in treatment arms have now been reported using probiotics as therapy for mild to moderate active colitis in adults (Table 27.1). The trials have included probiotics as sole therapy [12–15] with one of these trials combining the probiotic with a low dose of the prebiotic (i.e. a food ingredient, that is usually a non-digestible oligosaccharide, that allows for selective microbial growth in order to enhance the health of the host) fructooligosaccharide/inulin [15] or as therapy combined with a conventional medicine [16] in either open label trials (n = 3) or double-blind, placebo controlled (n = 2). The probiotics have either been a blend of several different strains (VSL#3® , Yakult® ) or single strain studies (Saccharomyces boulardii, Bifidobacterium longum no strain specified). Rates of inducing remission and response are reported in the 70–80% range for those reporting successful intervention [12–14, 16] but one negative trial was reported without clinical benefit of the 8 participants in the treatment group compared to the 8 participants receiving placebo over the 4-week intervention period [15]. As comparison, in a trial of 268 UC patients with moderate severity of disease 4.8 grams of delayed release oral mesalamine was found to have clinical benefit in 70% and superior to a response rate of 59% for those using a lower dose of 2.4 grams of a delayed release oral mesalamine for moderate UC [17]. Maintenance Therapy Only a few probiotic products either combined as blends (n = 2) or administered as single strain monotherapy (n = 4) have been studied in adult UC maintenance trials. Indeed, 3 of the trials have utilized E. coli strain Nissle 1917 however; these trials have included larger numbers of participants Table 27.1. Trials of probiotics used as therapy of active ulcerative colitis. Total Participants (# Treated)
Trial Design
20 [10] 34 [32] 25 [25]
DBRPC Open Open
16 [8]
DBRPC
90 [30]
R
Probiotic (Strains)
Blend (Yakult® ) Blend (VSL#3® ) Single strain (S. boulardii) Single strain (B. longum no strain) Blend (VSL#3® )
Daily Dosing (CFU)
Trial Length (Weeks)
Reference
1 × 1010 3.6 ×10 12
12 6 4
12 13 14
2 × 1011
4
15
1 × 1012
6
16
DBPC: double-blind randomized placebo-controlled; R: randomized; Blend: combination of two or more probiotic organisms
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Table 27.2. Trials of probiotics used as maintenance therapy for ulcerative colitis. Total Participants (# Treated)
Trial Design
103 [50]
DBRPC
83 [39]
DBRPC
20 [20] 21 [11] 327 [162]
Open R DBRPC
187 [127]
R
Probiotic (Strains)
Single strain (E. coli Nissle) Single strain (E. coli Nissle) Blend (VSL#3® ) Blend (Yakult® ) Single strain (E. coli Nissle) Single strain (L. rhamnosus GG)
Daily Dosing (CFU)
Trial Length (Months)
Reference
5 × 1010
3
19
1 × 1011
12
20
3 × 1012 2 × 1010 5 × 109
12 12 12
21 22 23
1.8 × 1010
12
24
DBPC: double-blind randomized placebo-controlled; R: randomized; Blend: combination of two or more probiotic organisms
than in studies evaluating treatment of active disease (See Table 27.2). With a background of up to a 70% relapse rate over a 1-year period for those with ulcerative colitis not taking any form of maintenance therapy [18], many of the trials have been for one year (Table 27.2) and studied remission rates in comparison with 5-aminosalicylate products [20, 23, 24]. One of these 12-month probiotic versus 5-aminosalicylate trials was initiated with active UC patients [20] and followed those achieving remission for a 12-month period. In this study the relapse rates were high in both the group maintained with E. coli Nissle 1917 and those maintained on 1.5 grams of daily mesalazine (67% and 72%, respectively). The other 12-month trials were initiated in participants with quiescent disease. In these studies, maintenance of remission rates varied between 45% and 75% [22–24] and studies in those receiving 5-aminosalicylates as a control group had a similar maintenance of remission rate as the probiotic intervention group [23, 24]. Interestingly in the trial comparing monotherapy L. rhamnosus strain GG, monotherapy mesalamine (2.4 grams per day) and combination probiotic and mesalamine, no synergistic benefit was derived form combination therapy but all three groups had equivalent rates for maintenance of remission [24]. The studies comparing probiotic with 5-aminosalicylates have used different total daily amounts (1.5–2.4 grams per day). Nevertheless, currently there is not clinical evidence of a direct dosedependent maintenance benefit above 1.6 grams daily dosing of 5-aminosalicylate but lower doses are not as effective [25]. It is not obvious from the trials done to date that there is any advantage to blends of probiotics as compared to single probiotics and there are no comparative trials to answer this question.
Pouchitis Pouchitis is the most common long-term complication following ileal pouch-anal anastomosis (See Chapter on Pouchitis). Most patients will develop this problem in their first year following the surgery and luminal flora play a prominent role in the pathogenesis of this problem. Antibiotics can be an effective form of therapy in many but in some discontinuation of the antibiotics can lead to recurrence of symptomatology, so called chronic relapsing antibiotic dependent pouchitis. As antibiotics can provide relief for most with pouchitis, a basic assumption has been the importance of the microbiota of the pouch in the development and chronicity of pouchitis. Thus, consideration of probiotics to alter the pouch microbiota as a form of treatment, prevent the onset of pouchitis immediately following surgery prior to the colonization with a deleterious microbiota and provide
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maintenance of remission following antibiotic treatment to reduce the deleterious microbiota of the pouch have been studies in adult patients. Probiotics as Treatment Trials for treating mild/moderate pouchitis are few and involve small numbers of participants. Kuisma et al. [26] recruited 20 patients (10 in the intervention arm) for a DBRPC trial of LGG 2 × 1010 CFU/day × 3 months. In contrast to the studies on prevention of recurrence of pouchitis, participants in this trial were excluded if they had received antibiotics in the previous month. As well, those with evidence of active proctitis were excluded. The Pouchitis Disease Activity Index [27] was utilized for evaluation of clinical effect. Prior to study entry, the mean PDAI was in the mild range (8.0 ± 0.8). There was no difference following the intervention period [26]. A lack of improvement of clinical scores was also reported on interviewing patients in an open-label trial of 51 UC patients post ileal pouch-anal anastomosis using a fermented milk product with a blend of probiotic strains (L. acidophilus strain La5 + B. lactis strain Bb12) containing 5 × 1010 CFU/day however, there was a reported improvement in endoscopic evaluation [28]. Thus, there is not evidence for a role of probiotics as monotherapy for mild/moderate pouchitis at the present time. Limiting access of microbiota to the mucosa of the pouch and subsequent development of inflammation may be a key mechanism whereby probiotics provide benefit, thus it may not be surprising that once the deleterious microbiota have colonized within the pouch there is little a probiotic as monotherapy can do to alter the situation. A somewhat analogous situation exists for use of probiotics as monotherapy in treating Helicobacter pylori. The eradication rate of probiotic monotherapy was very poor compared to standard triple therapy (a proton pump inhibitor + 2 antibiotics) in children colonized with H. pylori [29]. Interestingly, a number of studies have reported indirect evidence suggesting reduced H. pylori colonization with probiotic monotherapy even though eradication rate is poor [30] and one study suggested reduced gastritis on biopsy [31]. The increased eradication rates of H. pylori using combined probiotic and antibiotic may take advantage of lower levels of pathogen in the stomach and/or decreased adverse effects of the antibiotics. Thus, if there is an analogy to be drawn it would be interesting in future studies of patients with pouchitis requiring continuous antibiotics or very frequent use of antibiotics whether probiotics had a role following short antibiotic courses of therapy. Prevention of Initial Post-operative Onset (Table 27.3) Two trials have studied whether there is an advantage to initiate probiotics immediately following ileal pouch-anal anastomosis and both found there to be benefit to the delay in onset of development of pouchitis. One of these was a placebo-controlled trial [32] whereas the other was an open trial with historical controls [33]. At the end of one year, 2 of 20 (10%) participants taking Table 27.3. Trials of probiotics in prevention of onset or recurrence of pouchitis. Total Participants (# Treated)
Trial Design
40 [20] 117 [39]
DBRPC Open
40 [20] 36 [20] 31 [31]
DBRPC DBRPC Open
Probiotic (Strains) Blend (VSL® ) Single strain (L. rhamnosus GG) Blend (VSL® ) Blend (VSL® ) Blend (VSL#3® )
Daily Dosing (CFU)
Trial Length (Months)
Reference
9 × 1011 1.4 × 1010
12 36
32 33
1.8 × 1012 1.8 × 1012 1.8 × 1012
9 12 8
34 35 36
DBPC: Double-blind randomized placebo-controlled; Blend: combination of two or more probiotic organisms
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a blend probiotic (VSL# 3™) had developed colitis as determined using the Pouchitis Disease Activity Index (PDAI) with endoscopy compared to 8 of 20 (40%) of the control arm participants (p < 0.05). For the open label trial with a 3-year follow-up period, 7% receiving the L. rhamnosus strain GG immediately post-ileal pouch-anal anastomosis developed pouchitis as compared to 29% (p=0.011) of those with ileal pouch-anal anastomosis performed between 1989–1996 that did not receive probiotic in the immediate post-operative period and served as historical controls. Thus, both trials showed benefit regardless of whether a single strain or a blend probiotic was administered. Maintenance of Remission (Table 27.3) The initial controlled trial for this indication was in the year 2000 using the blend probiotic product, VSL#3® and reported on outstanding effect in prevention of the recurrence of pouchitis in patients with antibiotic-dependent pouchitis. Prior to the administration of the blend probiotic, participants in this trial were successfully treated with a combination of antibiotics (ciprofloxacin + rifaximin). At the end of the study period of 9 months, only 3 of 20 (15%) had developed pouchitis in the intervention group whereas all 20 participants in the control group had a recurrence of pouchitis (p < 0.001) and this had occurred 4 months following the antibiotics [34]. A similar result was noted in another European trial of VSL#3® that also evaluated the prevention of recurrence of pouchitis in relapsing or chronic pouchitis patients [35]. Remission of the pouchitis was induced in these participants by administering 4 weeks of a combination of antibiotics (metronidazole + ciprofloxacin) that was followed by either VSL#3® or a placebo. In the treatment group remission was maintained in 17 of 20 (85%) but only 1 of 16 (6%, p < 0.0001) on placebo. In sharp contrast is a recent open label trial reported on by Shen and colleagues at Cleveland Clinic Foundation in antibiotic-dependent pouchitis patients [36]. In their trial, 31 subjects received a 2-week treatment of a single antibiotic (ciprofloxacin) followed by VSL#3® at the same dose as the 2 European trials. The patients did not have endoscopy to visualize whether inflammation was still present but all clinically responded to the antibiotic therapy. By 7 weeks 9 of 31 (29%) and by 8 months 25 of 31 (81%) had discontinued the probiotic because of failure to prevent pouchitis (n=23) or side effects of the probiotic administration (n=2) leaving only 6 of 31 (19%) that did not develop clinical evidence of pouchitis by the end of the 8-month trial period. Even among these 6 subjects endoscopy revealed some level of pouch inflammation. Prevention of microbial induced relapsing mucosal inflammation is as intriguing a possibility in pouchitis as it is in recurrent Clostridia difficile associated disease [37]. There have been case reports that the use of probiotics may reduce the total amount of antibiotics required in relapsing C. difficile [38] and optimization of the combination of antibiotic with probiotic may be a key in relapsing pouchitis to at least reduce antibiotic exposure for those that are antibiotic-dependent. Nevertheless, it is clear that further study is required to resolve the significant differences between the open trial and the previous double-blind, randomized, placebo-controlled trials.
Crohn’s Disease Maintenance Therapy Initial trials (See Table 27.4) in Crohn’s disease were done in diverse clinical protocols including being used as sole maintenance therapy following corticosteroid therapy to treat active disease [39], in combination with lower does of 5-aminosalicylate therapy compared to controls for
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Table 27.4. Trials of probiotics in Crohn’s disease. Total Participants (# Treated)
Trial Design
28 [16]
DBRPC
32 [16] 4 [4]
R Open
11 [5]
DBRPC
75 [39]
DBRPC
45 [23]
DBRPC
98 [48]
DBRPC
Probiotic (Strains)
Daily Dosing (CFU)
Trial Length (Months)
Reference
Single strain (E. coli Nissle 1917) Single strain (S. boulardii) Single strain (L. rhamnosus strain GG) Single strain (L. rhamnosus strain GG) Single strain (L. rhamnosus strain GG) Single strain (L. rhamnosus strain GG) Single strain (L johnsonii strain LA1)
5 × 1010
12
39
? 2 × 1010
6 6
40 41
2 × 109
6
42
2 × 1010
42
43
1.2 × 109
12
46
4 × 109
6
47
DBPC: double-blind randomized placebo-controlled; R: randomized
maintenance therapy in those already in remission [40], or as additional therapy in those that had not reached remission despite other therapies [41]. There were suggestions that benefit could be obtained with these approaches [39, 41] and greater benefit with the combination therapy [40]. Subsequent trials have focused on L. rhamnosus strain GG for maintenance therapy following induction of remission with corticosteroids [42] and maintenance of remission with probiotic used as additional maintenance therapy. In contrast to the earlier studies, neither a statistical benefit nor even a trend to benefit was recognized in these more recent trials. In the largest maintenance trial to date and one of the very few trials in children and adolescents, Bousvaros et al. [43] reported no difference in the proportion of those developing relapse on L. rhamnosus strain GG 2 × 1010 CFU/day (31%; 12 of 39) or placebo (17%; 6 of 36, p=0.18). The time to relapse is shown in Figure 27.1, and although the placebo arm had a longer time to relapse, comparison between it and the intervention group taking the probiotic was not statistically different (p=0.10). Prevention of Post-operative Recurrence Studies have been conducted on Crohn’s post-operative recurrence. Reviews of a single-blind trial involving patients randomized to receive high-does rifaximin followed by VSL#3 or mesalazine, the authors reported fewer endoscopic recurrences in the combination antibiotic/probiotic intervention group [44]. However, this has only been available as an abstract or discussions by the authors and antibiotics have been shown to possibly provide Crohn’s post-operative benefit in prevention of recurrence [45]. There are however, 2 adult based trials [46, 47] that have been published. Each study used a single probiotic, administered about the same dose and the strains utilized demonstrate benefit for other intestinal non-IBD conditions. In the L. rhamnosus GG trial [46], 9 of 15 (60%) in LGG group in clinical remission had endoscopic recurrence and 6 of 17 (35%) in placebo group in clinical remission had endoscopic recurrence (p=0.297). In the L. johnsonii LA1 trial [47], at 6 months endoscopic recurrence was seen in 21 of 43 (43%) in LA1 group and 30 of 47 (64%) of placebo group and (p=0.15). Thus, neither study showed benefit in the prevention of post-operative recurrence of Crohn’s disease.
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Figure 27.1. Kaplan-Meier Survival Curves showing probability of staying relapse free during the study treatment duration for participants administered Lactobacillus rhamnosus GG or placebo. Source: (Figure reproduced from Inflamm Bowel Dis 2005;11:833–839 with permission from Dr. A Bousvaros and Lippincott, Williams & Wilkins).
Associated Conditions Arthralgia In an open label trial with a drop-out rate of 45%, 16 patients with either Crohn’s disease or ulcerative colitis completed a 3-month trial of ingesting 9 × 1011 CFU/day of a blend probiotic (VSL# 3™) to assess whether there was a clinical improvement in arthralgia [48]. Patients had quiescent IBD and no clinical or laboratory evidence of arthritis, were not taking non-steroidal antiinflammatory medications and other medications were unchanged. An improvement in peripheral but not axial arthralgia was reported using an articular index score but no improvement was reported using a patient-completed visual analog scoring system used for subjective joint pain.
Summary Our current knowledge regarding the use of probiotics is limited with small studies, control drug dosing issues and delineating effects of probiotics from combination probiotic and prescription medication studies as outlined in this chapter and by others [49, 50]. That being said, specific probiotic products might have more potential for modest effect in maintenance of remission of ulcerative colitis especially for those unable to use 5-aminsalicylate products. Whether there is efficacy in active mild to moderate disease remains to be determined. Clinical practice for use in chronic relapsing pouchitis demonstrates that far fewer patients benefit from probiotics than some of the early small trials and there is a lack of evidence for their use as sole treatment in active pouchitis. There is little persuasive evidence that patients with Crohn’s disease should ingest probiotics. A deleterious effect in those taking specific strains for maintenance or prevention of
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post-operative recurrence has not been statistically demonstrated but it seems a prudent course at the present time to discourage their use until there are further studies to ensure no trends are developing that may not be uncovered, except in large trials or meta-analysis of smaller trials. As well, at this point in time understanding what sub-groups of patients (i.e. specific genotype, specific phenotype, specific age group) do demonstrate benefit require study before advocacy of probiotics in Crohn’s disease. It is important to not generalize reports of positive benefit from specific strain studies to either Genus or Species effects and it is equally as important not to generalize negative reports of a specific strain to a Genus or Species effect. Clearly there is a need for knowledge with regards to dosing, duration of therapy, delivery methods and whether blends of different strains of probiotics offer any benefit over single strains. As well, without significant regulatory controls quality control, viability and the potential for differences of microbe phenotype expression between studied probiotic products and commercially available products has led to debatable results [51, 52] and ones that make it difficult for health care providers and consumers to discern. Given the current situation of parental and self-prescribing of alternative care products including those described as probiotics for IBD, it behooves those providing care for IBD patients to know exactly all prescription and non-prescription items being administered to the children and adolescents with IBD so when problems in care are occurring comprehensive strategization of care can be co-coordinated. There are a number of clinical situations in which this could potentially be important. Among the most serious clinical scenarios to consider is that in which a patient is initiating immunosuppressive therapy. While most patients undergo the initiation of immune altering medications without incident, immunosuppression is a possibility. There is no evidence for the efficacy of probiotics in any form of severe IBD and in general, there is little clinical experience in the use of probiotics administration to severely immunocompromised IBD patients. However, in ill patients in ICU settings fungemia has developed from the use of S. boulardii as probiotic [53] and sepsis from a Lactobacillus strain has also been reported in an ulcerative colitis patient [54]. Another reason it would be good to know if patients are ingesting probiotics is related to the reported link to gastrointestinal side effects following ingestion of heat-killed probiotics. In a clinical trial evaluating the benefits of heat-killed, non-viable L. rhamnosus GG with live, viable L. rhamnosus GG for atopic dermatitis, increased gastrointestinal side effects in those administered the non-viable microbes lead to premature termination of the study [55]. Viability is affected by a number of issues that include practices of retailers (i.e. shelf time, product storage), distributors (warehouse storage, distribution) and manufacturers [56]. Poor practices at any level will lead to loss of viable microorganisms in a probiotic product with potential for problems associated with ingestion of non-viable probiotics as reported by Kirjavainen et al. [55] the symptoms of which may be mistaken for active IBD. Ingestion of S. boulardii has also been linked to worsening of diarrhea in two patients with ulcerative colitis [57]. Although the commercialization of probiotics is ahead of scientific and clinical investigation, as practitioners we should demand that the various aspects of IBD care are critically appraised before encouraging patients to ingest undocumented probiotic products as therapy in IBD. References 1. Lilley DM, Stillwell RH. Probiotics: growth factors produced by microorganisms. Science 1965;147:747–748. 2. FAO/WHO. Evaluation of health and nutritional properties of powder milk and live lactic acid bacteria. Food and Agriculture Organization of the United Nations and World health Organization Expert Consultation Report, 2001. http://www.fao.org 3. Szajewska H, Setty M, Mrukowicz J, et al. Probiotics in gastrointestinal diseases in children: hard and not-so-hard evidence of efficacy. J Pediatr Gastroenterol Nutr 2006;42:454–475. 4. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004;118:229–241.
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5. Lorenz RG, McCracken VJ, Elson CO. Animal models of intestinal inflammation: ineffective communication between coalition members. Springer Semin Immunopathol 2005;27:233–247. 6. Li FX, Verhoef MJ, Best A, et al. Why patients with inflammatory bowel disease use or do not use complementary and alternative medicine: a Canadian national survey. Can J Gastroenterol 2005;19: 567–573. 7. Quattropani C, Ausfeld B, Straumann A, et al. Complementary alternative medicine in patients with inflammatory bowel disease: use and attitudes. Scand J Gastroenterol 2003;38:277–282. 8. Heuschkel R, Afzal N, Wuerth A, et al. Complementary medicine use in children and young adults with inflammatory bowel disease. Am J Gastroenterol 2002;97:382–388. 9. Day AS, Whitten KE, Bohane TD. Use of complementary and alternative medicines in children and adolescents with inflammatory bowel disease. J Paediatr Child Health 2004;40:681–684. 10. Hilsden RJ, Verhoef MJ, Best A, et al. Complementary and alternative medicine use in Canadian patients with inflammatory bowel disease: results of a national survey. Am J Gastroenterol 2003;98:1563–1568. 11. Joos SS, Rosemann TT, Szecsenyi JJ, et al. Use of complementary and alternative medicine in Germany – a survey of patients with inflammatory bowel disease. BMC Complementary Alt Med 2006;6:19 doi:10.1186/1472–6882–6–19. 12. Kato K, Mizuno S, Umesaki Y, et al. Randomized placebo-controlled trial assessing the effect of bifidobacteria-fermented milk on active ulcerative colitis. Aliment Pharmacol Ther 2004;20:1133–1141. 13. Bibiloni R, Fedorak RN, Tannock GW, et al. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol 2005;100:1539–1546. 14. Guslandi M, Giollo P, Testoni PA. A pilot trial of Saccharomyces boulardii in ulcerative colitis. Eur J Gastroenterol Hepatol 2003;15:697–698. 15. Furrie E, Macfarlane S, Kennedy A, et al. Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomized controlled pilot trial. Gut 2005;54:242–249. 16. Tursi A, Brandimarte G, Giorgetti GM, et al. Low-dose balsalazide plus a high-potency probiotic preparation is more effective than balsalazide alone or mesalazine in the treatment of acute-mild-tomoderate ulcerative colitis. Med Sci Monit 2004;10:Pl126–Pl131. 17. Hanauer SB, Sandborn WJ, Kornbluth A, et al. Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the Ascend II trial. Am J Gastroenterol 2005;100:2478–2485. 18. Hanauer SB. Medical therapy for ulcerative colitis 2004. Gastroenterology 2004;126:1582–1592. 19. Kruis W, Schutz E, Fric P, et al. Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 1997;11:853–858. 20. Rembacken BJ, Snelling AM, Hawkey PM, et al. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomized trial. Lanect 1999;354:635–639. 21. Venturi A, Gionchetti P, Rizzello F, et al. Impact on the composition of the faecal flora by a new probiotic preparation: preliminary data on maintenance treatment of patients with ulcerative colitis. Aliment Pharmacol Ther 1999;13:1103–1108. 22. Ishikawa H, Akedo I, Umesaki Y, et al. Randomized controlled trial of the effect of Bifidobacteriafermented milk on ulcerative colitis. J Am Coll Nutr 2002;22:56–63. 23. Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004;53:1617–1623. 24. Zocco MA, Zileri Dal Verme L, Cremonini F, et al. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 2006;23:1567–1574. 25. Sandborn WJ. Treatment of ulcerative colitis with oral mesalamine: advances in drug formulation, efficacy expectations and dose response, compliance, and chemoprevention. Rev Gastroenterol Disord 2006;6:97–105. 26. Kuisma J, Mentula S, Jarvinen H, et al. Effect of Lactobacillus rhamnosus GG on ileal pouch inflammation and microbial flora. Aliment Pharmacol Ther 2003;17:509–515. 27. Sandborn WJ, Tremaine WJ, Batss KP, et al. Pouchitis following ileal pouch-anal anastomosis: a pouchitis disease activity index. Mayo Clin Proc 1994;69:409–415. 28. Laake KO, Bjorneklett A, Aamodt G, et al. Outcome of four weeks’ intervention with probiotics on symptoms and endoscopic appearance after surgical reconstruction with a J-con uration ileal-pouchanal-anastomosis in ulcerative colitis. Scand J Gastroenterol 2005;40:43–51.
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29. Gotteland M, Poliak L, Cruchet S, et al. Effect of regular ingestion of Saccharomyces boulardii plus inulin or Lactobacillus acidophilus in children colonized with Helicobacter pylori. Acta Paediatr 2005;94:1747–1751. 30. Gotteland M, Brusner O, Cruchet S. Systematic review: are probiotics useful in controlling gastric colonization by Helicobacter pylori. Aliment Pharmacol Ther 2006;23:1077–1086. 31. Pantoflickova D, Corthesy-Theulaz I, Dorta G, et al. Favourable effect of regular intake of fermented milk containing Lactobacillus johnsonii on Helicobacter pylori associated gastritis. Aliment Pharmacol Ther 2003;18:805–813. 32. Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastoenterology 2003;124:1202–1209. 33. Gosselink MP, Schouten R, van Lieshout LMC, et al. Delay of the first onset of pouchitis by oral intake of the probiotic strain Lactobacillus rhamnosus GG. Dis Colon Rectum 2004;47:876–884. 34. Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy a maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119:305–309. 35. Mimura T, Rizzello F, Helwig U, et al. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 2004;53:108–114. 36. Shen B, Brzezinski A, Fazio VW, et al. Maintenance therapy with a probiotic in antibiotic-dependent pouchitis: experience in clinical practice. Aliment Pharmacol Ther 2005;22:721–728. 37. Dendukuri N, Costa V, McGregor M, et al. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. Can Med Assoc J 2005;173:167–170. 38. Benchimol EI, Mack DR. Probiotics for chronic and relapsing diarrhea. J Pediatr Hematol/Oncol 2004;26:515–517. 39. Malchow H. Crohn’s disease and Escherichia coli: A new approach in therapy to maintain remission of colonic Crohn’s disease. J Clin Gastroenterol 1997;25:653–658. 40. Guslandi M, Mezzi G, Sorghi M, et al. Saccharomyces boulardii in maintenance treatment of Crohn’s disease. Dig Dis Sci 2000;45:1462–1464. 41. Gupta P, Andrew H, Kirschner BS, et al. Is Lactobacillus GG helpful in children with Crohn’s disease? Results of a preliminary, open-label study. J Pediatr Gastroenterol Nutr 2000;31:453–457. 42. Schultz M, Timmer A, Herfarth HH, et al. Lactobacillus GG in inducing and maintaining remission of Crohn’s disease. BMC Gastoenterol 2004;4:5. 43. Bousvaros A, Guandalini S, Baldassano RN, et al. A randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn’s disease. Inflamm Bowel Dis 2005;11:833–839. 44. Gionchetti P, Amandini C, Rizzello F, et al. Probiotics for the treatment of postoperative complications following intestinal surgery. Best Prac Res Clin Gastroenterol 2003;17:821–831. 45. Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995;108:856–861. 46. Prantera C, Scribano ML, Falasco G, et al. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: a randomized controlled trial with Lactobacillus GG. Gut 2002;51:405–409. 47. Marteau P, Lemann M, Seksik P, et al. Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn’s disease: a randomized, double blind, placebo controlled GETAID trial. Gut 2006;55:842–847. 48. Karimi O, Pena S, van Bodegraven AA. Probiotics (VSL#3) in arthralgia in patients with ulcerative colitis and Crohn’s disease: a pilot study. Drugs Today 2005;41:453–459. 49. Tamboli CP, Caucheteux C, Cortot A, et al. Probiotics in inflammatory bowel disease: a critical review. Best Prac Res Clin Gastroenterol 2003;17:805–820. 50. Rioux KP, Fedorak RN. Probiotics in the treatment of inflammatory bowel disease. J Clin Gastroenterol 2006;40:260–263. 51. Huff BA. Caveat emptor. ‘Probiotics’ might not be what they seem. Can Family Physician 2004;50: 583–587. 52. Katz JA, Pirovano F, Matteuzzi D, et al. Commercially available probiotic preparations: are you getting what you pay for? Gastroenterology 2002;122:A459. 53. Munoz P, Bouza E, Cuenca-Estrella M, et al. Saccharomyces cerevisiae fungemia: an emerging infectious disease. Clin Infect Dis 2005;40:1625–1634.
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54. Farina C, Arosio M, Mangia M, et al. Lactobacillus casei subsp. rhamnosus sepsis in a patient with ulcerative colitis. J Clin Gastroenterol 2001;33:251–252. 55. Kirjavainen PV, Salminen SJ, Isolauri E. Probiotic bacteria in the management of atopic disease: underscoring the importance of viability. J Pediatr Gastroenterol Nutr 2003;36:223–227. 56. Prakash S, Martoni C. Toward a new generation of therapeutics: artificial cell targeted delivery of live cells for therapy. Appl Biochem Biotech 2006;128:1–22. 57. Candelli M, Nista EC, Nestola M, et al. Saccharomyces cerevisiae-associated diarrhea in an immunocompetent patient with ulcerative colitis. J Clin Gastroenterol 2003;36:39–40.
28 Corticosteroid Therapy Johanna C. Escher∗
Introduction Glucocorticosteroids have been used for decades as a first-line treatment to induce remission in Crohn disease and ulcerative colitis in children and adults. Systemic corticosteroid treatment causes disfiguring cosmetic side effects during short-term use and bone demineralization as well as growth failure in long-term treatment, therefore limiting its use in children and adolescents. In addition to the side effects, corticosteroid resistance and dependence are common. The current trend is to minimize or even avoid corticosteroid use in pediatric as well as adult inflammatory bowel disease (IBD). In pediatric Crohn disease, enteral nutrition as primary therapy is a safe and effective alternative to prednisolone, whereas introduction of immune modulating therapy early in the course of disease is a successful steroid-sparing strategy [1]. In this chapter, the working mechanism, efficacy, side effects and pharmacokinetics of “classic” (systemic) as well as topical corticosteroids such as budesonide will be reviewed.
The Working Mechanism of Corticosteroids Under homeostatic conditions, activation of the innate and adaptive immune system is counteracted by endogenous glucocorticoids [2, 3]. At lower dosages, steroids may well follow these physiological pathways, whereas at higher concentrations other mechanisms may be involved. Upon binding of the high affinity glucocorticoid receptor, a cascade of events takes place starting with the dissociation of molecular chaperones followed by nuclear translocation. At this location, specific DNA sequences in the promoter region of steroid-responsive genes (glucocorticoid response elements) are bound leading to suppression of the genes encoding for the transcription of inflammatory proteins such as those involved in the mitogen-activated protein kinase (MAPK) pathway. Subsequently, the production of inflammatory mediators such as prostaglandins is reduced. Inflammation may also become suppressed by increasing the synthesis of the anti-inflammatory mediators such as interleukin-10, and of Inhibitor of kappa Ba (IBa), which is regarded as an inhibitor of the key-inflammatory transcription factor NFB. Although direct effects at the level of gene transcription are thought to play a major role, nongenomic mechanisms may also be involved. An example is the activation of endothelial nitric oxide synthase by glucocorticoids leading to the production of nitric oxide (NO). NO is ∗
Erasmus MC-Sophia Children’s Hospital, University Medical Center, Department of Pediatric Gastroenterology, Dr Molewaterplein 60, 3015 GJ Rotterdam, the Netherlands, Phone: 31 10 4636049, Fax: 31 10 4636811, Email:
[email protected]
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an important modulator of the inflammatory cascade in IBD by affecting leukocyte-endothelial interactions, leukocyte infiltration and vasodilatation. In summary, it has become clear that glucocorticoids interact with wide range of molecules and therefore exert their immunosuppression by affecting various inflammatory pathways.
Systemic Corticosteroids Placebo-controlled trials on the safety and efficacy of prednisolone have not been performed in children with Crohn disease or ulcerative colitis. Multiple studies however, as reviewed by Heuschkel et al. [4], have compared the results of enteral nutrition versus a course of steroids in the treatment of active Crohn disease in children and reported clinical remission in 85% of children treated with predniso(lo)ne. It has long been known that corticosteroids do not heal the mucosa in IBD [5, 6]. From recent excellent data, drawn from a multicenter observational registry in the USA, we are now informed about the natural history of corticosteroid therapy in children with Crohn disease [7] as well as ulcerative colitis [8]. Despite the use of immunomodulators, 31% of children with CD and 45% of children with UC were found to be corticosteroid dependent at one year after diagnosis [7, 8]. This is in accordance with data from adults [9, 10].
Topical Corticosteroids For targeting local and systemic inflammatory processes in IBD therapeutic agents of first choice (e.g. aminosalicylates, corticosteroids) have been developed in special galenic forms to accomplish the topical delivery of the active compounds to the terminal ileum (Crohn disease) and/or the colon (Crohn disease and ulcerative colitis). Since 10 years ago, non-systemic corticosteroids such as budesonide, beclomethasone diproprionate, fluticasone and hydrocorticone thiopivalate have been of interest for the targeted therapy of IBD. Budesonide is currently the drug of choice for the topical treatment of IBD by oral and rectal application. Budesonide is a glucocorticosteroid with a weak mineralocorticosteroid activity. It has a favorable ratio between anti-inflammatory activity and systemic glucocorticosteroid effect. This is explained by a high local glucocorticosteroid activity and an extensive first-pass hepatic degradation to metabolites with very low glucocorticosteroid activity. Due to these circumstances the well-known glucocorticosteroid adverse effects are less frequent than with the conventional corticosteroids. Pharmacokinetics The absolute bioavailability of budesonide is very low, which results from gastrointestinal afflux mediated by P-glycoprotein, the product of the multidrug resistance 1 (MDR1) gene, and from biotransformation via cytochrome p450 3A (CYP3A) in gut and liver. After this extensive first-pass metabolism, the metabolites 6-hydroxybudesonide and 16-hydroxyprednisolone are formed. Glucocorticoid activity of these metabolites amounts to only 1–10% of the parent drug. Two pharmacokinetic studies have been performed in children with Crohn disease [11, 12]. Absolute bioavailability of budesonide (Entocort® ) was found to be similar in children (9 ± 5%) compared to healthy adults (11 ± 7%) [12]. Consistently, overall systemic elimination of budesonide (Budenofalk® ) reflected by clearance and half-life was not different in children and adults [11]. Conversion to 6-hydroxybudesonide was shown to be 1.5-fold higher in children than in adults, suggesting enhanced biotransformation via CYP3A enzymes in children [11]. Corrections
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in dosing of budesonide based on body weight or body surface may not adequately reflect differences in pharmacodynamics. Therefore, the dose of budesonide (9 mg, once daily) decided on in both pediatric clinical trials [13, 14] was the same as used in adults with Crohn disease. Topical Steroid Formulations There are two oral formulations of budesonide used for treatment of Crohn disease: controlledileal release (Entocort® ) and pH-dependent release (Budenofalk® ). The controlled-ileal release capsules contain 3 mg of budesonide distributed in approximately 100 pellets that have an outer coating of Eudragit L100-55 that dissolves at pH of 5.5 or higher. Absorption of Entocort® in the ileocaecal region ranges from 52 to 79 percent. The pH-dependent Budenofalk® capsules also contain 3 mg of budesonide in 400 pellets of a 1 mm diameter and are coated with eudragit, resistant to pH below 6. For rectal treatment of left-sided ulcerative colitis, budesonide is available as enemas containing 2 mg per 100 ml of enema (Entocort® enema).
Efficacy of Oral Budesonide Treatment in Crohn Disease Two randomized clinical trials have been performed comparing safety and efficacy of budesonide versus prednisolone in children with active ileocaecal Crohn disease [13, 14]. In the non-blinded study by Levine et al. 33 patients (mean age 14.3 years) with active mild to moderate pediatric Crohn disease were randomized to 12 weeks of treatment with pH modified release budesonide (Budenofalk® 9 mg, once daily) or prednisone (40 mg, once daily) [15]. The groups treated with budesonide and prednisone did not differ by age, onset of disease, location of disease, or disease activity. Remission (defined as Pediatric Crohn Disease Activity Index PCDAI ≤ 10) at 12 weeks was reported in 9/19 patients (47%) of the budesonide treatment group and in 7/14 patients (50%) of the prednisone treatment group (difference not statistically significant). Side effects occurred in 32% and 71% of patients treated with budesonide and prednisone, respectively (p< 0.05). Severity of cosmetic side effects was significantly lower in patients treated with budesonide (p< 0.01). The study by Escher et al. was a randomized, double blind, double-dummy, controlled multicenter clinical trial. In a joined effort by the IBD working group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), 36 centers located in eight European countries took part [14]. Planned sample size was 120, but the study was terminated prematurely due to low enrolment numbers, with 48 patients (mostly new patients) with active Crohn disease involving ileum and/or ascending colon completing the 12-week study. Patients (mean age 13 years) were randomized to budesonide (Entocort 9 mg, once daily for 8 weeks, tapered to 6 mg for 4 weeks) or prednisolone (1 mg per kg bodyweight, once daily for 4 weeks, followed by 4 week tapering down to a 2.5 mg daily dose). Primary outcome parameter was clinical remission (modified Crohn Disease Activity Index CDAI ≤ 150) at 8 weeks. As shown in Figures 28.1 and 28.2, about 50% of the patients in both groups were in clinical remission within 2 weeks of treatment. At week 8, 12/22 patients in the budesonide group (55%) and 17/24 patients in the prednisolone group (71%) were in clinical remission (p=0.25). The observed 16% difference in remission rate in favor of prednisone was statistically not significant. In case of planned enrolment of 120 patients, the extrapolated difference in remission rates would still not have reached significance. Mean disease activity of the patients was 239 (budesonide group) and 268 (prednisolone), representing mild to moderate disease. It is unknown whether prednisolone may be more effective than budesonide in patients with severe disease. A Cochrane systematic review demonstrated that budesonide is more effective than mesalazine but inferior to conventional corticosteroids in adults with mild to moderately active Crohn disease in the terminal ileum and/or ascending colon [16]. Four trials comparing budesonide versus
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100 80 60 40 20 0
0
2
4 treatment week
Prednisolone
8
12
Budesonide
Figure 28.1. Remission rates of budesonide versus prednisolone in children with ileocaecal Crohn disease. Notes: Randomized clinical trial by Escher, et al. [14] with permission. Mean (±SE) proportion of patients with Crohn disease in remission after 2, 4, 8, and 12 weeks of treatment with budesonide or prednisolone. Remission was defined as a score of 150 or lower in the Crohn Disease Activity Index (CDAI). No significant difference was reached at any of the time points.
prednisolone in adults showed less corticosteroid-related adverse events in the budesonide group [17–20]. Based on the above evidence, recent European guidelines state that oral budesonide (9 mg once daily) is the preferred treatment for mild and moderate ileocaecal Crohn disease in adults [6].
Side Effects of Budesonide in Children Glucocorticosteroid (GCS) associated side effects such as moon face and acne were shown to occur significantly less in children treated with budesonide compared to prednisolone [14]. In the randomized clinical trial by Escher et al. moon face was almost three times as common in the prednisolone group. All short-term GCS-associated side effects of budesonide versus prednisolone are listed in Table 28.1. Adrenal suppression, expressed as a decrease in mean morning plasma cortisol levels, was evident during budesonide remission induction while being significantly less compared to prednisolone treatment, as shown in Figure 28.3. Headache was reported in both 300 250
CDAI
200 150
∗
100 50 0
0
2
4 treatment week Prednisolone
8
12
Budesonide
Figure 28.2. Mean ((SE) Crohn Disease Activity Index (CDAI) scores at baseline and during treatment with budesonide or prednisolone. Notes: Randomized clinical trial by Escher, et al.[14] with permission. At week 8, the difference between the treatment groups was statistically significant (*p = 0.047).
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Table 28.1. Glucocorticosteroid-associated side effects of budesonide versus prednisolone in children with ileocaecal Crohn disease. Budesonide n=22 Moon face Buffalo hump Acne Hirsutism Skin striae Bruising easily Swollen ankles Hair loss Mood swings Depression Insomnia Any such sign**
Prednisolone n=26*
5 0 1 2 0 1 0 1 3 2 5 11
p-value
15 1 7 3 1 1 1 3 2 1 4 20
0.01 NS 0.033 NS NS NS NS NS NS NS NS 0.030
RCT by Escher, et al. [14], with permission * One of these had no on-treatment data regarding possible glucocorticosteroid side effects. ** Some patients had more than one sign. NS = not statistically significant
morning plasma cortisol (nmol/L)
treatment groups in 4/22 (budesonide group) and 4/26 patients (prednisolone group) and may be associated with benign intracranial hypertension as reported by Levine et al. [21]. A retrospective review of 6 prepubertal children with Crohn disease showed linear growth to be subnormal (2 cm/year) during budesonide maintenance treatment [22]. It remains unclear however whether impaired growth in these children (with PCDAI’s of 15–27.5, indicating active disease) was due only to budesonide treatment or to ongoing mucosal inflammation.
500 400 300 200
∗
100 0
0
∗
2
4 treatment week
Prednisolone
∗
8
12
Budesonide
Figure 28.3. Adrenal suppression as measured by morning plasma cortisol. Notes: Randomized clinical trial by Escher, et al. [14], with permission. Mean (±SE) plasma cortisol concentrations in patients with active Crohn disease at baseline and after 2, 4, 8, and 12 weeks of treatment with budesonide or prednisolone. Plasma cortisol was measured between 8 and 10 a.m. at each visit. A value of 150 nmol/l (5.4 g/dl) or more was considered to be normal. To convert plasma cortisol values to g/dl, divide by 27.6. At week 2, 4 and 8, the difference in cortisol levels between the treatment groups was statistically significant (*p < 0.0001, p = 0.0026, and p = 0.0028, respectively).
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Maintenance Treatment in Crohn Disease Maintenance treatment with budesonide has not been studied prospectively in children. Systemic corticosteroids however have not been shown to be effective in prolonging clinical remission. A Cochrane review based on four placebo-controlled randomized trials in adults with Crohn disease [19, 23–25] concluded that maintenance treatment with oral budesonide at 6 mg/day is not effective in preventing relapses of Crohn disease in adults [26]. ln view of this evidence, and the concerns on longitudinal growth in children, maintenance treatment with budesonide should not be recommended.
Budesonide Enemas in Ulcerative Colitis No studies have been performed in children. In adults, topical steroid treatment is less effective in left-sided UC compared to 5-ASA.
Conclusion Corticosteroids have been the first line treatment in Crohn disease for many years. Disfiguring acute and serious long-term side effects, such as growth retardation and bone demineralization limit their use. The current trend in pediatric as well as adult Crohn disease, is to minimize and avoid repeated corticosteroid use by introducing immunomodulators early in the course of disease. In Europe, primary treatment of active Crohn disease by a 6–8 week course of enteral nutrition is favored over remission induction by prednisolone. Systemic or topical corticosteroids are not effective as maintenance treatment. Adrenal suppression is less during budesonide treatment compared to prednisolone, and glucocorticosteroid-associated side effects such as acne and moon face occur less frequently. Budesonide however seems to be less effective, and is only indicated in localized ileocecal disease with mild to moderate disease activity. Corticosteroids do not heal the mucosa, do not prevent relapse and do not alter the course of disease. In the current era, confidence with early immunomodulator and biological treatment is growing, with a tendency towards step-down instead of step-up treatment. While this strategy needs to be substantiated by prospective studies, it is clear that corticosteroids are losing their position as first-line treatment of pediatric IBD. References 1. Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn disease. Gastroenterology 2000;119(4):895–902. 2. Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann Intern Med 2003; 139(5 Pt 1): 359–70. 3. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med 2005;353(16):1711–23. 4. Heuschkel RB, Menache CC, Megerian JT, Baird AE. Enteral nutrition and corticosteroids in the treatment of acute Crohn disease in children. J Pediatr Gastroenterol Nutr 2000;31(1):8–15. 5. Beattie RM, Nicholls SW, Domizio P, Williams CB, Walker-Smith JA. Endoscopic assessment of the colonic response to corticosteroids in children with ulcerative colitis. J Pediatr Gastroenterol Nutr 1996;22(4):373–9. 6. Travis SP, Stange EF, Lemann M, Oresland T, Chowers Y, Forbes A, et al. European evidence based consensus on the diagnosis and management of Crohn disease: current management. Gut 2006;55(Suppl 1):16–35.
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7. Markowitz J, Hyams J, Mack D, Leleiko N, Evans J, Kugathasan S, et al. Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn disease. Clin Gastroenterol Hepatol 2006;4(9):1124–9. 8. Hyams J, Markowitz J, Lerer T, Griffiths A, Mack D, Bousvaros A, et al. The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol 2006;4(9):1118–23. 9. Faubion WA, Jr., Loftus EV, Jr., Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001;121(2):255–60. 10. Ho GT, Chiam P, Drummond H, Loane J, Arnott ID, Satsangi J. The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort. Aliment Pharmacol Ther 2006;24(2):319–30. 11. Dilger K, Alberer M, Busch A, Enninger A, Behrens R, Koletzko S, et al. Pharmacokinetics and pharmacodynamic action of budesonide in children with Crohn disease. Aliment Pharmacol Ther 2006;23(3):387–96. 12. Lundin PD, Edsbacker S, Bergstrand M, Ejderhamn J, Linander H, Hogberg L, et al. Pharmacokinetics of budesonide controlled ileal release capsules in children and adults with active Crohn disease. Aliment Pharmacol Ther 2003;17(1):85–92. 13. Levine A, Weizman Z, Broide E, Shamir R, Shaoul R, Pacht A, et al. A comparison of budesonide and prednisone for the treatment of active pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2003;36(2):248–52. 14. Escher JC. Budesonide versus prednisolone for the treatment of active Crohn disease in children: a randomized, double-blind, controlled, multicentre trial. Eur J Gastroenterol Hepatol 2004;16(1):47–54. 15. Levine A, Broide E, Stein M, Bujanover Y, Weizman Z, Dinari G, et al. Evaluation of oral budesonide for treatment of mild and moderate exacerbations of Crohn disease in children. J Pediatr 2002;140(1):75–80. 16. Otley A, Steinhart AH. Budesonide for induction of remission in Crohn disease. Cochrane Database Syst Rev 2005(4):CD000296. 17. Rutgeerts P, Lofberg R, Malchow H, Lamers C, Olaison G, Jewell D, et al. A comparison of budesonide with prednisolone for active Crohn disease. N Engl J Med 1994;331(13):842–5. 18. Bar-Meir S, Chowers Y, Lavy A, Abramovitch D, Sternberg A, Leichtmann G, et al. Budesonide versus prednisone in the treatment of active Crohn disease. The Israeli Budesonide Study Group. Gastroenterology 1998;115(4):835–40. 19. Gross V, Andus T, Ecker KW, Raedler A, Loeschke K, Plauth M, et al. Low dose oral pH modified release budesonide for maintenance of steroid induced remission in Crohn disease. The Budesonide Study Group. Gut 1998;42(4):493–6. 20. Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG. Oral budesonide is as effective as oral prednisolone in active Crohn disease. The Global Budesonide Study Group. Gut 1997;41(2):209–14. 21. Levine A, Watemberg N, Hager H, Bujanover Y, Ballin A, Lerman-Sagie T. Benign intracranial hypertension associated with budesonide treatment in children with Crohn disease. J Child Neurol 2001;16(6):458–61. 22. Kundhal P, Zachos M, Holmes JL, Griffiths AM. Controlled ileal release budesonide in pediatric Crohn disease: efficacy and effect on growth. J Pediatr Gastroenterol Nutr 2001;33(1):75–80. 23. Greenberg GR, Feagan BG, Martin F, Sutherland LR, Thomson AB, Williams CN, et al. Oral budesonide as maintenance treatment for Crohn disease: a placebo-controlled, dose-ranging study. Canadian Inflammatory Bowel Disease Study Group. Gastroenterology 1996;110(1):45–51. 24. Lofberg R, Rutgeerts P, Malchow H, Lamers C, Danielsson A, Olaison G, et al. Budesonide prolongs time to relapse in ileal and ileocaecal Crohn disease. A placebo controlled one year study. Gut 1996;39(1):82–6. 25. Ferguson A, Campieri M, Doe W, Persson T, Nygard G. Oral budesonide as maintenance therapy in Crohn disease–results of a 12-month study. Global Budesonide Study Group. Aliment Pharmacol Ther 1998;12(2):175–83. 26. Simms L, Steinhart AH. Budesonide for maintenance of remission in Crohn disease. Cochrane Database Syst Rev 2001(1):CD002913.
29 6-Mercaptopurine Therapy Carmen Cuffari∗
Introduction 6-Mercaptopurine (6-MP) and its parent drug azathioprine (AZA) are well-known for their immunosuppressive and lymphocytotoxic properties. [1, 2] These anti-metabolite drugs have been shown to suppress disease activity in up to 70% of children with IBD; and among these patients, 50% will achieve a clinical response after 4 months of continuous therapy. [3, 4] Although the overall risk of 6-MP induced toxicity is low, [5, 6] not all patients achieve disease remission despite presumed therapeutic drug dosing; thereby suggesting that inherent differences in either drug metabolism [7] or immune modulation [2] may influence clinical responsiveness to therapy. Herein, we will review the use of AZA and 6-MP in the management of pediatric patients with IBD. Furthermore, the application of pharmacogenomic and 6-MP metabolite testing will also be discussed based on an analysis of the literature. Several recommendations will also be provided on applying this technology into clinical practice.
Clinical Indication Maintenance Therapy 6-MP and AZA are often considered the immunosuppressant drugs of choice in the management of patients with steroid dependent IBD. Pearson and coworkers published a meta-analysis of nine controlled clinical trials in adult patients with CD that showed clinical responsiveness to either 6-MP or AZA therapy was largely dependant on duration of therapy. In that study, 40–70% of patients successfully achieved corticosteroid withdrawal after a median delay in clinical response time of 16 weeks. [8] On account of this delay in clinical response time, many clinicians are either reluctant to prescribe these slow-acting agents or will prematurely discontinue anti-metabolite drug therapy in favor of the more rapid onset biological therapies. [9] Although the delay in clinical response precludes the use of 6-MP as an induction therapy, the notion of using prednisone as a bridge to anti-metabolite therapy was first studied by Markowitz and coworkers. In that study, 55 children with newly diagnosed (<6 wks) CD were randomized in a prospective placebo controlled clinical trial to receive corticosteroids either with or without 6-MP therapy. All patients were placed on a corticosteroid weaning schedule. Patients on combination 6-MP and corticosteroid therapy had achieved clinical remission more effectively, and with a ∗ The Johns Hopkins Hospital, Department of Pediatrics, Division of Gastroenterology, 600 N. Wolfe St. Brady 308, Baltimore, MD 21287, Tel: 410-955-8765, Fax: 410-955-1464, E-mail:
[email protected]
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lower cumulative dose of corticosteroids than patients on placebo. Indeed, 92% of patients on 6-MP, and just 6% of patients on placebo maintained clinical remission after 12 months of follow-up. [10] Interestingly, these investigators chose not to use mesalamine in either treatment arm, despite a probable therapeutic benefit in using slow released 5-ASA formulations in patients with mild to moderate CD. [11] Although, this study would support the notion of initiating anti-metabolite as a first line therapy in patients with severe and aggressive disease phenotypes, most pediatric gastroenterologists will try to determine steroid dependency prior to instituting anti-metabolite therapy. Future studies are needed to improve our understanding of genotypephenotype correlations in clinical practice. This would allow clinicians to identify aggressive disease phenotypes and tailor medical therapy more effectively while minimizing the overall need for corticosteroids. [12] Adjunct Therapy It has been the practice in many institutions, including our own to initiate maintenance antiTNF alpha therapy in patients that have shown clear refractoriness to either long-term 6-MP or AZA therapy. In a double blind randomized control trial of maintenance infliximab therapy over a 54 weeks trial period (ACCENT 1), 41% of all adult patients with CD achieved and maintained a favorable clinical response. Patients on maintenance infliximab therapy were also more likely to discontinue corticosteroids (29%) and sustain a protracted clinical response than patients on placebo (9%). This study was the first large multi-centered study to have shown that re-treatment with infliximab was more effective than placebo for maintaining clinical remission in patients with CD. Although 29% of all the patients recruited into the study were on concurrent immunosuppressive therapy, it should be noted that most patients had previously been unsuccessful in achieving disease remission on either 6-MP or AZA. [13] Several important questions come to mind when reviewing the ACCENT I study, including whether all individuals with CD who are treated with infliximab should receive concurrent immunosuppressive therapy despite having not benefited from them in the past. The answer to this question is best addressed by the apparent need for some form of adjunct immunosuppressive therapy in order to prevent antibody against infliximab formation (HACA). The concurrent use of immunosuppressive therapy has in the past been shown by Rutgeerts and coworkers to maintain a favorable clinical response on maintenance infliximab therapy, presumably due to the prevention of HACA antibody formation. In that study, 75% (12/16) of patients on concurrent 6-mercaptopurine maintained a favorable clinical response, compared to 50% (9/18) on no concurrent immunosuppressive therapy. [14] In the ACCENT 1 study, only 18% of the patients on neither concurrent prednisone nor immunosuppressive drug therapy developed HACA, compared to just 10% of patients on concurrent azathioprine or methotrexate therapy. [13] The use of induction infliximab therapy as a bridge to maintenance antimetabolite therapy is attractive in light of its corticosteroid sparing effects. In a recently presented study, patients with severe active CD were randomized to receive 3 intravenous doses of induction infliximab in addition to AZA (2.0–2.5 mg/Kg/day) therapy. Among these patients, those with relapsing disease were also given repeated infliximab infusions. Corticosteroids were added in those patients who failed to respond to combination AZA and infliximab therapy. This treatment group was compared to patients receiving a “step up” approach, including systemic corticosteroids in patients that failed to respond to maintenance budesonide therapy. In those patients with corticosteroid dependency, AZA was added, and among these, refractoriness to AZA allowed for the introduction of infliximab therapy. At the end of a 24 month follow-up period, those patients on “top down” therapy required significantly less corticosteroids (5.6 days) compared to patients on “step up” (79.7 days) therapy. [15] Although these results clearly demonstrate the steroid sparing effects of a “top down” therapeutic approach in patients with severe active disease, physicians must appreciate that CD is a life-long disease, and the risk for lymphomas and other neoplasia with combination
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immunosuppression cannot be downplayed. [16] This is of critical importance, especially in a pediatric population who would be anticipated to receive maintenance infliximab therapy for many years. Indeed, the recent association between hepatosplenic T-cell lymphoma in pediatric patients on combination infliximab and 6-MP is most disconcerting and may compel pediatricians to reassess the safety of adjunct anti-metabolite therapy. [17] Furthermore, experience with infliximab indicates that it is also associated with infusion-site reactions and serious infections, including Herpes zoster that may also preclude its use as a first line monotherapy. [18] Post-operative Prophylaxis In patients with ileocolonic disease, the re-operation rate after surgical correction ranges from 25–60% after 5 years to up to 91% after 15 years. The recurrence risk after colocolic re-anastomosis is much less. A good predictor of disease recurrence is disease behavior. Patients with perforating disease are twice more likely than patients with non-perforating disease to require subsequent surgeries. [19] It still remains difficult to accurately predict the course of disease in any particular patient with CD, and the clinical value of prophylactic therapy remains unclear. In a recent placebo controlled trial, 131 adult patients with CD who underwent intestinal resection and ileo-colonic anastomosis were randomized to receive either placebo, 6-MP (50 mg/day) or mesalamine (3 g/day) as prophylactic therapy. Patients were evaluated prospectively with serial colonoscopies and small bowel barium enemas. In that study, 6-MP was shown to significantly (p<0.05) lower the clinical (50%) and endoscopic recurrence (43%) of CD compared to the mesalamine [clinical (58%); endoscopic (63%)] and placebo [clinical (77%); endoscopic (64%)] treatment groups. Although the dose of 6-MP used in this study was lower than that used for maintenance therapy, a well-defined prophylactic dose has yet to be defined. Despite the fact that clinical recurrence was similar between the 6-MP and mesalamine treatment groups, this study may support the continued use of anti-metabolite drugs post-operatively in patients with aggressive disease phenotypes. [20]
Drug Monitoring Most often, pediatricians will measure drug efficacy, based on either an improvement in their patients’ clinical symptoms and quality of life or their ability to maintain remission while weaning off of corticosteroid therapy. In general, most physicians will tend to rely on their clinical judgment and experience in determining the dosage of AZA (1.5–2.5 mg/kg/day) [21, 22] or 6-MP (1–1.5 mg/kg/day) [23, 24] in treating patients with IBD. However, not all patients achieve clinical remission with this treatment approach despite presumed therapeutic drug dosing. This has led some physicians to adopt a dose escalation treatment strategy beyond traditional 6-MP dosages. In these patients, 6-MP induced leucopenia is used as a clinical end-point to gauge drug dosing. Although Colonna and coworkers have shown that clinical response time is less in those patients with 6-MP-induced leucopenia, overall clinical response to therapy was shown to be independent of either 6-MP dose or total leukocyte count. In that study, none of their patients developed clinical signs of bone marrow suppression, required hospitalization for concurrent infection or required transfusions despite total leukocyte counts <5000. [25] A true separation between immunosuppression [1] and cytotoxicity [5, 6] has yet to be defined since the dosing of 6-MP and AZA has been based largely on clinical outcome. Indeed, the wide range in antimetabolite drug doses used in clinical practice would suggest that a safe and established therapeutic dose has yet to be determined. [20–25] As a consequence, the clinician must always remain aware of potential adverse effects, including allergic reactions, hepatitis, pancreatitis, bone marrow suppression and lymphoma while attempting to achieve an optimal therapeutic response. [5, 6]
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In comparison, the pediatric oncologist will effectively tailor the dose of either 6-MP or AZA based on the measure of erythrocyte 6-MP metabolite levels. Indeed, the notion of a therapeutic window of clinical efficacy and toxicity based on the measurement of AZA therapy has now become the standard of care in most pediatric practices treating patients with leukemia. [26–28] 6-Mercaptopurine Metabolism 6-MP and its prodrug AZA are by themselves inactive, and must be transformed into their active ribonucleotides that function, as purine antagonists. These anti metabolites are then incorporated into DNA, thereby interfering with ribonucleotide replication. [29, 30] The metabolism of 6-MP and AZA occurs intra-cellularly along the competing routes catalyzed by hypoxanthine phosphoribosyl transferase and thiopurine S-methyltransferase (TPMT), giving rise to 6-thioguanine nucleotides (6-TGn) and 6-methyl-mercaptopurine (6-MMP), respectively (Figure. 29.1). [7] 6-TGn is the active ribonucleotide of 6-MP that functions as a purine antagonist inducing lymphocytotoxicity and immunosuppression. [1, 2] An apparent genetic polymorphism has been observed in TPMT activity in both the Caucasian and African-American population. Negligible activity was noted in 0.3%, and low levels (<5 U/mL of blood) in 11% of individuals. [7] TPMT enzyme deficiency is inherited as an autosomal recessive trait, and to date, 10 mutant alleles and several silent and intronic mutations have been described. [31] In patients with the heterozygous TPMT genotype, 6-MP metabolism is shunted preferentially into the production of 6-TG nucleotides. Although 6-TG nucleotides are thought to be lymphocytoxic, and beneficial in the treatment of patients with leukemia and lymphoma, patients with low (<5) TPMT activity are at risk for bone marrow suppression by achieving potentially toxic erythrocyte 6-TGn levels on standard doses of 6-MP. [32] Despite low TPMT enzyme activity levels, therapeutic erythrocyte 6-TGn metabolite levels can still be achieved without untoward cytotoxicity by lowering the dose of 6-MP 10–15 fold. [33] 6-MP Metabolite Monitoring in IBD The measurement of the erythrocyte 6-MP metabolites 6-TGn and 6-MMP have been proposed as a useful clinical tool for measuring clinical efficacy, documenting patient compliance to therapy and explaining some drug induced toxicity in patients with IBD. In our preliminary study in 25 adolescent patients with CD on long-term 6-MP therapy, high performance liquid chromatography measurement of erythrocyte 6-TG metabolite levels showed an inverse correlation with disease activity. Although a wide range of metabolite levels was associated with a favorable 6-Methyl Mercaptopurine
TPMT HPRT AZA
6-MP
Thioinosine 5’ monophosphate 6-TG XO
6-Thiouric Acid
Figure 29.1. The metabolism of azathioprine. Notes: AZA, azathioprine; 6-MP, 6-mercaptopurine, TPMT, thiopurine methyl transferase, XO, xanthine oxidase, HPRT, hypoxanthine phosphoribosyl transferase; 5-ASA, mesalamine.
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clinical response, patients with high 6-TGn levels (>250 pmoles/8×108 RBCs) were uniformly asymptomatic. [34] Similar results have been reported in 93 pediatric and 45 adult patients with IBD in whom disease remission correlated well with erythrocyte 6-TGn levels between 230 and 260 pmoles/8×108 RBCs, respectively. [35–37] Although these studies and others would support the notion of a therapeutic index of clinical responsiveness based on the measurement of erythrocyte 6-TGn levels, several studies have shown no clinical correlation with metabolite monitoring (Table 29.1). [37–40] This lack of consensus may in part be due to the heterogeneous nature of CD and ulcerative colitis, and may also be dependent on disease severity. In a recent study of adult patients with CD, high (>290) erythrocyte 6-TGn level showed a positive predictive value of 86% of obtaining a favorable clinical response to induction AZA therapy in patients with steroid refractory CD. [41] Our institution is presently involved in a multi-centered prospective controlled clinical study that will help clarify the therapeutic advantage of metabolite testing in clinical practice. TPMT Activity Genetic polymorphism in TPMT enzyme activity can be quantitatively measured by TPMT phenotype testing. One in three hundred patients have absent TPMT enzyme activity, and are at risk for severe bone marrow suppression. [32] There have been a number of cases of irreversible bone marrow suppression both in patients with IBD and in patients with leukemia on standard doses of 6-MP or AZA therapy (personal communications). 6-MP metabolism is clearly influenced by inherent differences in TPMT activity present within the population. In a prospective openlabeled study in patients with IBD, the response rate to induction AZA therapy was highest in patients with less than average (<12 U/mL blood) TPMT activity. Clinical response also correlated well with achieving high erythrocyte (>250) 6-TGn metabolite levels. Indeed, the knowing of the low (<5) TPMT activity before initiating AZA therapy in 2 patients, led to a low dosing strategy (1 mg/kg/day) with a favorable clinical response without untoward side effects. [41] Moreover, a recent study by Kaskas and coworkers would also suggest that an effective low (0.25 mg/kg/day) treatment approach can be safely and effectively adopted in patients with the homozygous recessive genotype. [42] Both of these studies would support a low dose treatment strategy to treat patients with low TPMT activity. In comparison, 10% of the population is considered to be rapid metabolizers’ of 6-MP, and in theory would require larger than standard doses of drug in order to achieve any therapeutic drug benefit. In these patients, 6-MP metabolism is shunted away from 6-TGn production and into the formation of 6-MMP. A study in children with IBD showed that a sub-group of these patients remain refractory to therapy despite a dose optimizing treatment strategy. [43] This may Table 29.1. Clinical Responsiveness to 6-MP and AZA therapy based on threshold (235–250*) erythrocyte 6-TGn metabolite levels. 6-TGn Response Threshold
Study Patients
Dubinsky [35] Gupta [38] Belaiche [39] Cuffari [37] Achar [36] Lowry [40] Goldenberg [41] *pmoles/8×108 RBCs
Odds Ratio
N (Response)
Above
Below
92 (30) 101 (47) 28 (19) 82 (47) 60 (24) 170 (114) 74 (14)
.78 .56 .75 .86 .51 .64 .24
.40 .43 .65 .35 .22 .68 .18
5.0 1.7 1.6 11.6 3.8 0.9 1.5
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in part be due to high hepatic TPMT activity that may draw most of the 6-MP from the plasma, thereby limiting the amount of substrate available for the bone marrow and peripheral leukocytes. A similar study in adult patients with IBD was also able to identify these rapid metabolizers based on the measure of erythrocyte TPMT activity levels. In that study, patients with above average (>12) TPMT activity levels were less likely to respond to AZA therapy, and more likely to require higher dosages (2 mg/Kg/day) of AZA from the outset in order to optimize erythrocyte 6-TGn metabolite levels. Moreover, patients with above average (>12) TPMT activity had a mean erythrocyte 6-TGn levels that leveled off below a presumed therapeutic (<250) treatment level after 8 weeks of continuous AZA therapy. Sixty-nine percent patients with TPMT activity levels ≤12 U/mL blood achieved a clinical response compared to just 30% of patients with above average (>12) TPMT activity after 4 months of continuous therapy. This study was the first to suggest that the pre-treatment knowledge of TPMT activity may allow physicians to predict clinical response, and effectively dose AZA in order to maximize efficacy while minimizing the risk of toxicity. Indeed, in that study, patients with a TPMT enzyme activity less than 15 U/mL of blood were six times (OR:6.2) more likely to show a favorable response to AZA therapy. [41] A recent study exploited the use of allopurinol, a potent inhibitor of xanthine oxidase, in patients with high (>16) TPMT activity who shunt 6-MP metabolism away from the production of 6-TGn metabolites, and remain refractory to presumed therapeutic anti-metabolite drug dosing. In that study, the concomitant use of allopurinol with either AZA or 6-MP in patients with presumed high TPMT activity levels achieved a significant increase in erythrocyte 6-TGn metabolite levels and the subsequent induction of disease remission. Although this treatment strategy led to a decrease in total leukocyte count, no patient developed clinical signs of toxicity. [44]
6-MP Toxicity Many pediatricians have been reluctant to prescribe 6-MP on account of potential drug related toxicity including pancreatitis 3%, bone marrow depression 2%, super-infection 7%, and hepatitis 0.3%. [5] Severe side-effects are either idiosyncratic or related to generic polymorphism as described above. Although Black and coworkers suggested the notion that pharmacogenetic differences in 6-MP metabolism influence a patient’s risk of drug toxicity, [45] TPMT polymorphism account for only 25% of all 6-MP induced side-effect. [46] However, genetic polymorphisms may play a role in determining the long-term risk for malignancy. In several pediatric oncology studies, the risk for secondary malignancies, including acute myeloblastic leukemia and myelodysplasia was higher in those children with low TPMT activity levels with acute lymphocytic leukemia on maintenance 6-MP therapy. [47] Larger longitudinal studies are necessary in order to draw conclusions about the long-term risk of anti-metabolite induced malignancy, especially in the context of concurrent biological therapies.
Conclusions 6-MP and AZA have proven efficacy in the maintenance of disease remission in children with IBD. The application of pharmacogenomic and metabolite testing in clinical practice has helped to improve the overall clinical response to antimetabolite therapy in children with IBD and reduce the risk of anti-metabolite induced side-effects. The careful monitoring of complete blood counts, and erythrocyte 6-TG metabolite levels are indicated in patients with either low (<5) or above average (>12) TPMT levels. Relying on either total leukocyte counts or mean corpuscular volume as the sole measure of dosing adequacy should be used with caution. [48, 49]
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References 1. Tiede I, Fritz G, Strand S. et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003;111:1122–4. 2. Carvalho RS, Mahoney JA, Oliva-Hemker MM, et al. Inherent resistance to 6-thioguanine induced apoptosis correlates with disease activity in children with IBD. Gastroenterology 2006; A203. 3. Markowitz J, Rosa J, Grancher K, Aiges H, Daum F. Long-term 6-mercaptopurine treatment in adolescents with Crohn’s disease. Gastroenterology 1990;99:1347–51. 4. Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr 1990;117:809–14. 5. Markowitz J, Grancher K, Mandel F, Daum F. Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for pediatric Gastroenterology and Nutrition. Subcommittee on immunosuppressive use of the pediatric IBD collaborative research forum. Am J Gastroenterol 1993;88:44–8. 6. Present DH, Meltzer SJ, Krumholz MP, et al. 6-mercaptopurine in the management of inflammatory bowel disease: short and long-term toxicity. Ann Intern Med 1995;111:641–9. 7. Weinshilboum RN, Sladek Sl. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyl transferase activity. Am J Hum Genet 1980;32:651–62. 8. Pearson DC, May GR, Fick GH, Sutherland SR. Azathioprine and 6-mercaptopurine in Crohn’s disease: a meta-analysis. Ann Intern Med 1995;122:132–42. 9. Markowitz J, Hyams J, Mack D. et al. Corticosteroid therapy in the age of infliximab: Acute and 1-year outcomes in newly diagnosed children with crohn’s disease. Clin Gastroenterol Hepatol. 2006;4: 1124–29. 10. Markowitz J, Grancher K, Kohn N, et. al. A multi-center trial of 6-mercaptopurine and prednisone therapy in children with newly diagnosed Crohn’s disease. Gastroenterology 2000;119:895–902. 11. Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn’s disease: a meta-analysis adjusted for confounding variables. Gastroenterology 1997;113:1465–73. 12. Brant SR, Panhuysen CI, Bailey-Wilson JE, et al. Linkage heterogeneity for the IBD1 locus in Crohn’s disease pedigrees by disease onset and severity. Gastroenterology. 2000;119:1483–90. 13. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCECT I randomized trial. Lancet 2002;359:1541–9. 14. Rutgeerts P, D’Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999; 117:761–9 15. Hommes D, Baert F, Van Assche G, et al. The ideal management of Crohn’s disease: top down versus step up strategies, a randomized control trial. Gastroenterology 2006; A108. 16. Siegel CA, Hur C, Korzenik JR, et al. Risks and Benefits of Infliximab for the Treatment of Crohn’s Disease. Clin Gastroenterol Hepatol 2006;8:1017–24. 17. Thayu M, Markowitz JE, Mamula P, et al. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr 2005;2:220–2. 18. Mamula P, Markowitz JE, Cohen LJ, et al. Infliximab in pediatric ulcerative colitis: two-year follow-up. J Pediatr Gastroenterol Nutr 2004;38(3):298–301. 19. Baldassano RN, Han PD, Jeshion WC, et al. Pediatric Crohn’s disease: risk factors for postoperative recurrence. Am J Gastroenterol 2001;7:2169–76. 20. Hanauer SB, Korelitz BI, Rutgeerts P, et al. Post-operative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine or placebo: a 2 year trial. Gastroenterology 2004;127:723–9. 21. Ewe K, Press AG, Singe CC, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease. Gastroenterology 1993;105:367–72. 22. Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease Gut. 1995;37:674–78. 23. Korelitz BI, Adler DJ, Mendelsohn RA, et al. Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol 1993;88:1198–205. 24. Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980;302:981–7. 25. Colonna T, Korelitz BI. The role of leukopenia in 6-mercaptopurine-induced remission of refractory Crohn’s disease. Am J Gastroenterol 1993;89:362–6.
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26. Lennard L, Rees CA, Lilleyman JS, et al. Childhood leukemia: a relationship between intracellular 6-mercaptopurine metabolites and neutropenia. Br J Clin Pharmacol 1993;16:359–63. 27. Zimm S, Collins JM, Riccardi R, et al. Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered. 1983;308:1005–9. 28. McLeod HL, Relling MV, Liu Q, Pui CH, Evans WE. Polymorphic thiopurine methyl transferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood 1995;1887–902. 29. Christie NT, Drake S, Meyn RE. 6-thioguanine induced DNA damage as a determinant of cytotoxicity in cultured hamster ovary cells. Cancer Res 1986;44:3665–71. 30. Fairchild CR, Maybaum J, Kennedy KA. Concurrent unilateral chromatid damage and DNA strand breaks in response to 6-thioguanine treatment. Biochem Pharmacol 1986;35:3533–41. 31. Alves S, Prata MJ, Ferreira F, Amorim A. Screening of thiopurine methyl s-transferase mutations by horizontal conformation-sensitive gel electrophoresis. Human Mutation 2000;15:246–53. 32. Evans WE, Horner M, Chu YQ, et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirements in a thiopurine methyltransferase deficient child with acute lymphoblastic leukemia. J Pediatr 1991;119:985–9. 33. McLeod HL, Krynetski EY, Relling MV, et al. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 2000;14:567. 34. Cuffari C, Theoret Y, Latour S, et al. 6-mercaptopurine metabolism in Crohn’s disease: correlation with efficacy and toxicity. Gut 1996;39:401–6. 35. Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Theoret Y, Seidman EG. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000;118;705–13. 36. Achar JP, Stevens T, Brzezinski A, Seidner D, Lashner B. 6-Thioguanine levels versus white blood cell counts in guiding 6-mercaptopruine and azathioprine therapy. Am J Gastroenterol 2000;95:A272. 37. Cuffari C, Hunt S, Bayless TM. Utilization of erythrocyte 6-thioguanine metabolite levels to optimize therapy in IBD. Gut 2001;48:642–6. 38. Gupta P, Gokhlae R, Kirschner BS. 6-mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2001;33:450–4. 39. Belaiche J, Desager JP, Horsman Y, Louis E. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease. Scand J Gastroenterol 2001;36:71–6. 40. Lowry PW, Franklin CL, Weaver AL, Szumlanski C, Mays DC, Loftus EV, Tremaine WJ, Lipsky JJ, Weinshilboum RM, Sandborn WJ. Leukopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine or balsalazide. Gut 2001;49:656–64. 41. Goldenberg BA, Rawsthorne P, Berstein CN. The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease. Am J Gastroenterol 2004;99:1744–8. 42. Cuffari C, Dassoupolus T. Bayless TM. Thiopurine methyl-transferase activity influences clinical response to azathioprine therapy in patients with IBD. Clin Gastroenterol Hepatol 2004;2:410–17. 43. Kaskas BA, Louis E, Hinderof U, et al. Safe treatment of thiopurine S-transferase deficient Crohn’s disease patients with azathioprine. Gut 2003;52:140–2. 44. Dubinsky MC, Yang H, Hassard PV, Seidman EG, Kam LY, Abreu MT, Targan SR, Vasiliauskas E. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 2002;122:904–15. 45. Sparrow MP, Hande SA, Friedman S, et al. Allopurinol safely and effectively optimizes thioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 2005;22:441–6. 46. Black AJ, McLeod HL, Capell HA. Thiopurine methyl transferase predicts therapy-limitingsever toxicity from azathioprine. Ann Intern Med 1998;129:716–18. 47. Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000;118(6):1025–30. 48. Bo J, Schroder H, Kristinsson J, Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism. Cancer 1999;86:1080–6. 49. Garza A, Sninsky CA. Changes in red cell mean corpuscular volume (MCV) during azathioprine or 6-mercaptopurine therapy for Crohn’s disease may indicate optimal dose titration. Gastroenterology 2001;120:A3166.
30 Methotrexate Therapy Joel R. Rosh∗
Introduction The inflammatory bowel diseases are characterized by chronic gastrointestinal inflammation in association with ongoing and inappropriate activation of the mucosal immune system [1, 2]. While mild disease can respond to topical anti-inflammatory therapy, patients with moderate disease activity or a relapsing course have been identified as those who should receive immune modifying agents [3]. The short-term goal of therapy remains the relief of clinical symptoms while the long-term goal is to improve quality of life while changing the natural history of the disease by decreasing the incidence of adverse outcomes such as the need for surgical intervention. Glucocorticosteroids have both anti-inflammatory as well as immunomodulatory effects. As such, steroids are likely the most commonly used immune-modifying agent and have the longest history of use. At a year after diagnosis, more than 30% of pediatric Crohn patients will remain dependant on glucocorticosteroids and almost 10% will already have undergone surgery demonstrating steroids’ inability to alter the course of Crohn disease [4]. This lack of long-term effect as well as the legion of steroid related side effects, especially in a growing child or adolescent, mandate the identification of more effective, steroid sparing agents. Concordantly, approximately 60% of pediatric patients will be placed on immunomodulatory therapy within the first year of diagnosis [5]. The thiopurines, 6 mercaptopurine (6MP) and azathioprine (AZA), have been shown to be efficacious as well as steroid sparing and are covered in more detail elsewhere in this book. The prospective multi-center trial by Markowitz, et al. showed that 91% of pediatric Crohn patients who underwent successful induction remain in remission on 6MP/AZA at 18 months [6]. For the 9% not maintained with 6MP/AZA another effective, non-steroid agent is needed. In addition, there are those who cannot tolerate 6MP/AZA because of the development of idiopathic pancreatitis or other idiosyncratic reactions including gastrointestinal toxicity and fever which is seen in 5–10% of patients [7]. Methotrexate has emerged as an effective and overall well-tolerated alternative to the thiopurines [8]. Controlled trials have confirmed methotrexate as an effective agent in inducing as well as maintaining clinical remission in adult patients with Crohn disease [9, 10]. While a prospective pediatric trial has not yet been performed, there is ample clinical experience with this agent in pediatric Crohn disease patients. A survey of Canadian pediatric gastroenterologists showed that more than 80% had used methotrexate in their IBD patients and two large multi-center
*Director, Pediatric Gastroenterology, Atlantic Health/Goryeb Children’s Hospital, Associate Professor of Pediatrics, UMD—New Jersey Medical School, 100 Madison Avenue, Morristown, NJ 07962, Phone: 973-971-5676, Fax: 973-290-7365, E-mail:
[email protected]
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retrospective reviews of the use of methotrexate in pediatric Crohn disease have been recently published [11, 12]. There have been trials of methotrexate in ulcerative colitis and these have not been as promising [14]. As a result, this chapter will focus on the use of methotrexate in Crohn disease. When methotrexate is administered in Crohn disease, a low dose is utilized. This results in a different mechanism of action as compared to that effected when high-dose methotrexate is given as a chemotherapy agent in cancer therapy.
Mechanism of Action Methotrexate is a folic acid derivative originally designed to act as an analogue of dihydrofolic acid. By being a competitive antagonist of folic acid, methotrexate inhibits folate dependent enzymes such as dihydrofolate reductase (DHFR) which is critical to both purine and pyrimidine synthesis. In this way, methotrexate is able to block DNA production and exert anti-proliferative as well as cytotoxic effects when administered in relatively high doses [15]. When given for immune mediated diseases, methotrexate is utilized at a low dose and, consequently, does not exert such anti-metabolite effects. Clinically, this is manifest by the absence of such side effects as hair loss as well as the fact that folate supplementation decreases the toxicity of the therapy rather than inhibiting its efficacy [16, 17]. The mechanism of action of low-dose methotrexate still needs to be fully elaborated. While not anti-proliferative, low-dose methotrexate my induce T-cell apoptosis [18, 19] although recent studies do not agree with this finding [20]. Another potential mechanism of action results from low dose methotrexate’s effect on both intra-cellular and extra-cellular concentrations of adenosine and the affects of adenosine on the adaptive immune response [21] (See Table 30.1). Methotrexate has also been shown to have a more direct effect on a variety of cytokines and these potential mechanisms of action have been recently reviewed [22, 23]. Improved understanding of the mechanism of action may also affect the recommended dosing of low-dose methotrexate. As has become appreciated with the thiopurines, metabolites of the parent drug may be the more clinically important compound. There is now evidence that intracellular methotrexate polyglutamates are the active immune modifying compounds [24] and that there are metabolic polymorphisms leading to great variability in intra-cellular methotrexate polyglutamate levels. Therefore, metabolic factors in addition to actual drug absorption may play a large role in the efficacy and potential toxicity of methotrexate in any individual. The importance of methotrexate polyglutamate levels in IBD patients has not yet been studied. Such studies may lead to dosing recommendations based upon pharmacogenomics rather than weight-based dosing. For now, however, dosing is based upon weight or body surface area measurements.
Table 30.1. Effects of adenosine related pathways on adaptive immune response. Increased interleukin (IL)-10 Increased IL-2 Inhibition of neutrophil chemotaxis Decreased leukotrien B4 (LTB4 ) Decreased tumor necrosis factor alpha Decreased IL-6 Decreased IL-8 Decreased selective adhesion molecules (SAM)
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Dose and Administration Methotrexate is administered once a week. The route of administration can be parenteral (subcutaneous or intra-muscular) or oral. Since there are no head-to-head prospective trials comparing the efficacy of oral and parenteral methotrexate for IBD, it remains controversial whether there is a preferred route of administration. Retrospective reports leave the answer to this question vague. For example two uncontrolled, observational studies published within a year of each other differed in their conclusions with one showing no difference between oral and parenteral methotrexate [25] and the other showing clear advantage to the parenteral route [26]. In an attempt to better understand potential differences between parenteral and oral methotrexate, pharmacokinetic studies have been performed to see if there is a significant difference in absorption between the two routes. Studies of adult patients [27] as well as pediatric IBD patients [28] have demonstrated a wide individual range of methotrexate bioavailability. Interestingly, the adult study showed the oral route to provide about 73% of the bioavailability that was seen with the parenteral route while no such difference was seen in the pediatric study. Before a recommendation of whether parenteral or oral administration is preferable, two important aspects of the study design shared by both of these reports should be considered. The first important aspect of these bioavailability studies is that both used study subjects who were clinically stable on methotrexate maintenance therapy. Therefore, neither provides bioavailability data on patients being induced with methotrexate. As a result, until further data is available, it seems prudent to recommend the parenteral route be utilized for induction with Table 30.2. Methotrexate (MTX) — dosing and monitoring. • Supplemental folic acid 1 mg/day to be given to all patients • Dose (subcutaneous injection on a weekly basis) • 20–29kg = 10mg MTX • 30–39 = 15mg MTX • 40–49kg = 20mg MTX • >50kg = 25mg MTX • Induction treatment (if laboratory values are within normal range) • 1/2 final dose given the first week • 3/4 final dose given the second week • full dose given the third week • Maintenance • Consider 20% dose reduction if stable > 3months • Consider conversion to oral dosing if stable > 3 months • Patient Monitoring • Complete blood count with differential and platelets (CBC), Erythrocyte Sedimentation Rate (ESR), Hepatic Function Panel weekly for the first month and then every 2-3 months if stable. • The dose should be reduced by 50% for elevation in alanine aminotransferase (ALT) > twice baseline • The dose should be reduced by 50% for white blood count (WBC) <4000, absolute neutrophil count (ANC) <1500 or platelet <120,000 and held for 2 weeks for WBC <3000, ANC <1000 or platelets <100,000. Notes: MTX should be held for two weeks for nonproductive cough >1 week, and discontinued for pneumonitis or serious infections.
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a possible conversion to the oral route once a durable remission is achieved. Indeed, a recent Cochrane review concluded that while parenteral methotrexate has been shown to be an effective induction agent, there is no evidence upon which to recommend oral methotrexate for the induction of remission in Crohn disease [29]. Additionally, for pediatric patients, looking at studies in JRA for guidance, there is evidence for improved efficacy of sub-cutaneous methotrexate compared to oral methotrexate in JRA [30]. In addition to the ongoing questions with regard to the optimal route of administration, the actual ideal dose of methotrexate that should be used for pediatric IBD patients remains undetermined. The dosing schedule that is utilized at our center is listed in Table 30.2. All patients are supplemented with folic acid 1mg orally daily while the methotrexate is administered once a week. The weekly methotrexate dose is escalated until the full, weight-based induction dose is achieved. Once clinical remission is achieved and maintained for three or more months, an attempt to reduce the weekly dose is made. The dosing and monitoring strategies are listed in Table 30.2 and further discussed in the toxicity section below.
Efficacy Kozarek first published on the utility of methotrexate in refractory IBD patients [31]. This open label pilot study of 21 patients was ultimately confirmed by the prospective, placebo-controlled trials led by Brian Feagan. In 1995, Feagan, et al. published their 16 week induction study demonstrating that weekly intra-muscular injections of 25mg of methotrexate is an effective, steroid-sparing, induction strategy in adult patients with active Crohn disease [9]. This study of 141 patients showed that 39% were in a steroid-free remission at 16 weeks compared to 19% of placebo patients. Those who achieved remission with methotrexate were then offered enrollment in a 40-week double-blind placebo-controlled maintenance trial of 15mg of methotrexate administered intra-muscularly on a weekly basis. 76 patients participated and demonstrated a methotrexate remission rate of 65% compared to 39% of placebo. No serious adverse events were noted [10]. These results have been confirmed in at least one other controlled, prospective trial [32]. In addition, there have been head-to-head trials suggesting that the effect of methotrexate is similar to that of the thiopurines [33, 34]. Two retrospective chart reviews have suggested efficacy out to 18 months [25, 26]. Published experience with methotrexate in pediatric IBD is scant. Mack et al. [35] reported on 14 patients with a mean age of 10.6 years who had active Crohn disease and were intolerant or unresponsive to 6-mercaptopurine. Sub-cutaneous administration of methotrexate was used and 64% of the patients showed clinical improvement by as early as 4 weeks. Steroid sparing was also demonstrated. Adverse events attributed to the methotrexate were nausea and headache leading to withdrawal of therapy in two patients. No patients demonstrated bone marrow suppression, abnormal liver chemistries or pulmonary complications. There was one death in a child who was also on steroids and had an acute intercurrent illness. Post-mortem examination was unrevealing and adrenal suppression from chronic corticosteroid use rather than the methotrexate was felt to have contributed to the patient’s demise. Certainly, there is a large clinical and trial experience with methotrexate in children resulting from its use in juvenile rheumatoid arthritis [36]. A six month, double-blind, placebo controlled trial demonstrated that 63% of children with JRA receiving a low dose of methotrexate (10mg per m2 of body surface area) had clinical improvement compared to 32% who received a very low dose (5mg per m2 of body surface area) and 36% who were in the placebo group [37]. With regard to the route of administration, it has been shown that in JRA patients who do not respond or who are intolerant to oral methotrexate, 70% will respond by switching to subcutaneous methotrexate. This increased efficacy was obtained without an increase in toxicity [30].
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Toxicity and Monitoring In patients with inflammatory bowel disease, low-dose methotrexate has been shown to be a well-tolerated agent with more than 90% of clinical trial patients able to complete study drug [23]. Side effects are usually transient or respond to dose reduction and, less commonly, drug withdrawal. There is the suggestion from the rheumatology literature that pediatric patients may be even more tolerant to methotrexate than adult patients [38]. A full discussion of potential side effects follows and is summarized in Table 30.3. Nausea is the most common side effect and has been correlated with inhibition of folatedependant enzymes. As a result, folic acid supplementation may help limit this side effect, which has been reported in more than 20% of the adult patients who participated in clinical IBD trials [23]. Other gastrointestinal side effects include abdominal pain, diarrhea and stomatitis that may even evolve into mucositis involving the esophagus [39]. In light of the potential for hepatic toxicity with high-dose methotrexate, liver related complications have been well studied with low-dose methotrexate. There may be a disease-related rate of liver complications following therapy with low-dose methotrexate. Patients with psoriasis were shown to have a 7% rate of hepatic fibrosis [40] as compared to the 1% rate in rheumatoid arthritis [41]. The low rate of hepatic fibrosis and cirrhosis in RA has led to the official recommendation of the American College of Rheumatology that routine, surveillance liver biopsies not be performed [41]. Studies in JRA patients have shown at least as good hepatic tolerance [42]. Similarly negligible rates of drug related hepatotoxicity have been seen in IBD patients treated with prolonged
Table 30.3. Side effects and toxicities of low-dose methotrexate. • TERATOGENICITY: Pregnancy class X. Contraindicated in women of child-bearing potential Contraindicated in breastfeeding women • Gastrointestinal—folate related Nausea—most common Abdominal pain, diarrhea Stomatitis including esophagitis • Bone Marrow Suppression Monitor with CBC (Table 3.2 for schedule) Increased with trimethoprim-sulfamethoxazole • Hepatic Monitor with routine liver chemistries (Table 3.2 for schedule) Increased risk with obesity, concomitant hepatotoxic medications Routine liver biopsy not recommended • Infections Upper respiratory most common Rarely herpetic as well Rarely clinically serious • Pneumonitis Immune-mediated Rare Suspect if prolonged non-productive cough Preliminary evaluation = chest radiograph and pulmonary function tests • Dermatologic Hypersensitivity reactions
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low-dose methotrexate [43]. Rather than biopsy, routine liver chemistry monitoring should be performed as shown in Table 30.2. Bone marrow suppression leading to leukopenia or thrombocytopenia occurs in about 1% of low-dose methotrexate treated patients [23]. This is usually transient and responds to dose reduction or holding of the drug. Routine monitoring of complete blood counts should be performed to look for bone marrow suppression (Table 30.2). Concomitant medications, especially antifolate agents such as trimethoprim-sulfamethoxazole should be avoided with methotrexate therapy as these can exacerbate potential bone marrow suppression. Theoretically, this may be true of sulfasalazine as well although the combination of low-dose methotrexate and sulfasalazine has been utilized without increased toxicity [44]. An immunologically mediatied pneumonitis can also rarely be seen with methotrexate therapy. Screening asymptomatic pediatric patients does not seem warranted [38]. Rather, a persistent cough or other symptoms should prompt a chest radiograph and pulmonary function studies with suspension of methotrexate therapy until clarification of the clinical picture is achieved. The most important toxicity of methotrexate is related to its teratogenicity. Methotrexate is labeled as a pregnancy class X substance—it is completely contraindicated in pregnancy as well as during breastfeeding. All patients and their families must be educated about this prior to starting methotrexate therapy and it is wisest not to use this agent in any female of childbearing potential.
Summary Through a variety of mechanisms including folate independent pathways, once weekly low-dose methotrexate, either oral or parenteral, has been demonstrated to exert immune-modifying effects. The currently published data shows the efficacy of methotrexate in Crohn disease while convincing data for ulcerative colitis is lacking. While there is robust prospective data in adult Crohn disease, the current data in pediatric patients is largely retrospective. However, there is strongly favorable data in juvenile rheumatoid arthritis patients. Until there is prospective, long-term efficacy and safety data on methotrexate in pediatric IBD, it is reasonable to consider the thiopurines to be the first line immunomodulators in this setting. The teratogenicity of methotrexate stands out as a distinguishing toxicity concern. Accordingly, for patients who are not of child-bearing potential and who do not respond or who cannot tolerate the thiopurines, methotrexate is a promising second line immunomodulator. References 1. Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417–29. 2. Nieuwenhuis EE, Blumberg RS. The role of the epithelial barrier in inflammatory bowel disease, In: Blumberg RE, Neurath MF, editors. Immune mechanisms in inflammatory bowel disease. Springer Science, Landes Bioscience, 2005;109–116. 3. Sandborn WJ. Evidence-based treatment algorithm for mild to moderate Crohn’s disease. Am J Gastroenterol 2003;98:S1–S5. 4. Markowitz J, Hyams J, Mack D, et al. Corticosteroid therapy in the age of infliximab: Acute and 1-year outcomes in newly diagnosed children with Crohn disease. Clin Gastroenterol Hepatol 2006;4:1124–29. 5. Jacobstein DA, Mamula P, Markowitz JE, Leonard M, Baldassano RN. Predictors of immunomodulatory use as early therapy in pediatric Crohn disease. J Clin Gastroenterol 2006;40:145–148. 6. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn disease. Gastroenterology 2000;119:895–902. 7. Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998;115:813–21. 8. Panaccione R. Methotrexate: lessons from rheumatology. Can J Gastroenterol 2005;9:541–42. 9. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn disease. The North American Crohn study group investigators. N Engl J Med 1995;332:292–97.
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10. Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn disease. North American Crohn study group investigators. N Engl J Med 2000;342:1627–32. 11. Uhlen S, Belbouab R, Narebski K, et al. Efficacy of Methotrexate in Pediatric Crohn’s Disease: A French Multicenter Study. Inflamm Bowel Dis 2006;12:1053–57. 12. Turner D, Grossman AB, Rosh J, et al. Methotrexate following unsuccessful thiopurine therapy in pediatric crohn’s disease. Am J Gastroenterol 2007;102:1–9. 13. Oren R, Arber N, Odes S, et al. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Gastroenterology 1996;110:1416–21. 14. Baron TH, Truss CD, Elson CO. Low-dose methotrexate in refractory inflammatory bowel disease. Dig Dis Sci 1993;38:1851–56. 15. Chabner BA, Allegra CJ, Curt GA, et al. Antineoplastic agents. In: Hardman JG, Limbird LE, Molinoff PB, et al., editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th edition. New York: McGraw-Hill, 1996;1243–47. 16. Ortiz Z, Shea B, Suarez-Almazor ME, et al. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol 1998;25:36–43. 17. Morgan SL, Baggott JE, Vaughn WH, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:9–18. 18. Paillot R, Genestier L, Fournel S, et al. Activation-dependent lymphocyte apoptosis induced by methotrexate. Transplant Proc 1998;30:2348–2350. 19. Genestier L, Paillot R, Quemeneur L, et al. Mechanisms of action of methotrexate. Immunopharmacology 2000;47:247–57. 20. Johnston A, Gudjonsson JE, Sigmundskottir H, et al. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation of adhesion molecules. Clin Immunol 2005;114:154–63. 21. Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin North Am 1997;23:739–55. 22. vanDieren JM, Kuipers EJ, Samsom JN, Nieuwenhuis EE, van derWoude J. Revisiting the immunomodulators tacrolimus. Methotrexate, and mycophenolate mofetil: their mechanisms of action and role in the treatment of IBD. Inflamm Bowel Dis 2006;12:311–27. 23. Schroder O, Stein J. Low dose methotrexate in inflammatory bowel disease: current status and future directions. Am J Gastroenterol 2004;98:530–37. 24. Angelis-Stoforidis P, Vajda FJE, Christophidis N. Methotrexate polyglutamate levels in ciruculating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis. Clin Exp Rheum 1999;17:313–20. 25. Lemann M, Zenjari T, Bouhnik Y, et al. Methotrexate in Crohn disease: long-term safety and toxicity. Am J Gastroenterol 2000;95:1730–34. 26. Chong RY, Hanauer SB, Cohen RD. Efficacy of parenteral methotrexate in refractory Crohn disease. Aliment Pharmacol Ther 2001;15:35–44. 27. Kurnik D, Loebstein R, Fishbein E, Almog S, Halkin H, Bar-Meir S, Chowers Y. Bioavailability of oral vs. subcutaneous low-dose methotrexate in patients with Crohn disease. Aliment Pharmacol Ther 2003;18:57–63. 28. Stephens MC, Baldassano RN, York A, Widemann B, Pitney AC, Jayaprakash N, Adamson PC. The bioavailability of oral methotrexate in children with inflammatory bowel disease. J Peditr Gastroenterol Nutr 2005;40:445–49. 29. Alfadhli AAF, McDonald JWD, Feagan BG. Methotrexate for induction of remission in refractory Crohn disease. Cochrane Database Syst Rev 2005;1:CD003459. 30. Alsufyani K, Ortiz-Alvarez O, Cabral DA, tucker LB, Petty RE, Malleson PN. The role of subcutaneous administration of methotrexate in children with juvenile idiopathic arthritis who have failed oral methotrexate. J Rheumatol 2004;31:179–82. 31. Kozarek RA, Patterson DJ, Gelfand MD, Alin Botoman A, Ball TJ, Wilske KR. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989;110:335–56. 32. Moshkowitz M, Oren R, Tishler M, et al. The absorption of low-dose methotrexate in patients with inflammatory bowel disease. Aliment Pharmacol Ther 1997;11:569–73.
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33. Ardizzone S, Bollani S, Manzionna G, et al. Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn disease: a randomized, investigator-blind study. Dig Liver Dis 2003;35:619–27. 34. Mate-Jimenez J, Hermida C, Canter-Perona J, et al. 6-mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000;12:1227–33. 35. Mack DR, Young R, Kaufman SS, Ramey L, Vanderhoof JA. Methotrexate in patients with Crohn disease after 6-mercaptopurine. J Pediatr 1998;132:830–35. 36. Woo P, Southwood TR, Prieur AM, et al. Randomized, placebo-controlled, crossover trial of low dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum 2000;43:1849–57. 37. Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. The pediatric rheumatology collaborative study group and the cooperative children’s study group. N Engl J Med 1992;326:1043–49. 38. Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr 1992;120:468–73. 39. Batres LA, Gabriel CA, Tsou VM. Methotrexate-induced esophagitis in a child with crohn disease. J Pediatr Gastroenterol Nutr 2003;37:514–16. 40. Roenigk HH Jr, Auerbach R, Maibach H, et al. Methotrexate in psoriasis: Revised guidelines. J Am Acad Dermatol 1988;19:145–56. 41. Kremer JM, Alarcon GS, Lightfood RW Jr, et al. Methotrexate for rheumatoid arthritis. Suggested guideline for monitoring liver toxicity. Arthritis Rheum 1994;37:316–28. 42. Kugathasan S, Newman AJ, Dahms BB, Boyle JT. Liver biopsy findings in patients with juvenile rheumatoid arthritis receiving long-term weekly methotrexate therapy. J Pediatr 1996;128:149–51. 43. Te HS, Schiano TD, Hanauer SB, et al. Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease. Am J Gastroenterol 2000;95:3150–56. 44. Rains CP, Noble S, Faulds D. Sulfasalazine: A review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis. Drugs 1995;50:137–56.
31 Infliximab Therapy Séverine Vermeire∗ , Gert Van Assche and Paul Rutgeerts
Introduction Goals of Therapy in Paediatric Inflammatory Bowel Disease and Shortcomings of Current Therapies The natural history of Crohn disease (CD) and ulcerative colitis (UC) is characterized by recurrent exacerbations interspersed with periods of inactive disease. The goal of therapy should be to induce and maintain clinical remission and strive for endoscopic healing of the intestinal mucosa and improve the quality of life. In paediatric patients with inflammatory bowel disease (IBD), common complications include failure to thrive and impaired psychosocial development [1]. Additional therapeutic goals in children should therefore include resuming weight gain and promoting growth and development. These goals need to be achieved within a relatively short window of opportunity, before growth retardation and development deficiencies become permanent. These goals are not achieved however with conventional therapeutic strategies (sulphasalazine, 5-aminosalicylates, corticosteroids). From the very first introduction of corticosteroids, 20% of patients do not respond and 36% of the responders develop steroid dependency. Glucocorticosteroids are ineffective to maintain remission and are associated with important side effects [2, 3]. Immunosuppression with azathioprine, 6-mercaptopurine (6-MP) or methotrexate (MTX) has long-term efficacy but only 40–65% of patients maintain in remission and the onset of action of these drugs is slow [4–7]. Relapsing or continuously active disease often leads to complications necessitating surgery, but it is well known that resection of the inflamed bowel, at least in CD, does not cure the disease and that recurrence occurs in most patients. The use of cyclosporin in severe active UC has a good short-term efficacy (>80%) but we showed that up to 88% of patients require colectomy at 7 years [8]. Hence, this does not present a long-term solution. Surgical options with total proctocolectomy and ileoanal pouch anastomosis carry the specific danger in young females of reducing fecundity to 20% of the reference population fecundability and therefore should be avoided if possible, at least until after child bearing period [9]. Enteral nutrition has an important role in the management of IBD, including prevention and correction of malnutrition, prevention of osteoporosis and in children the promotion of optimal growth and development. Enteral nutrition is an effective primary therapy for children with CD but does not have a primary therapeutic role in ulcerative colitis. Corticosteroids, however, are more effective than enteral diet therapy in adults [10, 11].
*Division of Gastroenterology University Hospital Leuven, Herestraat 49., 3000 Leuven, Belgium, Phone: 011 32 16 34 42 25, Fax: 011 32 16 34 43 99, E-mail:
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The nineties have been characterized by the introduction of biological therapies, designed to block or neutralize pro-inflammatory cytokines which play a role in the pathogenesis of the disease. Biologic treatment with the anti-tumour-necrosis-factor-alpha (TNF) antibody infliximab has dramatically changed the therapeutic approach also in paediatric CD. Infliximab is a chimeric monoclonal IgG1 antibody to TNF and is the first biological therapy that was approved for IBD. It is composed of a (±75%) human constant and (±25%) murine variable region. TNF is a prominent pro-inflammatory cytokine. The number of TNF producing cells is greatly increased in the lamina propria in the bowel of patients with CD and increased concentrations of TNF have been found in the stool of children with CD [12–14]. Besides neutralisation of TNF, infliximab also blocks leucocyte migration and induces apoptosis of T-lymphocytes and monocytes [15–19]. The latter is believed to be one of the key mechanisms of action of the drug. A third mechanism of action involves complement fixation and complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) [20]. In this chapter, we will review the general outcomes of infliximab therapy in CD and UC and we will focus on some very important treatment goals which are of specific interest for the paediatric population namely restoration of growth and discontinuation of corticosteroids.
Efficacy of Infliximab in Adult Crohn Disease The pivotal study by Targan et al. clearly showed the superiority of infliximab for the treatment of moderate to severe adult CD [21]. In adults, more than 80% of patients showed clinical improvement 4 weeks after a single infusion of 5 mg/kg infliximab, as compared with 17% of patients treated with a placebo infusion. One third of patients went into remission (defined as a score below 150 on the Crohn Disease Activity Index CDAI), and this was only 4% in the placebo group. The first re-treatment study followed by the large ACCENT 1 study (573 patients included) demonstrated that repeated administration of infliximab every 8 weeks is effective to maintain the initial response and remission [22, 23]. In ACCENT 1, 48% of the patients receiving infliximab as maintenance treatment (5 and 10 mg/kg combined) still had a clinical response at the end of the year, compared to only 17% in patients randomized to the placebo arm. However, many patients in the placebo group were switched to active medication on relapse during the trial, hence representing an episodic treatment schedule. Virtually all corticosteroid-dependent patients could taper and discontinue their steroids completely after a mean of 22 weeks. Endoscopic studies have demonstrated the rapid mucosal and histological healing after infliximab administration [24]. In the long term, systematic 8 weekly treatment with infliximab maintains this healing in 50% of patients, compared to patients treated episodically where only 7% maintained a healed bowel (p=0.007). Given that the clinical symptoms of CD patients in part reflect transmural and/or superficial mucosal inflammation, a treatment which induces healing of the intestinal mucosa may provide particular clinical benefits. If a treatment induces profound and long-lasting mucosal healing, it may reduce complications including need for surgical interventions and therefore it is hypothesised that such a drug could slow down or even stop the progression of the disease. Mucosal healing was associated with a clear trend for reduced hospitalizations in the ACCENT I endoscopic substudy [24]. Patients with complete mucosal healing short term (week 10) and long term (week 54) did not require hospitalization and patients with mucosal healing at only one visit required fewer hospitalizations compared to patients without mucosal healing (18.8% versus 28%). These data are the first to suggest that sustained mucosal healing as introduced by infliximab may lead to fewer complications necessitating hospitalization and that in this way the natural progression of CD could be altered. Besides luminal CD, infliximab has also superiority in healing perianal fistulas. The initial study by Present showed response (defined as ≥ 50% reduction of draining fistulas) in 68% of patients and complete cessation of drainage in 55% of the patients [25]. In the subsequent maintenance
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ACCENT 2 study, the median time to loss of response was significantly longer for patients who received infliximab maintenance (>40 weeks) as compared with those who received placebo maintenance (14 weeks, p<0.001) [26]. At week 54, 23% of patients on placebo maintained a response and 19% a complete response as compared with 46% and 36% respectively for patients maintained on infliximab 5 mg/kg every 8 weeks (both p<0.01). Data on the efficacy of infliximab to change the long-term outcome of fistulizing disease is scarse. Healing of the fistula tracks during therapy with infliximab takes some time and can be followed using MRI and endoscopic ultrasonography [27, 28]. Van Assche et al. reported that although active inflammation associated with fistula tracks improves greatly short term, the fistula tracks persist long term with varying degrees of residual inflammation in patients treated episodically with infliximab for perianal fistulizing disease. Similar findings were reported by Bell et al. [29]. Therefore, long-term treatment plan with maintenance therapy and MRI to guide duration of therapy is necessary.
Efficacy of Infliximab in Paediatric Crohn Disease The first reports on the use of infliximab in paediatric CD showed spectacular results and response and remission rates were superior to data obtained in adults [30–35]. Most of these studies were however small and uncontrolled, and hence susceptible to publication bias. Cezard et al. prospectively treated and followed 21 children with CD (mean age 15 +/– 2 years) who were given a three-dose induction of infliximab 5 mg/kg [35]. Eighteen (86%) children were corticosteroid dependent and 3 were resistant. At week 6, 90% of children were in complete remission and the other 2 children showed improvement. TNF in the stools also decreased significantly. Fourteen children (67%) were able to taper and completely stop steroids at 3 months. In the open-label study by Baldassano et al. all 21 paediatric CD patients experienced approximately 50% improvement in the PCDAI by week 2 [31]. During the study, all patients achieved clinical response, and 10 patients (48%) achieved clinical remission. A Danish study reported outcome of episodic administration of infliximab in 24 children with active CD treated from 1999 to 2003 (median age 15.4 years; range 9.8–18.6 years and median disease duration of 26 (range 0.7–93) months) [36]. Four weeks following the first infusion, response was observed in 75% of patients (33% complete response and 42% partial response). Almost half of the patients needed repeated infusions to maintain remission. There were no serious adverse events. Following these initial promising results in small studies, the REACH study (Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF alpha Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate to Severe Crohn Disease) evaluated the safety and the efficacy of infliximab in paediatric CD [37]. A total of 112 patients (median age 13 years, range 6–17; median disease duration 1.6 years) with moderate to severe CD (defined as a Paediatric Crohn disease activity index (PCDAI) of more than 30 points) despite treatment with immunomodulators all received a three-dose induction scheme of infliximab 5 mg/kg at weeks 0, 2 and 6 and patients who responded were then randomized at week 10 to either 5 mg/kg maintenance every 8 weeks (group 1) or every 12 weeks (group 2) through week 46 and were followed up through week 54 (Figure 31.1). Cross-over to a higher dose of 10 mg/kg was allowed in case of loss of response. The primary endpoint was clinical response at week 10, defined as a decrease from baseline in the PDCDAI of 15 points or more and a total PCDAI of 30 points or less. The results of the induction treatment showed an overall response rate of 88% and remission (defined as a PCDAI score of 10 points or less) in 59% of patients. At week 54, 64% of patients receiving infliximab every 8 weeks were in clinical response and 56% in clinical remission compared with 33% and 23% of patients receiving treatment every 12 weeks.
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All Patients
Week 0 Week 2 Week 6
Infliximab 5 mg/kg
Nonresponders No further infliximab
Responders
Week 10 Infliximab 5 mg/kg q 8 weeks
Infliximab 5 mg/kg q 12 weeks
Week 14 Week 22 Week 30
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LOR<8Wk Infliximab 5 mg/kg q 8 weeks
LOR 8-12WK Infliximab 10 mg/kg q 8 weeks
Week 18
Week 30
Week 38 Week 42 Week 46
Evaluation at Week 54
Figure 31.1. Design of the REACH study in paediatric Crohn’s disease.
This is the first and only study so far comparing q8 weeks to q12 weeks maintenance and showed superiority for the 8-weekly treatment schedule. Restoration of Height with Infliximab in Paediatric CD Impaired linear growth is a common complication of CD in children. The reasons for this are multiple. Cytokines released from the inflamed intestine may directly inhibit and limit growth through interference with insulin-like Growth Factor (IGF-1). Chronic nutritional deficiencies may also limit growth and medications, particularly corticosteroids are associated with growth inhibition. Therefore, restoration or maintenance of growth is a marker of therapeutic success. A number of studies, including REACH, have reported beneficial effects of infliximab in restoring growth and height in children with CD, as early as 6 months after start of therapy [34–35, 38]. An important finding is that weight and height gain are significantly higher in patients on systematic re-treatment than in those treated only with three baseline infusions of infliximab [34]. The effect of infliximab therapy on linear growth was a specific endpoint in the REACH study [38]. Linear growth was measured and prospectively recorded and height but also height velocity (cm/year) was recorded at predefined time points. When looking only at the subgroup of 38 patients with at least one year delay in bone age (measured by wrist X-ray) at the start of the trial, the mean height status Z score significantly improved from –1.5 to +0.3 from week 0 to week 30 (p<0.001) and to 0.5 at week 54 (p<0.001) in the combined infliximab groups. The benefit was greater in the children randomized to the q8 weekly treatment arm (43.5% improvement in Z score by at least 0.5 standard deviation) in contrast to the children randomized to the q12 treatment arm (20% improvement in z score by at least 0.5 standard deviation). Corticosteroid Withdrawal with Infliximab Although corticosteroids are an effective short-term therapy to control active inflammation, they do not maintain remission and are associated with serious side effects. Infliximab is steroidsparing as clearly demonstrated in the adult ACCENT I and II studies. There are also data from paediatric CD that infliximab therapy allows children to wean and completely stop steroids. A retrospective study by Stephens and colleagues of 432 infusions administered to 82 patients showed that 57.6% of children taking corticosteroids (n=33) at the start of infliximab became
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independent and remained free of corticosteroids [39]. Lamireau et al. looked at the outcome of 88 children and adolescents receiving infliximab (39 girls and 49 boys, median age 14 years (range 3.3–17.9)) [32]. Infliximab was indicated for active disease (66%) and/or fistulas (42%) which were refractory to corticosteroids (70%), and/or other immunosuppressive (82%) agents, and/or parenteral nutrition (20%). Patients received 1 to 17 infusions (median 4) of 5 mg/kg of infliximab during a median time period of 4 months (range 1–17 months). At month 3, 78% of patients had a response (49%) or remission (29%). The dosage of corticosteroids decreased from 0.59 mg/kg/day before to 0.17 mg/kg/day 3 months after infliximab (p < 0.001) and 53% of patients could be weaned off corticosteroids and 92% off parenteral nutrition. A more recent prospective multicenter study looked at the 3-month and 1-year outcomes of children with CD treated with corticosteroids within 30 days of diagnosis, and investigated the influence of infliximab on steroid withdrawal [40]. Although at 3 months, 84% of children had a complete (60%) or partial (24%) response, at 1 year and despite concomitant immunomodulators, 31% of children became corticosteroid dependent and 8% required surgery. The authors demonstrated that infliximab improved the outcomes of corticosteroid-dependent/resistant patients since 16/24 (67%) patients who were corticosteroid resistant or dependent could discontinue their corticosterids after starting infliximab therapy. Also, the REACH study showed that infliximab is alowing patients to decrease their dose of corticosteroids. The proportion of patients in the REACH study who, at week 54 were in remission and off steroids was higher in the q8 weeks arm (46%) as compared to the q12 weeks arm (17%). Data in Paediatric CD Show Evidence in Favour of Early Therapy It is clear that altering the natural history of IBD will not merely be achieved by mucosal healing alone. The time of initiation of therapy will be of crucial importance if one takes into consideration that a longer disease duration inevitably leads to more irreversible damage. When comparing the initial response rates from REACH study with those of the adult ACCENT studies, the superior response in children is noted. The reasons for this can be multiple. In the REACH study, the median disease duration was 1.6 years as compared to 7.9 years in ACCENT 1 and 12.3 years in ACCENT 2. There is evidence from previous paediatric studies in CD that more aggressive treatment early in the disease is associated with better response and remission rates. In an Italian study, the best response to infliximab was observed in children with a disease duration of less than one year and 5/6 children with early CD had complete closure of all fistulas following therapy as compared to only 2/7 children with a disease duration of more than one year [41]. A longer sustained remission in children with early CD was also the conclusion of the study by Kugathasan et al. [30]. However, in the REACH study, the clinical response rate of patients with early disease <1 year was equal to the response observed in patients with a disease duration of more than one year. It is therefore possible that children in general respond better than adults. A better response of children to medication is a phenomenon which is known and which is possibly related to a more active adaptive and innate immune system in children. There is an immune senescence in humans, explained by a reduction in the synthesis and release of hormones or neurotransmitters, alterations in the number, density and affinity of receptors and diminished receptor responsiveness [42]. Another reason for the high response rates in the REACH study is the fact that 98% were on concomitant immunomodulators and this is much higher than what was observed in the adult population of ACCENT 1 (29%) and ACCENT 2 (37%). Again, concomitant use of immunomodulators improves clinical efficacy of infliximab in adults [43–46]. The benefit of early therapy with infliximab has been investigated in a Benelux study in adult CD [47]. In this study, patients with early-onset CD were randomized to the classical treatment algorithm which includes first induction of remission with corticosteroids, followed by repeat course of steroids and azathioprine in case of new flares, and eventually infliximab if active
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Year 1
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p = 0.018 20 0 14 20 26 32 38 44 50 56 62 68 74 80 86 92 98 104
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Figure 31.2. Step up top Down study: clinical remission without surgery and off corticosteroids at year 2 [47].
disease under immunomodulator therapy, or a more aggressive first-line treatment where a threecourse induction therapy with infliximab together with azathioprine was initiated. Two years following randomization, complete mucosal healing was observed in 75% in the top down group, compared to only 21% in the step-up treatment arm (Figure 31.2). A similar Top-Down approach was presented by Romeo et al. in paediatric CD patients [48]. This was a retrospective study of 32 children with newly-diagnosed active ileocaecal CD, where 13 patients received infliximab 5 mg/kg body weight at weeks 0-2-6 (Group A, n=13 patients) and 19 traditional treatment regimens for induction (nutritional therapy n=5, corticosteroids (n=14)), together with maintenance therapy with azathioprine. The clinical relapse at one year was much higher in Group B (17/19) as compared to group A (1/13; p<0.01) with also significant lower Crohn disease Endoscopic Index of Severity at one year in Group A (Top down group). More recently, better response and remission rates to certolizumab pegol, a humanized pegylated Fab’ fragment of an anti-TNF monoclonal antibody have been reported in early onset of disease [49]. In the Precise 2 study, the week 26 response increased from 57% over 62% and 75% to 90% for patients with a disease duration >5 years, between 2–5 years, between 1–2 years and <1 year, respectively. The respective numbers for week 26 remission were 44%, 47%, 55% and 68%.
Infliximab for Paediatric Ulcerative Colitis Previously, CD was always seen as a typical Th1-driven disease with high levels of interferon-, TNF and IL-12 and UC as a Th2- disease. However, more recent work has questioned this partition as also INF- and TNF are abundantly present in UC patients. The results of open studies and also the first small randomized-trials with infliximab in adult patients with UC were conflicting and the definitive evidence for the efficacy of infliximab in the treatment of UC was provided by the large ACT 1 and ACT 2 controlled clinical trials [50]. In ACT-1, the clinical response at week 8 (following a three-dose induction with infliximab) was 69% and 62% for patients receiving infliximab 5 and 10 milligrams per kilogram, respectively, compared with 37% of those who received placebo (p<0.002 for both comparisons). In ACT-2, very similar results were obtained with 65% and 69% of patients receiving infliximab 5 and 10 milligrams per kilogram, respectively, in clinical response at week 8, compared with 26 percent of those who received placebo (p<0.001 for both comparisons). In both studies, the proportions of patients who
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achieved clinical response at weeks 8, 30, or 54 (ACT-1) or clinical remission at weeks 30 or 54 (ACT-1) were several-fold higher among infliximab-treated patients than placebo-treated patients. We lack extensive data at present on the colectomy rates following infliximab in UC. This hard endpoint is important, as this could show the major advance of infliximab over older therapies as cyclosporine. In a first investigator-initiated study by Jarnerot et al. infliximab was given as rescue therapy to avoid colectomy in severely active UC patients, necessitating hospitalisation and IV steroid treatment [51]. Seventy-one percent of patients resistant to steroids escaped colectomy at three months when treated with a single infusion of infliximab 5 mg/kg versus 33% of the patients treated with placebo (p=0.017). It is currently unknown if this effect is maintained long-term. The data on the use of infliximab in paediatric ulcerative colitis are still scarce. Edelwein et al. reported the outcome of 12 paediatric patients with UC who received infliximab for the treatment of fulminant colitis (3 patients), acute exacerbation of colitis [3], steroid-dependent colitis [5], and steroid-refractory colitis [1] [52]. Nine patients had a complete short-term response, and 3 had partial improvement. With a median follow-up time of 10.4 months in this study, 3 patients underwent colectomy. In this small series, patients receiving 6-MP had a better response. Another study by Mamula et al. reported the response to infliximab in 9 patients and showed a decrease in the median Lichtiger colitis activity index (LCAI) from 11 to 1, two weeks after a first infusion of infliximab 5 mg/kg body weight (p=0.01) [53]. Concomitant corticosteroids could be discontinued in 6 (66%) patients. After 2-year follow-up 2 patients underwent colectomy [54]. Although these initial results in paediatric UC are promising, larger studies with more extensive follow up are needed to adequately position this drug in also paediatric UC. Does Infliximab Reduce the Number of Surgeries in Paediatric CD? The cumulative incidence of surgery 10 years after diagnosis in CD ranges from 40%–70% in adults. The ACCENT studies showed that infliximab reduces the number of surgeries. In a large paediatric cohort of 989 consecutive CD patients (age 0–17 years at diagnosis), collected from 6 different paediatric centers, 13% of children needed intestinal resection already after a median of 2.8 years, a number which increased to 17% at 5 years and 28% at 10 years from diagnosis [55]. The treatment with infliximab in this cohort was associated with a 64% reduced risk for surgery (OR=0.36; p=0.0005).
Side Effects and Safety Profile of Infliximab Immunogenicity and Autoimmunity One of the most common problems of infliximab includes its chimeric properties and the formation of antibodies (ATI) to the murine portion of the drug. These ATIs are neutralizing and interfere with the safety and efficacy of the drug. ATIs are associated with acute infusion reactions and loss of response and with delayed hypersensitivity phenomena. Acute infusion reactions are manifested by shortness of breath, chest pain, palpitations, flushing, headache, urticaria and hypotension. The prevalence of acute infusion reactions varies greatly between studies depending on the sample size, the dosing regimen (episodic or maintenance) and concomitant therapies, but ranges in most studies between 15–25% (Table 31.1) [23, 32, 37, 56–62]. In the REACH study, 18 patients (16.1%), evenly distributed among both treatment arms, developed infusion reactions and 1 patient had an anaphylaxis in the q8 week treatment arm [37]. Acute infusion reactions are often easily controlled by slowing down (in case of mild) or temporarily stopping (in case of severe) the infusion, followed by administration of antihistamines and/or hydrocortisone. Future infusions are best given with prophylactic hydrocortisone. Delayed infusion reactions or serum sickness-like reactions occur typically 4–9 days after an infusion and are characterized by arthralgias (which often include jaw claudication), back pain,
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Table 31.1. Frequency of different types of infusion reactions. The numbers represent % of patients with the given condition. Reference
REACH* Friesen 2004* Hanauer 2004 Lamireau 2004* Seiderer 2004 Colombel 2004 Miele 2004* Cheifetz 2003 Baert 2003 Crandall 2003* Kugathasan 2002*
n
prospective
Acute infusion reactions (%)
112 111 573 88 100 500 34 165 125 57 86
Yes No Yes No No No Yes Yes Yes No No
16.1** 6.3** 23.2 15.0 NA NA 23.5 9.7 27.0** 38.6 NA
Serious Delayed React resulting acute infusion in treatment infusion reactions (%) Interruption (%) reactions (%) NA NA 3.8 NA 2.0 3.8 2.0 2.4 NA NA 4.7
0 1.8 2.3 NA 1.0 2.8 0.9 1.8 NA 7.0 9.3
0.9 2.8 NA NA 4.8 0 1.2 NA 1.7 NA
* paediatric studies ** all types of infusion reactions grouped
myalgias, fever, skin rash, and leukocytosis. This type of allergic reaction is rare (0–3%) but needs more aggressive therapy with 5 days of oral corticosteroids administered around the infusions (2–3 days before and after). In most cases however, patients will benefit from switching to humanized anti-TNF. There were no delayed type hypersensitivity reactions observed in the REACH study. A large single center safety study was reported by Friesen et al. [57]. The authors performed a retrospective review of 594 infliximab infusions administered to 111 IBD patients at the Children’s Mercy Hospital and Clinics in Kansas City. Most children were treated for CD (n=88) and 23 for UC. There were as many males as females and the mean age was 13.4 years. The mean number of infusions was 5.4 ranging from 1 to 24. Infusion reactions occurred in 8.1% of patients (seven early and two delayed), representing 1.5% of all infusions. Infusion reactions occurred more frequently in female patients (14% versus 2%; p = 0.03) but all were mild and responded rapidly to treatment. The adult study of Baert et al. demonstrated that the formation of ATIs may be suppressed by concomitant therapy with immunosuppressants [56]. In this respect, azathioprine and methotrexate are equally effective [63]. Pretreatment with hydrocortisone has also shown to suppress ATI formation [64], but probably the most efficacious way to prevent immunogenicity is systematic therapy as opposed to episodic therapy [65] (Table 31.2). Most patients who develop ATI with loss of response will benefit from reducing the interval or from switching to humanized or fully human antibodies. In a small series of 8 paediatric CD patients who had lost response to infliximab, a complete response was observed in 50% of patients, a partial response in one and failure in 3 patients [66]. Remission induced with adalimumab was maintained in 6 patients using 40 mg/1.73 m2 q2 weeks. Among adverse events, the authors noted fever and flu-like symptoms with local pain and erythema around the site of injection. During follow up, one patient developed pneumonia and pleural effusion. Another immunologic phenomenon associated to anti-TNF use is the formation of anti nuclear antibodies (ANA) and antibodies to double stranded DNA (anti-dsDNA) after infliximab [67]. More than 50% of patients develop ANA and 25% anti-dsDNA. Development of auto-immunity does not seem to have clinical consequences as drug-induced lupus rarely occurs and has never been associated with major organ damage. No routine screening for ANA should therefore be undertaken in patients treated with infliximab nor is the development of ANAs a reason to
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Table 31.2. Comparison of episodic versus maintenance therapy on response and remission, immunogenicity, mucosal healing, hospitalizations and surgeries. Episodic therapy Response week 30 Remission week 30 Mucosal Healing Normal quality of life (IBDQ >170) Steroid free at week 30 % patients needing hospitalizations % patients needing surgery ATI formation
Maintenance therapy
p value
52% 32% 18% 30%
62% 40% 44% 40%
0.024 0.07 0.041 0.012
29% 38%
44% (5 mg/kg) 47% (10 mg/kg) 24%
0.03 0.01 0.014
7.4%
2.8%
0.01
28%
9% (5 mg/kg) 6% (10 mg/kg)
<0.0001 <0.0001
(adapted from Rutgeerts et al. Gastroenterology 2004, Hanauer et al. Lancet 2002)
discontinue the therapy. The formation of ANA occurs more often in females and is associated with development of papulosquamous or butterfly rash. Infections There is an increased risk of reactivation of latent tuberculosis associated with therapy with anti-TNF, the reason for this being that the human immune system needs TNF to kill intracellular pathogens such as Mycobacterium tuberculosis [68]. The median time from the first infliximab infusion to the onset of symptoms in most reported patients was 123 days. There were a total of 62 reports with tuberculosis as the underlying cause of death. Since the initial reports, educational programs have resulted in a gradual decrease in the reporting rate of tuberculosis. All patients who will undergo treatment with an anti-TNF agent should now be screened for latent tuberculosis. Recommendation for TB screening and treatment are proposed nationally. In patients with signs of earlier TB exposure, prophylactic treatment with INH during the first 6–12 months of infliximab treatment is warranted. Infections occur commonly in patients with chronic diseases treated with several potentially toxic drugs. The Mayo Clinic experience in 500 consecutive patients treated with infliximab showed infections in 8.2% including 20 patients with serious infections: 2 patients had fatal sepsis, 8 had pneumonia (2 were fatal), 6 viral infections, 2 abdominal abscess, one cellulitis and 1 histoplasmosis [59]. In the REACH study, overall infections occurred more frequently in the q8 week arm (73.6%) versus the q12 week arm (38%) [37]. There were 3 children developing pneumonia in the q8 and one child in the q12 week arm. Five patients developed an abscess (4 in the q8 wk maintenance arm). Serious infections were equally distributed among both arms: 3 in the q8 weeks (colitis, pneumonia and furunculosis, adenitis and abscess with MRSA) and 4 in the q12 week arm (abscess, abdominal pain, fever and vomiting, worsening CD and enterocolitis). Two patients developed herpes zoster in the q8 maintenance arm. A recent meta-analysis of patients treated with infliximab for rheumatoid arthritis (RA), showed an increased risk for serious infections with a pooled odds ratio (OR) of 2.0 (95% confidence intervals (CI) 1.3–3.1) [69]. Mainly respiratory tract infections are more common in patients treated with infliximab but these respond well to supportive therapy and antibiotics. Although in the North-American large TREAT safety registry, the unadjusted analysis also showed an increased risk for infection with infliximab use, multivariate logistic regression
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suggested that infliximab was not an independent predictor of serious infections (OR 0.99; 95% CI 0.64–1.54) [70]. Instead, the factors which were independently associated with serious infections included prednisone use (OR 2.21; 95% CI 1.46–3.34; p<.001), the use of narcotic analgesics (OR 2.38; 95% CI 1.56–3.63; p<.001), and moderate-to-severe disease activity (OR 2.11; 95% CI 1.10–4.05; p=.024). The results of the European registry ENCORE are expected soon. Morley and colleagues followed 16 patients receiving infliximab for the occurrence of cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Human Herpes virus 6 (HHV6) infections over a period of 18 months [71]. All received combination of infliximab with AA for their underlying IBD. Scheduled blood tests were performed and viral DNA was extracted and analyzed by quantitative Real Time Taqman PCR to detect CMV, EBV, HHV6 viral load. A quarter of children were not yet on therapy with IFX when infection was detected. However, this increased to 63% following infliximab treatment. In a recent case-control study of all opportunistic infections at the Mayo Clinic between 1998– 2003, it seemed that especially combination of immunosuppressive agents leads to an increased risk [72]. In this study, 100 opportunistic infections were identified. Corticosteroids (OR 3.4; 95% CI 1.8–6.2), azathioprine or 6-mercaptopurine (OR 3.1; 95% CI 1.7–5.5) and infliximab (OR 4.4; 95% CI 1.2–17.1) were all identified as risk factors. The type of infections differed between drugs (more Candida infections with corticosteorids, viral infections with azathioprine and histoplasmosis with infliximab). However, the combination of 2 or 3 immunosuppressive agents greatly increased the risk (OR 12.9 for 2 or more drugs; 95% CI 4.5–37). Taken together, in patients treated with infliximab, caution towards occurrence of infections is needed, especially when patients are also on concomitant corticosteroids and/or immunomodulators. Therefore, corticosteroids should be tapered and stopped as quickly as possible, and azathioprine or 6mercaptopurine can also be stopped safely after an initial period of 6 months, when maintenance therapy with infliximab is continued [73]. Malignancy There were no malignancies reported during the REACH study. However, as in most clinical trials, follow-up might have been too short. Post-clinical trial registries are therefore very important to pick up eventual malignancies developing after end of clinical studies. The TREAT registry did not report an increased risk for malignancies related to the use of infliximab in patients with CD [70]. The safety meta-analysis by Bongartz et al. showed an increased risk for malignancy in patients treated with infliximab for RA, with a pooled OR of 3.3 (95% CI 1.2–9.1) [69]. The risk of malignancies was only increased in patients receiving higher (≥6 mg/kg) doses of anti-TNF (OR 4.3; 95% CI 1.6–11.8) as compared to patients treated with lower doses (≤3 mg/kg) (OR 1.4; 95% CI 0.3–5.7). Although no data in this meta-analysis are given on concomitant therapies or illnesses, nor on subgroups of patients at risk, these figures warrant careful follow up also in patients with CD treated with infliximab. In the adult CD and RA trials 6 lymphomas were diagnosed during a follow-up of 4.148 patient years and this compared to 0 for 691 placebo patient years. All lymphomas occurred in patients treated with concomitant immunosuppression. Four of these lymphomas occurred in patients with RA. It is well known that in RA the background incidence of lymphoma is increased in comparison with the general population. Recently however six cases of hepatosplenic T-cell lymphoma occurring in young individuals with CD following infliximab therapy have been reported [74–75]. Of interest, all patients were on concomitant treatment with azathioprine or 6-mercaptopurine. Five of the six patients were between 12 and 19 years of age (a sixth patient was 31 years old). The same type of lymphoma has also been described (and was fatal) in 3 CD patients on azathioprine monotherapy [76–78]. It is therefore still unclear at present which drug(s) is (are) causal but special attention is certainly needed, and combination therapy of azathioprine and infliximab might be best avoided if possible until a more clear view on this event is obtained.
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Mortality In general, mortality in patients with IBD is mostly the consequence of complications of the disease. The mortality rate in the infliximab trials with 3 years post-study follow up was 1.7% for patients treated with infliximab and 4.2% for placebo treated patients. In post-marketing surveillance infection accounted for 37% of deaths and neoplasms for 23%. Alarming reports on mortality due to infections or lymphomas must be interpreted with caution as a number of patients in such observational studies have often been treated off label for life threatening conditions. In the systematic review of the 500 consecutive patients treated with infliximab at the Mayo Clinic, 5 deaths occurred (1%) that were according to the authors likely or possibly related to infliximab [59]. However, as the authors themselves point out in their discussion, many of these patients nowadays would not be given infliximab. A systematic review of all patients with IBD (n=217) treated with infliximab between 1999 and 2001 in Stockholm County reported similar figures with a mortality rate of 1.2% [79].
Summary The advent of infliximab has been very beneficial for patients suffering from Crohn disease and ulcerative colitis. In children and young adolescents, the short-term response and remission rates are as high as 90 and 60% respectively. Infliximab in children with IBD has shown to be steroid sparing and restores growth, two most important goals of therapy in this patient group. As in the adult situation, systematic maintenance dosing with infliximab infusions every 8 weeks is superior than episodic therapy or even maintenance therapy every 12 weeks in maintaining response and remission. The safety profile of infliximab is overall favourable although continued vigilance especially for the occurrence of infrequent but serious events, including opportunistic infection and lymphomas remains necessary. These risks seem increased especially in patients with concomitant immunosuppressive treatment and/or steroids and in patients receiving higher doses of infliximab. In the near future more humanized anti-TNF antibodies will become available with more convenient route of administration (SC) and lower immunogenicity. The efficacy of these drugs in comparison with infliximab seems similar although data in the paediatric population are scarce. References 1. Burnham JM, Shults J, Semeao E, et al. Body-composition alterations consistent with cachexia in children and young adults with Crohn disease. Am J Clin Nutr 2005; 82:413–20. 2. Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn disease. Gut 1994; 35:360–2. 3. Faubion WA Jr, Loftus EV Jr, Harmsen WS, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001; 121:255–60. 4. Candy S, Wright J, Gerber M, et al. A controlled double blind study of azathioprine in the management of Crohn disease. Gut 1995; 37:674–8. 5. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn disease. Gastroenterology 2000; 119:895–902. 6. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn disease. The North American Crohn Study Group Investigators. N Engl J Med 1995; 332:292–7. 7. Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn disease. North American Crohn Study Group Investigators. N Engl J Med 2000; 342:1627–32. 8. Moskovitz DN, Van Assche G, Maenhout B, et al. Incidence of colectomy during long-term followup after cyclosporine-induced remission of severe ulcerative colitis. Clin Gastroenterol Hepatol 2006; 4:760–5.
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9. Ording Olsen K, Juul S, Berndtsson I, et al. Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample. Gastroenterology 2002; 122:15–9. 10. Griffiths AM, Ohlsson A, Sherman PM, et al. Meta-analysis of enteral nutrition as a primary treatment of active Crohn disease. Gastroenterology 1995; 108:1056–67. 11. Lochs H, Dejong C, Hammarqvist F, et al. ESPEN Guidelines on Enteral Nutrition: Gastroenterology. Clin Nutr 2006; 25:260–74. 12. Reinecker HC, Steffen M, Witthoeft T, et al. Enhanced secretion of tumour necrosis factor-alpha IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn disease. Clin Exp Immunol 1993; 94:174–181. 13. Nicholls S, Stephens S, Braegger CP, et al. Cytokines in stools of children with inflammatory bowel disease or infective diarrhoea. J Clin Pathol 1993; 46:757–760. 14. Breese E, Michie C, Nicholls S, et al. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology 1994; 106:1455–1466. 15. Cornillie F, Shealy D, D’Haens G, et al. Infliximab induces potent anti-inflammatory and local immunomodulatory activity but no systemic immune suppression in patients with Crohn disease. Aliment Pharmacol Ther 2001; 15:463–473. 16. Lugering A, Schmidt M, Lugering N, et al. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn disease by using a caspase-dependent pathway. Gastroenterology 2001; 121:1145–1157. 17. ten Hove T, van Montfrans C, Peppelenbosch MP, van Deventer SJ. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn disease. Gut 2002; 50:206–211. 18. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn disease. Gastroenterology 2003; 124:1774– 1785. 19. Shen C, Maerten P, Geboes K, et al. Infliximab induces apoptosis of monocytes and T lymphocytes in a human-mouse chimeric model. Clin Immunol 2005; 115:250–259. 20. Scallon BJ, Moore MA, Trinh H, et al. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995; 7: 251–9. 21. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn disease. Crohn Disease cA2 Study Group. N Engl J Med 1997; 337:1029–1035. 22. Rutgeerts P, D’Haens G, Targan S, et al. Safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn disease. Gastroenterology 1999; 117:761–769. 23. Hanauer SB, Feagan BG, Lichtenstein GR, et al. ACCENT I Study Group. Maintenance infliximab for Crohn disease: the ACCENT I randomised trial. Lancet 2002; 359:1541–1549. 24. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn disease. Gastrointest Endosc 2006; 63:433–42. 25. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn disease. N Engl J Med 1999; 340:1398–1405. 26. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn disease. N Engl J Med 2004; 350:934–936. 27. Van Assche G, Vanbeckevoort D, Bielen D, et al. Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn disease. Am J Gastroenterol 2003; 98:332–339. 28. van Bodegraven AA, Sloots CE, Felt-Bersma RJ, Meuwissen SG. Endosonographic evidence of persistence of Crohn disease-associated fistulas after infliximab treatment, irrespective of clinical response. Dis Colon Rectum 2002; 45:39–45; discussion 45–46. 29. Bell SJ, Halligan S, Windsor AC, et al. Response of fistulating Crohn disease to infliximab treatment assessed by magnetic resonance imaging. Aliment Pharmacol Ther 2003; 17:387–393. 30. Kugathasan S. Prolonged duration of response to infliximab in early pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2001; 33:S40–43. 31. Baldassano R, Braegger CP, Escher JC, et al. Infliximab (REMICADE) therapy in the treatment of pediatric Crohn disease. Am J Gastroenterol 2003; 98:833–838.
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32. Lamireau T, Cezard JP, Dabadie A, et al. French-speaking group for pediatric gastroenterology nutrition. Efficacy and tolerance of infliximab in children and adolescents with Crohn disease. Inflamm Bowel Dis 2004; 10:745–750. 33. de Ridder L, Escher JC, Bouquet J, et al. Infliximab therapy in 30 patients with refractory pediatric Crohn disease with and without fistulas in the Netherlands. J Pediatr Gastroenterol Nutr 2004; 39:46–52. 34. Borrelli O, Bascietto C, Viola F, et al. Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn disease. Dig Liver Dis 2004; 36:342–347. 35. Cezard JP, Nouaili N, Talbotec C, et al. A prospective study of the efficacy and tolerance of a chimeric antibody to tumor necrosis factors (remicade) in severe pediatric crohn disease. J Pediatr Gastroenterol Nutr 2003; 36:632–6. 36. Wewer V, Riis L, Vind I. Infliximab dependency in a national cohort of children with Crohn disease. J Pediatr Gastroenterol Nutr 2006; 42:40–5. 37. Hyams J, Crandall W, Kugathasan S. Induction and maintenance infliximab therapy for the treatment. Gastroenterol 2007; 132:863–73. 38. Griffiths A, Hyams J, Crandall W et al. Height of growth delayed children with active Crohn disease improves during treatment with infliixmab. Gastroenterol 2006 Suppl; 130:A12. 39. Stephens MC, Shepanski MA, Mamula P, et al. Safety and steroid-sparing experience using infliximab for Crohn disease at a pediatric inflammatory bowel disease center. Am J Gastroenterol. 2003; 98: 104–11. 40. Markowitz J, Hyams J, Mack D, et al. (for the Pediatric IBD Collaborative Research Group). Corticosteroid therapy in the age of infliximab: Acute and 1-year outcomes in newly diagnosed children with crohn disease. Clin Gastroenterol Hepatol. 2006; [Epub ahead of print]. 41. Lionetti P, Bronzini F, Salvestrini C, et al. Response to infliximab is related to disease duration in paediatric Crohn disease. Aliment Pharmacol Ther 2003; 18:425–31. 42. Butcher S, Chahel H, Lord JM. Ageing and the neutrophil: no appetite for killing? Immunology 2000; 100:411–6. 43. Vermeire S, Louis E, Carbonez A, et al. Belgian Group of Infliximab Expanded Access Program in Crohn Disease. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn disease. Am J Gastroenterol 2002; 97:2357–2363. 44. Parsi MA, Achkar JP, Richardson S, et al. Predictors of response to infliximab in patients with Crohn disease. Gastroenterology 2002; 123:707–713. 45. Arnott ID, McNeill G, Satsangi J. An analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn disease. Aliment Pharmacol Ther 2003; 17:1451–1457. 46. Mortimore M, Gibson PR, Selby WS, et al. Early Australian experience with infliximab, a chimeric antibody against tumour necrosis factor-alpha, in the treatment of Crohn disease: is its efficacy augmented by steroid-sparing immunosuppressive therapy? The Infliximab User Group. Intern Med J 2001; 31:146–150. 47. Hommes D, Baert F, Van Assche G, et al. A randomized controlled trial evaluating the ideal medical management for Crohn disease (CD): top-down versus step-up strategies. Gastroenterology 2005; 128: A-577. 48. Romeo E, Viola F, De Angelis G, Vernuccio A, Pannone V, Bizzarri B, Borrelli O, Cucchiara S. Infliximab as a first choice therapy in children with newly diagnosed Crohn’s disease (CD) promotes long-term sustained remission and alters the course of the disease. Gastroenterol 2006 Suppl; 130:A11. 49. WJ Sandborn, JF Colombel, J Panes J, et al. Higher remission and maintenance of response rates with subcutaneous monthly certolizumab pegol in patients with recent-onset crohn disease: Data from PRECiSE 2. 50. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353:2462–76. 51. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005; 128:1805–11. 52. Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis 2005; 11:213–8. 53. Mamula P, Markowitz JE, Brown KA, et al. Infliximab as a novel therapy for pediatric ulcerative colitis. J Pediatr Gastroenterol Nutr 2002; 34:307–11.
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54. Mamula P, Markowitz JE, Cohen LJ, et al. Infliximab in pediatric ulcerative colitis: two-year follow-up. J Pediatr Gastroenterol Nutr 2004; 38:298–301. 55. Gupta N, Cohen SA, Bostrom AG, et al. Risk factors for initial surgery in pediatric patients with Crohn disease. Gastroenterology 2006; 130:1069–77. 56. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn disease. N Engl J Med 2003; 348:601–608. 57. Friesen CA, Calabro C, Christenson K, et al. Safety of infliximab treatment in pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2004; 39:265–9. 58. Seiderer J, Goke B, Ochsenkuhn T. Safety aspects of infliximab in inflammatory bowel disease patients. A retrospective cohort study in 100 patients of a German University Hospital. Digestion 2004; 70:3–9. 59. Colombel JF, Loftus EV Jr, Tremaine WJ, Egan LJ, Harmsen WS, Schleck CD, Zinsmeister AR, Sandborn WJ. The safety profile of infliximab in patients with Crohn disease: the Mayo clinic experience in 500 patients. Gastroenterology 2004; 126:19–31. 60. Miele E, Markowitz JE, Mamula P, Baldassano RN. Human antichimeric antibody in children and young adults with inflammatory bowel disease receiving infliximab. J Pediatr Gastroenterol Nutr 2004; 38:502–8. 61. Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, Plevy S. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003; 98:1315–24. 62. Crandall WV, Mackner LM. Infusion reactions to infliximab in children and adolescents: frequency, outcome and a predictive model. Aliment Pharmacol Ther 2003; 17:75–84. 63. Noman M, Vermeire S, Van Assche G, et al. The effectiveness of immunosuppression to suppress the formation of antibodies to infliximab in Crohn disease. Gastroenterology 2004; 126:A-54–55. 64. Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn disease: a randomized controlled trial. Gastroenterology 2003; 124:917–924. 65. Rutgeerts P, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Hanauer SB. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn disease. Gastroenterology 2004; 126:402–413. 66. Deslandres C, Faure C, Dirks M, et al. Open label experience with adalimumab in pediatric Crohn disease patients who lost response or were intolerant to infliximab. Gastroenterol Suppl 2006; AW1199. 67. Vermeire S, Noman M, Van Assche G, et al. Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn disease: a prospective cohort study. Gastroenterology 2003; 125:32–39. 68. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098–1104. 69. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295:2275–85. 70. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections and mortality in association with therapies for Crohn disease: TREAT registry. Clin Gastroenterol Hepatol 2006; 4:621–30. 71. Morley-Fletcher A, Borrelli O, Viola F, Barbato M, Gaeta A, et al. Outcome of viral infections in children with Inflammatory Bowel Disease (IBD) treated with infliximab and immunosuppressive drugs. PG2–20. 72. Toruner M, Loftus EV, Colombel JF, et al. Risk factors for opportunistic infections in inflammatory bowel diseases: a case-control study. Gastroenterol Suppl 2006; A-71. 73. Van Assche G, Paintaud G, D’Haens G, Baert F, Vermeire S, Noman M, Watier H, Magdelaine C, Rutgeerts P. Continuation of immunomodulators is not required to maintain adequate infliximab efficacy in patients with Crohn disease but may improve pharmacokinetics. Gastroenterol Suppl 2006; 130: A-142. 74. Rosh JR, Gross T, Mamula P, Griffiths A, Hyams J. Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn’s disease: a cautionary tale? Inflamm Bowel Dis 2007; 13:1024–30. 75. Thayu M, Markowitz JE, Mamula P, Russo PA, Muinos WI, Baldassano RN. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr 2005; 40(2):220–2.
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76. Mittal MS, Milner BJ, Johnston PW, Culligan DJ. A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to fludarabine and alemtuzumab. Eur J Haematol 2006; 76:531–4. 77. Navarro JT Ribera JM, Mate JL, et al. Hepatosplenic T-gammadelta lymphoma in a patient with Crohn disease treated with azathioprine Leuk Lymphoma. 2003; 44:531–3. 78. Lemann M, et al. Gastroenterolog Suppl 1998; 114:A1020. 79. Ljung T, Karlen P, Schmidt D, et al. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut 2004; 53:849–53.
32 Biologic Therapies Jeanne Tung∗ and William J. Sandborn
Introduction This chapter will review the use of biologic therapies other than infliximab for the treatment of Crohn disease and ulcerative colitis, with an emphasis on use in pediatric patients (Table 32.1). Included in the review will be information on the mechanisms of action for the various agents (Figure 32.1), efficacy and toxicity. When appropriate, data from clinical trials of these agents in children with dermatologic and rheumatologic disease will be included in order to give the reader the maximum information currently available on the use of these agents in children.
Anti-tumor Necrosis Factor The anti-tumor necrosis factor (TNF)- agents other than infliximab that have been evaluated for the treatment of Crohn disease include adalimumab (D2E7), certolizumab pegol (CDP871), CDP571, etanercept, and onercept. Adalimumab Adalimumab is a fully human IgG1 monoclonal antibody to TNF that fixes complement, mediates antibody-dependent cytotoxicity, and induces T cell apoptosis [1, 2]. It is administered subcutaneously, and has a half-life of 12–14 days. Controlled trials have shown that adalimumab is effective for the treatment of rheumatoid arthritis [3–10], psoriatic arthritis [11], and ankylosing spondylitis [12], and have led to regulatory approval for these indications. In addition, 4 placebocontrolled trials have demonstrated that adalimumab is effective for the induction and maintenance of remission in adult patients with Crohn disease and based on these studies it recently received regulatory approval in the United States for this indication [13–16]. In the CLASSIC I trial, 299 patients with moderate to severe Crohn disease who were naïve to TNF therapy were randomized to receive one of four subcutaneous induction loading dose regimens at weeks 0 and 2: adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. The 40 mg/20 mg loading dose was anticipated to be sub-therapeutic. The adalimumab loading doses of 80 mg/40 mg and 160 mg/80 mg were chosen to achieve adalimumab serum concentrations at week 4 that would be seen at steady state (12–16 weeks) with adalimumab 40 mg every other week and 40 mg weekly, respectively. The rates of remission (Crohn disease
*Mayo Clinic, 200 First Street SW, Rochester, MN 55905, Phone: 507-284-0959, Fax: 507-266-0335, Email:
[email protected]
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Table 32.1. Biotechnology agents currently under investigation for treating inflammatory bowel disease. Anti-tumor necrosis factor
Adalimumab Certolizumab pegol CDP571 Etanercept
Onercept Anti-adhesion
Natalizumab MLN-02 Alicaforsen
Anti-Interleukin 12/23
ABT-874 (J695) CNTO 1275
Anti-interleukin2 receptor (anti-CD25)
Apilimod mesylate (STA-5326) Daclizumab Basiliximab
Miscellaneous
Sargramostim Filgrastim Interleukin 10 Fontolizumab (antiinterferon ) Visilizumab (anti-CD3) RDP58 Abatacept (anti-CTLA-4)
Antagonist to chemokine receptor 9
CCX282-B
Monoclonal antibody
Crohn disease Ulcerative colitis
Pegylated antibody fragment Monoclonal antibody Soluble receptor fusion protein Soluble receptor Monoclonal antibody Monoclonal antibody Antisense
Crohn disease
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Monoclonal antibody Recombinant protein Recombinant protein Recombinant protein Monoclonal antibody
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Crohn disease Ulcerative colitis Crohn disease Ulcerative colitis Crohn disease Ulcerative colitis
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Monoclonal antibody Monoclonal antibody Small molecule
Receptor fusion protein Small molecule
Approved Phase 3
2 2 3 – failed 2 2
2 3 2 – failed 2 –failed 3 3
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Figure 32.1. Novel therapeutic targets in inflammatory bowel disease (IBD). Potential therapies in IBD encompass interventions at a variety of pathways in the inflammatory cascade. These include altering luminal factors, enhancing intestinal repair, augmenting the intestinal innate immune barrier function, inhibiting cell adhesion and blocking cytokine activity. GM-CSF, granulocyte–macrophage colony-stimulating factor; ICAM1, intercellular adhesion molecule 1; IFN, interferon; IL, interleukin; Mø, macrophage cell; PMN, peripheral blood mononuclear cell; SAM, selective adhesion molecule. Reprinted with permission from: Korzenik JR, Podolsky DK. Evolving knowledge and therapy of inflammatory bowel disease. Nature Reviews Drug Discovery 2006;5:197–209.
activity index [CDAI] < 150 points) at week 4 in the adalimumab 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups were 18%, 24%, and 36%, respectively, and 12% in the placebo group [13]. These results demonstrated that 160 mg/80 mg (equivalent to 40 mg weekly dosing) was the optimal induction regimen. Two hundred seventy six of 299 patients enrolled in CLASSIC I continued in the CLASSIC II maintenance trial. All patients received adalimumab 40 mg at week 0 (week 4 of CLASSIC I) and week 2. Fifty five patients who remained in remission at week 0 and 4 were re-randomized to receive adalimumab 40 mg every other week, adalimumab 40 mg every week, or placebo. The rates of remission at week 56 in the placebo, adalimumab 40 mg every other week, and adalimumab every week were 39%, 69%, and 83%, respectively [14]. The remaining 221 patients that did not maintain remission at week 0 and/or week 4 received open-label adalimumab 40 mg every other week, with escalation to weekly doses of 40 mg for flare or non-response. The rates of response (decrease from baseline in the Crohn disease activity index [CDAI] ≥ 70 points) and remission at week 56 were 69% and 44%, respectively. Forty-six percent required dose escalation to adalimumab 40 mg weekly [14]. Concomitant immunodulator therapy did not significantly affect the rates of response and remission [14, 17]. The CHARM trial examined maintenance of remission in patients with moderate to severe Crohn disease who responded to induction therapy with adalimumab, including those who had previously been treated with infliximab (these patients were a mixture of patients who responded to infliximab and stopped therapy, and patients who responded to infliximab and lost response
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or became intolerant). Eight hundred fifty-four patients received open-label adalimumab 80 mg at week 0, then 40 mg at week 2. At week 4, 58% of patients achieved response, and were randomized to receive adalimumab 40 mg weekly, 40 mg every other week, or placebo up to week 56 [15]. Those who had a flare or non-response could switch to open-label 40 mg every other week after week 12. At week 26, the rates of response in the placebo, adalimumab 40 mg every other week, and adalimumab every week groups were 28%, 54%, and 56%, respectively [15]. The rates of remission in the placebo, adalimumab 40 mg every other week, and adalimumab every week groups were 17%, 40%, and 47%, respectively [15]. The rates of response at week 56 in the placebo, adalimumab 40 mg every other week, and adalimumab every week groups were 18%, 43%, and 49%, respectively [15]. The rates of remission at week 56 in the placebo, adalimumab 40 mg every other week, and adalimumab every week were 12%, 36%, and 41%, respectively [15]. There was no statistical significance between the rates of response and remission in the groups randomized to receive adalimumab weekly or every other week. The rates of remission were similar regardless of whether patients received prior infliximab or not, and whether they received concomitant immunosuppressive therapy (azathioprine, 6-mercaptopurine, methotrexate) or not [18]. Of 117 patients with fistulas, complete healing was achieved in 33% of those who received adalimumab, compared to 13% who received placebo [15, 19]. Adalimumab was also steroid-sparing [15, 20]. These results demonstrated that 40 mg every other week was the optimal maintenance regimen, with dose escalation to 40 mg weekly for sustained non-response or loss of response. A pilot study showed that patients who had intolerance to or prior loss of response to infliximab could respond to adalimumab [21]. Twenty-four patients recruited at two centers initially received adalimumab 80 mg at week 0, then 40 mg every other week for 10 weeks. Nineteen patients required dose escalation to 40 mg weekly after week 4 for incomplete response (it should be noted that these patients did not receive a loading dose of adalimumab). Clinical response and remission rates at week 4 were 41% and 12%. Clinical response and remission rates at week 12 were 59% and 29%. Fistula improvement and closure rates at week 4 were 44% and 33%, while rates at week 12 were 56% and 33%. In a similar single-center, open-label study of 13 patients with Crohn disease who had lost response to infliximab, adalimumab was given at a loading dose of 80 mg, followed by 40 mg every other week without dose escalation [22]. Initially, 62% had clinical response, 8% went into clinical remission, and 62% maintained clinical response at a median of 5 months. Another pilot study from the same center demonstrated that patients intolerant to infliximab could be treated with adalimumab [23]. A higher induction dose was used in another open-label multi-center study of 48 patients with Crohn disease who failed or become intolerant to infliximab. Patients were treated with a loading dose of adalimumab 160 mg at week 0 and 80 mg at week 2, then 40 mg every other week for 52 weeks. Subanalyses include 36 patients with moderate to severe disease, and 22 with fistulizing disease. At week 4, 75% of patients with moderate to severe Crohn disease had clinical response, while 42% achieved clinical remission [24]. At week 4, partial and complete closure of fistulas was achieved in 41% and 23% of patients, respectively [25]. These uncontrolled results were recently confirmed in the GAIN trial. The GAIN trial examined maintenance of remission in patients with moderate to severe Crohn disease who had previously responded to infliximab and then lost response or became intolerant [16]. Three hundred twenty-five patients were randomized to receive adalimumab 160 mg at week 0 and 80 mg at week 2 or placebo. At week 4, the rates of response in the placebo and adalimumab 160 mg/80 mg groups were 34% and 52% [16]. The rates of remission in the placebo and adalimumab 160 mg/80 mg groups were 7% and 21%, respectively [16]. In patients with rheumatoid arthritis, the rate of formation of anti-adalimumab antibodies is 5% (1% for patients receiving concomitant therapy with methotrexate and 12% for patients not receiving methotrexate) [26]. The incidence of anti-adalimumab antibodies in the CLASSIC II trial was 3% [14].
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Pediatric Data An open-label study of 9 pediatric patients with Crohn disease who had failed or become intolerant to infliximab has been conducted [27]. All were given an induction regimen of 80 or 160 mg/1.73m2 at week 0, followed by 40 or 80 mg/1.73m2 at week 2. At one month, 50% had complete response, 12.5% partial, and 37.5% failed. Those who responded were maintained on adalimumab 40 mg/1.73m2 every 2 weeks (mean follow-up 3.6 months, range 1.5–8.5). Remission was maintained in 75% of patients. One patient required temporary cessation of adalimumab after developing pneumonia and a pleural effusion. In addition there is a case report of a 15 yr old female with ileocolonic Crohn disease who had an anaphylactoid reaction to infliximab and worsened on etanercept, who had clinical and endoscopic improvement after 12 doses of adalimumab [28]. The results of an open-label study of 171 pediatric patients with juvenile idiopathic arthritis were reported in 2005 at the American Conference of Rheumatology. The patients were maintained on 24mg/m2 every other week, with response achieved 88% of patients given concomitant methotrexate, compared to 69% of patients given methotrexate alone [29]. Another report of adalimumab therapy for the uveitis of childhood has been recently published [30]. Pregnancy Published data on the use of adamimumab in pregnant women is limited to case reports. The initial report was of a woman with Crohn disease who received infliximab during one pregnancy and adalimumab throughout a second pregnancy. Both children were born full term. The second child was delivered via cesareans section due to perianal disease. Both were developmentally normal at 6 months of age [31]. Subsequently, 3 additional pregnancies in patients with Crohn disease have been reported [32–34]. Safety The most common adverse effect in the Phase II and Phase III trials in patients with Crohn disease was localized injection reactions. In patients with rheumatoid arthritis treated with adalimumab, drug-induced lupus, demyelination, lymphoma, and serious and opportunistic infections have all been reported [35]. The serious infections include pneumonia, tuberculosis, histoplasmosis, aspergillosis, and nocardiosis. In clinical trials, infections occurred at a rate of 1 per patient year in adalimumab treated patients and 0.9 per patient year in placebo treated patients [35]. Serious infections occurred at a rate of 0.04 per patient year in adalimumab treated patients and 0.02 per patient year in placebo treated patients [35]. Two patients with Crohn disease in the CHARM trial developed tuberculosis [15]. A recent meta-analysis of serious infection and malignancy rates in patient with rheumatoid arthritis treated with adalimumab and infliximab may have over-estimated the infection rates due to flaws in methodology [36]. In postmarketing surveillance, the rate of serious infections in adalimumab-treated patients was 4.1 per 100 patientyears, which was similar to the general rheumatoid-arthritis population. The rate of tuberculosis in post-marketing surveillance after initiation of TB screening is 0.27 per 100 patient-years. The rate of reported cases of lupus-like syndrome is 0.1 per 100 patient-years. The rate of demyelinating disorders (including multiple sclerosis and Guillain-Barré syndrome) was 0.08 per 100 patientyears. Analysis of the incidence of lymphoma in adalimumab clinical trials, in comparison with that of the normal population in the SEER database, resulted in an SIR of 3.19 (95% CI 1.78 to 5.26). The types of lymphomas include Hodgkin’s disease, B cell lymphoma, T-cell lymphoma, central nervous system lymphoma, and mucosa associated lymphoid tissue (MALT) lymphoma; none of which are predominant [37]. No lupus-like illness has been reported; however, ANA and dsDNA positivity has been reported [4, 5, 9, 14].
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Certolizumab Pegol (CDP870) Certolizumab is a humanized TNF Fab monoclonal antibody fragment linked to polyethylene glycol (PEG) that is administered subcutaneously. In vitro, certolizumab pegol has a high affinity for TNF-, it is devoid of the Fc portion of the antibody and does not induce complement activation or antibody-dependent cellular cytotoxicity, and it does not induce apoptosis in T-cells or macrophages [38–40]. In a placebo-controlled, phase II study, patients with Crohn disease with moderate to severely active Crohn disease were randomized to receive subcutaneous certolizumab pegol 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The response rates in the certolizumab pegol 400 mg group were significantly greater than in the placebo group at 2, 4, 6, and 10 weeks, but not at 12 weeks (which was the primary endpoint of the study) [41]. The best separation of certolizumab pegol treated patients from placebo treated patients occurred in a sub-group of patients with elevated concentrations of C-reactive protein (≥ 10 mg/L) at baseline. Another small phase II study of intravenous certolizumab pegol also failed to achieve the primary endpoint of the study [42]. The PRECiSE trials are phase 3 trials of certolizumab in patients with active Crohn disease. PRECiSE 1 is a randomized, double-blinded induction with a late efficacy measurement (26 weeks) [43]. Six hundred sixty patients were stratified according to their baseline CRP concentration (< 10 mg/L, ≥ 10 mg/L) and use of immunosuppressants and then randomized to receive certolizumab 400 mg subcutaneously or placebo at weeks 0, 2, 4, then every 4 weeks up to 24 weeks. At week 4, in the overall patient population (both CRP < 10 mg/L and ≥ 10 mg/L), there was a higher rate of clinical remission (19.5% versus 11.3%) and clinical response (defined as a ≥ 100 point decrease in the CDAI score from baseline) (28.7% versus 21.8%) in the certolizumab pegol group compared to placebo. At week 26, the rate of clinical response in the certolizumab pegol group was significantly higher than the placebo group (23.1% vs. 16%, respectively), while the rate of clinical remission trended in favor of certolizumab pegol. The co-primary endpoints for the study, clinical response at week 6 and 26, were also significantly greater in the certolizumab pegol group. Median CRP concentrations were significantly reduced in the certolizumab pegol group at weeks 6 and 26. PRECiSE 2 is a randomized, double-blinded maintenance trial after initial open-label induction [44]. In PRECiSE 2, 668 patients with active Crohn disease received openlabel certolizumab 400 mg subcutaneously at weeks 0, 2, and 4 weeks. Those who had clinical response at week 6 (n=428, 64%) were than randomized to receive double-blinded certolizumab 400 mg or placebo every 4 weeks up to week 24. Remission rates at week 26 (after 20 weeks of blinded therapy) were 47.9% in the certolizumab group compared to 28.6% in the placebo group [44]. Pediatric Data There are no published data on the use of certolizumab in children or adolescents. Safety The most common side effect reported in both patients with Crohn disease and rheumatoid arthritis is headache [41–46]. Nasopharyngitis was also common in the Crohn disease trials. [41– 45]. Serious infection occurred in 2–3% of patients treated with certolizumab pegol (including one patient who developed tuberculosis) and ≤ 1% of patients treated with placebo [43, 44]. Malignancy occurred in two patients treated with certolizumab pegol (metastatic lung cancer and adenocarcinoma of the rectum) and two patients treated with placebo (cervical cancer and nonHodgkins lymphoma) [43, 44]. The two deaths that occurred during the PRECiSE trials (fentanyl overdose and myocardial infarction in a patient with metastatic lung cancer) were not thought to be related to certolizumab [43, 44]. No cases of lupus have been reported in any trial. In the PRECiSE trials the proportion of antinuclear antibodies was ≤ 8.3%, with ≤ 1.4% anti-dsDNA [43, 44].
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CDP571 CDP571 is a humanized monoclonal IgG4 antibody to TNF which does not fix complement or mediate antibody-dependent cytotoxicity. A small phase IIa study suggested that CDP571 might be efficacious in patients with active Crohn disease [47]. In, a subsequent phase II study 169 patients with active Crohn disease were randomized to receive an initial dose of CDP571 10 mg/kg or 20 mg/kg, or placebo [48]. At week 2, clinical response was significantly greater in the 10 mg/kg group as compared to placebo, but not the 20 mg/kg group [48]. Patients were then retreated with CDP571 10 mg/kg or placebo either every 8 or 12 weeks over a 24-week period. Significant differences in clinical response or remission over placebo were not achieved. A phase III study compared treatment of 396 patients with active Crohn disease randomized to CDP571 10 mg/kg or placebo every 8 weeks to week 24 [49] CDP571 showed efficacy in achieving a statistically significant clinical response at week 2, but not at week 28. Post-hoc analysis showed that patients with a baseline CRP ≥ 10 mg/L demonstrated higher clinical response over placebo at both week 2 (49.5% vs. 15.5%) and week 28 (28.7% vs. 12.1%) [49]. One study of 82 patients with active Crohn disease showed steroid-sparing effects of CDP571 over placebo at week 16 after an induction dose of 20 mg/kg at week 0, followed by 10 mg/kg dose at week 8 [50]. However, another study of 271 patients comparing CDP571 10 mg/kg or placebo administered every 8 week to week 32 failed to show steroid-sparing benefit in active Crohn disease [51]. Pediatric Data An open-label study was conducted in 20 pediatric patients with active Crohn disease [52]. All were given a single dose of intravenous CDP571 10 mg/kg and were followed for 12 weeks. At week 2, 65% had responded to treatment. Safety Headaches, abdominal pain, and infusion reactions occur most commonly with CDP571. Development of autoantibodies ranged from 2.6–9% [48–51]. Concomitant use of immunosuppressants may reduce the rate of autoantibody formation. Up to 4% of patients may develop anti-dsDNA [48]. Etanercept Etanercept is a fully human recombinant fusion protein comprised of an IgG1 Fc antibody fragment and two soluble p75 receptors to TNF. Etanercept does not fix complement, mediate antibody dependent cellular cytotoxicity, or induce T cell apoptosis. [53] It is administered subcutaneously. Controlled trials have shown that etanercept is effective for the treatment of psoriasis [54–57], psoriatic arthritis [58, 59], rheumatoid arthritis [60, 61], ankylosing spondylitis [62–66], and juvenile rheumatoid arthritis [67], and have led to regulatory approval for these indications. A controlled trial at a dose effective for rheumatoid arthritis (25mg subcutaneously twice weekly) over an 8-week period failed to show efficacy in patients with moderate to severe Crohn disease [68]. Pediatric Data and Safety There are no published data on the safety or efficacy of etanercept in children or adolescents with ulcerative colitis or Crohn disease. Given the lack of efficacy of etanercept for Crohn disease in adults, the dosing of etanercept in children and adolescents with juvenile rheumatoid arthritis and the safety profile of etanercept will not be discussed here.
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Onercept Onercept is a recombinant human soluble p55 TNF receptor. Although an open-labeled pilot study of 2 dosages of onercept in patients with active Crohn disease showed a dose-response effect in rates of remission and response [69], a subsequent phase II placebo-controlled trial failed to demonstrate efficacy over placebo [70].
Anti-adhesion Natalizumab Natalizumab is a humanized IgG4 monoclonal antibody against the adhesion molecule 4 integrin, which is involved in migration of leukocytes across the endothelium, and is up-regulated in sites of inflamed endothelium. It is administered intravenously every 4 weeks. Controlled trials have shown that natalizumab is effective for the treatment of multiple sclerosis [71–73]. It received FDA approval for the treatment of multiple sclerosis in November 2004, was withdrawn from the market in February 2005, and was reintroduced with restrictions for the treatment of multiple sclerosis in September 2006 (see below). Six placebo-controlled trials of natalizumab have been conducted in patients with Crohn disease and one uncontrolled pilot study has been conducted in patients with ulcerative colitis. An initial phase IIa trial in patients with Crohn disease demonstrated a higher rate of clinical remission at week 2 in patients given natalizumab 3mg/kg compared to placebo (39% vs. 8%) [74]. A second larger trial Phase IIb trial compared patients with moderate to severe Crohn disease treated with natalizumab at a single 3mg/kg dose, two 3mg/kg doses given at a 4 week interval, two 6 mg/kg doses at a 4 week interval, or placebo [75]. At 6 weeks, clinical remission occurred in 29% in the natalizumab single dose of 3 mg/kg group, 46% in the natalizumab two doses of 3 mg/kg group, and 31% in the natalizumab two doses of 6 mg/kg group compared to 27% of patients who received placebo [75]. Only the group treated with two doses of natalizumab 3mg/kg had statistically higher rates of remission over placebo. Three Phase III trials have been conducted in Crohn disease. In ENACT-1, 905 patients with moderate to severe Crohn disease were randomly assigned to receive induction therapy at weeks 0, 4, and 8 with either natalizumab 300mg or placebo [76]. At 10 weeks, the rates of clinical remission between the natalizumab and placebo groups (56% vs. 49%, respectively) and clinical response (37% vs. 30%, respectively) were similar (p=0.051). Subgroup analysis demonstrated efficacy in patients with an elevated concentration of C-reactive protein above the upper limit of normal at baseline [76]. In ENACT-2, 339 patients who had a response to natalizumab in ENACT-1 were randomly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56 [76]. At week 60, patients continued on natalizumab sustained higher rates of clinical remission (39% vs. 15%) and clinical response (54% vs. 20%) compared to patients switched to placebo [76]. Concomitant immunosuppressants did not improve the rates of clinical remission or response [77]. Durability of remission was demonstrated in an open label extension trial. In this trial, patients who completed maintained remission over 12 months in the ENACT-2 trial were enrolled into a phase 3, open-label, 2-year study to examine long-term efficacy and safety. Ninety-eight percent of patients were enrolled from the ENACT-2 trial. The rate of remission was 89% after an additional 24 weeks (6 infusions) of natalizumab, and 84% at 48 weeks (12 infusions) [78]. In the ENCORE trial, 509 patients with moderate to severe Crohn disease with elevated C-reactive protein concentrations at baseline were randomized to receive natalizumab 300mg or placebo at weeks 0, 4, and 8 [79]. Four weeks after the first infusion, clinical response was seen in 51% of patients treated with natalizumab and 37% treated with placebo [79]. At week 12, patients treated with natalizumab had higher rates of clinical remission (26% vs. 16%) and clinical response (48% vs. 32%) compared to placebo [79]. A Phase IIa controlled trial of natalizumab 300 mg or placebo every 4 weeks in patients
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with Crohn disease not in remission while receiving infliximab demonstrated good tolerability and possible efficacy in this patient setting [80]. An uncontrolled pilot study of natalizumab in patients with active ulcerative colitis also suggested efficacy [81]. Pediatric Data An open-label study was conducted in 38 pediatric patients with active Crohn disease [82]. All patients were given an induction regimen of natalizumab 3 mg/kg at weeks 0, 4, and 8 [82]. At week 10, 2 weeks after the last infusion; 55% of patients were in clinical response and 29% were in remission [82]. Safety In one study in patients with Crohn disease, 7% of patients given 1 or 2 induction doses of natalizumab (at weeks 0 and 4) had formed anti-natalizumab antibodies at 12 weeks [75]. Patients in the ENACT-2 trial who received concomitant immunosuppressants did not develop persistent anti-natalizumab antibodies, compared to 7.5% of patients who received natalizumab alone [76]. In patients with multiple sclerosis, the rate of formation of anti-natalizumab antibodies was 9%, with persistence in 6% (antibodies detected ≥ 2 times more than 42 days apart) [83]. Clinical trials and marketing of natalizumab were suspended in February 2005 after 2 patients with multiple sclerosis treated with natalizumab and interferon beta-1A developed progressive multifocal leukoencephalopathy (PML) from reactivation of the latent human Jacob Creutzfeldt polyoma virus [84, 85]. A third patient treated with natalizumab and prior exposure to azathioprine was reclassified from malignant astrocytoma to PML [86]. An independent adjudication committee performed a safety evaluation in all patients who had recently been treated with natalizumab in clinical trials [87]. Evaluation consisted of a referral to a neurologist, brain magnetic resonance imaging, and polymerase chain reaction analysis of cerebral spinal fluid and serum for JC virus. Of 3826 initial patients enrolled in clinical trials of natalizumab, safety evaluation included 87% (1,275), 91% (2,248), and 92% (296) of patients with Crohn disease, multiple sclerosis, and rheumatoid arthritis. No additional cases of PML were identified [87]. The median duration of treatment for all patients was 17.9 months, while that of patients with Crohn disease was 7 months. The absolute risk of developing PML during treatment with natalizumab was 1:1000 (0.1%) with 95% confidence intervals of 1:200–1:2800 [87]. The FDA re-approved natalizumab for multiple sclerosis in September 2006, with the requirement of mandatory participation in a risk management and registry program called the TOUCH program [83]. Natalizumab is currently under regulatory review for the treatment indication of Crohn disease. MLN02 MLN02 is an IgG1 humanized monoclonal antibody against the adhesion molecule 47 integrin. The Fc receptor recognition and binding sites are deleted, preventing complement fixation and subsequent cytokine release. It is administered intravenously every 4 weeks. A phase II study of MLN02 in 185 patients with active Crohn disease showed a significant difference in remission as compared with placebo at 8 weeks at a dose of 2mg/kg, and a trend toward a greater response rate that did not reach statistical significance [88]. A small phase IIa study indicated that MLN-02 might be effective for the treatment of active ulcerative colitis [89]. A phase II study of MLN02 in 181 patients with active ulcerative colitis was conducted in which patients were randomized to receive MLN02 at 0.5 mg/kg, 2 mg/kg, or placebo on day 1 and day 29 [90]. Patients took either concomitant mesalamine or no other treatments. At week 6, the rates of clinical remission for the MLN-02 at 0.5 mg/kg, 2mg/kg compared to placebo were 33%, 32%, and 14%, respectively. Clinical response rates in the same groups were 66%, 53%, and 33% [90]. Endoscopic remission at week 6 was 28% in the MLN02 at 0.5 mg/kg, 12% in the MLN02 at 2 mg/kg, and 8% in the placebo group [90].
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Pediatric Data There are no published data on the use of MLN-02 in children or adolescents. Safety No significant differences in adverse events over placebo were reported in the phase II studies of MLN02 for Crohn disease or ulcerative colitis. One patient developed a primary cytomegalovirus infection, there were no malignancies or deaths [88–90]. Antibodies developed in 44% of the patients treated with MLN02, and one person had an infusion reaction with angioedema. Twenty-four percent of patients developed antibody titers greater than 1:125, and had lower rates of clinical remission [90]. Alicaforsen (ISIS 2302) Alicaforsen (ISIS 2302) is a 20 base phosphorothioate oligodeoxy-nucleotide that hybridizes to a sequence in the 3’ untranslated region of inter-cellular adhesion molecule 1 (ICAM-1) mRNA. The translated oligonucleotide-RNA serves as a substrate for the nuclease RNase-H, an ubiquitous intracellular endoribonuclease that recognizes DNA:RNA heteroduplexes as substrate for selective RNA hydrolysis. This results in reduction of ICAM-1 RNA expression and protein levels. Intravenous, subcutaneous, and rectal enema formulations have been studied. A phase IIA trial suggested that intravenous alicaforsen might be efficacious in patients with active Crohn disease [91]. Subsequent phase II and III studies with subcutaneous and intravenous formulations did not show significant rates of clinical remission or response [92, 93]. Subgroup analysis of the phase III trial of intravenous alicaforsen and a subsequent phase IIa dose ranging pilot study suggested efficacy with higher dosing of alicaforsen [93, 94], but two subsequent phase III trials failed to demonstrate efficacy [95]. A phase II trial for patients with active rheumatoid arthritis given 13 infusions of ISIS 2302 over a 4-week period failed to show efficacy over placebo [96]. Phase IIa pilot studies reported that alicaforsen administered as an enema might be effective for the treatment of chronic pouchitis [97], and active distal ulcerative colitis [98]. A subsequent Phase IIa placebo controlled trial also suggested that alicaforsen enemas might be an effective treatment for active distal ulcerative colitis [99]. A Phase II study of alicaforsen enemas was conducted in 112 patients with active left-sided ulcerative colitis compared placebo to four treatment regimens of alicaforsen over a 6 week period—120 mg daily for 10 days, then every other day; 240 mg every other day; 240 mg daily for 10 days, then every other day; and 240 mg daily [100]. At 6 weeks, there was no significant difference in the mean percentage change of Disease Activity Index between placebo and the alicaforsen treatment arms. However, a higher percentage of prolonged clinical improvement was seen in the group that received alicaforsen 240 mg daily compared to placebo at week 18 (51% vs. 18%) and week 30 (50% vs. 11%) [100]. Another Phase II study compared 2 dosages of daily alicaforsen enemas (120 mg and 240 mg) to mesalamine 4 gm over a 6 week period in 190 patients with mild to moderate left-sided ulcerative colitis [101]. At week 6, there was no difference in clinical response between the three groups. However, at week 18, the rate of clinical remission was higher in the alicaforsen 240 mg group than placebo (20% vs. 6%) [101]. Safety Infusion-site and hypersensitivity reactions were the most common side effects of intravenous alicaforsen. Reported infections included abscesses, bronchitis, pharyngitis, and upper respiratory infections [91–95]. Transient elevations of mean activated partial thromboplastin time have been reported [96]. Gastrointestinal complaints are associated with the alicaforsen enemas in a dose-dependent fashion. Community-acquired pneumonia and sinusitis were also reported [97–101].
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Anti-interleukin 12/23 Interleukin-12 and interleukin-23 are key pro-inflammatory cytokines involved in type 1 helper T (Th1) cell response which is characterized by a marked accumulation of macrophages making interleukin-12, the major Th1-inducing factor, in Crohn disease mucosa [102, 103]. A recent genome wide association study demonstrated a highly significant association between Crohn disease and ulcerative colitis and the interleukin 23 receptor gene on chromosome 1p31, which encodes a subunit of the receptor for interleukin-23 [104]. ABT-874 (J695) Anti-interleukin 12/23 p40 Subunit Antibody ABT-874 (J695) is a human IgG1 monoclonal antibody to the interleukin-12/23 p40 subunit. A Phase II trial of ABT-874 was conducted in 79 patients with active Crohn disease [105, 106]. Patients were randomized to receive seven weekly injections of ABT-874 at 1 mg/kg, 3 mg/kg, or placebo. In addition, there was a four-week interval between the first 2 injections in one group (Cohort 1), and no interruption in a second cohort (Cohort 2). There was no significant difference between the placebo group and the ABT-874 groups in Cohort 1. In the groups that received uninterrupted treatment (Cohort 2), the clinical response rates after 7 injections was 25% for placebo, 27% in the 1 mg/kg group, and 75% in the 3 mg/kg group. The clinical rates of remission were 0% for placebo, 8% for 1 mg/kg, and 38% for 3 mg/kg. However, at week 18 of the follow-up phase, the rates of clinical response and remission were not statistically significant [105, 106]. The most common adverse reactions with ABT-874 were localized site reactions. No serious infections were reported. Hyperuricemia and hyperamylasemia were reported, but did not result in study withdrawal [105]. Three patients had anti-drug antibodies detected; one had antibodies detected prior to treatment. All three had low serum ABT-874 serum concentrations and rapid clearance of ABT-874 [105]. CNTO 1275 Anti-interleukin 12/23 p40 Subunit Antibody CNTO 1275 is a fully human IgG1 monoclonal antibody to the interleukin-12/23 p40 subunit. Phase IIa and II studies have demonstrated efficacy in psoriasis [107, 108, 109] and safety and possible efficacy in multiple sclerosis [110]. A Phase II trial of CNTO 1275 was conducted in patients with active Crohn disease [111]. A total of 104 patients with moderate to severe Crohn Disease despite treatment with 5-ASA, antibiotics, corticosteroids, infliximab, and/or immunomodulators (Population 1) were randomized to 1 of 4 groups. Group 1: subcutaneous placebo at weeks 0, 1, 2, 3, and subcutaneous CNTO 1275 (90mg) at weeks 8, 9, 10, 11. Group 2: subcutaneous CNTO 1275 (90mg) at weeks 0, 1, 2, 3, and placebo at weeks 8, 9, 10, 11. Group 3: intravenous placebo at week 0 and intravenous CNTO 1275 (4.5mg/kg) at week 8. Group 4: intravenous CNTO 1275 (4.5mg/kg) at week 0 and intravenous placebo at week 8. At total of 27 patients who previously failed to respond or lost response to infliximab (Population 2) were randomized to open-label therapy with subcutaneous CNTO 1275 (90mg) at weeks 0, 1, 2, 3, (Group 5) or intravenous CNTO 1275 (4.5mg/kg) at week 0 (Group 6). The primary endpoint was clinical response at week 8 for Population 1 (subcutaneous and intravenous combined). At week 8, 49.0% of patients in Population 1 receiving CNTO 1275 were in clinical response versus 39.6% who received placebo (p=0.34). At week 4 and at week 6, 52.9% of patients receiving CNTO 1275 were in clinical response versus 30.2% receiving placebo (p=0.02). 49.0% of patients receiving CNTO 1275 were in response at week 8 using >100 point CDAI reduction vs. 30.2% receiving placebo (p=0.05). For patients with prior infliximab experience in Population 1 (n=49), 59.1% receiving CNTO 1275 were in clinical response at
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week 8 versus 25.9% receiving placebo (p=0.02). In Population 2, clinical response rates at week 8 for CNTO 1275 were 42.9% (SC) and 53.8% (IV), respectively. In the Phase II trial in patients with Crohn disease, similar proportions of adverse events were reported for CNTO 1275 and placebo [111]. No serious infections occurred in Population 1; two occurred in Population 2: disseminated histoplasmosis [in a patient receiving prednisone (80 mg/d), azathioprine and approximately 3 years prior infliximab use] and food poisoning [111]. Three patients experienced injection site reactions in both of the CNTO 1275 and placebo groups [111]. Apilimod Mesylate (STA-5326) Apilimod mesylate (STA-5326) is a small molecule that inhibits interleukin-12 and interleukin-23 through the prevention of nuclear translocation of c-Rel. A Phase IIa trial of apilimod mesylate in patients with active Crohn disease suggested efficacy [112]. An additional Phase II trial in patients with Crohn disease has been completed but to date the results have not been made public.
Anti-interleukin-2 Receptor (Anti-CD25) Daclizumab Daclizumab is a humanized IgG1 monoclonal antibody directed against the -chain of interleukin2 receptor (CD25). Administered intravenously, it has been used for the prevention of renal allograft rejection. A Phase IIa pilot study in patients with active ulcerative colitis suggested efficacy [113]. A Phase II controlled trial in 159 patients with moderate to severe active ulcerative colitis failed to show efficacy over placebo [114]. Although this trial included children as young as 12 years of age, details of pediatric outcomes were not reported [114]. No opportunistic infections, malignancies, or deaths were reported [114]. Basiliximab Basiliximab is a chimeric IgG1 monoclonal antibody directed against the -chain of interleukin-2 receptor (CD25). Administered intravenously, it has been used for the prevention of renal allograft rejection. A Phase IIa pilot study in patients with active steroid-refractory ulcerative colitis suggested efficacy [115, 116]. A Phase II placebo-controlled trial in patients with moderate to severe steroid-refractory ulcerative colitis is currently underway.
Miscellaneous Biotechnology Agents Sargramostim (GM-CSF) The gut inflammation seen in Crohn disease is phenotypically similar to chronic granulomatous disease, glycogen storage disease, and Chediak-Higashi syndrome [117, 118]. In these disorders, sargramostim (granulocyte macrophage-colony stimulating factor [GM-CSF]) has been beneficial. It is a myeloid growth factor involved in development and function of phagocytic cells, and is expressed on CD4+ T cells and Paneth cells in the intestines. It is administered subcutaneously. A phase IIA pilot study suggested that sargramostim might be effective for the treatment of active Crohn disease [119]. A Phase II controlled trial (NOVEL-1) in 125 patients with active Crohn disease randomized to sargramostim 6mcg/kg or placebo for eight weeks showed higher rates of clinical remission (40 vs. 19%) and response (48% vs. 26%) [120]. These patients did not receive concomitant steroids, immunosuppressive agents, or infliximab [119, 120]. A Phase II
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placebo-controlled trial (NOVEL-2) demonstrated that sargramostim may be effective for steroid sparing in patients with steroid dependent Crohn disease [121]. A Phase III placebo-controlled trial designed to demonstrated that sargramostim could be used to re-induce remission in patients who had previously responded to open-label treatment with sargramostim and then relapsed (NOVEL-3) was discontinued prematurely. A Phase III placebo-controlled trial (NOVEL-4) failed to demonstrate efficacy for patients with active Crohn disease who were not receiving concomitant steroids, immunosuppressive agents, or infliximab [122]. Safety Injection site and bone pain are the most common adverse events. In the phase II trial, one patient developed hemiparesis consistent with a stroke syndrome and another patient died from mesenteric ischemia. The rate of neutralizing antibodies was 1% [120]. Filgastrim (G-CSF) Filgastrim (granulocyte-colony stimulating factor [G-CSF]) is used to increase the leukocyte count. Through inhibition of IL-12R2 expression and subsequent reduction of IL-12, it may influence antigen presenting cells to induce a T-helper 2 response. This would decrease the abnormal T-helper 1 response seen in Crohn disease. It is administered subcutaneously. An open-label study of 9 patients given filgramostim 5 mcg/kg subcutaneously for 29 days showed that 6 of 9 (67%) had clinical response and 2 of 9 (22%) achieved clinical remission that was durable by 24 weeks [123]. Clinical response was associated with increased production of IL-10 production. Another open-label study of 20 patients with moderate to severe Crohn disease showed efficacy with filgramostim 300 mcg daily over 12 weeks. Doses were adjusted to achieve a neutrophil count between 25 and 35 × 10 (9) [124]. At week 12, 55% achieved clinical response and 25% achieved clinical remission [124]. Safety Mild bone pain with filgramostim has been reported. Pediatric Data Successful treatment of perianal fistulae with filgramostim in a teenage boy with Crohn disease has been reported [125]. Interleukin 10 Interleukin-10 is secreted by T helper cells, B cells, monocytes, macrophages, dendritic cells and keratinocytes. It suppresses inflammation by reducing HLA class I expression, decreasing secretion of IL-2, and diminishing production of IL-1, Il-1, IL-6, IL-8, and TNF-. The recombinant human rHuIL-10 may be administered subcutaneously, intravenously, or orally via a genetically modified Lactococcus lactis (LL-Thy12) in which the thymidylate synthase gene is replaced with a synthetic sequence encoding mature human interleukin-10. Interleukin-10 has shown efficacy in treatment of chronic hepatitis C [126], and modest improvement in skin but not arthritic manifestations of psoriasis in a Phase II trial [127]. Openlabel and Phase I trials in patients with rheumatoid arthritis failed to show clinical efficacy or decrease in inflammation from synovial biopsies [128, 129]. A Phase IIa study suggested that intravenous rhuIL-10 might be efficacious for the treatment of active Crohn disease [130]. A subsequent Phase II trial in 95 patients with mild to moderate Crohn disease randomized patients to receive subcutaneous rhuIL-10 at one of four dosages (1, 5, 10, or 20 mcg/kg) or placebo daily for 28 days. At 20 weeks, only the group that received 5 mcg/kg had
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statistically significant rates of clinical remission over placebo (23.5% vs. 0%) [131]. A Phase III trial of 329 patients with moderate to severe Crohn disease randomized patients to receive one of four dosages (1, 4, 8, or 20 mcg/kg) or placebo daily for 28 days. At the end of therapy, rHuIL-10 was not efficacious in clinical remission. The group that received 8 mcg/kg/day had a trend toward clinical remission (46% vs. 27%) [132]. A subsequent Phase III studied did not demonstrate efficacy for rhuIL-10 in patients with steroid dependent and steroid refractory Crohn disease [133]. There is some evidence that IL-10 at higher doses may increase the production of IFN-, in turn increasing proinflammatory cytokines TNF-, IL-1 and increasing nitric oxide production [134]. Subcutaneous rHuIL-10 was not efficacious in preventing postoperative endoscopic recurrence of Crohn disease over placebo, either when given at 4 mcg/kg daily or 8 mcg/kg twice weekly over 12 weeks [135]. Successful treatment of a murine model of colitis with Lactococcus lactis secreting interleukin-10 has been reported [136]. Methods for biological containment and formulation for delivery to the human intestine have been developed [137–139]. A pilot Phase Ia study has demonstrated the feasibility of orally administering a genetically modified Lactococcus lactis (LL-Thy12) in which the thymidylate synthase gene is replaced with a synthetic sequence encoding mature human interleukin-10 to patients with active Crohn disease [140]. Additional studies of the treatment of inflammatory bowel disease using this approach are planned. Safety Reversible anemia and thrombocytopenia are common, as are mild-to moderate headaches, fever, back pain, diarrhea, arthralgias, and dizziness. Antibodies to IL-10 have not been detected [132, 135]. Fontolizumab (Anti-interferon ) Fontolizumab is a humanized antibody directed against interferon-. It is administered intravenously. Phase II studies of fontolizumab in patients with active Crohn disease failed to demonstrate efficacy, but each had high placebo response rates. A subgroup of patients in one study suggested benefit with multiple infusions at higher dosages [141, 142]. Safety Adverse reactions to fontolizumab include chills, headache, flu-like symptoms, nausea and vomiting. One case each of herpes zoster and condyloma acuminata were reported [142]. No deaths or malignancies occurred in the phase 2 studies. Development of anti-fontolizumab antibodies was transient [141, 142]. Visilizumab (Anti-CD3) Visilizumab is a humanized IgG2 anti-CD3 antibody that induces activated T cell apoptosis. It is administered intravenously. A Phase IIa study of visilizumab 10 or 15 mcg/kg on two consecutive days in hospitalized patients with severe steroid-refractory ulcerative colitis suggested efficacy and indicated that 15 mcg/kg might be associated with dose-limiting toxicity (cytokine release syndrome) [143]. A Phase II dose -finding study of visilizumab in the same patient population was subsequently conducted [144]. Patients were administered 2 doses on consecutive days at doses of 5 mcg/kg, 7.5 mcg/kg, 10 mcg/kg, or 12.5 mcg/kg. Fifty-six of 71 patients showed both clinical and histological response. The response rates were similar in all four treatment groups. Phase III trials of visilizumab in hospitalized patients with severe steroid-refractory ulcerative colitis are currently underway. A Phase IIa study in patients with active Crohn disease suggested possible efficacy [145].
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Safety A moderate cytokine-release syndrome has been reported in a majority of patients in the Phase 1 study. Transient elevations of transaminases has been reported [143–145]. RDP58 RDP58 (delmitide acetate) is a protease resistant decapeptide that prevents the formation of the MyD88/IRAK/TRAF6 protein complex, preventing the activation of the IB, JNK and p38 map kinase pathways. This ultimately inhibits synthesis of NFB, TNF-, gamma interferon, and interleukin 12. A Phase II study of RDP58 studied 127 patients with active ulcerative colitis over a period of 4 weeks. Of three doses (100mg, 200mg, or 300mg), significant clinical response was seen at week 4 in the two higher doses over placebo (71%, 72%, and 43%, respectively) [146]. A Phase II study of RDP58 in patients with active Crohn disease failed to demonstrate efficacy [147]. Abatacept (CTLA-4 Fusion Protein) Abatacept is a fusion protein consisting of the extracellular domain of human soluble CTLA-4 linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Abatacept is dosed intravenously every 2–4 weeks. Phase II and III studies have demonstrated efficacy of abatacept for the treatment of rheumatoid arthritis [148–152]. Phase III studies of abatacept in patients with moderate to severe ulcerative colitis and Crohn disease are currently ongoing. Interestingly, one case report detailed the new onset of ulcerative colitis in a patient undergoing treatment with abatacept for another indication [153]. CCX282-B (Antagonist to Chemokine Receptor 9) Chemokines are cytokine proteins expressed in lymphoid and nonlymphoid tissue, thought to be involved in leukocyte trafficking. Their effects are mediated by g-protein coupled transmembrane receptors, which are classified by cysteine residues. Persistent, aberrant leukocyte chemotaxis to inflamed mucosa is thought to play a role in the pathogenesis of inflammatory bowel disease. Increased expression of several chemokines has been reported in patients with ulcerative colitis and Crohn disease. Abnormal chemokine receptor 7 (CCR7) expression has been found in inflamed intestinal tissue of patients with inflammatory bowel disease. Abnormal chemokine receptor 9 (CCR9) expression is localized to inflamed small bowel. A Phase II placebo-controlled trial of an oral highly-specific antagonist to CCR9 (CCX282-B) suggested efficacy in patients with active Crohns’s disease [154]. References 1. Shen C, Assche GV, Colpaert S, Maerten P, Geboes K, Rutgeerts P, Ceuppens JL. Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Alimentary Pharmacology & Therapeutics 2005;21:251–8. 2. Shen C, Van Assche G, Rutgeerts P, Ceuppens JL. Caspase activation and apoptosis induction by adalimumab: demonstration in vitro and in vivo in a chimeric mouse model. Inflammatory Bowel Diseases 2006;12:22–8. 3. den Broeder A, van de Putte L, Rau R, Schattenkirchner M, Van Riel P, Sander O, Binder C, Fenner H, Bankmann Y, Velagapudi R, Kempeni J, Kupper H. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. J Rheumatol 2002;29:2288–98.
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4. van de Putte LB, Rau R, Breedveld FC, Kalden JR, Malaise MG, van Riel PL, Schattenkirchner M, Emery P, Burmester GR, Zeidler H, Moutsopoulos HM, Beck K, Kupper H. Efficacy and safety of the fully human anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study. Annals of the Rheumatic Diseases 2003;62:1168–77. 5. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial. Arthritis Rheum 2003;48:35–45. 6. Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, Teoh LS, Velagapudi RB, Noertersheuser PA, Granneman GR, Fischkoff SA, Chartash EK. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clinical Therapeutics 2003;25:1700–21. 7. Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). Journal of Rheumatology 2003;30:2563–2571. 8. van de Putte LB, Atkins C, Malaise M, Sany J, Russell AS, van Riel PL, Settas L, Bijlsma JW, Todesco S, Dougados M, Nash P, Emery P, Walter N, Kaul M, Fischkoff S, Kupper H. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Annals of the Rheumatic Diseases 2004;63:508–16. 9. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis & Rheumatism 2004;50:1400–11. 10. Rau R, Simianer S, van Riel PL, van de Putte LB, Kruger K, Schattenkirchner M, Allaart CF, Breedveld FC, Kempeni J, Beck K, Kupper H. Rapid alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous administration of adalimumab in combination with methotrexate. Scandinavian Journal of Rheumatology 2004;33:145–53. 11. Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH, Sharp JT, Ory PA, Perdok RJ, Weinberg MA, Adalimumab Effectiveness in Psoriatic Arthritis Trial Study G. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a doubleblind, randomized, placebo-controlled trial. Arthritis & Rheumatism 2005;52:3279–89. 12. van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BA, Braun J, Dougados M, Reveille JD, Wong RL, Kupper H, Davis JC, Jr., Group AS. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis & Rheumatism 2006;54:2136–46. 13. Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, Panaccione R, Wolf D, Pollack P. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn disease: the CLASSIC I trial. Gastroenterology 2006;130:323–333. 14. Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, Panaccione R, Wolf D, Kent JD, Bittle B, Li J, Pollack PF. Adalimumab for maintenance treatment of Crohn disease: results of the CLASSIC II trial. Gut 2007;56(9):1232–9. 15. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, Schreiber S, Byczkowski D, Li J, Kent JD, Pollack PF. Adalimumab for maintenance of clinical response and remission in patients with Crohn disease: the CHARM trial. Gastroenterology 2007;132:56–65. 16. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, D’Haens G, Rosenfeld MR, Kent JD, Pollack P. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Annals of Internal Medicine 2007;146(12):829–38. 17. Panaccione R, Hanauer SB, Fedorak R, Rutgeerts P, Sandborn WJ, Pollack P. Concomitant immunosuppressive and adalimumab therapy in Crohn disease: 1-year results of the Classic II study. Gastroenterology 2006;130(Suppl 2):A-479.
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18. Hanauer SB, D’Haens GR, Colombel JF, Sandborn WJ, Kent JD, Pollack PF. Sustained clinical remission in patients with moderate to severe Crohn disease with adalimumab, regardless of antiTNF history or concomitant immunosuppressant therapy. American Journal of Gastroenterology 2006;101:S457 (Abstract 1173). 19. Schwartz D, Rutgeerts P, Colombel JF, Sandborn WJ, Hanauer SB, Kent JD, Pollack PF. Induction, maintenance, and sustainability of the healing of draining fistulas in patients with Crohn disease treated with adalimumab: results of the CHARM study. American Journal of Gastroenterology 2006;101:S458–459 (Abstract 1177). 20. Hanauer SB, Kamm MA, Colombel JF, Sandborn WJ, Rutgeerts P, Kent JD, Pollock PF. Sustained steroid-free clinical remission in patients with moderate to severe Crohn disease treated with adalimumab. American Journal of Gastroenterology 2006;101:S460 (Abstract 1181). 21. Sandborn WJ, Hanauer S, Loftus EV, Tremaine WJ, Kane S, Cohen R, Hanson K, Johnson T, Schmitt D, Jeche R. An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn Disease. American Journal of Gastroenerology 2004;99:1984–1989. 22. Papadakis KA, Shaye OA, Vasiliauskas EA, Ippoliti A, Dubinsky MC, Loane J, Paavola J, Lee SK, Price J, Targan SR, Abreu MT. Safety and efficacy of adalimumab (D2E7) in Crohn disease patients with an attenuated response to infliximab. American Journal of Gastroenterology 2005;100:75–79. 23. Youdim A, Vasiliauskas EA, Targan SR, Papadakis KA, Ippoliti A, Dubinsky MC, Lechago J, Paavola J, Loane J, Lee SK, Gaiennie J, Smith K, Do J, Abreu MT. A pilot study of adalimumab in infliximab-allergic patients. Inflammatory Bowel Diseases 2004;10:333–338. 24. Gassull MA, Hinojosa J, Garcia S, Bastida G, Saro C, Cabriada JL. Efficacy and safety of 4 weeks of adalimumab treatment in subjects with active luminal Crohn disease who lost response or showed intolerance to infliximab. Gastroenterology 2006;130(Suppl 2):W1197. 25. Gomollan F, Hinojosa J, Nos P, Penate M, Ceballos D, Gassull M. Four-week results of adalimumab treatment in subjects with fistulizing Crohn disease who have failed response or showed intolerance to infliximab. Gastroenterology 2006;130(Suppl 2):A-815. 26. Prescribing information for Humira (adalimumab). Package Insert 2004. 27. Deslandres C, Faure C, Dirks MH, Gervais F, Seidman EG. Open label experience with adalimumab in pediatric Crohn disease patients who lost response or were intolerant to infliximab. Gastroenterology 2006;130:A-656 Abstract W1199. 28. Mian S, Baron H. Adalimumab, a novel anti-tumor necrosis factor-alpha antibody in a child with refractory Crohn disease. Journal of Pediatric Gastroenterology and Nutrition 2005;41:357–359. 29. Lovell D, Ruperto N, Cuttica R, et al. Comparison of safety, efficacy and pharmacokinetics for 3 and 6mg/kg infliximab plus methotrexate therapy in JRA patients. Arthritis & Rheumatism 2005;52 (Suppl):S724. 30. Biester S, Deuter C, Michels H, Haefner R, Kuemmerle-Deschner J, Doycheva D, Zierhut M. Adalimumab in the therapy of uveitis in childhood. The British Journal of Ophthalmology 2007;91:319–324. 31. Vesga L, Terdiman JP, Mahadevan U. Adalimumab use in pregnancy. Gut 2006;54:890. 32. Sanchez Munoz D, Hoyas Pablos E, Ramirez Martin Del Campo M, Nunez Hospital D, Guerrero Jimenez P. Gestacion a termino en paciente con enfermedad de Crohn en tratamiento con adalimumab. Gastroenterologia y Hepatologia 2005;28:435. 33. Mishkin DS, Van Deinse W, Becker JM, Farraye FA. Successful use of adalimumab (Humira) for Crohn disease in pregnancy. Inflammatory Bowel Diseases 2006;12:827–8. 34. Coburn LA, Wise PE, Schwartz DA. The successful use of adalimumab to treat active Crohn disease of an ileoanal pouch during pregnancy. Digestive Diseases & Sciences 2006;51:2045–7. 35. Prescribing information for Humira (adalimumab). 2007. 36. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295:2275–85. 37. Schiff MH, Burmester GR, Kent JD, Pangan AL, Kupper H, Fitzpatrick SB, Donovan C. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 2006;65:889–94. 38. Nesbitt AM, Henry AJ. High affinity and potency of the pegylated FAB’ fragment CDP870 – a direct comparison with other anti-TNF agents. American Journal of Gastroenterology 2004;99:S253.
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39. Fossati G, Nesbitt A. In vitro complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity by the anti-TNF agents adalimumab, etanercept, infliximab, and certolizumab pegol (CDP870). American Journal of Gastroenterology 2005;100(Supplement):S299. 40. Fossati G, Nesbitt A. Effect of the anti-TNF agents, adalimumab, etanercept, infliximab, and certolizumab PEGOL (CDP870) on the induction of apoptosis in activated peripheral blood lymphocytes and monocytes. American Journal of Gastroenterology 2005;100(Supplement):S298–S299. 41. Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, Bernstein CN, Staun M, Thomsen OO, Innes A, for the CCsDSG. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn disease. Gastroenterology 2005;129:807–818. 42. Winter TA, Wright J, Ghosh S, Jahnsen J, Innes A, Round P. Intravenous CDP870, a PEGylated Fab’ fragment of a humanized antitumour necrosis factor antibody, in patients with moderate-to-severe Crohn disease: an exploratory study. Alimentary Pharmacology & Therapeutics 2004;20:1337–1346. 43. Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, Bloomfield R, Schreiber S. Certolizumab pegol for the treatment of Crohn disease. New England Journal of Medicine 2007;357:228–38. 44. Schreiber S, Khaliq-Kareemi M, Lawrance I, Ostergond Thomsen O, Hanauer SB, McColm J, Bloomfield R, Sandborn WJ. Certolizumab pegol maintenance therapy for Crohn disease. New England Journal of Medicine 2007;357:239–50 45. Schreiber S, Feagan B, Hanauer SB, Rutgeerts P, McColm JA, Sandborn WJ. Safety and tolerability of subcutaneous (sc) certolizumab pegol in active Crohn disease (CD): results from two Phase III studies (PRECiSE program). Gastroenterology 2006;130:A-479 Abstract T1126. 46. Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, Patel J, Sopwith M, Isenberg DA. Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. Rheumatology 2002;41:1133–7. 47. Stack WA, Mann SD, Roy AJ, Heath P, Sopwith M, Freeman J, Holmes G, Long R, Forbes A, Kamm MA. Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn disease. Lancet 1997;349:521–4. 48. Sandborn WJ, Feagan BG, Hanauer SB, Present DH, Sutherland LR, Kamm MA, Wolf DC, Baker JP, Hawkey C, Archambault A, Bernstein CN, Novak C, Heath PK, Targan SR. An engineered human antibody to TNF (CDP571) for active Crohn disease: a randomized double-blind placebo-controlled trial. Gastroenterology 2001;120:1330–8. 49. Sandborn WJ, Feagan BG, Radford-Smith G, Kovacs A, Enns R, Innes A, Patel J. CDP571, a humanised monoclonal antibody to tumour necrosis factor alpha, for moderate to severe Crohn disease: a randomised, double-blind, placebo-controlled trial. Gut 2004;53:1485–1493. 50. Feagan BG, Sandborn WJ, Baker JP, Cominelli F, Sutherland LR, Elson CO, Salzberg BA, Archambault A, Bernstein CN, Lichtenstein GR, Heath PK, Cameron S, Hanauer SB. A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn disease. Alimentary Pharmacology & Therapeutics 2005;21:373–384. 51. Feagan BG, Sandborn WJ, Lichtenstein G, Radford-Smith G, Patel J, Innes A. CDP517, a humanized monoclonal antibody to tumor necrosis factor-a, for steroid-dependent Crohn disease: a randomized, double-blind, placebo-controlled trial. Alimentary Pharmacology & Therapeutics 2006;23:617–628. 52. Mamula P, Cohen SA, Ferry GD, Kirschner BS, Winter HS, Innes A, Patel J, Baldassano RN, Pediatric Inflammatory Bowel Disease C. CDP571, a humanized anti-tumor necrosis factor-alpha monoclonal antibody in pediatric Crohn disease. Inflammatory Bowel Diseases 2004;10:723–30. 53. van den Brande JMH, Braat H, van den Brink GR, Versteeg HH, Bauer CA, Hoedemaeker I, van Montfrans C, Hommes DW, Peppelenbosch MP, van Deventer SJH. Infliximab but not etanercept induces apopotosis in lamina propria T-lymphocytes from patients with Crohn disease. Gastroenterology 2003;124:1774–1785. 54. Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, Gottlieb AB, Etanercept Psoriasis Study G. Etanercept as monotherapy in patients with psoriasis.[see comment]. New England Journal of Medicine 2003;349:2014–22. 55. Gottlieb AB, Matheson RT, Lowe N, Krueger GG, Kang S, Goffe BS, Gaspari AA, Ling M, Weinstein GD, Nayak A, Gordon KB, Zitnik R. A randomized trial of etanercept as monotherapy for psoriasis. Archives of Dermatology 2003;139:1627–32; discussion 1632.
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139. Huyghebaert N, Vermeire A, Neirynck S, Steidler L, Remaut E, Remon JP. Development of an enteric-coated formulation containing freeze-dried, viable recombinant Lactococcus lactis for the ileal mucosal delivery of human interleukin-10. European Journal of Pharmaceutics & Biopharmaceutics 2005;60:349–59. 140. Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn disease. Clinical Gastroenterology & Hepatology 2006;4:754–9. 141. Reinisch W, Hommes DW, Van Assche G, Colombel JF, Gendre JP, Oldenburg B, Teml A, Geboes K, Ding H, Zhang L, Tang M, Cheng M, van Deventer SJ, Rutgeerts P, Pearce T. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn disease. [see comment]. Gut 2006;55:1138–44. 142. Hommes DW, Mikhajlova TL, Stoinov S, Stimac D, Vucelic B, Lonovics J, Zakuciova M, D’Haens G, Van Assche G, Ba S, Lee S, Pearce T. Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn disease.[see comment]. Gut 2006;55:1131–7. 143. Plevy S, Salzberg B, van Assche G, Regueiro M, Sandborn W, Hanauer S, Targan S, Mayer L, Mahadevan U, Lowder J. A humanized anti-CD3 monoclonal antibody, visilizumab, for treatment of severe steroid-refractory ulcerative colitis: Results of a phase I study. Gastroenterology 2004;126:A75. 144. Targan SR, Salzberg BA, Mayer L, Hommes D, Hanauer S, Mahadevan U, Reinisch W, Plevy SE, Dignass AU, Van Assche G, Buchman A, Mechkov G, Krastev Z, Lowder JN. A phase I-II study: multiple dose levels of visilizumab are well tolerated and produce rapid and sustained improvement in ulcerative colitis patients refractory to treatment with IV steroids (IVSR-UC). Gastroenterology 2005;128(Suppl 4):A75. 145. Hommes DW, Targan SR, Dignass A, Baumgart DC, Mayer L, Zang L, Wilson K, Lowder J, Frankel M. Visilizumab therapy in subjects with moderate-to-severe, refractory Crohn disease. Gastroenterology 2007;132(Suppl 2):A157. 146. Travis S, Yap LM, Hawkey C, Warren B, Lazarov M, Fong T, Tesi RJ, Group RDPIS. RDP58 is a novel and potentially effective oral therapy for ulcerative colitis. Inflammatory Bowel Diseases 2005;11:713–9. 147. Preliminary results of Sangstat’s phase 2 studies of RDP58 show peak response of 77% and a 71% remission rate in ulcerative colitis patients. Additional investigation needed to determine efficacy in Crohn disease. Internet Press Release 2003. 148. Moreland LW, Alten R, Van den Bosch F, Appelboom T, Leon M, Emery P, Cohen S, Luggen M, Shergy W, Nuamah I, Becker JC. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis & Rheumatism 2002;46:1470–9. 149. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, Russell A, Dougados M, Emery P, Nuamah IF, Williams GR, Becker JC, Hagerty DT, Moreland LW. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. New England Journal of Medicine 2003;349:1907–15. 150. Kremer JM, Dougados M, Emery P, Durez P, Sibilia J, Shergy W, Steinfeld S, Tindall E, Becker JC, Li T, Nuamah IF, Aranda R, Moreland LW. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. [see comment] [erratum appears in Arthritis Rheum. 2005 Oct;52(10):3321]. Arthritis & Rheumatism 2005;52:2263–71. 151. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition.[erratum appears in New England Jounal of Medicine 2005 Nov 24;353(21):2311]. New England Journal of Medicine 2005;353:1114–23. 152. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, Szechinski J, Li T, Ge Z, Becker JC, Westhovens R. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial.[see comment][summary for patients in Annals of Internal Medicine. 2006 Jun 20;144(12):I18; PMID: 16785473]. Annals of Internal Medicine 2006;144:865–76.
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33 Treatment of Perianal Crohn Disease Fistulae Mark T. Osterman and Gary R. Lichtenstein∗
Introduction Crohn disease is a chronic inflammatory disorder that may affect any part of the bowel, from mouth to anus. Three main patterns of disease have been described: inflammatory, structuring, and fistulizing. Fistulae were first described by Crohn et al. in 1932 in their initial description of regional ileitis [1]. Although no perianal lesions were noted by these authors, perianal fistulae were observed in association with Crohn disease soon after by Bissell [2]. Fistulae are now recognized as a common and important aspect of this disease. The treatment of perianal Crohn fistulae has improved greatly over the last ten years as new medical therapies, especially infliximab, have been developed. The purpose of this chapter is to discuss our current knowledge of perianal fistulizing Crohn disease, focusing on its medical management.
Background Classification Perianal fistulae historically have been classified in a variety of ways. The most clinical useful way to classify fistulae was recently proposed by the American Gastroenterological Association in a position statement and technical review on perianal Crohn disease [3, 4]. They stratify perianal fistulae into two groups: simple and complex. Simple fistulae are low, i.e. below the dentate line, and have a superficial, low intersphincteric, or low transsphincteric origin. These fistulae also have a single external opening, have no associated pain or fluctuation to suggest an abscess, and have no evidence of a rectovaginal fistula or anorectal stricture. Complex fistulae, on the other hand, are high in origin (high intersphincteric, high transsphincteric, or suprasphincteric), may have multiple external openings, may have associated pain or fluctuation to suggest an abscess, and may have evidence of a rectovaginal fistula or anorectal stricture. The distinction between the two types of perianal fistula is clinically important, not only because the management varies, but also because several studies have demonstrated higher rates of healing with simple fistulae [5–8].
∗
Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Division of Gastroenterology, 3rd Floor Ravdin Building, 3400 Spruce Street, Philadelphia, PA 19104-4283, Phone: 215-662-4310 or 215-349-8222, Fax: 215-349-5915, Email:
[email protected]
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Pathogenesis The transmural nature of the inflammation that typifies Crohn disease predisposes patients to fistula formation. Although the pathogenesis of perianal fistulae is not known precisely, two mechanisms seem plausible [9]. Perianal fistulae may develop locally as deep penetrating ulcers in the anus or rectum, which then extend over time as feces is forced into the ulcers during defecation [10]. Alternatively, these fistulae may develop after anal gland infections or abscesses [11]. Since some of the anal glands penetrate into the intersphincteric space, infection in this space can readily extend to the external anal sphincter or skin. Natural History The reported incidence of fistulae in Crohn disease patients ranges from 17% to 43% in referralcenter-based case series [12–21]. Only two population-based studies examining the natural history of Crohn fistulae have been published to date [22, 23]. The first, a study by Hellers et al. included 826 patients diagnosed with Crohn disease in Stockholm County, Sweden, from 1955 to 1974 and observed a 23% cumulative incidence of perianal fistulae [22]. The authors noticed that the frequency of perianal fistulae increased as the inflammatory disease became more distal, with a 12% incidence in ileal disease, 15% in ileocolonic disease, 41% in colonic without rectal disease, and 92% in colonic with rectal disease. More recently, Schwartz et al. examined 176 patients diagnosed with Crohn disease in Olmsted County, Minnesota, from 1970 to 1993 and found a cumulative incidence of at least one fistula (at any site) of 21% at 1 year, 26% at 5 years, 33% at 10 years, and 50% at 20 years [23]. The corresponding cumulative incidences of at least one perianal fistula were 12% at 1 year, 15% at 5 years, 21% at 10 years, and 26% at 20 years. Taken collectively, fistulae were located as follows: 54% perianal, 24% enteroenteric, 9% rectovaginal, 6% enterocutaneous, 3% enterovesical, and 3% entero-intraabdominal. Interestingly, 45% of patients developed a perianal fistula before or at the time of diagnosis of Crohn disease, an observation first noted by Gray et al. in 1965 [24] and also seen in the study by Hellers et al. [22]. This observation highlights the frequent difficulties encountered in attempting to diagnose Crohn disease in patients with isolated perianal disease. The clinical course of perianal fistulae depends somewhat on their complexity. Simple fistulae may heal spontaneously in up to 50% of cases [16, 25], whereas complex fistulae rarely heal spontaneously [26]. A number of studies have demonstrated that simple perianal fistulae tend to heal more completely and recur less than complex fistulae [6, 8, 25, 27, 28]. Diagnosis Since healing rates seem to decrease when fistulae transform from simple to complex, it is tantamount to recognize and treat perianal Crohn fistulae as soon as symptoms manifest themselves. Thus, fistula location and extent must be accurately ascertained prior to commencing therapy. Unfortunately, digital rectal examination alone is not sufficient in this capacity, with accuracy as low as 62% [29]. Fortunately, a variety of other modalities exist, including fistulography, pelvic CT, pelvic magnetic resonance imaging (MRI), anorectal endoscopic ultrasound (EUS), and examination under anesthesia (EUA). Fistulography, which may cause significant patient discomfort and more importantly may disseminate septic fistula content, has a reported diagnostic accuracy of 16–50%, which is too low to be clinical useful [30–34]. Similarly, CT, with its limited diagnostic accuracy of 24–60%, is also not particularly useful [35–41]. Pelvic MRI, on the contrary, represents a vast improvement with a reported diagnostic accuracy of 76–100% and is often used to delineate anorectal and pelvic anatomy [42–50]. Anorectal EUS is also a clinically useful diagnostic modality with diagnostic accuracy ranging from 56–100% [41, 49, 51–56. Of note, both pelvic MRI and anorectal EUS have been found to change surgical management in
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10–15% of cases [44–50, 56]. EUA performed by an experienced colorectal surgeon has long been considered the gold standard for diagnosis of perianal fistulae in Crohn disease. However, this view has recently been challenged by Schwartz et al. who compared EUA, MRI, and EUS in a prospective blinded study of 34 patients with suspected Crohn perianal fistulae [49]. In this study, a consensus gold standard was determined for each patient. The authors observed a diagnostic accuracy exceeding 85% for all three modalities, specifically 91% for EUA and EUS and 87% for MRI. Of note, when any two of the tests were combined, diagnostic accuracy increased to 100%.
Medical Treatment 5-Aminosalicylic Acid Derivatives Although modestly efficacious in inducing remission in patients with mild-to-moderate Crohn disease, the treatment of Crohn fistulae with 5-aminosalicylic acid derivatives has never been studied in controlled trials. Thus, they cannot be recommended for the treatment of fistulizing Crohn disease. Corticosteroids There are no controlled studies evaluating the use of steroids in the management of Crohn fistulae. Unfortunately, neither the National Cooperative Crohn Disease trial nor the European Cooperative Crohn Disease trial provided data on response in the subgroup of patients with fistulae. However, two large uncontrolled studies have shown that corticosteroid use may actually be detrimental to patients with fistulizing Crohn disease, as it was associated with higher rates of surgical intervention [57, 58]. A recent retrospective case-control study of 432 patients with Crohn disease studied risk of intra-abdominal or pelvic abscess with systemic corticosteroid use during the previous 3 months [59]. The authors found a significant 9-fold increased risk of intraabdominal or pelvic abscess in patients with perforating Crohn disease who had received systemic corticosteroids during the prior 3 months (adjusted OR = 9.03, 95% CI = 2.40–33.98). In patients with relapsed active disease, they also reported a significant 9-fold increased risk of abscess in patients receiving systemic steroids in the 3 months prior to presentation (unadjusted OR = 9.31, 95% CI = 1.03–83.91). For these reasons, corticosteroids should not be used in patients with fistulizing Crohn disease. Antibiotics Although antibiotics are the most commonly used medication for the treatment of fistulae in Crohn disease, there are no controlled data indicating that these agents are effective in this regard. The use of antibiotics in fistulizing Crohn disease is based upon a number of uncontrolled case series, each with a small number of patients [60–69]. Metronidazol, the most commonly used antibiotic, was first discovered in 1975 to have possible efficacy by Ursing and Kamme, who reported perianal fistula closure in 3 patients [60]. Five years later, Bernstein et al. treated 21 consecutive patients with perianal Crohn fistulae with metronidazol at a dose of 20 mg/kg/day and observed clinical improvement in all patients, fistula closure in 83%, and complete healing in 56% [61]. These responses typically occurred within 6–8 weeks of commencement of therapy. In 1982, the same group published a follow-up study, comprised of 17 of the 21 original patients and 9 additional consecutive patients, and found that dosage reduction was associated with relapse in all patients [63]. However, rapid healing was noted in all patients upon readministration of metronidazol. Thus, while efficacious in the induction of improvement, metronidazol is limited in that maintenance therapy is often required. Three other small, uncontrolled studies have also observed efficacy with metronidazol in fistulizing Crohn disease with fistula closure rates of
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40–50%, but a high rate of relapse after cessation of therapy was seen in one of these studies [62, 64, 65]. The typical dose of metronidazol in the treatment of fistulizing Crohn disease ranges from 750–1500 mg/day. Adverse events associated with metronidazol are quite common, often leading to intolerance and discontinuation of the drug, and include a distal sensory neuropathy with paresthesias, nausea, dyspepsia, fatigue, glossitis, metallic taste, and a disulfiram-like reaction to alcohol ingestion [70]. Given that adverse events are commonly problematic with metronidazol, ciprofloxacin began to be used in the late 1980s and early 1990s to treat Crohn fistulae [66–69]. The first report of ciprofloxacin use in this setting was by Turunen et al. who studied 8 patients with severe perianal disease and 1 patient with enterocutaneous fistula refractory to metronidazol [66]. In this study, in which patients were given 1000–1500 mg/day of ciprofloxacin for 3–12 months, the authors found that all patients demonstrated initial improvement, but 50% continued to have persistent drainage, which required surgical intervention in several patients. As with metronidazol, relapses were common upon cessation of therapy, but improvement was seen upon reinstitution of therapy in most cases. A subsequent study, published only in abstract form by Wolf et al. noted improvement in 4 out of 5 patients with severe perianal disease within 5 weeks of treatment [67]. Combination therapy with ciprofloxacin and metronidazol has been examined by Solomon et al. in a retrospective study of 14 patients [68]. They observed improvement in 9 patients and fistula closure in 3 patients within 12 weeks, but like previous antibiotic studies, they also reported that relapse was the norm following discontinuation of therapy. The typical dose of ciprofloxacin in the treatment of fistulizing Crohn disease ranges from 1000–1500 mg/day. Adverse events with ciprofloxacin are uncommon and include headache, nausea, diarrhea, rash, and spontaneous tendon rupture [71, 72]. In pediatric population caution should be exercised regarding possible effect on developing musculoskeletal system due to toxicity observed in juvenile animal data. To date, there has been no comparative study published comparing metronidazol and ciprofloxacin in the treatment of fistulizing Crohn disease. There is now a trial ongoing evaluating metronidazol versus ciprofloxacin versus placebo for Crohn fistula funded by the Crohn and Colitis Foundation of America. 6-Mercaptopurine/Azathioprine No controlled trials examining fistula healing with 6-mercaptopurine (6-MP) or azathioprine as a primary endpoint have ever been published. In the very first publication documenting use of azathioprine in Crohn disease, Brooke et al. reported that all 6 patients with fistulizing disease who had received azathioprine demonstrated marked clinical improvement in their fistulae [73]. Since then, five randomized controlled trials, which investigated healing of fistulae as a secondary endpoint, have been published (Table 33.1) [74–78]. The studies used improvement or complete healing of fistulae as the outcome measure. With the exception of the trial by Present et al. the studies had very few patients with fistulizing disease. The studies were quite heterogeneous with respect to duration of therapy; there was also some variability in medication used and dosage. Three of the five trials observed higher rates of fistula improvement with 6-MP or azathioprine [75, 76, 78]. Of note, the study by Present et al. observed a 31% rate of complete closure of the fistulae in the group receiving 6-MP versus 6% for the placebo group [78]. A meta-analysis of these five trials reported an overall response rate (defined as improvement or complete healing) in 54% of patients treated with 6-MP or azathioprine compared to 21% in patients treated with placebo [80]. The corresponding pooled odds ratio for fistula healing with 6-MP or azathioprine was 4.44 (95% CI = 1.50–13.20). When interpreting the results of this meta-analysis, it is important to keep in mind that the majority of the fistulous cases (46 out of 70, or 66%) were derived from a single study conducted at a single center [78]. Thus, the results of the meta-analysis were driven largely by that one study. Moreover, as mentioned previously, fistula healing was not a primary
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Table 33.1. Randomized controlled trials for treatment of fistulizing Crohn’s disease with 6-MP or azathioprine. Author, Year
N
Drug, Dose
Rx Time
Willoughby et al., 1971 [74] Rhodes et al., 1971 [75] Klein et al., 1974 [76] Rosenberg et al., 1975 [77] Present et al., 1980 [78]
3
Azathioprine, 2 mg/kg/d Azathioprine, 2 mg/kg/d Azathioprine, 3 mg/kg/d Azathioprine, 2 mg/kg/d 6-MP, 1.5 mg/kg/d
24 wk
0/2 (0%)
0/1 (0%)
NR
2 mo
2/4 (50%)
0/2 (0%)
NR
4 mo
4/5 (80%)
2/5 (40%)
NR
26 wk
0/4 (0%)
1/1 (100%)
NR
1 yr
16/29 (55%)
4/17 (24%)
NR
6 10 5 46
Response Drug
Response Placebo
P-value
Abbreviations: 6-MP, 6-mercaptopurine; N, number of patients; Rx, treatment; NR, not reported
endpoint for any of the individual trials. In addition, two uncontrolled case series, one in adults and one in children, have been published [80, 81]. The adult series, by Korelitz et al. treated 34 patients with 6-MP at a dose of 1.5 mg/kg/day with various types of fistulae, including perianal (18 patients), abdominal wall (8 patients), enteroenteric (7 patients), rectovaginal (6 patients), and vulvar (2 patients) [80]. Complete fistula closure was achieved in 39% of patients, with an additional 26% showing improvement. This study also underscored the importance of maintenance therapy. Fistulae remained closed for 1–5 years in 46% of patients (6 out of 13) who remained on 6-MP, and relapses tended to occur within 2 weeks to 9 months after discontinuation of the drug. Healing was once again achieved upon readministration of 6-MP. Furthermore, the authors noted that although all types of fistulae responded to 6-MP, abdominal wall and enteroenteric fistulae responded particularly well. The pediatric retrospective series evaluated 6-mercaptopurine or azathioprine therapy for fistulas, drainage, induration, and tenderness by Irvine Perianal Disease Activity Index score ranging from 0–20. Twenty patients met the study criteria and five (25%) were considered treatment failures. Of the remaining 15 patients who were treated for minimum of six months, 67% had an improvement in drainage, 73% in tenderness, 60% in induration, and 40% in fistula closure. The mean Irvine PDAI was 7.67 ± 2.19 initially and 4.40 ± 1.72 after six months of therapy (p<0.001). The combination of azathioprine and antibiotics has also been investigated. Recently, Dejaco et al. published a prospective, open-label study evaluating the use of an 8-week course of ciprofloxacin and/or metronidazol as a bridge to azathioprine in the treatment of 52 patients with perianal fistulae [82]. In this trial, 17 patients had been taking azathioprine prior the start of the study, and another 14 patients were initiated on azathioprine after the 8-week course of antibiotics. At week 8, 50% of patients had improved and 25% had achieved complete healing. At week 20, improvement was seen overall in 35% of patients with complete healing in 18%. Patients who received azathioprine were significantly more likely to achieve response at week 20 than those who did not receive azathioprine (48% vs. 15%, p = .03). Thus, more evidence is provided that maintenance therapy is critical to continued fistula healing. The cost-utility of the combination of metronidazol and 6-MP with or without infliximab has been studied by Arseneau et al. who designed a 1-year Markov model for therapy of perianal Crohn fistulae [83]. They observed that all treatment strategies had similar effectiveness, but strategies involving infliximab were much more expensive. Their conclusion, therefore, was that the incremental benefit of infliximab may not justify the higher cost over a 1-year period. Metronidazol combined with 6-MP appears to have the highest initial cost-utility in the treatment of fistulizing perianal Crohn disease.
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Typical doses of 6-MP and azathioprine used in clinical trials were 1–1.5 mg/kg/day and 2–3 mg/kg/day, respectively. Currently, there is some debate as to whether dosing according to level of the active metabolites, the 6-thioguanine nucleotides, should be employed routinely. A recent meta-analysis has demonstrated that higher 6-thioguanine nucleotide levels (especially > 230–260 pmol/108 red blood cells) were associated with clinical remission [84]. Adverse events are common with 6-MP and azathioprine, occurring in 9–15% of patients, and include allergic reactions, bone marrow suppression (especially leukopenia), pancreatitis, infection, hepatotoxicity, non-Hodgkin’s lymphoma, and other gastrointestinal side effects (nausea, vomiting, and abdominal pain) [79, 85, 86]. Methotrexate Methotrexate has been shown to be effective in the induction and maintenance of remission of Crohn disease in several controlled trials. Unfortunately, these studies did not address fistulizing disease. To date, only two retrospective case series have been published which examined the use of methotrexate for Crohn fistula [87, 88]. The first, by Vandeputte et al. analyzed 20 patients, 8 of whom had fistulae, refractory to azathioprine and requiring continuous corticosteroid treatment [87]. The authors reported improvement in 70% of patients overall with parenteral methotrexate within 12 weeks but did not specify the outcome of the patients with fistulae. The other series, by Mahadevan et al. included 37 courses of intramuscular and/or oral methotrexate given to 33 patients, 16 of whom had fistulae and were intolerant or refractory to 6-MP [88]. Complete fistula closure was achieved in 25% with another 31% showing improvement. Similar to other medications, fistulae often recurred when the dose of intramuscular methotrexate was decreased or when the route of administration was changed to oral. Thus, methotrexate may represent a reasonable alternative to patients who fail or cannot tolerate 6-MP or azathioprine, and long-term maintenance therapy is likely necessary; however, prospective randomized placebocontrolled trials are still needed to evaluate formally the efficacy of methotrexate for fistulizing Crohn disease. The initial dose of methotrexate suggested is 25 mg intramuscularly every week. Concurrent administration of folate is advocated to lessen nausea. Adverse events are common and include hepatic fibrosis, bone marrow suppression, pneumonitis and pulmonary fibrosis, nausea, and teratogenicity [89, 90]. Cyclosporine A There are no controlled trials documenting efficacy of cyclosporine for the treatment of fistulizing Crohn disease. To date, ten case series, with a total of 64 patients, assessing cyclosporine in Crohn fistula have been published [91–100]. The largest series, by Present and Lichtiger, looked at 16 patients with various types of Crohn fistulae (perianal, rectovaginal, and enterocutaneous) treated with intravenous cyclosporine at a dose of 4 mg/kg/day and observed improvement in 88% with complete fistula closure in 44% [95]. The mean time to response was rather short at just over 7 days. The authors noted that 36% of patients relapsed when converted to oral cyclosporine. Taken collectively, the ten case series showed an initial response rate of fistulizing Crohn disease to intravenous cyclosporine of 83% at doses of 2.5–5 mg/kg/day (mostly 4 mg/kg/day). The overall rate of fistula recurrence after discontinuing oral cyclosporine was 62%, however, and thus, most authorities will use cyclosporine as a bridge to other maintenance therapies, such as 6-MP or azathioprine [9, 26, 101]. The recommended initiation intravenous dose of cyclosporine is 4 mg/kg/day for one week, followed by oral formulation, typically 6–8 mg/kg/day, all dosed by levels. Adverse events are common and include paresthesias, hirsutism, hypertension, tremor, renal insufficiency, headache, opportunistic infections, gingival hyperplasia, seizures, and hepatotoxicity [89, 102].
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Tacrolimus Several uncontrolled case series, with a total of 16 patients with Crohn fistulae, have suggested that tacrolimus may have efficacy in the management of fistulizing disease [103–106]. The only controlled trial of tacrolimus for fistulizing Crohn disease is a randomized, double-blind, placebocontrolled study of 48 patients with perianal or enterocutaneous fistulae by Sandborn et al. [107]. In this study, patients received oral tacrolimus at 0.2 mg/kg/day or placebo for 10 weeks. The primary endpoint, fistula improvement (defined as closure of > 50% of draining fistulae and maintenance of closure for at least 4 weeks), occurred in 43% of patients receiving tacrolimus, compared to 8% of patients on placebo (p = .004). There was no difference in the secondary endpoint, fistula remission (defined as closure of all fistulae and maintenance of that closure for at least 4 weeks), between the two groups (10% of tacrolimus-treated patients vs. 8% of placebo-treated patients). Of note, 38% of patients treated with tacrolimus developed increases in serum creatinine to > 1.5 mg/dL, necessitating dose reduction. Recently, Gonzalez-Lama et al. conducted a small, uncontrolled, prospective, open-label study of long-term oral tacrolimus at a dose of 0.1 mg/kg/day in 10 patients with Crohn fistulae refractory to all conventional therapy, including infliximab [108]. Patients in the study had perianal, enterocutaneous, and rectovaginal fistulae. The authors found that after 6–24 months of follow-up, 50% of patients achieved complete response and an additional 40% showed improvement. Importantly, no relapses and no cases of nephrotoxicity occurred throughout the follow-up period. In addition to nephrotoxicity, other adverse events associated with tacrolimus include headache, insomnia, paresthesias, tremor, and leg cramps [107]. Infliximab Given that inflammation in Crohn disease is associated with high levels of tissue tumor necrosis factor- (TNF-) expression, therapies directed against this cytokine have become a recent focus of interest. Infliximab, a chimeric (75% human, 25% murine) IgG1 monoclonal antibody directed against TNF-, is the prototype anti-TNF- agent and has now become the cornerstone in medical therapy of fistulizing Crohn disease. Several uncontrolled studies have shown efficacy of infliximab in this regard [109–111]. Infliximab has also been shown to be efficacious in the treatment of Crohn fistula in two multicenter randomized, double-blind, placebo-controlled trials [112, 113]. The first, by Present et al. randomized 94 patients with draining abdominal (10% of patients) or perianal (90% of patients) fistulae to placebo, infliximab at a dose of 5 mg/kg, or infliximab at 10 mg/kg, administered intravenously at weeks 0, 2, and 6 [112]. The primary endpoint was a reduction in the number of draining fistulae by > 50%, which was maintained for at least 4 weeks, and a secondary endpoint was closure of all fistulae. The authors found that the primary endpoint was achieved in 68% of patients who received infliximab at 5 mg/kg and 56% of patients who received infliximab at 10 mg/kg, compared to 26% of patients who received placebo (p = .002 and p = .02, respectively). Closure of all fistulae was achieved in 55% of patients who received infliximab at 5 mg/kg and 38% of patients who received infliximab at 10 mg/kg, compared to only 13% of patients who received placebo (p = .001 and p = .04, respectively). The median time to response was 14 days for infliximab-treated patients vs. 42 days for patients assigned to placebo, and the majority of patients of infliximab-treated patients achieved fistula closure prior to the third infusion. Eleven percent of infliximab-treated patients developed a perianal abscess, possibly resulting from premature closure of the cutaneous end before closure of the rest of the fistula tract. However, the overall rates of infection did not differ between the infliximab and placebo groups. In the study by Present et al. the median duration of response was three months, suggesting that, similar to the treatment of Crohn fistula with other medications, maintenance therapy may be required. In addition, since the treatment of luminal Crohn disease with infliximab often necessitates maintenance therapy, it should not come as a surprise that maintenance infliximab may
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be of benefit in the management of fistulizing Crohn disease. The other multicenter, randomized, double-blind, placebo-controlled trial of infliximab for Crohn fistula, the ACCENT II trial (A Crohn Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen in Patients with Fistulizing Crohn Disease) reported by Sands et al. followed 282 patients with draining perianal, abdominal, and rectovaginal fistulae [113]. All patients were induced with infliximab at 5 mg/kg at weeks 0, 2, and 6, and response, defined as a reduction in the number of draining fistulae by > 50% for at least 4 weeks, was achieved in 195 patients (69%), similar to the induction response rate reported by Present et al. At week 14, these 195 responders were then randomly assigned to receive infusions of either infliximab 5 mg/kg or placebo every 8 weeks until week 54. The primary endpoint was time to loss of response. The authors observed a median time to loss of response of 40 weeks in infliximab-maintained patients vs. 14 weeks in placebo-assigned patients (p = .001). Overall, 42% of patients in the infliximab group had a loss of response, compared to 62% in the placebo group. At week 54, 46% of patients treated with infliximab still had a response, versus 23% of patients treated with placebo (p = .001). In addition, at week 54, 36% of patients in the infliximab group had a complete absence of draining fistulae, compared to 19% in the placebo group (p = .009). Sands et al. subsequently performed a post-hoc analysis of the ACCENT II data looking at the efficacy of infliximab induction and maintenance in the subset of women with rectovaginal fistulae [114]. Twenty-five of the original 138 women had a total of 27 draining rectovaginal fistulae at baseline. At week 14, 64% of these 25 women had responded and were then randomized to receive infliximab or placebo maintenance therapy. The authors reported a median time to loss of response of 46 weeks for the infliximab group vs. 33 weeks in the placebo group. The social impact of infliximab in patients with active fistulizing Crohn disease has also been investigated in two recent studies. Cadahia et al. were interested in the effect of infliximab induction treatment on health-related quality of life, and thus, they conducted a prospective observational study of 25 patients who received three-dose induction infliximab therapy for single or multiple draining abdominal or perianal fistulae [115]. The authors found that health-related quality of life, as measured by the SF-36, demonstrated significant improvement in the physical domain after 4 and 10 weeks. In addition, a significant increase in IBDQ score was seen after 4 weeks. More recently, Lichtenstein et al. evaluated the impact of infliximab maintenance therapy on the number of hospitalizations, surgeries, and procedures in patients with fistulizing Crohn disease [116]. Using data from the ACCENT II trial, they revealed that compared to patients who received placebo, patients who received maintenance infliximab had significantly fewer number of mean hospitalization days (0.5 vs. 2.5 days), hospitalizations (0.11 vs. 0.31), total surgeries and procedures (65 vs. 126), inpatient surgeries and procedures (7 vs. 41), and major surgeries (2 vs. 11). Mechanistically, infliximab’s effects on mucosal cytokine profiles may predict which patients with fistulizing Crohn disease will relapse. Agnholt et al. recently collected tissue samples for cytokine analysis from 26 patients with Crohn fistulae [117]. They observed that fistula healing was associated with decreased production of TNF-, interferon-, and interleukin-10, while relapse was associated with increased production of interferon-. Despite all of its reported success, the use of infliximab may not obviate the need for surgical management of Crohn fistulae in many cases. Poritz et al. retrospectively examined surgical rates in patients treated with infliximab for fistulizing Crohn disease at a single institution [118]. Among the 26 patients with various types of fistulae, 46% experienced a partial response to infliximab, and an additional 23% had fistula closure. However, 54% of patients overall still required surgery after infliximab therapy and another 23% continued to open fistulous drainage but refused surgery. Of note, none of the patients with either enterocutaneous or peristomal fistulae were healed with infliximab treatment. Moreover, as alluded to previously, infliximab therapy may not be the most cost-effective initial strategy in the management of Crohn perianal fistulae, according to the costutility analysis performed by Arseneau et al. [83]. Compared to the combination of 6-MP and
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metronidazol, any initial intervention involving infliximab resulted in an increase in incremental cost-utility by more than $350,000 per quality-adjusted life year, due exclusively to the high cost of infliximab. The effectiveness of infliximab in combination with other medical therapies for fistulizing Crohn disease has also been investigated in several studies [119–121]. West et al. conducted a double-blind, placebo-controlled trial of ciprofloxacin overlapping with infliximab in patients with perianal Crohn fistulae [119]. In this study, 24 patients were randomized to receive either ciprofloxacin at 1000 mg/day or placebo for 12 weeks in addition to infliximab at 5 mg/kg at weeks 6, 8, and 12. Patients were followed for 18 weeks, and the primary endpoint was reduction in the number of draining fistulae by > 50%. The authors reported that 73% of the ciprofloxacin-treated patients responded, compared to 39% in the placebo group. One caveat is that the response rate to infliximab alone was much less than in other infliximab studies, in which at least 60% of patients responded. Infliximab has also been evaluated in combination with immunomodulator therapy. Ochsenkühn et al. performed an uncontrolled pilot study of long-term 6-MP (at 1 mg/kg/day) or azathioprine (at 2–2.5 mg/kg/day) in combination with induction infliximab in 16 patients [120]. They found that 75% of patients achieved complete fistula closure which persisted for more than 6 months (median time of 10 months). As seen previously, the median time to fistula closure was 14 days. A similar uncontrolled pilot study by Schröder et al. followed 12 consecutive patients with Crohn fistulae intolerant or resistant to azathioprine [121]. Patients were treated with induction infliximab and long-term methotrexate at 20 mg/week (intravenously for 6 weeks, followed by oral thereafter). The authors observed that 33% of patients experienced complete fistula closure for at least 6 months (median 13 months), and 25% had a partial response. While providing a suggestion of efficacy of combination therapy for treatment of fistulizing Crohn disease, controlled trials have yet to be performed. The combination of infliximab with surgical intervention in the treatment of Crohn perianal fistulae has also been recently assessed in a several studies [6, 7, 122, 123]. Regueiro and Mardini retrospectively analyzed 32 consecutive patients with perianal Crohn fistulae, all of whom had received at least 3 induction doses of infliximab and some of whom had additionally undergone an EUA with seton placement prior to infliximab treatment [6]. Response was defined as complete closure and cessation of drainage from the fistula. They found that compared to patients treated with infliximab alone, patients who had a preinfusional EUA with seton placement had a significantly higher rate of initial response (100% vs. 83%, p = .014), lower rate of recurrence (44% vs. 79%, p = .001), and longer time to recurrence (13.5 months vs. 3.6 months, p = .0001). Another study, by van der Hagen et al. compared 10 patients treated with seton placement followed by infliximab to 7 patients treated with surgery alone in a retrospective review of consecutive patients with complex perianal fistulae [122]. After a median follow-up of 19 months, all patients achieved fistula healing. Fistula recurrence was seen in one patient (10%) in the combined therapy group vs. two patients (29%) in the surgery alone group. Two other case series have also documented favorable rates of fistula healing with seton placement followed by induction and maintenance infliximab, with complete and partial healing rates of 67% and 19%, respectively, in one study [8] and 47% and 53%, respectively, in the other [123]. Adverse events with infliximab treatment are common and include infusion reactions, delayedtype hypersensitivity reactions, formation of human antichimeric antibodies (currently known as antibodies to infliximab [ATI]), formation of antinuclear and anti-double-stranded DNA antibodies, and drug-induced lupus-like reactions [124–126]. In addition, infectious complications seem to be increased, but serious infections, such as pneumonia, sepsis, tuberculosis, and opportunistic infections, including listeriosis, aspergillosis, histoplasmosis, coccidiomycosis, and Pneumocystis carinii pneumonia, occur only rarely [127–131]. Finally, there have been isolated case reports of hepatic necrosis and non-Hodgkin’s lymphoma in patients treated with infliximab, although it has not been determined whether these events were the direct consequence of infliximab therapy.
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Other Anti-TNF-alpha Agents Several other anti-TNF- medications have shown promise in the treatment of fistulizing Crohn disease and may provide an alternative option for patients in whom infliximab either is not tolerated, has lost efficacy, or was never effective. Adalimumab, a fully human IgG1 monoclonal antibody, was investigated by Sandborn et al. in a recent pilot study of 24 patients with Crohn disease who had lost responsiveness or developed intolerance to infliximab [132]. In this 12-week, uncontrolled trial, patients received 80 mg of subcutaneous adalimumab at week 0, followed by 40 mg every other week starting at week 2. Nine patients in the study had fistulizing disease with open and draining perianal or enterocutaneous fistulae. The authors observed fistula improvement, defined as a reduction in the number of draining fistulae by > 50%, in 2 patients (22%) at week 2, 4 patients (44%) at week 4, and 5 patients (56%) at week 12. Complete fistula closure was achieved in 1 patient (11%) and week 2, 3 patients (33%) at week 4, and 3 patients (33%) at week 12. Overall, among the 24 patients, 71% experienced adverse events, which were serious in only 2 patients (8%) and required withdrawal in 1 patient with new-onset seizure. Reported adverse events included upper respiratory infection, headache, bronchitis, rash, fatigue, arthritic pain, abdominal pain, back ache, nausea, perianal abscess, numbness, and injection site reaction. However, since this study was not placebo-controlled, it is difficult to say which of these adverse reactions can be attributed directly to adalimumab. CDP571, a humanized (95% human, 5% murine) IgG4 monoclonal antibody, has been also been assessed for efficacy in the treatment of Crohn fistulae in two multicenter, randomized, double-blind, placebo-controlled trials [133, 134]. The first study, by Feagan et al. published only in abstract form, treated 71 patients with steroid-dependent Crohn disease with intravenous CDP571 at 20 mg/kg or placebo at week 0, followed by a second infusion of CDP571 at 10 mg/kg or placebo at week 8 [133]. At week 16, among the subgroup of patients with draining perianal fistulae, fistula closure was achieved in 25% of patients who received CDP571, compared to none in the placebo group. The other study, by Sandborn et al. followed 169 patients for 24 weeks, during which patients received an initial infusion of CDP571 at either 10 mg/kg or 20 mg/kg or placebo, followed by CDP571 at 10 mg/kg or placebo every 8–12 weeks [134]. This study included 37 patients with open perianal or enterocutaneous fistulae and reported that 50% of patients treated with CDP571 achieved fistula closure vs. 15% of patients who received placebo. Adverse events due to CDP571 include infusion reactions, formation of anti-idiotype antibodies, development of new antinuclear or anti-double-stranded DNA antibodies, insomnia, pruritus, and rash [133, 134]. Thalidomide has also been preliminarily evaluated in the treatment of fistulizing Crohn disease in two open-label pilot studies [135, 136]. The first study, by Ehrenpreis et al. enrolled 22 patients with refractory Crohn disease to receive oral thalidomide at 200 or 300 mg/day for 12 weeks [135]. At week 4, of the 13 patients with fistulae, 9 patients (69%) responded, 3 patients (23%) achieved remission, and 2 patients (15%) had closure of all fistulae. Nine patients with fistulizing disease completed the 12 weeks of treatment. Of these 9 patients, all (69%) were responders, 6 patients (46%) achieved remission, and 5 patients (38%) had complete closure of all fistulae. The other pilot study, by Vasiliauskas et al. treated 12 patients with steroid-dependent Crohn disease with 50 or 100 mg/day of thalidomide for 12 weeks [136]. Of the 6 patients with active perianal fistulae at the time of entry into the study, five (83%) had improvement in symptoms after 4 weeks. Four of these 6 patients with fistulizing disease completed 12 weeks of treatment. Fistula closure was achieved in 1 patient (17%) at week 12, with improvement in another 2 patients (33%). Adverse events are common with thalidomide therapy and include severe somnolence, peripheral neuropathy, teratogenicity, peripheral edema, constipation, seborrheic dermatitis, hypertension, muscle spasm, and diffuse rash [135, 136]. Novel Therapies A variety of other therapies for fistulizing Crohn disease have been suggested to be of possible benefit in uncontrolled case series or anecdotally. These include elemental diets, bowel rest with
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total parental nutrition, mycophenolate mofetil, granulocyte-colony stimulating factor, hyperbaric oxygen, and coagulation factor XIII [137–157]. However, controlled trials are required before any of these modalities can be recommended for routine use.
Summary The treatment of perianal fistulizing Crohn disease has evolved greatly in the last fifteen years, due largely to improvements in medical therapy. Tables 33.2 and 33.3 summarize all published controlled and uncontrolled trials of immunomodulator and biological therapy for the treatment of Crohn fistulae. The advent of immunomodulators and anti-TNF- agents has transformed the treatment of Crohn fistulae from almost exclusively surgical to placing a much larger emphasis on medical therapy, either as initial therapy alone, with surgery reserved for refractory cases, or Table 33.2. Controlled trials for treatment of fistulizing Crohn’s disease with immunomodulators and biological agents. Author, Year Immunomodulators Azathioprine/6-MP Willoughby et al., 1971 [74] Rhodes et al., 1971 [75] Klein et al., 1974 [76] Rosenberg et al., 1975 [77] Present et al., 1980 [78] Total Tacrolimus Sandborn et al., 2003 [107] Biological agents Infliximab Present et al., 1999 [112] Sands et al., 2004 [113]
N
Drug, Dose
Rx Time
3
Azathioprine, 2 mg/kg/d Azathioprine, 2 mg/kg/d Azathioprine, 3 mg/kg/d Azathioprine, 2 mg/kg/d 6-MP, 1.5 mg/kg/d
24 wk
0/2 (0%)
0/1 (0%)
NR
2 mo
2/4 (50%)
0/2 (0%)
NR
4 mo
4/5 (80%)
2/5 (40%)
NR
26 wk
0/4 (0%)
1/1 (100%)
NR
1 yr
16/29 (55%)
4/17 (24%)
NR
22/44 (50%)
7/26 (27%)
6 10 5 46 70
Response Drug
Response Placebo
P-value
48
Tacrolimus, 0.2 mg/kg/d
10 wk
9/21 (43%)
2/25 (8%)
.004
94
Infliximab, 5 mg/kg Infliximab, 10 mg/kg Infliximab, 5 mg/kg
14 wk
21/31 (68%)
8/31 (26%)
.002
195
Total
289
CDP571 Sandborn et al., 2001 [134]
37
18/32 (56%) 54 wk
42/91 (46%)
23/98 (23%)
.001
Time to loss of response = > 40 wk
Time to loss of response = 14 wk 31/129 (24%)
< .001
2/13 (15%)
.074
81/154 (53%)
CDP571, 10 or 20 mg/kg
24 wk
.02
12/24 (50%)
Abbreviations: N, number of patients; Rx, treatment; NR, not reported; 6-MP, 6-mercaptopurine
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Table 33.3. Uncontrolled trials for treatment of fistulizing Crohn disease with immunomodulators and biological agents. Author, Year Immunomodulators Methotrexate Mahadevan et al., 2003 [88] Cyclosporin A Fukushima et al., 1989 [91] Lichtiger, 1990 [92] Markowitz et al., 1990 [93] Hanauer et al., 1993 [94] Present et al., 1994 [95] Abreu-Martin et al., 1996 [96] O’Neill et al., 1997 [97] Hinterleitner et al., 1997 [98] Egan et al., 1998 [99] Gurudu et al., 1999 [100] Total Biological agents Adalimumab Sandborn et al., 2004 [132] Thalidomide Ehrenpreis et al., 1999 [135] Vasiliauskas et al., 1999 [136] Total
N
Drug, Dose
Initial Response
Sustained Response
16
Methotrexate, 25 mg/wk im
9/16 (56%)
3/16 (19%)
1 10 1 5 16 2 8 7 9 3 64
Cyclosporin Cyclosporin Cyclosporin Cyclosporin Cyclosporin Cyclosporin Cyclosporin Cyclosporin Cyclosporin Cyclosporin
1/1 (100%) 6/10 (60%) 0/1 (0%) 5/5 (100%) 14/16 (88%) 2/2 (100%) 7/8 (88%) 9/9 (100%) 7/9 (78%) 2/3 (67%) 53/64 (83%)
1/1 (100%) NR 0/1 (0%) 2/5 (40%) 9/16 (56%) 1/2 (50%) 0/8 (0%) 4/9 (44%) 2/8 (25%) NR 19/50 (38%)
Adalimumab, 80/40 mg qow
5/9 (56%)
NR
Thalidomide, 200 or 300 mg/d Thalidomide, 50 or 100 mg/d
9/13 (69%) 1/6 (17%) 10/19 (53%)
NR NR NR
9 13 6 19
A, A, A, A, A, A, A, A, A, A,
8 mg/kg/d po 4 mg/kg/d iv 4 mg/kg/d iv 4 mg/kg/d iv 4 mg/kg/d iv 2.5 mg/kg/d iv 4 mg/kg/d iv 5 mg/kg/d iv 4 mg/kg/d iv 4 mg/kg/d iv
Abbreviations: N, number of patients; NR, not reported; im, intramuscular; po, oral; iv, intravenous; qow, every other week
in combination with surgery from the start. For this reason, gastroenterologists and surgeons must work in concert in order to provide the best care for each patient. Proper fistula management also relies heavily on accurate diagnosis, especially defining the anatomy of the fistula, ascertaining whether abscess formation is present, and determining the location and extent of intestinal inflammation. References 1. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. JAMA 1932;99:1323–9. 2. Bissell AD. Localized chronic ulcerative colitis. Ann Surg 1934;99:957–66. 3. American Gastroenterological Association. American Gastroenterological Association medical position statement: perianal Crohn disease. Gastroenterology 2003;125:1503–7. 4. American Gastroenterological Association. AGA technical review on perianal Crohn disease. Gastroenterology 2003;125:1508–30. 5. Scott HJ, Northover JM. Evaluation of surgery for perianal Crohn fistulas. Dis Colon Rectum 1996;39:1039–43. 6. Regueiro M, Mardini H. Treatment of perianal fistulizing Crohn disease with infliximab alone or as an adjunct to exam under anesthesia with seton placement. Inflamm Bowel Dis 2003;9:98–103. 7. Topstad DR, Panaccione R, Heine JA, Johnson DR, MacLean AR, Buie WD. Combined seton placement, infliximab infusion, and maintenance immunosuppressives improve healing rates in fistulizing anorectal Crohn disease: a single center experience. Dis Colon Rectum 2003;46:577–83. 8. Bell SJ, Williams AB, Wiesel P, Wilkinson K, Cohen RC, Kamm MA. The clinical course of fistulating Crohn disease. Aliment Pharmacol Ther 2003;17:1145–51.
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60. Ursing B, Kamme C. Metronidazol for Crohn disease. Lancet 1975;1:775–7. 61. Bernstein LH, Frank MS, Brandt LJ, Boley SJ. Healing of perianal Crohn disease with metronidazol. Gastroenterology 1980;79:357–65. 62. Schneider MU, Strobel S, Riemann JF, Demling L. [Treatment of Crohn disease with metronidazol]. Dtsch Med Wochenschr 1981;106:1126–9. 63. Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazol therapy for perianal Crohn disease: a follow-up study. Gastroenterology 1982;83:383–7. 64. Jakobovits J, Schuster MM. Metronidazol therapy for Crohn disease and associated fistulae. Am J Gastroenterol 1984;79:533–40. 65. Schneider MU, Laudage G, Guggenmoos-Holzmann I, Riemann JF. [Metronidazol in the treatment of Crohn disease. Results of a controlled randomized prospective study]. Dtsch Med Wochenschr 1985;110:1724–30. 66. Turunen U, Farkkila M, Seppala K. Long-term treatment of perianal or fistulous Crohn disease with ciprofloxacin. Scand J Gastroenterol Suppl 1989;24:144. 67. Wolf JL. Ciprofloxacin may be useful in Crohn disease (abstr). Gastroenterology 1990;98:A212. 68. Solomon MJ, McLeod RS, O’Connor BI, Steinhart AH, Greenberg GR, Cohen Z. Combination ciprofloxacin and metronidazol in severe perianal Crohn disease. Can J Gastroenterol 1993;7:571–3. 69. Turunen U, Farkkila M, Valtonen V. Long-term outcome of ciprofloxacin treatment in severe perianal or fistulous Crohn disease (abstr). Gastroenterology 1993;104:A793. 70. Freeman CD, Klutman NE, Lamp KC. Metronidazol. A therapeutic review and update. Drugs 1997;54:679–708. 71. Davis R, Markham A, Balfour JA. Ciprofloxacin. An updated review of its pharmacology, therapeutic efficacy and tolerability. Drugs 1996;51:1019–74. 72. Casparian JM, Luchi M, Moffat RE, Hinthorn D. Quinolones and tendon ruptures. South Med J 2000;93:488–91. 73. Brooke BN, Hoffman DC, Swarbrick ET. Azathioprine for Crohn disease. Lancet 1969;2:612–4. 74. Willoughby JM, Beckett J, Kumar PJ, Dawson AM. Controlled trial of azathioprine in Crohn disease. Lancet 1971;2:944–7. 75. Rhodes J, Bainton D, Beck P, Campbell H. Controlled trial of azathioprine in Crohn disease. Lancet 1971;2:1273–6. 76. Klein M, Binder HJ, Mitchell M, Aaronson R, Spiro H. Treatment of Crohn disease with azathioprine: a controlled evaluation. Gastroenterology 1974;66:916–22. 77. Rosenberg JL, Levin B, Wall AJ, Kirsner JB. A controlled trial of azathioprine in Crohn disease. Am J Digest Dis 1975;20:721–6. 78. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn disease with mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980;302:981–7. 79. Pearson D, May G, Fick G, Sutherland L. Azathioprine and 6-mercaptopurine in Crohn disease: a meta analysis. Ann Intern Med 1995;123:132–42. 80. Korelitz BI, Present DH. Favorable effect of mercaptopurine on fistulae of Crohn disease. Digest Dis Sci 1985;30:58–64. 81. Jeshion WC, Larsen KL, Jawad AF, Piccoli DA, Verma R, Maller ES, Baldassano RN. Azathioprine and 6-mercaptopurine for the treatment of perianal Crohn disease in children. J Clin Gastroenterol 2000;30:294–8. 82. Dejaco C, Harrer M, Waldhoer T, Miehsler W, Vogelsang H, Reinisch W. Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn disease. Aliment Pharmacol Ther 2003;18:1113–20. 83. Arseneau KO, Cohn SM, Cominelli F, Connors AF Jr. Cost-utility of initial medical management for Crohn disease perianal fistulae. Gastroenterology 2001;120:1640–56. 84. Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology 2006;130:1047–53. 85. Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989;111:641–9. 86. Dayharsh GA, Loftus EV Jr, Sandborn WJ, Tremaine WJ, Zinsmeister AR, Witzig TE, Macon WR, Burgart LJ. Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology 2002;122:72–7.
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87. Vandeputte L, D’Haens G, Beart F, Rutgeerts P. Methotrexate in refractory Crohn disease. Inflamm Bowel Dis 1999;5:11–5. 88. Mahadevan U, Marion JF, Present DH. Fistula response to methotrexate in Crohn disease: a case series. Aliment Pharmacol Ther 2003;18:1003–8. 89. Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 1996;91:423–33. 90. Lemann M, Zenjari T, Bouhnik Y, Cosnes J, Mesnard B, Rambaud JC. Methotrexate in Crohn disease: long-term efficacy and toxicity. Am J Gastroenterol 2000;95:1730–4. 91. Fukushima T, Sugita A, Masuzawa S, Yamazaki Y, Tsuchiya S. Effects of cyclosporine A on active Crohn disease. Gastroenterol Jpn 1989;24:12–5. 92. Lichtiger S. Cyclosporin therapy in inflammatory bowel disease: open-label experience. Mt Sinai J Med 1990;57:315–9. 93. Markowitz J, Rosa J, Grancher K, Aiges H, Daum F. Long-term 6-mercaptopurine treatment in adolescents with Crohn disease. Gastroenterology 1990;99:1347–51. 94. Hanauer SB, Smith MB. Rapid closure of Crohn disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993;88:646–9. 95. Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn disease. Dig Dis Sci 1994;39:374–80. 96. Abreu-Martin J, Vasilauskas E, Gaiennie J, Voigt B, Targan SR. Continuous infusion cyclosporine is effective for acute severe Crohn disease...but for how long (abstr)? Gastroenterology 1996;110:A851. 97. O’Neill J, Pathmakanthan S, Goh J, Costello S. MacMathuna P, O’Connell R, Crowe J, Lennon J. Cyclopsorine A induces remission in fistulous Crohn disease but relapses occur upon cessation of treatment (abstr). Gastroenterology 1997;112:A1056. 98. Hinterleitner TA, Petritsch W, Aichbichler B, Fickert P, Ranner G, Krejs GJ. Combination of cyclosporine, azathioprine and prednisone for perianal fistulas in Crohn disease. Z Gastroenterol 1997;35:603–8. 99. Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn disease with intravenous cyclosporine. Am J Gastroenterol 1998;93:442–8. 100. Gurudu SR, Griffel LH, Gialanella RJ, Das KM. Cyclosporine therapy in inflammatory bowel disease: short- and long-term results. J Clin Gastroenterol 1999;29:151–4. 101. Present DH. Crohn fistula: current concepts in management. Gastroenterology 2003;124:1629–35. 102. Sandborn WJ. A critical review of cyclosporine therapy in inflammatory bowel disease. Inflamm Bowel Dis 1995;1:48–63. 103. Sandborn WJ. Preliminary report on the use of oral tacrolimus (FK506) in the treatment of complicated proximal small bowel and fistulizing Crohn disease. Am J Gastroenterol 1997;92:876–9. 104. Fellerman K, Ludwig D, Stahl M, David-Walek T, Stange EF. Steroid-unresponsive acute attacks of inflammatory bowel disease: immunomodulation by tacrolimus (FK506). Am J Gastroenterol 1998;93:1860–6. 105. Lowry PW, Weaver AL, Tremaine WJ, Sandborn WJ. Combination therapy with oral tacrolimus (FK506) and azathioprine or 6-mercaptopurine for treatment-refractory Crohn disease perianal fistulae. Inflamm Bowel Dis 1999;5:239–45. 106. Ierardi E, Principi M, Rendina M, Francavilla R, Ingrosso M, Pisani A, Amoruso A, Panella C, Francavilla A. Oral tacrolimus (FK506) in Crohn disease complicated by fistulae of the perineum. J Clin Gastroenterol 2000;125:30:200–2. 107. Sandborn WJ, Present DH, Isaacs KL, Wolf DC, Greenberg E, Hanauer SB, Feagan BG, Mayer L, Johnson T, Galanko J, Martin C, Sandler RS. Tacrolimus for the treatment of fistulas in patients with Crohn disease: a randomized, placebo-controlled trial. Gastroenterology 2003;125:380–88. 108. Gonzalez-Lama Y, Abreu L, Vera MI, Pastrana M, Tabernero S, Revilla J, Duran JG, Escartin P. Long-term oral tacrolimus therapy in refractory to infliximab fistulizing Crohn disease: a pilot study. Inflamm Bowel Dis 2005;11:8–15. 109. Cohen RD, Tsang JF, Hanauer SB. Infliximab in Crohn disease: first anniversary clinical experience. Am J Gastroenterol 2000;95:3469–77. 110. Farrell RJ, Shah SA, Lodhavia PJ, Alsahli M, Falchuk KR, Michetti P, Peppercorn MA. Clinical experience with infliximab therapy in 100 patients with Crohn disease. Am J Gastroenterol 2000;95:3490–7.
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111. Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Sandborn WJ. Infliximab for Crohn disease in clinical practice at the Mayo Clinic: the first 100 patients. Am J Gastroenterol 2001;96:722–9. 112. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJH. Infliximab for the treatment of fistulas in patients with Crohn disease. N Engl J Med 1999;340:1398–405. 113. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. Infliximab maintenance therapy for fistulizing Crohn disease. N Engl J Med 2004;350:876–85. 114. Sands BE, Blank MA, Patel K, van Deventer SJ. Long-term treatment of rectovaginal fistulas in Crohn disease: response to infliximab in the ACCENT II study. Clin Gastroenterol Hepatol 2004;2:912–20. 115. Cadahia V, Garcia-Carbonero A, Vivas S, Fuentes D, Nino P, Rebollo P, Rodrigo L. Infliximab improves quality of life in the short-term in patients with fistulizing Crohn disease in clinical practice. Rev Esp Enferm Dig 2004;96:369–74. 116. Lichtenstein GR, Yan S, Bala M, Blank M, Sands BE. Infliximab maintenance treatment reduces hospitalization, surgeries, and procedures in fistulizing Crohn disease. Gastroenterology 2005;128: 862–9. 117. Agnholt J, Dahlerup JF, Buntzen S, Tøttrup A, Lyhne Nielsen S, Lundorf E. Response, relapse and mucosal immune regulation after infliximab treatment in fistulating Crohn disease. Aliment Pharmacol Ther 2003;17:703–10. 118. Poritz LS, Rowe WA, Koltun WA. Remicade does not abolish the need for surgery in fistulizing Crohn disease. Dis Colon Rectum 2002;45:771–5. 119. West RL, van der Woude CJ, Hansen BE, Felt-Bersma RJF, van Tilburg AJP, Drapers JAG, Kuipers EJ. Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn disease with infliximab: a double-blind placebo-controlled study. Aliment Pharmacol Ther 2004;20:1329–36. 120. Ochsenkühn T, Göke B, Sackmann M. Combining infliximab with 6-mercaptopurine/azathioprine for fistula therapy in Crohn disease. Am J Gastroenterol 2002;97:2022–5. 121. Schröder O, Blumenstein I, Schulte-Buckholt A, Stein J. Combining infliximab and methotrexate in fistulizing Crohn disease resistant or intolerant to azathioprine. Aliment Pharmacol Ther 2004;19: 295–301. 122. Van der Hagen SJ, Baeten CG, Soeters PB, Russel MGVM, Beets-Tan RG, van Gemert WG. AntiTNF- (infliximab) used as induction treatment in case of active proctitis in a multistep strategy followed by definitive surgery of complex anal fistulas in Crohn disease: a preliminary report. Dis Colon Rectum 2005;48:758–67. 123. Talbot C, Sagar PM, Johnston MJ, Finan PJ, Burke D. Infliximab in the surgical management of complex fistulating anal Crohn disease. Colorectal Disease 2005;7:164–8. 124. Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis 1999;5:119–33. 125. Schaible TF. Long-term safety of infliximab. Can J Gastroenterol 2000;14:29C-32C. 126. Remicade (infliximab) for IV injection. Package Insert, 2002. 127. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098–104. 128. Morelli J, Wilson FA. Does administration of infliximab increase susceptibility to listeriosis? Am J Gastroenterol 2000;95:841–2. 129. Kamath BM, Mamula P, Baldassano RN, Markowitz JE. Listeria meningitis after treatment with infliximab. J Pediatr Gastroenterol Nutr 2002;34:410–2. 130. Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med 2001;344:1099–100. 131. Nakelchik M, Mangino JE. Reactivation of histoplasmosis after treatment with infliximab. Am J Med 2002;112:78. 132. Sandborn WJ, Hanauer SB, Loftus EV Jr, Tremaine WJ, Kane S, Cohen R, Hanson K, Johnson T, Schmitt D, Jeche R. An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn disease. Am J Gastroenterol 2004;99:1984–9.
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133. Feagan BG, Sandborn WJ, Baker JP, Cominelli F, Sutherland LR, Elson CD, Salzberg B, Archambault A, Bernstein CN, Lichtenstein GR, Heath PK, Hanauer SB. A randomized, double-blind, placebocontrolled multicenter trial of the engineered human antibody to TNF (CDP571) for steroid sparing and maintenance of remission in patients with steroid-dependent Crohn disease (abstr). Gastroenterology 2000;118:A655. 134. Sandborn WJ, Feagan BG, Hanauer SB, Present DH, Sutherland LR, Kamm MA, Wolf DC, Baker JP, Hawkey C, Archambault A, Bernstein CN, Novak C, Heath PK, Targan SR. An engineered human antibody to TNF (CDP571) for active Crohn disease: a randomized double-blind placebo-controlled trial. Gastroenterology 2001;120:1330–8. 135. Ehrenpreis ED, Kane SV, Cohen LB, Cohen RD, Hanauer SB. Thalidomide therapy for patients with refractory Crohn disease: an open-label trial. Gastroenterology 1999;117:1271–7. 136. Vasilauskas EA, Kam LY, Abreu-Martin MT, Hassard PV, Papadakis KA, Yang H, Zeldis JB, Targan SR. An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn disease. Gastroenterology 1999;117:1278–87. 137. Voitk AJ, Echave V, Brown RA, Gurd FN. Use of elemental during the adaptive stage of short gut syndrome. Gastroenterology 1973;65:419–26. 138. Segal AW, Levi AJ, Loewi G. Levamisole in the treatment of Crohn disease. Lancet 1977;2:382–5. 139. Axelsson C, Jarnum S. Assessment of the therapeutic value of an elemental diet in chronic inflammatory bowel disease. Scand J Gastroenterol 1977;12:89–95. 140. Russell RI, Hall MJ. Elemental diet therapy in the management of complicated Crohn disease. Scott Med J 1979;24:291–5. 141. Calam J, Crooks PE, Walker RJ. Elemental diets in the management of Crohn perianal fistulae. J Parenter Enteral Nutr 1980;4:4–8. 142. Jones VA. Comparison of total parenteral nutrition and elemental diet in induction of remission of Crohn disease. Dig Dis Sci 1987;32:100S-107S. 143. Fukuda Y, Kosaka T, Okui M, Hirakawa H, Shimoyama T. Efficacy of nutritional therapy for active Crohn disease. J Gastroenterol 1995;30:83–7. 144. Harford FJ, Fazio VW. Total parenteral nutrition as primary therapy for inflammatory bowel disease of the bowel. Dis Colon Rectum 1978;21:555–7. 145. Milewski PJ, Irving MH. Parenteral nutrition in Crohn disease. Dis Colon Rectum 1980;23:395–400. 146. Greenberg GR, Fleming CR, Jeejeebhoy KN, Rosenberg IH, Sales D, Tremaine WJ. Controlled trial of bowel rest and nutritional support in the management of Crohn disease. Gut 1988;29: 1309–15. 147. Fickert P, Hinterleitner TA, Wenzl HH, Aichbichler BW, Petritsch W. Mycopheylate mofetil in patients with Crohn disease. Am J Gastroenterol 1998;93:2529–32. 148. Vaughan D, Drumm B. Treatment of fistulas with granulocyte colony-stimulating factor in a patient with Crohn disease. N Engl J Med 1999;340:239–40. 149. Korzenik J, Dieckgraefe B. Immunostimulation in Crohn disease: results of a pilot study of G-CSF (R-Methug-CSF) in mucosal and fistulizing Crohn disease (abstr). Gastroenterology 2000; 118:A874. 150. Dieckgraefe BK, Korzenik JR. Treatment of active Crohn disease with recombinant human granulocytemacrophage colony-stimulating factor. Lancet 2002;360:1478–80. 151. Brady CE III, Cooley BJ, Davis JC. Healing of severe perianal and cutaneous Crohn disease with hyperbaric oxygen. Gastroenterology 1989;97:756–60. 152. Nelson EW Jr, Bright DE, Villar LF. Closure of refractory perianal Crohn lesion. Integration of hyperbaric oxygen into case management. Dig Dis Sci 1990;35:1561–6. 153. Brady CE III. Hyperbaric oxygen and perianal Crohn disease: a follow-up. Gastroenterology 1993;105:1264. 154. Lavy A, Weisz G, Adir Y, Ramon Y, Melamed Y, Eidelman S. Hyperbaric oxygen for perianal Crohn disease. J Clin Gastroenterol 1994;19:202–5. 155. Colombel JF, Mathieu D, Bouault JM, Lesage X, Zavadil P, Quandalle P, Cortot A. Hyperbaric oxygen in severe perianal Crohn disease. Dis Colon Rectum 1995;38:609–14. 156. Oshitani N, Nakamura S, Matsumoto T, Kobayashi K, Kitano A. Treatment of Crohn disease fistulas with coagulation factor XIII. Lancet 1996;347:119–20. 157. Teahon K, Bjarnason I, Pearson M, Levi AJ. Ten years’ experience with an elemental diet in the management of Crohn disease. Gut 1990;31:1133–7.
34 Treatment of Fulminant Colitis Harland Winter∗
Case A 10-year old boy was previously well until he acutely developed non-bloody diarrhea while on a skiing vacation. The illness was attributed to an Italian ice he had eaten the previous day, although no one else in the family was ill. The following day he continued to have nausea, vomiting and diarrhea, and started a clear liquid diet. On day three of this acute illness, he continued to pass 6-8 liquid stools daily and first noted red blood. He was treated in the emergency room with intravenous hydration and discharged. Stool cultures for enteric pathogens including Escherichia coli 0157, ova and parasites and Clostridium difficile were all negative. His white blood cell count (WBC) was 15,900, hemoglobin 13.0 g/l, and hematocrit 37%. Liver function tests, amylase and lipase were all normal. C-reactive protein (CRP) was elevated at 25 mg/dl. On day six of the illness, he noted increased bloody diarrhea and was admitted to a local hospital. Despite being kept nil per os (NPO), he continued to pass 3–4 loose, bloody stools daily. On day 10 he became febrile to 39 degrees Centigrade and continued to pass 5–6 bloody stools daily. His albumin was decreased at 2.2 g/l. He was transferred to a tertiary care facility. His past medical illness was significant for hydronephrosis noted at 20 weeks gestation that resolved two weeks post partum. He had a Coxsackie infection at age two years and had five episodes of otitis media in his first year of life. In the past nine years, he has only had two ear infections and occasional streptococcal pharyngitis. His family history revealed that maternal great grandfather and a maternal granduncle developed colon cancer when they were over 50 years of age. On transfer, his vital signs were stable and he was afebrile. He appeared pale but was resting comfortably. He had no oral ulcers. His chest and cardiac examinations were normal. His abdomen was soft with diffuse, but mild tenderness without guarding or rebound. He had no organomegaly. Following admission, an upper endoscopy was performed and it was normal, but the ileocolonoscopy revealed pancolitis (Figure 34.1) with a normal appearing terminal ileum. He was made NPO, given intravenous fluids at 1.5 times maintenance, 1 g/kg salt poor albumin and started on intravenous methylprednisolone sodium succinate 20 mg every 12 hours. Repeat stool analysis was negative. Biopsies of the colon were consistent with ulcerative colitis. Electrolytes were monitored daily and corrected as necessary; hematocrit was maintained over 30% with transfusion; albumin was replaced with salt poor albumin when below 3.0 g/dl. Because of ongoing diarrhea and bleeding, a peripherally inserted central catheter (PICC) was placed on day five for nutritional support and he was changed from peripheral intravenous nutrition to total parenteral
*Pediatric GI Unit-MGH, 175 Cambridge Street-CPZS-560, Boston, MA 02114, Phone: 617 726-1450, Fax: 617 724-2710, E-mail:
[email protected]
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Figure 34.1. Diffuse inflammation with loss of vascular pattern and ulceration, typical of the pattern seen in ulcerative colitis.
nutrition. On day six, methylprednisolone was increased to 30 mg intravenously every 12 hours. On day 10 because of the need for ongoing transfusions, he was given 5 mg/kg infliximab intravenously. Over the next two days, stool output decreased, he was started on oral feedings and was discharged on day 16 on a tapering dose of prednisone, mesalamine, and 6-mercaptopurine (6-MP) 50 mg daily. He returned in two weeks for his second infliximab infusion passing formed stools without visible blood. He continued to do well and infliximab was stopped after the fourth infusion and he remained in remission on 6-MP and mesalamine. Seven months later his lipase was noted to be three times normal and the amylase was twice normal. 6-MP was discontinued. An abdominal ultrasound and a magnetic resonance cholangio-pancreatography (MRCP) were normal. One week later, the lipase was nine times normal, but he remained asymptomatic. Mesalamine was stopped at that time. Amylase and lipase began to decrease, but three weeks later he began to experience crampy abdominal pain and hematochezia. He was restarted on mesalamine, but within one week his amylase and lipase began to rise, and mesalamine was stopped. Because he was having hematochezia without diarrhea, he was started on corticosteroid enemas and oral prednisone; however, the rectal bleeding continued and his stools increased in frequency and became more watery. He was admitted to the hospital, made NPO and started on intravenous methylprednisolone sodium succinate 20 mg every 12 hours. A colonoscopy revealed pancolitis with sparing of the terminal ileum. When he developed fever, triple antibiotics were added. He was started on total parenteral nutrition and after one week of no response to intravenous corticosteroids, he received an infliximab infusion. His stool output fell and his abdominal pain subsided, but when he began to advance his diet he became febrile and he passed greater than one liter of stool daily. His C-reactive protein was 20 times normal. He underwent a total colectomy and ileostomy on day 10. He was discharged six days later and subsequently returned for creation of a pouch.
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Discussion Children with ulcerative colitis are more likely to have pancolitis whereas, disease limited to the left colon and the rectum is more common in adults. About 20% of children at presentation with ulcerative colitis will have severe disease and require intravenous corticosteroids [1]. About 43% of children presenting with ulcerative colitis have mild disease and 57% have moderate to severe disease. At six months 90% and 81% of the children with mild and moderate/severe disease respectively have resolution of symptoms. After five years, 9% of children presenting with mild disease and 26% of children presenting with moderate/severe disease underwent colectomy [2]. At one year after diagnosis, 50% of children who were treated within 30 days of diagnosis had a response to steroids, 45% were steroid dependent and 5% underwent colectomy [1]. Severe ulcerative colitis is defined as more than six bloody stools daily and evidence of toxicity such as fever, tachycardia, anemia or an elevated erythrocyte sedimentation rate [3]. Fulminant disease is defined as passing more than 10 bowel movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, need for blood transfusions and evidence for colonic dilatation on a plain film of the abdomen [3]. The management of fulminant colitis is based on controlling gastrointestinal hemorrhage using immunosuppression and avoiding complications of the disease or the therapy [4]. For children with severe disease initial therapy is often bowel rest and intravenous methylprednisolone at a dose of 2 mg/kg divided every 12 hours with a maximum dose of 20 mg every 12 hours. Randomized controlled studies in adults suggest that bowel rest is not beneficial and may impact negatively on nutritional status [5], but children often have less abdominal cramping when they are not eating. Although the value of being NPO in promoting healing is not clear, when a child is not fed, one can determine if the amount of blood and stool frequency is truly decreasing without having to factor in the effects of enteral feeding on secretion and motility. Despite the lack of randomized controlled clinical trials to provide evidence-based guidance for optimal therapy, expert opinion suggests that healing is best achieved by keeping the hematocrit over 30%, the albumin over 3.0 g/l and the electrolytes in the normal range. In theory, avoiding anemia and hypoalbuminemia may enhance delivery of oxygen and improve mucosal blood flow. Normal electrolytes decrease the possibility of stasis related to poor motility. Antibiotics are generally not indicated unless there is evidence for toxicity or fever. Since perforations may be silent in patients on high doses of corticosteroids, any sign of infection should be investigated and treated. If a child does not respond within three days with decreasing stool and blood, parenteral nutritional support should be started. Some clinicians increase the dose of methylprednisolone to a maximum dose of 60 mg daily, but again there are no data to suggest that patients who do not respond to 40 mg daily will respond to 60 mg daily. Anecdotal experience suggests that nutrition may enhance mucosal healing and is best achieved initially by placing a PICC line to provide total parenteral nutrition. Many adult and some pediatric gastroenterologists do not believe that keeping a patient wtih ulcerative colitis NPO enhances healing and therefore some patients are fed orally as long as they tolerate the feedings. If by day 5–7, there is no improvement in the volume of bloody diarrhea, consideration of adding a second medication should be discussed with the family. Although retrospective data suggest that 75% of pediatric patients benefit from 6-MP or azathioprine after tapering off prednisone [6], these immunomodulators require about three months to become effective and do not play a role in the management of a child with fulminant colitis. However for the child with severe colitis, immunomodulators are effective maintenance medications and often permit the successful taper of corticosteroids. The options for additional therapy for the child who is not responding include cyclosporine, tacrolimus or infliximab. Tacrolimus may be given at a dose of 0.1 mg/kg/dose twice daily with subsequent dose adjustment to achieve blood levels of 10–15 ng/ml. In a small retrospective series of 14 children
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treated with tacrolimus, 69% responded and were discharged. However, at one year only 38% had achieved long-term remission [7]. Similar data exist for adults with severe colitis. In a placebo-controlled trial of adults treated with tacrolimus, those patients who were maintained at blood levels 10–15 ng/ml had significant improvement in disease activity, but only 20% achieved clinical remission. The most common side effect was tremor [8]. Intravenous cyclosporine is effective at inducing remission in up to 80% of children with severe colitis, but by one year most require colectomy [9]. In adults, the response to cyclosporine after six months is as high as 60%, but declines to about half that level after 3–5 years [10–13]. A randomized, controlled trial of two doses of cyclosporine suggest that 2 mg/kg/day was as effective as higher doses and did not have as much toxicity [14]. Patients receiving cyclosporine are at increased risk for infection, lymphoma and other neoplasms, renal insufficiency, seizures, paresthesias, hypertension, hypertrichosis, gingival hyperplasia, headache, hyperkalemia, tremor and elevated liver function tests [15]. Infliximab is more commonly being used to treat the child with ulcerative colitis who does not respond to corticosteroids. Children who are taking 6-MP have a better response to infliximab [16], but the recent reports of hepatosplenic T-cell lymphoma in children receiving the combination of 6-MP and infliximab are causing clinicians to reevaluate how best to use these medications. Infliximab appears to be less effective in steroid dependent patients [17] and a recent follow-up report suggests that infliximab is more effective when given in the acutely ill patient compared with the patient on chronic corticosteroids [18]. Similar observations have been made in the adult population in which 83% of adults who were non-steroid dependent improved with infliximab, while 33% of adults who were steroid dependent responded [19]. Outcome data are limited in children, but a series of nine children who received infliximab were assessed after two years and one third were off the medication [20]. Infusion reactions are the most common complication and are usually managed by pre-medication with diphenhydramine and acetaminophen [21]. The indications for surgical treatment for fulminant colitis are perforation, toxic megacolon, massive hemorrhage or failure to respond to maximal medical management. Surgical options include: abdominal colectomy with ileostomy and Hartmans’s pouch, which is then followed by a mucosectomy, ileal anastomosis and diverting ileostomy. At a subsequent surgery, the diverting ileostomy is taken down. Alternatively, the abdominal colectomy may be performed with mucosectomy, ileoanal anastomosis and diverting ileostomy. A second surgery is performed to take down the ileostomy. At our center, abdominal colectomy with mucosectomy and ileoanal anastomosis may be done as a single operation. The management for fulminant ulcerative colitis hinges on the response to initial treatment with corticosteroids [22]. Beginning treatment prior to the development of malnutrition and metabolic complications may improve outcomes. In one study, after three days of intravenous corticosteroid therapy, 85% of adults with greater than 8 stools daily and a C-reactive protein >4.5 mg/dl will undergo colectomy [23]. In the case presented above the CRP was elevated at the initial presentation. Extending treatment with intravenous corticosteroids beyond 14 days may increase the risk of complications without improving the chance for remission [24]. Kugathasan et al. do not recommend continuing intravenous corticosteroid therapy beyond 10 days and suggest presenting other therapeutic options such as cyclosporine, infliximab or therapy after 5–10 days of unresponsive intravenous corticosteroid therapy [5]. Toxic megacolon is always a concern, but in 70% of patients with toxic megacolon, anticholinergics, opiates, barium enema or colonoscopy were thought to be precipitating events [25]. In addition to medical management, stress management and support for the patient and family are essential components to the multidisciplinary approach needed to optimally care for children with fulminant colitis.
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References 1. Hyams J, Markowitz J, Lerer T, et al. Pediatric Inflammatory Bowel Disease Collaborative Research Group. The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol & Hepatol 4(9):1118–23, 2006. 2. Hyams J, Davis P, Grancher K, et al. Clinical outcome of ulcerative colitis in children, J Pediatr 129:81–88, 1996. 3. Kornbluth A, Sachar DB. Ulcerative colitis: practice guidelines in adults (update): American College of Gastroenterology Practice Parameters Committee. Am J Gastroenterol 99:1371–85, 2004. 4. Markowitz J, Mamula P, Baldassano R, Piccoli D. Ulcerative Colitis. http://www.emedicine.com/ ped/topic1183.htm. Last Updated March 1, 2007. 5. Kugathasan, S, Dubinsky, MC, Keljo, D, et al. Severe Colitis in Children. J Pediatr Gastroenterol Nutr 41(4):375–385, 2005. 6. Kader HA, Mascarenhas MR, Piccoli DA, et al. Experiences with 6-mercaptopurine and azathioprine therapy in pediatric patients with severe ulcerative colitis. J Pediatr Gastroenterol Nutr 28:54–58, 1999. 7. Bousvaros A, Kirschner BS, Werlin SL, et al. Oral tacrolimus treatment of severe colitis in children. J Pediatr 137(6):794–9, 2000. 8. Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 55:1255–1262, 2006. 9. Treem WR, Davis PM, Justinich CJ, Hyams JS. Cyclosporine for the treatment of fulminant ulcerative colitis in children. Immediate response, long-term results, and impact on surgery. Dis Colon Rectum 38(5):474–9, 1995. 10. McCormack G, McCormick PA, Hyland JM, et al. Cyclosporine therapy in severe ulcerative colitis: is it worth the effort? Dis Colon Rectum 45:1200–5, 2002. 11. Carbonnel F, Boruchowicz A, Duclos B, et al. Intravenous cyclosporine in attacks of ulcerative colitis: short-term and long-term responses. Dig Dis Sci 41:2471–6, 1996. 12. Arts J, D’Haens G, Zeegers M, et al. Long-term outcome of treatment with intravenous cyclosporine in patients with severe ulcerative colitis, Inflamm Bowel Dis 10:73–8, 2004. 13. Naftali T, Novis B, Pomeranz I, et al. Cyclosporine for severe ulcerative colitis. Isr Med Assoc J 2:588–91, 2000. 14. Van Assche G, D’Haens G, Noman M, et al. Randomized double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology 125:1025–31, 2003. 15. Sandborn WJ. Cyclosporin in ulcerative colitis: state of the art. Act Gastroenterol Beg 64:201–4, 2001. 16. Eidelwein AP, Cuffari C, Abadom V, Oliva-Hemker M. Infliximab efficacy in pediatric ulcerative colitis. Inflamm Bowel Dis 11(3):213–8, 2005. 17. Russell GH, Katz AJ. Infliximab is effective in acute but not chronic childhood ulcerative colitis. J Pediatr Gastroenterol Nutr 39(2):166–70, 2004. 18. Fanjiang G, Russell GH, Katz AJ. Short- and Long-term response to and weaning from infliximab therapy in pediatric ulcerative colitis. J Pediatr Gastro and Nutr 44:312–7, 2007. 19. Su C, Salzberg BA, Lewis JD, et al. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol 97:2577–84, 2002. 20. Mamula P, Markowitz JE, Cohen LJ, von Allmen D, Baldassano RN. Infliximab in pediatric ulcerative colitis: two-year follow-up. J Pediatr Gastroenterol Nutr 38(3):298–301, 2004. 21. Crandall WV, Mocker LM. Infusion reactions to infliximab in children and adolescents: frequency, outcome and a predictive model. Aliment Pharmacol Ther 17:75–84, 2003. 22. Fabio, WA. Step-Up Versus Top-Down: Application of New Biological Agents in Pediatric Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 4(9):1094–1096, 2006. 23. Travis SP, Arrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut 38:905–10, 1996. 24. Werlin SL, Grand RJ. Severe colitis in children and adolescents: diagnosis. Course, and treatment. Gastroenterology 73:828–32, 1977. 25. Hurting WA, Arvanitakis C, Skibba RM, Klotz AP. Treatment of toxic megacolon. A comparative review of 29 patients. Am J Dig Dis 22:195–200, 1977.
Section 5 Surgical Therapy
35 Surgical Management of Crohn’s Disease Daniel von Allmen∗
Introduction Surgery plays an important role in the treatment of Crohn’s disease. Crohn’s disease has a major impact on quality of life in the pediatric population [1] and unfortunately, despite the dramatic improvements in medical therapies, 70–80% of patients who carry the diagnosis of Crohn’s disease undergo some type of surgical procedure at some point during the course of their disease [2–4]. The indications for surgery have evolved over time with a trend toward less invasive procedures [5] and fewer emergency surgery operations because of an acute complication of the disease. However, the basic role of surgery has not changed. Crohn’s disease cannot be cured in the operating room so the procedures are palliative by nature. Surgery is unavoidable in some cases and the preferred treatment option in many others. As with many diseases in children, studies specific to the pediatric population are not always available making it necessary to extrapolate the results of adult series when considering treatment options for younger patients. Although some differences between the patient populations exist, the philosophy remains the same. Surgical intervention is an integral part of the management of patients with Crohn’s disease but should be invoked judiciously to avoid the potential for long term consequences of multiple bowel resections and procedures should always be carried out with the long term potential for short bowel syndrome in mind.
History of Surgical Therapy When Crohn’s disease was first described in the early 1930’s, the surgical therapy typically involved resection of the terminal ileum with an ileocolic anastomosis. In this era, before the development of antibiotics and sophisticated electrolyte replacement and nutritional support, the mortality for this operation was 25% [6]. In an effort to improve the surgical outcomes and reduce mortality, many surgeons moved to a two-stage approach in which the diseased segment of bowel was bypassed with an ileocolostomy leaving the diseased segment of terminal ileum as a blind pouch emptying into the cecum. Months later the patient was returned to the operating room for resection of the diseased segment. Although this approach required a second trip to
*Division of Pediatric Surgery, The University of North Carolina Chapel Hill, CB# 7223, 3010 Old Clinic Building, Chapel Hill, NC 27599, Phone: (919) 966-4643, Fax: (919) 843-2497, Email:
[email protected]
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the operating room to resect the bypassed segment, surgical mortality was substantially reduced. As experience with this approach increased it became clear that the bypassed segment often improved and ceased causing problems. Many surgeons subsequently abandoned resection of the diseased segment altogether resulting in a dramatic improvement in surgical mortality. In one study mortality in 145 patients was 16% for one stage operations, 12% for two-stage operations and 0% in ileotransversecolostomy with exclusion [7]. Unfortunately, it became apparent that there were long-term consequences to bypassing the diseased segment and right side of the colon and leaving it in-situ. Function of normal colonic tissue was sacrificed and increased risks of malignant changes in the small bowel were reported [8]. Fortunately, with improvements in perioperative surgical care, the risk of a primary definitive procedure has been reduced to the point where it has once again become the operation of first choice and is associated with extremely low mortality rates.
Operative Indications The indications for surgical intervention in Crohn’s disease are varied and often patient specific, especially in children. However, the principles regarding surgical intervention are similar regardless of the age of the patient. The goal of an operation for Crohn’s disease is to control one of the many mechanical complications resulting from the inflammatory process in the intestine. It is palliative rather than curative although it may be unavoidable. There are many clinical situations that warrant consideration of a surgical procedure during the course of a child’s disease (Table 35.1). Some require urgent operation while most are more elective in nature. The most common complications leading to a surgical intervention are obstruction, abscesses, fistulas, and failure or intolerance of pharmacological treatment [9–11]. The indications for surgery have evolved somewhat as medical treatments have improved. A study examining surgical indications in the period from 1970–1990 compared to the period from 1991–1997 revealed that active disease as an indication for surgery decreased from 64% to 25% of cases while chronic stricture increased from 9% to 50% of cases. In addition, the time from diagnosis to initial operation increased from 3.5 to 11.5 years [12]. This evolution suggests that medical therapy has been successful in altering the course of disease by controlling acute flairs but not necessarily preventing ultimate progression in many cases. Fortunately, the shift to less emergent operation reduces the morbidity associated with a surgical intervention. Absolute indications for surgery are rare and many patients present with multiple relative indications rather than an acute precipitating event. In a large cohort of adults with Crohn’s disease the decision to proceed with surgery were distributed as follows: failure of medical management in 220, obstruction in 94, intestinal fistula in 68, mass in 56, abdominal abscess in 33, hemorrhage in 7, and peritonitis in 9 [13]. As our understanding of inflammatory bowel disease has increased, it has become clear that there are different variants of Crohn’s disease and some phenotypes are more likely develop complications likely to require operative intervention. Studies of genotype-phenotype relationship
Table 35.1. Complications of Crohn’s Disease Obstruction Perforation Phlegmon Drug allergies Perineal disease Progression
Bleeding Fistula Abscess Drug resistance Urologic complications Growth failure
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indicate that patients with disease characterized by Nod2/CARD15 gene are particularly prone to the development of intestinal strictures [14] and these patients may require surgical intervention more often and earlier in the course of their disease. As our understanding of the relationship between genotype and phenotype grows, it may be possible to target specific patient populations for specific types of surgical intervention based on response rates and specific disease characteristics. In the pediatric population there are a number of relative indications for surgery that differ from those in adults. Medical therapy for Crohn’s disease can have devastating side effects and many of these adverse consequences can be greatly reduced by treating segmental areas of disease surgically allowing reduction or discontinuation of the offending agent. While all of the medications used to treat Crohn’s disease have side effects, steroid therapy is the most common culprit for causing problems in children. Growth failure, osteoporosis, psychological/emotional alterations and body habitus changes can all prove intolerable. The surgeon treating children must appreciate the impact of the issue of growth and development in that patient population [15]. In as many as 50% of pediatric patients the indication for surgery may be failure of medical therapy with growth retardation rather than obstruction or other mechanical complication [16]. In one study of children who had received extensive medical and or nutritional treatment before surgery, 26 patients underwent intestinal resections. The indication for surgery was chronic intestinal obstruction in 13 cases and chronic intestinal disability leading to growth failure in 13 cases [17]. Furthermore, the timing of surgery for growth issues is critical in the adolescent. Surgical intervention must occur well before epiphyseal plates close to allow sufficient time for subsequent catch up growth following the operation [18]. Fortunately, surgical treatments have evolved along with medical therapy and current surgical procedures are safer and less invasive than at any time in the past. Surgery has progressed from a treatment of last resort for life threatening complications to therapy for use in conjunction with medical interventions to maximize the patient’s quality of life. While the specter of short bowel syndrome must be kept in mind, elective procedures to treat the complications of Crohn’s disease can be accomplished safely and effectively [19]. While medical therapy may one day render surgical therapy unnecessary, at present, the surgeon remains an integral part of the treatment team for patients with any inflammatory bowel disease and Crohn’s disease in particular.
Surgical Emergencies Patients who develop either perforation with diffuse peritonitis or obstruction that is unresponsive to medical management are rare but may require an urgent operation. The operative goal in this situation is to control sepsis and decompress the intestine with as little risk to the patient as possible. The peritoneal cavity may be very hostile with inflammatory adhesions, fistulas, friable bowel, and diffuse peritonitis that make any extensive dissection ill advised. Rather than proceed with extensive surgery, often the most prudent approach is to divert the fecal stream with a proximal ostomy [20]. Resection of the involved segment may or may not be possible and occasionally a proximal diversion is necessary without addressing the actual diseased bowel. In other cases the perforated or obstructed segment can be resected but sepsis or lack of bowel integrity make bowel anastomosis unsafe. Fortunately, permanent ileostomy is rare in the pediatric patient which is important since ileostomies are associated with significant complications at the ileostomy site in addition to the accompanying social stigmata [21]. Once the intra-abdominal sepsis is controlled and the inflammatory adhesions are allowed to resolve for at least 6–8 weeks following emergent ileostomy, a more definitive procedure with ostomy closure should be undertaken. Although no one, especially teenagers and their parents, want an ileostomy, attempting an extensive dissection or bowel anastomosis in the face of severe inflammation can result in the loss of large segments of small bowel which is more detrimental in the long run.
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Similarly, patients with a complete bowel obstruction that does not respond to medical therapy of the Crohn’s disease require surgical intervention [22]. In patients without evidence of abdominal sepsis or bowel compromise, medical management may allow complete obstruction to resolve and should be attempted prior to surgery. This is especially true in cases involving difficult areas to treat surgically such as the duodenum where avoiding surgical intervention is desirable [23]. If the obstruction fails to resolve or evidence of bowel compromise is present, operation must be undertaken without the ability to prepare the bowel for primary anastomosis. At surgery the bowel is often inflamed and friable and although a definitive resection with reanastomosis may be possible, the patient and family must be prepared for a temporary diverting ostomy to avoid the risks of a bowel anastomosis. Temporary ileostomy with subsequent closure avoids the risk of an anastomotic leak with potentially devastating complications. Patients that have had multiple previous abdominal operations may be particularly challenging because of preexisting adhesions and scar tissue. Studies suggest that as many as half of the patients undergoing reoperative surgery will require ileostomy formation [24]. In many pediatric patients this is less of an issue because often patients are making their first trip to the operating room but one should never hesitate to perform a temporary bowel diversion when primary anastomosis may be unsafe.
Elective Surgery The indication for surgical intervention is more commonly not emergent and the timing of the intervention requires the careful consideration of the surgeon, the gastroenterologist and the family. The typical indications for surgery include failure of medical management, stricturing disease with near obstructing lesions, fistulas, and complications related to the side effects of medical therapy. The presence of a stricture alone is not an indication for operation. Areas of diseased bowel that do not present a mechanical impediment to the flow of the intestinal contents do not require intervention. However, significant chronic obstruction is suggested by dilation of bowel loops proximal to the diseased area (Figure 35.1). These changes signify a possible impending complete obstruction and elective resection prior to that allows the opportunity for bowel preparation and resection with primary anastomosis rather than a two-stage procedure requiring temporary diversion with subsequent ileostomy closure. Entero-entero fistulas, chronic phlegmon, and enterocutaneous fistulas are other mechanical indications for operative intervention which can be dealt with after careful radiographic studies to delineate the anatomy and preoperative patient preparation. Fistulas to the urinary tract with recurrent urinary tract infections may not constitute an urgent indication for operation but continued soiling of the urinary tract could result in progressive renal dysfunction arguing for earlier rather than later intervention in these situations. Although some patients will respond to medical therapy, vast majority of patients will require surgical intervention [25–28]. Enterovesical fistulas are treated with takedown of the fistula and closure of the bladder while ureteral fistulas may require resection with reanastomosis or reimplantation of the ureter. Finally, progression of the disease with persistent symptoms despite maximal medical therapy may also be the impetus for considering the surgical option. Regardless of the indication, the philosophy of therapy remains the same. The surgical procedure must be tailored to the individual patient with an eye toward preserving all possible small bowel length while providing the most effective palliation of the presenting complication of the Crohn’s disease. Surgical intervention in patients with progressive or chronic symptoms related to stricturing or fistulizing disease in the abdomen is effective in relieving symptoms and can minimize absence from school and improve overall well being when compared to non-operative therapy [29].
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Figure 35.1. Ileal stricture secondary to Crohn’s disease.
Surgical Therapy The procedure performed at the time of operation depends on the clinical situation and extent of the disease. As mentioned previously, in patients that are acutely ill with sepsis or complete obstruction, simple diversion may be the most appropriate response. However, in most patients a more definitive procedure is performed. In pediatric patients with stricturing disease, the terminal ileum is the most common site involved Figure 35.3. Often the disease extends up to include the ileocecal valve and the most common approach is bowel resection extending from the proximal extent of the disease in the ileum to the ascending colon, which is usually uninvolved. Bowel continuity is restored with a primary anastomosis (Figure 35.2). In an effort to preserve as much bowel length as possible only gross disease is resected since recurrent disease may require additional surgery and bowel length may be shorter than normal in patients with Crohn’s disease leaving less margin for resection before developing issues with poor absorption [30]. The actual technical aspects of the procedure vary somewhat by surgeon and are largely a matter of training and experience. Bowel resection is carried out in the standard fashion with no need to obtain clear margins or mesenteric lymph nodes as might be required for a cancer operation. The only technical aspect of the procedure that may impact outcome is the manner in which the bowel is anastomosed. There are a number of techniques for reanastomosing bowel with the most surgeons performing either a hand sewn end to end anastomosis or a side to side, functional end to end stapled anastomosis. There is some evidence to suggest that a stapled anastomosis may reduce the time to recurrence in patients with Crohn’s disease [31–38]. The reason for this is unclear and may have to do with the diameter of the resulting anastomosis or the non-reactive nature of the staples. Alternatively, it may have more to do with the anatomic orientation of the anastomosis rather than the manner in which the bowel is reapproximated [39]. The other reported benefit of a stapled
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Figure 35.2. Surgical resection of terminal ileal disease with primary anastomosis (Fazio).
anastomosis has to do with the incidence of post-operative complications. Anastomotic leaks and intra-abdominal abscesses are less common with the stapled anastomosis in some series but not in others [35, 40–43]. Complications following bowel resection and anastomosis in Crohn’s patients are common and are most often infectious in nature. Wound infections are most common and occur in as may as 20% of patients while more serious intra-abdominal infection related to anastomotic leak occur in
Figure 35.3. Gross appearance of disease ileum with fat wrapping and bowel wall thickening.
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3–10% [35, 44]. Wound complications are treated with local care while anastomotic complications may require reoperation with revision or temporary diversion with an ostomy.
Stricturoplasty Diffuse small bowel disease with skip lesions or strictures that do not involve the ileocecal valve allows for some additional options in surgical treatment. Short segments are often resected with primary anastomosis when it represents the only area of disease. However, multiple short segments or longer segments up to 20 cm in length may be amenable to stricturoplasty rather than resection in an effort to preserve bowel length. The technique entails a longitudinal enterotomy through the strictured segment with closure in a transverse fashion to relieve the obstruction (Heineke-Mikulicz stricturoplasty)(Figure 35.4). While it seems somewhat counterintuitive to leave the diseased bowel in-situ, the results following this operation are quite good even when applied to multiple strictures in the same patient [45]. Surprisingly, the rate at which recurrent disease occurs at the stricturoplasty site is low [46] and the technique has been used for many years with results from long term follow-up studies supporting its use. Recurrence rates following stricturoplasty are on the order of 15% at 2 years and 20% at 5 years [47]. There are a number of technical modifications of this technique that allow for longer segments to be preserved while relieving obstruction [48–52]. In a study of 102 patients undergoing a non-conventional strictureplasty from a longer segment of intestine, there were 48 ileoileal side-toside isoperistaltic strictureplasties, 41 widening ileocolic stricturoplasties, 32 ileocolic side-to-side isoperistaltic strictureplasties, which were associated with Heineke-Mikulicz strictureplasties in
Figure 35.4. Stricturoplasty technique (Fazio).
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80 procedures or with short segmental bowel resections or both in 47 procedures. The postoperative complication rate was 5.7% which is consistent with the complication rate from the more common Heineke-Mikulicz strictureplasty. The 10 year clinical recurrence rate was 43% and the recurrence rate at the previously affected site was only 0.8% [50]. In another study long segment stricturoplasty (>20 cm) was reported to have recurrence rates that are not significantly different than that for shorter segment disease. Recurrence rates were 20–35% at 3 years, 50% at 5 yrs and 60% at 10 yrs with no difference in complications between the groups [49]. In some very difficult situations such as long duodenal strictures, other modifications of the stricturoplasty technique can be applied. In one such case a jejunal patch was used to successfully relieve the obstruction and avoid intestinal bypass in a patient with a difficult duodenal stricture [53].
Laparoscopy The most recent advances in surgical treatment of intra-abdominal complications of Crohn’s disease have been the application of minimally invasive surgical techniques. As with many of the other conditions to which laparoscopic techniques have been applied, multiple studies have demonstrated a decrease in hospital length of stay, more rapid return to work, less postoperative narcotic use and improved cosmetic results. Similarly, the application of laparoscopic techniques to Crohn’s disease in children and adults also yields shorter hospital stays, decreased need for parenteral narcotics, and faster return to a regular diet [54–63]. The techniques employed often use laparoscopic exploration of the abdomen with mobilization of the diseased bowel segment. Various sealer/cutting devices facilitate taking the mesentery of involved segments without additional blood loss and stapling devices allow for dividing the bowel at the margins of disease. Anastomosis may be carried out extracorporeally after the diseased segment is delivered from the abdomen through a small incision or intracorporeally using the laparoscopic stapling devices. Although complicated disease involving fistulas or phlegmon was considered a relative contraindication to the laparoscopic approach, many cases are now handled by experienced surgeons without an increase in complication rate [64–69]. One potential benefit of the laparoscopic approach is a reduction in post-operative adhesion formation. This carries added importance in the Crohn’s populations where disease recurrence is more the rule than the exception and reoperation is often necessary. Approaching recurrent disease laparoscopically is also feasible without an increased complication rate [70, 71]. In the long run, patients’ quality of life does not appear to be impacted by the technique used at the time of surgery [71, 72]. However, the advantage of the minimally invasive approach likely extends beyond quality of life measurements. Reduced intra-abdominal adhesion formation, faster resumption of full enteral nutrition and perhaps less psychological trauma related to body image issues are all of particular significance to the pediatric patient population.
Colonic Disease Crohn’s colitis requires a different approach than for small bowel disease. Colonic disease is traditionally regarded as being more aggressive and the colon is not necessary for the nutritional function of the intestinal tract so some advocate subtotal colectomy rather than segmental resections when colonic involvement requires surgical intervention. However, segmental resection offers the opportunity to preserve colonic function and avoid or delay the potential for permanent ileostomy and has become the more common approach [12]. Fewer symptoms, fewer loose stools and better anorectal function have been reported following segmental resection and the
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re-resection rate did not differ from patients undergoing subtotal colectomy [73, 74]. Conversely, patients with pancolitis or severe distal colonic disease have been reported to have longer disease free intervals [75] and wean from chronic medications more often when treated with subtotal colectomy or proctocolectomy when compared to those undergoing segmental resection. However, these patients also had a higher incidence of permanent diverting ileostomy [76, 77] suggesting that segmental resection for pediatric patients with colonic Crohn’s disease is preferable when possible. Laparoscopic techniques are possible and show similar advantages of those described in small bowel resection [78].
Perineal Disease Fistulizing perineal disease is an area in which surgical intervention has classically been avoided given the risk of non-healing wounds and incontinence. More recently, however, the use of early surgical evaluation has been found to provide important information to help guide the medical management. While fistulotomy and incision and drainage of local abscesses were fraught with long term complications in the past, the use of new biologic agents such as infliximab have rendered early surgical intervention not only safe, but necessary for rapid control of the disease. Medical therapy for perineal disease has been greatly improved with the advent of biologic agents. Two controlled trials support the efficacy of infiximab in achieving closure of perineal fistulas [79] and the combination of infliximab and surgical treatment of fistulizing perineal disease can result in marked improvement of perineal disease which is superior to infliximab alone [80–82]. Conversely, infliximab treatment does not prevent the need for surgery for fistulizing Crohn’s disease [83]. Treatment algorithms in pediatric inflammatory bowel disease centers have evolved to include an aggressive surgical approach early. Examination under anesthesia is particularly useful in the pediatric population. Comprehensive rectal examination is often difficult in the clinic setting in younger patients that are unable to cooperate fully with the exam. General anesthesia in the operating room provides the ideal environment to carefully evaluate the extent of disease with delineation of fistula tracts, abscesses and rectal strictures. A complete assessment of the extent of the disease is important to help guide medical therapy. Once the extent of disease is determined, therapeutic measures can be performed during the same anesthetic. If fistulae-in-ano are present, they can be probed to ascertain the anatomy. Superficial tracts are treated with fistulotomy while for more complex tracts a non-cutting seton placement is placed. Initial surgical treatment may improve the response to subsequent pharmacologic therapy. Local infection can be controlled, strictures dilated and complex fistulas delineated and controlled with seton placement. Following initiation of treatment with infliximab, the seton is removed to allow the fistula tract to close. Abscesses are drained and strictures can be sized and dilated.
Rectal Strictures Low rectal and anal strictures caused by chronic fibrosis from chronic inflammation can be successfully treated with transanal dilations [79]. Younger pediatric patients may require dilations under anesthesia on a regular basis while older patients will tolerate dilations in the office or at home. Incontinence can result from over dilation of rectal strictures or operative damage to the muscles during fistulotomy but it is often difficult to separate the impact of the dilations relative to the underlying disease process. Tight irregular strictures longer than 3–4 cm without a clear lumen are a relative contraindication to dilation because perforation of the rectum is possible, particularly in small pediatric patients. Initial dilation in the operating room guided by fluoroscopy
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may reduce the risk of subsequent outpatient dilations. Treatment with dilations may be needed for many months and ultimately the result is dependent on systemic control of the disease process. Strictures that do not respond to chronic dilations may eventually require a diverting colostomy. The combination of anal stricture and colonic Crohn’s disease ultimately leads to fecal diversion in more than 50% of patients [84].
Impact of Medical Therapy Many of the drugs used to treat Crohn’s disease have the potential to increase complications following surgical procedures. Steroids significantly impair wound healing. Risks of abdominal wound infection, abdominal wound dehiscence, and anastomotic dehiscence are all potentially increased in the presence of steroids. While the risks of operating on Crohn’s patients being treated concurrently with steroids is likely increased, the data in the literature to support that fear is circumstantial. Studies have demonstrated an apparent increase risk of early complications in patients with ulcerative colitis undergoing definitive surgery while on chronic steroids while complications were not increased in patients weaned off steroids prior to surgery [85]. Asthma patients treated with steroids during the perioperative period failed to show an increased complication rate over controls [86] suggesting that the impact of steroids on Crohn’s patients may be cumulative with the other risk factors in these patients. Infliximab therapy does not appear to increase the rate of perioperative complications associated with bowel resections for Crohn’s disease [44, 87].
Post-operative Recurrence Recurrence of Crohn’s disease following a surgical resection is common. In many cases medical therapy is discontinued following surgical treatment but continued therapy with a number of drugs has been investigated to improve disease free intervals. Agents including the 5-aminosalicylate formulations, antibiotics, steroids and azathioprine have been examined. None of these therapies has convincingly been shown to prevent recurrent lesions [88]. Infliximab has been reported effective in a single case report [89]. The antibiotics metronidazole and ornidazole have shown efficacy, but cannot be used in the long-term because of side effects [90]. 6-Mercaptopurine and azathioprine may be more effective than mesalamine [79, 91, 92].
Adjuvant Procedures Finally, there are well documented complications of growth and development in the pediatric population [93]. Pediatric patients are at particular risk for nutritional complications because of the normal rapid growth and development in children. Delayed puberty, short stature and bone demineralization may all be indications for supplemental nutritional support. Surgical adjuncts to care such as gastrostomy tubes and devices for chronic parenteral access may prove to be lifesaving measures for some patients. Compliance with medical regimens in the pediatric population can be challenging and providing these types of devices early with minimal trauma may help minimize the impact of the disease on these nutritional issues. Low residue diets are frequently used in pediatric patients with progressive stricturing disease in the small bowel. The social impact of an in-dwelling nasogastric feeding tube may inhibit compliance in the teenage population making these children candidates for percutaneous or laparoscopically placed gastrostomy tubes. The laparoscopic approach allows direct visualization of the stomach to properly site the tube, secure the stomach to the abdominal wall and place a primary button device without the scarring associated with the open approach.
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Patients unable to tolerate adequate enteral feedings are often candidates for supplemental parenteral nutritional support. In these cases, surgically placed central venous access devices may significantly improve lifestyle by providing stable chronic venous access for infusions and blood sampling. Either cuffed catheters or part devices may be indicated. References 1. Rabbett H, Elbadri A, Thwaites R, et al. Quality of life in children with Crohn’s disease. J Pediatr Gastroenterol Nutr. 1996 Dec;23(5):528–33. 2. Hancock L, Windsor AC, Mortensen NJ. Inflammatory bowel disease: the view of the surgeon. Colorectal Dis. 2006 May;8 Suppl 1:10–4. 3. Schraut WH. The surgical management of Crohn’s disease. Gastroenterol Clin North Am. 2002 Mar;31(1):255–63. 4. Poggioli G, Pierangeli F, Laureti S, Ugolini F. Review article: indication and type of surgery in Crohn’s disease. Aliment Pharmacol Ther. 2002 Jul;16 Suppl 4:59–64. 5. Leowardi C, Heuschen G, Kienle P, et al. Surgical treatment of severe inflammatory bowel diseases. Dig Dis. 2003;21(1):54–62. 6. Aufses AH, Jr. The history of Crohn’s disease. Surg Clin North Am. 2001 Feb;81(1):1–11, vii. 7. Garlock JH, Crohn’s BB. Appraisal of results of surgery in the treatment of regional enteritis. J Am Med Assoc. 1945;127:205–8. 8. Greenstein AJ Sachar D, Pucillo A, et al. Cancer in Crohn’s disease after divisionary surgery. A report of seven carcinomas occurring in excluded bowel. Am J Surg. 1978;135:86–90. 9. Dziki A, Galbfach P. Crohn’s disease–when to operate? Acta Chir Iugosl. 2004;51(2):61–8. 10. McLeod RS. Surgery for inflammatory bowel diseases. Dig Dis. 2003;21(2):168–79. 11. Veroux M, Angriman I, Ruffolo C, et al. Severe gastrointestinal bleeding in Crohn’s disease. Ann Ital Chir. 2003 Mar–Apr;74(2):213–5; discussion 6. 12. Andersson P, Olaison G, Bodemar G, et al. Surgery for Crohn’s colitis over a twenty-eight-year period: fewer stomas and the replacement of total colectomy by segmental resection. Scand J Gastroenterol. 2002 Jan;37(1):68–73. 13. Hurst RD, Molinari M, Chung TP, et al. Prospective study of the features, indications, and surgical treatment in 513 consecutive patients affected by Crohn’s disease. Surgery. 1997 Oct;122(4):661–7; discussion 7–8. 14. Alvarez-Lobos M, Arostegui JI, Sans M, et al. Crohn’s disease patients carrying Nod2/CARD15 gene variants have an increased and early need for first surgery due to stricturing disease and higher rate of surgical recurrence. Ann Surg. 2005 Nov;242(5):693–700. 15. Rufo PA, Bousvaros A. Current Therapy of Inflammatory Bowel Disease in Children. Paediatr Drugs. 2006;8(5):279–302. 16. Patel HI, Leichtner AM, Colodny AH, Shamberger RC. Surgery for Crohn’s disease in infants and children. J Pediatr Surg. 1997 Jul;32(7):1063–7; discussion 7–8. 17. Dokucu AI, Sarnacki S, Michel JL, et al. Indications and results of surgery in patients with Crohn’s disease with onset under 10 years of age: a series of 18 patients. Eur J Pediatr Surg. 2002 Jun;12(3):180– 5. 18. Konno M, Kobayashi A, Tomomasa T, et al. Guidelines for the treatment of Crohn’s disease in children. Pediatr Int. 2006 Jun;48(3):349–52. 19. Nissan A, Zamir O, Spira RM, et al. A more liberal approach to the surgical treatment of Crohn’s disease. Am J Surg. 1997 Sep;174(3):339–41. 20. Berg DF, Bahadursingh AM, Kaminski DL, Longo WE. Acute surgical emergencies in inflammatory bowel disease. Am J Surg. 2002 Jul;184(1):45–51. 21. Ecker KW, Gierend M, Kreissler-Haag D, Feifel G. Reoperations at the ileostomy in Crohn’s disease reflect inflammatory activity rather than surgical stoma complications alone. Int J Colorectal Dis. 2001 Apr;16(2):76–80. 22. Froehlich F, Juillerat P, Mottet C, et al. Obstructive fibrostenotic Crohn’s disease. Digestion. 2005;71(1):29–30. 23. Karaoglu AO, Yukselen V. Obstructing Crohn’s disease of the duodenum: is surgery always mandatory? Int J Clin Pract. 2004 Feb;58(2):221–3.
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24. Heimann TM, Greenstein AJ, Lewis B, et al. Comparison of primary and reoperative surgery in patients with Crohn’s disease. Ann Surg. 1998 Apr;227(4):492–5. 25. Solem CA, Loftus EV, Jr., Tremaine WJ, et al. Fistulas to the urinary system in Crohn’s disease: clinical features and outcomes. Am J Gastroenterol. 2002 Sep;97(9):2300–5. 26. Present DH. Urinary tract fistulas in Crohn’s disease: surgery versus medical therapy. Am J Gastroenterol. 2002 Sep;97(9):2165–7. 27. Gruner JS, Sehon JK, Johnson LW. Diagnosis and management of enterovesical fistulas in patients with Crohn’s disease. Am Surg. 2002 Aug;68(8):714–9. 28. Ben-Ami H, Ginesin Y, Behar DM, et al. Diagnosis and treatment of urinary tract complications in Crohn’s disease: an experience over 15 years. Can J Gastroenterol. 2002 Apr;16(4):225–9. 29. Akobeng AK, Suresh-Babu MV, Firth D, et al. Quality of life in children with Crohn’s disease: a pilot study. J Pediatr Gastroenterol Nutr. 1999 Apr;28(4):S37–9. 30. Glehen O, Lifante JC, Vignal J, et al. Small bowel length in Crohn’s disease. Int J Colorectal Dis. 2003 Sep;18(5):423–7. 31. Yamamoto T, Bain IM, Mylonakis E, et al. Stapled functional end-to-end anastomosis versus sutured end-to-end anastomosis after ileocolonic resection in Crohn’s disease. Scand J Gastroenterol. 1999 Jul;34(7):708–13. 32. Ikeuchi H, Kusunoki M, Yamamura T. Long-term results of stapled and hand-sewn anastomoses in patients with Crohn’s disease. Dig Surg. 2000;17(5):493–6. 33. Tersigni R, Alessandroni L, Barreca M, et al. Does stapled functional end-to-end anastomosis affect recurrence of Crohn’s disease after ileocolonic resection? Hepatogastroenterology. 2003 Sep–Oct;50(53):1422–5. 34. Yamamoto T. Factors affecting recurrence after surgery for Crohn’s disease. World J Gastroenterol. 2005 Jul 14;11(26):3971–9. 35. Resegotti A, Astegiano M, Farina EC, et al. Side-to-side stapled anastomosis strongly reduces anastomotic leak rates in Crohn’s disease surgery. Dis Colon Rectum. 2005 Mar;48(3):464–8. 36. Larson DW, Pemberton JH. Current concepts and controversies in surgery for IBD. Gastroenterology. 2004 May;126(6):1611–9. 37. Munoz-Juarez M, Yamamoto T, Wolff BG, Keighley MR. Wide-lumen stapled anastomosis vs. conventional end-to-end anastomosis in the treatment of Crohn’s disease. Dis Colon Rectum. 2001 Jan;44(1): 20–5; discussion 5–6. 38. Yamamoto T, Allan RN, Keighley MR. Strategy for surgical management of ileocolonic anastomotic recurrence in Crohn’s disease. World J Surg. 1999 Oct;23(10):1055–60; discussion 60–1. 39. Scarpa M, Angriman I, Barollo M, et al. Role of stapled and hand-sewn anastomoses in recurrence of Crohn’s disease. Hepatogastroenterology. 2004 Jul–Aug;51(58):1053–7. 40. Smedh K, Andersson M, Johansson H, Hagberg T. Preoperative management is more important than choice of sutured or stapled anastomosis in Crohn’s disease. Eur J Surg. 2002;168(3):154–7. 41. Yamamoto T, Keighley MR. Stapled functional end-to-end anastomosis in Crohn’s disease. Surg Today. 1999;29(7):679–81. 42. Galandiuk S. Stapled and hand-sewn anastomoses in Crohn’s disease. Dig Surg. 1998;15(6):655. 43. Hashemi M, Novell JR, Lewis AA. Side-to-side stapled anastomosis may delay recurrence in Crohn’s disease. Dis Colon Rectum. 1998 Oct;41(10):1293–6. 44. Colombel JF, Loftus EV, Jr., Tremaine WJ, et al. Early postoperative complications are not increased in patients with Crohn’s disease treated perioperatively with infliximab or immunosuppressive therapy. Am J Gastroenterol. 2004 May;99(5):878–83. 45. Dietz DW, Fazio VW, Laureti S, et al. Strictureplasty in diffuse Crohn’s jejunoileitis: safe and durable. Dis Colon Rectum. 2002 Jun;45(6):764–70. 46. Laurent S, Detry O, Detroz B, et al. Strictureplasty in Crohn’s disease: short- and long-term follow-up. Acta Chir Belg. 2002 Aug;102(4):253–5. 47. Hurst RD, Michelassi F. Strictureplasty for Crohn’s disease: techniques and long-term results. World J Surg. 1998 Apr;22(4):359–63. 48. Poggioli G, Laureti S, Pierangeli F, Ugolini F. A new model of strictureplasty for multiple and long stenoses in Crohn’s ileitis: side-to-side diseased to disease-free anastomosis. Dis Colon Rectum. 2003 Jan;46(1):127–30.
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49. Shatari T, Clark MA, Yamamoto T, et al. Long strictureplasty is as safe and effective as short strictureplasty in small-bowel Crohn’s disease. Colorectal Dis. 2004 Nov;6(6):438–41. 50. Sampietro GM, Cristaldi M, Maconi G, et al. A prospective, longitudinal study of nonconventional strictureplasty in Crohn’s disease. J Am Coll Surg. 2004 Jul;199(1):8–20; discussion -2. 51. Michelassi F, Upadhyay GA. Side-to-side isoperistaltic strictureplasty in the treatment of extensive Crohn’s disease. J Surg Res. 2004 Mar;117(1):71–8. 52. Tonelli F, Fedi M, Paroli GM, Fazi M. Indications and results of side-to-side isoperistaltic strictureplasty in Crohn’s disease. Dis Colon Rectum. 2004 Apr;47(4):494–501. 53. Eisenberger CF, Izbicki JR, Broering DC, et al. Strictureplasty with a pedunculated jejunal patch in Crohn’s disease of the duodenum. Am J Gastroenterol. 1998 Feb;93(2):267–9. 54. Milsom JW, Hammerhofer KA, Bohm B, et al. Prospective, randomized trial comparing laparoscopic vs. conventional surgery for refractory ileocolic Crohn’s disease. Dis Colon Rectum. 2001 Jan;44(1):1–8; discussion -9. 55. Dutta S, Rothenberg SS, Chang J, Bealer J. Total intracorporeal laparoscopic resection of Crohn’s disease. J Pediatr Surg. 2003 May;38(5):717–9. 56. Tilney HS, Constantinides VA, Heriot AG, et al. Comparison of laparoscopic and open ileocecal resection for Crohn’s disease: a metaanalysis. Surg Endosc. 2006 Jul;20(7):1036–44. 57. Bonnard A, Fouquet V, Berrebi D, et al. Crohn’s disease in children. Preliminary experience with a laparoscopic approach. Eur J Pediatr Surg. 2006 Apr;16(2):90–3. 58. Maartense S, Dunker MS, Slors JF, et al. Laparoscopic-assisted versus open ileocolic resection for Crohn’s disease: a randomized trial. Ann Surg. 2006 Feb;243(2):143–9; discussion 50–3. 59. Casillas S, Delaney CP. Laparoscopic surgery for inflammatory bowel disease. Dig Surg. 2005;22(3):135–42. 60. Hirayama I, Ide M, Shoji H, et al. Laparoscopic-assisted partial ileectomy for Crohn’s disease associated with chronic anemia due to frequent hemorrhage. Hepatogastroenterology. 2005 May–Jun;52(63):823–5. 61. Huilgol RL, Wright CM, Solomon MJ. Laparoscopic versus open ileocolic resection for Crohn’s disease. J Laparoendosc Adv Surg Tech A. 2004 Apr;14(2):61–5. 62. von Allmen D, Markowitz JE, York A, et al. Laparoscopic-assisted bowel resection offers advantages over open surgery for treatment of segmental Crohn’s disease in children. J Pediatr Surg. 2003 Jun;38(6):963–5. 63. Shore G, Gonzalez QH, Bondora A, Vickers SM. Laparoscopic vs conventional ileocolectomy for primary Crohn’s disease. Arch Surg. 2003 Jan;138(1):76–9. 64. Wu JS, Birnbaum EH, Kodner IJ, et al. Laparoscopic-assisted ileocolic resections in patients with Crohn’s disease: are abscesses, phlegmons, or recurrent disease contraindications? Surgery. 1997 Oct;122(4):682–8; discussion 8–9. 65. Milsom JW. Laparoscopic surgery in the treatment of Crohn’s disease. Surg Clin North Am. 2005 Feb;85(1):25–34; vii. 66. Seymour NE, Kavic SM. Laparoscopic management of complex Crohn’s disease. Jsls. 2003 Apr– Jun;7(2):117–21. 67. Benoist S, Panis Y, Beaufour A, et al. Laparoscopic ileocecal resection in Crohn’s disease: a casematched comparison with open resection. Surg Endosc. 2003 May;17(5):814–8. 68. Evans J, Poritz L, MacRae H. Influence of experience on laparoscopic ileocolic resection for Crohn’s disease. Dis Colon Rectum. 2002 Dec;45(12):1595–600. 69. Watanabe M, Ohgami M, Teramoto T, et al. Laparoscopic ileocecal resection for Crohn’s disease associated with intestinal stenosis and ileorectal fistula. Surg Today. 1999;29(5):446–8. 70. Uchikoshi F, Ito T, Nezu R, et al. Advantages of laparoscope-assisted surgery for recurrent Crohn’s disease. Surg Endosc. 2004 Nov;18(11):1675–9. 71. Hasegawa H, Watanabe M, Nishibori H, et al. Laparoscopic surgery for recurrent Crohn’s disease. Br J Surg. 2003 Aug;90(8):970–3. 72. Thaler K, Dinnewitzer A, Oberwalder M, et al. Assessment of long-term quality of life after laparoscopic and open surgery for Crohn’s disease. Colorectal Dis. 2005 Jul;7(4):375–81. 73. Andersson P, Olaison G, Hallbook O, Sjodahl R. Segmental resection or subtotal colectomy in Crohn’s colitis? Dis Colon Rectum. 2002 Jan;45(1):47–53. 74. Martel P, Betton PO, Gallot D, Malafosse M. Crohn’s colitis: experience with segmental resections; results in a series of 84 patients. J Am Coll Surg. 2002 Apr;194(4):448–53.
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75. Bernell O, Lapidus A, Hellers G. Recurrence after colectomy in Crohn’s colitis. Dis Colon Rectum. 2001 May;44(5):647–54; discussion 54. 76. Fichera A, McCormack R, Rubin MA, et al. Long-term outcome of surgically treated Crohn’s colitis: a prospective study. Dis Colon Rectum. 2005 May;48(5):963–9. 77. Rieger N, Collopy B, Fink R, et al. Total colectomy for Crohn’s disease. Aust N Z J Surg. 1999 Jan;69(1):28–30. 78. Proctor ML, Langer JC, Gerstle JT, Kim PC. Is laparoscopic subtotal colectomy better than open subtotal colectomy in children? J Pediatr Surg. 2002 May;37(5):706–8. 79. Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB. AGA technical review on perianal Crohn’s disease. Gastroenterology. 2003 Nov;125(5):1508–30. 80. Judge TA, Lichtenstein GR. Treatment of fistulizing Crohn’s disease. Gastroenterol Clin North Am. 2004 Jun;33(2):421–54, xi-xii. 81. Regueiro M, Mardini H. Treatment of perianal fistulizing Crohn’s disease with infliximab alone or as an adjunct to exam under anesthesia with seton placement. Inflamm Bowel Dis. 2003 Mar;9(2):98–103. 82. Topstad DR, Panaccione R, Heine JA, et al. Combined seton placement, infliximab infusion, and maintenance immunosuppressives improve healing rate in fistulizing anorectal Crohn’s disease: a single center experience. Dis Colon Rectum. 2003 May;46(5):577–83. 83. Poritz LS, Rowe WA, Koltun WA. Remicade does not abolish the need for surgery in fistulizing Crohn’s disease. Dis Colon Rectum. 2002 Jun;45(6):771–5. 84. Galandiuk S, Kimberling J, Al-Mishlab TG, Stromberg AJ. Perianal Crohn’s disease: predictors of need for permanent diversion. Ann Surg. 2005 May;241(5):796–801; discussion -2. 85. Rintala RJ, Lindahl HG. Proctocolectomy and J-pouch ileo-anal anastomosis in children. J Pediatr Surg. 2002 Jan;37(1):66–70. 86. Su FW, Beckman DB, Yarnold PA, Grammer LC. Low incidence of complications in asthmatic patients treated with preoperative corticosteroids. Allergy Asthma Proc. 2004 Sep–Oct;25(5):327–33. 87. Marchal L, D’Haens G, Van Assche G, et al. The risk of post-operative complications associated with infliximab therapy for Crohn’s disease: a controlled cohort study. Aliment Pharmacol Ther. 2004 Apr 1;19(7):749–54. 88. Rutgeerts P. Review article: recurrence of Crohn’s disease after surgery - the need for treatment of new lesions. Aliment Pharmacol Ther. 2006 Oct;24 Suppl 3:29–32. 89. Sorrentino D, Terrosu G, Avellini C, et al. Prevention of postoperative recurrence of Crohn’s disease by infliximab. Eur J Gastroenterol Hepatol. 2006 Apr;18(4):457–9. 90. Lemann M. Review article: can post-operative recurrence in Crohn’s disease be prevented? Aliment Pharmacol Ther. 2006 Oct;24 Suppl 3:22–8. 91. Sandborn WJ, Feagan BG. The efficacy of azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in patients with Crohn’s disease remains uncertain. Gastroenterology. 2004 Sep;127(3):990–3. 92. Rutgeerts P. Strategies in the prevention of post-operative recurrence in Crohn’s disease. Best Pract Res Clin Gastroenterol. 2003 Feb;17(1):63–73. 93. Stephens M, Batres LA, Ng D, Baldassano R. Growth failure in the child with inflammatory bowel disease. Semin Gastrointest Dis. 2001 Oct;12(4):253–62.
36 Surgical Treatment of Ulcerative Colitis Peter Mattei∗ and John L. Rombeau
Introduction The surgical treatment of ulcerative colitis (UC) has evolved considerably over the past one hundred years. The first attempts to treat UC with surgery included the use of an appendicostomy to allow colonic irrigation or ileostomy to divert the fecal stream, but the diseased colon remained an ongoing source of symptoms and complications as well as a potential site for malignant degeneration [1]. As surgical techniques and perioperative care improved, proctocolectomy with permanent ileostomy became the standard of care for most of the 20th century. Further refinements during the 1980s included the construction of a functional neo-rectum using the ileum and minimally invasive techniques that have improved recovery and cosmesis. Nevertheless, despite recent technical advances and often remarkable functional outcomes in many patients, the surgical therapy of UC remains less than perfect. There is increasing emphasis on achieving normal bowel function, minimizing complications, and improving overall quality of life. This has been especially true for children with UC, for whom seemingly minor lifestyle concerns can have significant developmental implications and harmful long-term consequences.
Indications for Surgery The treatment of UC is primarily medical [2, 3]. In fact, with modern drug treatment programs, most patients with UC remain largely free of debilitating symptoms for many years. However, approximately 30–40% of patients with UC will ultimately require an operation [4]. Indications for surgical intervention fall generally into one of three categories (Table 36.1): disease that is refractory to medical management, the development of a serious disease-related complication, and the risk of malignancy. The most common indication for surgical referral in children is the persistence of bleeding, severe diarrhea, or pain despite maximal medical therapy, but patterns of disease progression are highly variable. Some patients present acutely and have rapidly progressive symptoms, sometimes being considered for surgery within a few weeks or months from the initial onset of their disease. Others have symptoms that steadily worsen, often requiring more frequent blood product replacement and repeated hospitalizations, until they are no longer responsive to
*Department of General, Thoracic and Fetal Surgery, The Children’s Hospital of Philadelphia, 34th St. & Civic Ctr. Blvd., Philadelphia, PA 19104, Phone: 215-590-4981, Fax: 215-386-4036, E-mail:
[email protected]
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Table 36.1. Indications for surgery. Urgent/Emergent Indications – intractable bleeding – unrelenting pain – unremitting sepsis – complications colonic perforation colonic stricture Elective Indications – refractory to or complications of medical management – chronic malnutrition poor growth delayed sexual maturation – steroid dependence
even the most aggressive treatment modalities. Still others, despite otherwise manageable chronic symptoms, will be referred because of poor growth or delayed sexual maturation due to persistent inflammation and chronic malnutrition. As always, the anticipated benefits and potential risks of an operation need to be weighed carefully against the expected consequences of disease progression. A complication of UC or its treatment is a relatively uncommon indication for operative intervention, especially in children. Although rare in the modern era, colonic perforation should be considered in patients with UC who develop frank peritonitis, which is an indication for urgent laparotomy. Severe bleeding that is not responsive to medical management is also an indication for urgent colectomy [5]. Toxic megacolon includes the combination of sepsis and a massively dilated colon (greater than 6cm in diameter) [6]. Though sometimes critically ill, these patients can usually be successfully treated with fluid resuscitation and broad-spectrum antibiotics [7]. Indications for immediate surgery include perforation, uncontrollable bleeding, or intractable sepsis. Some complications of UC are due to the effects of having long-standing disease and are therefore rare in children. These include colonic stricture, debilitating extra-intestinal manifestations of the disease, and malignancy. Patients are sometimes referred to a surgeon because of complications from medical management or dependence on corticosteroids. Most of the drugs commonly used in the treatment of UC are well tolerated and there are few serious complications that would prompt consideration of an operation; but patients who require long-term high-dose corticosteroid therapy will occasionally develop serious side effects such as diabetes, hypertension, infections, or psychiatric complications. They can also develop disfiguring somatic changes, acne, obesity, growth failure or severe osteopenia. Patients who develop debilitating side effects of medication and have no effective alternative should be considered for operative intervention. Although rare in children, mucosal dysplasia identified on colonic biopsy during routine surveillance is an indication for colectomy. Colonoscopic surveillance is recommended to begin for most patients approximately eight years after onset of the disease [8]. As UC is being identified in younger patients, we may begin to see more adolescents with dysplasia being referred for consideration of early colectomy. Modern medical therapeutics have significantly reduced the indications for emergency surgery in patients with UC. The typical scenario in which one begins to contemplate a surgical option is the patient whose chronic symptoms are refractory to medical therapy or who is corticosteroiddependent. As always, the risks of surgery are to be considered in the context of the risks of continued non-operative management. Perhaps more important is to consider the anticipated functional result and lifestyle implications of having a proctocolectomy with pelvic reconstructive surgery.
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Surgical Procedures In the past, proctocolectomy (complete removal of the colon and rectum, Table 36.2) with permanent ileostomy was the standard operation for UC, and to this day remains the benchmark by which all other operations are compared. The operation removes the organ responsible for nearly all of the symptoms of the disease, and can be performed in even the sickest patients with a very low complication rate and negligible mortality. Patients are usually able to resume normal activities fairly soon after surgery and most adapt well to the ileostomy. Nevertheless, many patients found the idea of a permanent ileostomy objectionable or, in some cases, unbearable, and so surgeons began to develop operations that result in removal of the offending organ but allow near-normal bowel function without the use of a permanent ileostomy. This led to the development of the ileal pouch-anal anastomosis procedure (IPAA). In current practice, the operation is performed in two or sometimes three stages, depending on the certainty of the diagnosis and whether the procedure is being done electively or as an emergency. Proctocolectomy with IPAA is a definitive operation for patients with UC, however the clinical circumstances might dictate that a lesser operation be performed, at least initially. For example, a diverting ileostomy might be considered in a patient with severe and intractable colitis of unclear etiology. This should rarely be necessary except perhaps in the unusual situation in which a young child has severe colitis, the diagnosis is uncertain, and an adequate trial of medical therapy has not been possible due to rapidity of onset. In these situations, it may be difficult for parents to accept the idea of taking such the seemingly drastic step as colectomy. Patients frequently improve dramatically after ileostomy, but clinical decision making often becomes very difficult. Table 36.2. Surgical options. Operation Ileostomy Abdominal colectomy + Hartmana + ileostomyb Abdominal colectomy + ileorectostomy Proctocolectomy + end ileostomy Proctocolectomy + Kock continent ileostomy Proctocolectomy + ileal pouch-anal anastomosisc
1. Mucosal proctectomy + hand-sewn IPAA
2. Proctocolectomy + double-stapled IPAA
a b
c
Comments - rarely performed as an isolated procedure - usually performed if an operation is needed urgently - usually performed for indeterminate or Crohn colitis - requires life-long surveillance of rectum - formerly the standard of care- overall very good results - not popular because ileostomy is permanent - rarely performed today - difficult operation with frequent complications - current standard of care - “J-pouch” is most common variation - nearly always done with protective ileostomy - good function - leaves no rectal mucosa - technically more difficult - good function - leaves short segment of rectal mucosa - requires life-long surveillance of rectal remnant
Hartman operation: the proximal end of the rectum is sutured or stapled closed; the anus is patent “three-stage” approach: I. abdominal colectomy/ileostomy, II. ileo-anal pouch procedure/ileostomy, and III. ileostomy closure “two-stage” approach: I. proctocolectomy/ileo-anal pouch procedure/ileostomy, and II. ileostomy closure
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Simple reversal of the ileostomy almost always results in prompt recurrence of severe colitis and a definitive diagnosis is often elusive despite a significant reduction of colonic inflammation. Therefore, in those rare patients in whom only an ileostomy is performed, one should anticipate that at some point a definitive procedure involving removal of the colon will need to be performed and parents should be prepared for this inevitability. If the diagnosis is confirmed to be UC, the operation will usually include a proctectomy, while the diagnosis of Crohn or indeterminate colitis might be an indication for partial colectomy and a restorative operation in which the rectum and part of the colon are preserved (ileo-colostomy or ileo-rectostomy). When a patient with UC requires an urgent operation, the more commonly accepted procedure is subtotal colectomy with closure of the rectum (Hartmann procedure) and ileostomy. The rectum is preserved at this initial operation with the idea that a restorative procedure will be performed on an elective basis after the patient has stabilized and can be prepared properly for such a delicate and demanding operation. Urgent colectomy is most commonly performed through a long midline incision but it can also be done laparoscopically. The principal risks are infection and bleeding, though the majority of children do well and recover within several days after surgery. The purported advantages of the minimally invasive approach include a shorter recovery time, a more rapid return to normal activities after discharge from the hospital, smaller incisions, and less scarring [9–11]. Disadvantages include a longer operating time and greater cost. Regardless of the technique, the goal of this urgent operation is to remove most of the diseased colon as quickly and as safely as possible, and to allow the patient to return to their usual state of good health until a more definitive restorative operation can be performed electively. Patients usually do quite well after subtotal colectomy, despite the fact that the rectum is not removed. After approximately four to six weeks, plans are made for proctectomy and neorectal reconstruction. In the past, some patients were given the option of having an ileorectostomy, in which the rectum is preserved and an anastomosis is created between the ileum and the rectum. This preserves relatively normal rectal sensory and motor function but also retains the rectal mucosa, placing the patient at risk for on-going proctitis and carcinoma. Patients therefore required frequent and meticulous endoscopic surveillance for dysplasia for the rest of their lives. Because of concerns about the risk of cancer and the burden of a lifetime of surveillance, ileorectostomy is no longer considered a suitable option for the treatment of UC, especially in children. However, due to a higher risk of infectious complications and fistulizing perianal disease after neorectal reconstruction, it is considered a reasonable option for children with Crohn or indeterminate colitis. Currently, the most popular restorative operation for UC in children is the ileal pouch-anal anastomosis procedure (IPAA), in which the colon and rectum are removed and the ileum is brought down through the pelvic floor musculature and an anastomosis is created between the ileum and the anus. This creates an ileal reservoir that is intended to function as a replacement for the rectum. The ileum may be unmodified (straight pull-through) or can be fashioned so as to create a more capacious reservoir, the ileal pouch. The most commonly used pouch configuration is the J-pouch, in which the ileum is folded back on itself for a distance of approximately 10 cm and the common wall is obliterated using a surgical stapling device. (Figure 36.1) Other options include the S-pouch, in which the ileum is folded twice to create a reservoir that is three times the diameter of the ileum, and the W-pouch, in which the ileum is folded yet again, resulting in an even larger reservoir. Given its relative ease of construction and proven track record of excellent functional results, the J-pouch is the preferred configuration. There are two accepted methods for creating the ileo-anal anastomosis, both of which produce excellent results. Although the decision is based on the preference of the operating surgeon, it is an important consideration, especially in children. The distinction is between mucosal proctectomy with hand-sewn ileo-anal anastomosis on the one hand, and total proctectomy with a stapled anastomosis on the other. (Figure 36.2) Mucosal proctectomy involves the development of a
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Figure 36.1. The two most commonly used ileal pouch configurations. The walls of the jejunal limbs that are brought together are opened using a surgical stapling device so as to create a single lumen that is larger than that of the ileum itself. The ileo-anal anastomosis is created by suturing or stapling the lower end of the pouch to the anus.
Figure 36.2. Two commonly used methods for creation of the ileal pouch-anal anastomosis: (A) Doublestapled anastomosis, so called because the rectum is first divided and stapled transversely, and then an anastomosis is created between the pouch and the rectum with a specialized stapling device that creates a circular staple line between two hollow viscera; (B) Mucosectomy with hand-sewn anastomosis, in which the mucosa is stripped from the distal rectum, preserving a short segment of rectal musculature, and the anastomosis is performed by hand. Note that with the double-stapled technique it is unavoidable that a short (1–2 cm) segment of rectal mucosa remains, while after mucosectomy the mucosa is excised all the way down to the anal transition zone. The J-pouch or S-pouch can be used with either method.
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Figure 36.3. Comparison of (A) the long midline incision used for the standard open colectomy and ileal pouch-anal anastomosis operation and (B) the smaller incisions used during laparoscopic colectomy and ileal pouch-anal anastomosis operation. The right lower quadrant laparoscopic incision is used for creation of an ileostomy. The low transverse incision is a Pfannenstiel incision, also referred to as a “bikini-line” incision, and is used for creation of the ileo-anal pouch after the colon is removed laparoscopically. It can also be used to allow insertion of the surgeon’s hand to facilitate the laparoscopic portion of the operation (“handassisted” laparoscopy). The primary advantage of the minimally invasive approach is improved cosmesis; other purported advantages include shorter hospital stay and faster recovery.
submucosal plane of dissection and removal of the rectal mucosa all the way down to the anal transition zone, with circumferential preservation of a portion of the muscular wall of the rectum. This was originally designed as a way to remove the mucosa and submucosa, which is where the inflammation resides, while, in theory, preserving the motor and sensory function of the rectal musculature. The ileo-anal anastomosis is then created using a hand-sewn technique through the anus. The submucosal dissection can be arduous and sometimes difficult, especially in patients with severe or long-standing rectal inflammation. The alternative approach is to remove the entire rectum, which is transected using a linear stapling device above the anal transition zone. The ileo-anal anastomosis is then created using an end-to-end stapling device, which creates a circular anastomosis. The advantages of this approach include an easier plane of dissection, less anal sphincter dilatation, and a shorter operating time, with functional results that appear to be the same or better than the hand-sewn technique. An important distinction, however, is that the double-stapled technique always results in the retention of a short segment of rectal mucosa, usually approximately 1 to 2 cm in length, which is at risk for ongoing inflammation and the development of cancer [12, 13] (Figure 36.2). Although it is recommended that all patients be followed indefinitely regardless of the surgical technique used, those with retained rectal mucosa require more diligent surveillance, including frequent routine biopsies, for their entire lives [14]. At the time of the ileo-anal reconstruction, most surgeons perform a temporary ileostomy, which decreases the risk of pelvic abscess and other postoperative septic complications. These complications are associated with poor pouch function and a significantly diminished quality of life [15, 16]. Although pelvic sepsis is relatively uncommon even in the absence of fecal diversion, most surgeons prefer to minimize the risk as much as possible by performing a temporary ileostomy. Some surgeons feel that the risk of a severe complication is low enough that protective ileostomy can be avoided in certain patients [17, 18], however this is not the most widely held view. The ileostomy can usually be reversed six to eight weeks after surgery, but only after a water-soluble contrast enema confirms good healing and a normal configuration and emptying of the pouch. For most patients, this will be the second or third stage of the operation, depending on whether a subtotal colectomy was done at the first stage. A procedure that is rarely performed anymore but deserves brief mention is the Kock pouch (or continent ileostomy) operation [19, 20]. The colon and rectum are completely removed and the ileum is used to create a reservoir that resides within the abdomen. The end of the ileum is bought out through a small abdominal incision in the manner of an ileostomy, but a small intussusception is created just proximal to the outlet effectively creating a valve that is designed
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to prevent the leakage of stool. The patient does not wear a standard ileostomy appliance, and instead uses a plastic tube to evacuate the pouch several times daily as needed. The concept is certainly appealing, however the long-term results of the Kock pouch have been somewhat disappointing and the complication rate has been unacceptably high. The procedure has for the most part been abandoned, except at a small number of institutions worldwide.
Preparation for Surgery Patients who need an urgent operation are prepared for surgery in the usual fashion (Table 36.3), namely intravenous fluid resuscitation and broad-spectrum antibiotics. Patients who are anemic may require a blood transfusion, depending on the surgical and anesthetic standards of the institution. At a minimum, two units of packed red blood cells should be made available for possible use during or after the operation. For patients receiving corticosteroids, it may be standard practice at some institutions to administer a “stress dose” of corticosteroids. Lastly, the patient should be evaluated by an enterostomal therapist so that an optimal ileostomy site can be identified and marked. Patients who are being prepared for an elective procedure should be formally assessed for the possibility of chronic malnutrition, which prolongs healing and increases the risk of complications after major surgery. Nutritional supplements may be necessary by enteral or parenteral means, depending on the degree of malnutrition, even if this means delaying the operation for two or three weeks. Since chronic high-dose corticosteroid therapy may also adversely affect wound healing and increase the risks of surgery, attempts should be made to gradually decrease the dose for patients who are scheduled for surgery, preferably down to less than 20 mg of prednisone daily. Some surgeons believe that a mechanical bowel preparation may decrease the risk of septic complications after major colorectal surgery. A typical regimen includes a clear liquid diet for 24 to 48 hours, and the administration of a cathartic such as polyethylene glycol or magnesium citrate solution. Antibiotics are given intravenously, but oral antibiotics are also sometimes used. There are recent data that suggest bowel preparation does not improve the outcome for most
Table 36.3. Preoperative checklist. Hydration intravenous fluids NPO 8 hours for solid food 2 hours for clear liquids Antibiotics intravenous broad-spectrum 30-60 minutes before incision Hemoglobin transfuse, if indicated blood typing and cross-matching for 2 units of packed RBCs Bowel preparation clear liquids for 24-48 hours prior to surgery mechanical bowel prep (laxatives, +/- enemas) Malnutrition correct weight loss, hypoalbuminemia enteral supplements parenteral nutrition, if indicated Corticosteroids wean daily dose, if possible “stress dose,” if indicated
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kinds of elective colorectal surgery [21, 22], but the potential benefit in patients who undergo proctectomy and ileo-anal reconstruction is not well-known.
Outcomes of Surgery The technical results of the operations described for children with UC are generally quite good. Infectious complications and bleeding are uncommon and usually easily managed without sequelae. Even after the most complicated operations, most patients recover nicely and are able to tolerate a regular diet within seven days of surgery. The short-term results for patients who undergo a minimally invasive procedure might be slightly better, and have the added benefit of improved cosmesis [9–11]. Regardless of the technique, the overall risk of serious complications or death is very low. Functional Results The functional results of the IPAA procedures are generally very good, though there is a great deal of variation between patients and in the same patient over time. The ultimate goal of surgical intervention is for the patient to be able to enjoy a normal lifestyle, however there are inherent limitations in duplicating normal rectal function with a surgical construct [23]. The ideal functional result after an IPAA procedure can be summarized as: (1) fecal continence during the day and at night, (2) four or fewer stools per day, (3) no more than one stool at night, (4) the ability to postpone defecation for at least 30 minutes, and (5) the ability to distinguish between flatus and stool. The J-pouch IPAA is currently the most popular operation for children and adolescents with UC who need surgical intervention, and several large studies in adults and children have confirmed that the majority of patients have good functional results [24–29]. In most large series, patients report an average stool frequency of three per day and once at night. Fewer than 5% have soiling or staining, most of which occurs only at night. Approximately 90% of patients can delay defecation for at least 30 minutes, and most report being able to pass flatus without a bowel movement. Many patients are able to participate in athletics and report being able to participate in a wide variety of normal activities [27]. Through the use of patient questionnaires, several studies have documented a very good quality of life for a majority of patients after IPAA with 90–95% of patients reported to be satisfied or very satisfied with the results of their operation [30, 31]. Because the anal dilatation required during completion of the mucosectomy and creation of the ileo-anal anastomosis might result in injury to the anal sphincter, some studies have assessed anorectal function after IPAA using rectal manometry [32, 33], although few have included children [34]. Most studies confirm that although there is usually a decrease in resting sphincter pressure and maximum squeeze pressure after IPAA relative to preoperative controls, these values gradually return to normal when patients are followed for more than a year after surgery. Furthermore, although the rectal inhibitory reflex is often noted to be absent, nearly all patients regain normal rectal sensation for the presence of stool. Most large series of patients who undergo IPAA report good results regardless of pouch anatomy or method of pelvic dissection. Some surgeons continue to advocate the use of a straight ileo-anal anastomosis [35, 36]. The purported benefits of avoiding a pouch include its relative ease of construction, the creation of less tension on the small bowel mesentery, and decreased stasis, which is thought to increase the risk of pouchitis. Nevertheless, the disadvantages of the procedure, including increased frequency and urgency of defecation, are felt by most surgeons to outweigh its potential advantages. A number of patients with a straight pull-through ask to be converted to a J-pouch because of the unacceptably high frequency of stooling [26]. When compared with colectomy and either Brooke or Kock ileostomy, most studies report improved
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functional results and quality of life in patients who have undergone colectomy with IPAA [37, 38]. However, at least one group has suggested that it is the colectomy that is responsible for most of the improvement in the quality of life for patients with UC and that restoration of normal defecation actually contributes very little [30]. When mucosal proctectomy with hand-sewn anastomosis is compared to extra-rectal proctectomy and double-stapled anastomosis, the functional results and quality of life parameters appear to be identical [14, 39–41], although the relative simplicity of the double-stapled technique may result in improved results in centers where few such procedures are performed [42]. Patients who require a revision of their pouch also tend to do better than expected [43], although it is certainly preferable for any complex reconstructive procedure to function well after the first attempt. All in all, careful analysis of the collective experience with the IPAA operation over the past two decades confirms that it is a good operation, with excellent functional results and improved quality of life for the majority of patients with UC who need surgery.
Complications Another important aspect of surgical outcomes is the risk of complications. As with any complex reconstructive operation, the complication rate for IPAA is not insignificant, occurring in as many as half of all patients [15, 27, 28, 44]. Most complications occur in the immediate postoperative period and are easily manageable. These include wound infections, postoperative ileus, and excessive ileostomy output. More serious complications such as small bowel obstruction due to adhesions, parastomal hernia, or pelvic abscess may require operative intervention. Long-term complications are often more significant as they can interfere with the function of the pouch and may result in less than satisfactory function [45, 46]. Approximately 10–15% of patients develop a stricture at the ileo-anal anastomosis, which increases the risk of pouch stasis and pouchitis. Symptomatic strictures usually respond to periodic anal dilatation and rarely require surgical revision or ileostomy. When an ileo-anal stricture is associated with a perirectal abscess or anal fistula, the diagnosis of Crohn disease should be considered. Prolapse, stenosis, or retraction of the ileostomy may occur, but because the ileostomy is generally temporary, these complications can often be managed by early closure. Pouchitis Perhaps the most significant potential complication after IPAA is pouchitis, which can be acute or chronic. The patient with acute pouchitis typically presents with increased stool frequency, urgency, or pain, and sometimes by bloody stools, tenesmus, abdominal distension, or fever. The diagnosis is usually made on clinical grounds, though endoscopic examination of the mucosa may reveal mucosal edema, ulceration, or friable granulation tissue [47]. Biopsies may reveal an acute inflammatory process, with polymorphonuclear leukocyte infiltration, crypt abscesses, or ulceration depending on the severity of the disease. The true incidence and relative severity of pouchitis has been very difficult to evaluate consistently between series, perhaps because of the variable presentation and somewhat subjective manner in which the diagnosis is made. Some have therefore proposed the use of a pouchitis disease activity index score so that therapeutic trials from different institutions can be more easily assessed and compared [45, 48, 49] (Table 36.4). Of patients who have had an IPAA for UC, perhaps as many as 40% will have at least one bout of pouchitis. Interestingly, the disease almost never occurs in patients who have had an IPAA for familial adenomatous polyposis. At the opposite extreme, it affects as many as 80% of patients with UC who have primary sclerosing cholangitis. Most patients with acute pouchitis respond promptly to a short course of oral metronidazole or ciprofloxacin. Chronic or relapsing acute pouchitis is less common but can be debilitating. Some have suggested that it represents a form
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Table 36.4. Pouchitis disease activity index. [48, 49] Criteria Clinical Stool frequency Usual postoperative stool frequency 1–2 stools/day > postoperative usual 3 or more stools/day > postoperative usual Rectal bleeding None or rare Present daily Fecal urgency or abdominal cramps None Occasional Usual Fever (temperature > 37.8 °C) Absent Present Endoscopic inflammation Edema Granularity Friability Loss of vascular pattern Mucous exudates Ulceration Acute histologic inflammation Polymorphonuclear leukocyte infiltration Mild Moderate + crypt abscess Severe + crypt abscess Ulceration per low-power field (mean) <25% 25–50% >50%
Score
0 1 2 0 1 0 1 2 0 1 1 1 1 1 1 1 1 2 3 1 2 3
A total score of =7 is considered consistent with a diagnosis of pouchitis. A modified pouchitis disease activity index (mPDAI) has been proposed [49] in which the histology component is excluded, thus avoiding the risk and cost of biopsies. Using the mPDAI, a score of =5 is considered diagnostic of pouchitis.
of “recurrent” UC, and clinically may behave as such. Approximately 5% of patients eventually require permanent ileostomy or removal of the pouch because of intractable pouchitis [46]. The treatment of severe chronic pouchitis is often similar to that of UC or Crohn colitis, including anti-inflammatory enemas, chronic antibiotic therapy, or infliximab [50]. The cause of pouchitis is unknown, though its almost exclusive occurrence in patients with UC would suggest a common underlying predisposition. A small but significant percentage of patients with severe pouchitis will eventually be identified as having Crohn disease. Regardless of the etiology, stasis appears to be an important factor that increases the risk of pouchitis. This is supported by the observation that pouchitis is less common when the pouch is small, for example after straight ileo-anal pull-through. Pouchitis is also more common in the presence of an ileo-anal stricture or an excessively dilated pouch. Some patients will respond to serial anal dilatations or daily rectal intubation or saline irrigation, however surgical revision of the pouch may need to be considered in these situations. Some have found that bulking agents in the form of dietary fiber supplements may reduce the incidence of pouchitis [51], perhaps by promoting more complete
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evacuation of the pouch. Probiotics may decrease the risk of pouchitis, however thus far the results of clinical trials have been mixed [52–54]. Children with Crohn disease who mistakenly undergo IPAA have more complications after IPAA, including pouchitis, sinus tracts, fistulae, and pelvic abscess [55]. Although some respond well to standard medical therapy, many will eventually require removal of the pouch and permanent ileostomy. Similarly, many consider indeterminate colitis a contraindication to IPAA, though there are some who advocate the use of pelvic pouch procedures in this subgroup of patients, citing an acceptable complication rate [56]. Interestingly, the presence of terminal ileitis (or “backwash” ileitis) at operation does not appear to increase the risk of complications, pouchitis, or pouch failure [55]. Patients who develop severe or recurrent pouchitis, anal fistula, or pelvic sepsis after IPAA should be evaluated for Crohn disease with small intestinal contrast imaging, upper and lower endoscopy with biopsies, and serologic analysis for markers of Crohn disease. Carcinoma Long-term complications of UC include colorectal carcinoma. Patients with UC are recommended to have yearly colonoscopy with frequent biopsies starting approximately eight years after onset of symptoms, and cancer is an indication for colectomy in patients with UC [57]. Patients with high-grade dysplasia are at high risk for carcinoma and are also recommended to undergo colectomy. Those with low-grade dysplasia are observed more closely with colonoscopy every six months, though there are proponents of colectomy for these patients as well [58, 59]. Although malignancy is rarely an issue in children, there are several important considerations for the pediatric gastroenterologist. First, as the incidence of UC is increasing [60] and appears to be increasing in younger age groups, it is more likely that patients will need to begin surveillance in adolescence. Secondly, patients who undergo IPAA using a double-stapled technique invariably have a 1 to 2 cm cuff of native rectal mucosa distal to the ileal pouch anastomosis, which necessitates life-long surveillance due to the risk of developing dysplasia or cancer within this remnant. This is an important technical detail that should be known to the patient’s gastroenterologist because of the long-term implications. Lastly, there are occasional reports of cancer developing within the ileal pouch itself or at the ileo-anal anastomosis [61, 62], suggesting that the risk of carcinoma can never be completely eliminated in patients with UC. The risk is thought to be higher in the setting of chronic pouchitis [63], which may not always be clinically apparent. Patients should therefore undergo periodic endoscopic evaluation of the pouch with biopsies, although the frequency of these assessments has not been standardized.
Current Trends and Future Considerations Patients with UC who have undergone IPAA surgery as children are now able to be evaluated as adults. Several series have reported a significant incidence of infertility in women who have undergone ileo-anal pouch procedures [64–68], with some series suggesting that the risk is double what is expected for women matched for age and severity of disease who are treated medically. Although fertility can be a difficult factor to assess accurately, especially in a select subgroup of chronically ill individuals, a preponderance of data appears to support this link. The risk of infertility is considerably higher for women with UC who undergo IPAA compared to those with familial polyposis and to those who have had an ileorectostomy. The risk is also significantly higher for those who require an intra-operative blood transfusion. The cause of infertility in these cases in unclear. It is thought that the degree of pelvic surgical dissection might generate adhesions, which are known to have a negative impact on fertility. This has led some groups to adopt empirically the use of enzymatic adhesion barriers during IPAA surgery, although there is no data to support that its use reduces infertility [67, 69, 70]. Nevertheless, it is an issue that
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should be discussed with any young woman with UC who is considering surgical intervention, as they may choose to delay the operation until after they have children. Outcomes research generally supports the view that the functional results are better and the complication rate is lower for complex operations performed at high-volume centers. The IPAA procedure is a technically demanding operation with many pitfalls and potential complications. Although there are no large series in which a direct comparison has been done specifically for IPAA in patients with UC, there appears to be a correlation between the experience of the surgeon and favorable outcomes in a variety of complex colorectal procedures [71–73]. In addition, several studies report a significant “learning curve” for surgeons who perform ileo-anal pouch procedures [74–76]. This suggests that the results of IPAA procedures that are done by experienced surgeons and at high-volume centers are likely to be better overall. Minimally invasive surgery offers potential advantages such as less scarring, less pain, more rapid postoperative recovery, and improved cosmesis. Many surgeons advocate the use of a laparoscopic-assisted approach [10, 11], in which the colectomy is performed laparoscopically while the more delicate pelvic dissection is done through an open incision but one that is much smaller than usual. The initial results with this approach have been encouraging, though it is too soon to know if the long-term functional results will be the same compared to the more standard open approach. As the technology continues to improve, minimally invasive approaches to complex colorectal surgery in children, including “robotic” techniques, will likely become more routine and may eventually become the standard of care for children with UC who need surgery.
Summary The goals of surgical intervention for UC are to remove the affected organs, to restore normal bowel function, and to minimize morbidity. The surgical treatment of children with UC has improved dramatically over the past few decades, mostly because of technical refinements of the ileal pouch-anal anastomosis procedure. Ileal pouch-anal anastomosis has become the standard of care for patients with UC who require surgical intervention. The majority of patients who undergo IPAA can expect to enjoy an essentially normal lifestyle, although the operation is technically demanding and is sometimes associated with significant morbidity. Surgeons continue to strive to develop restorative operations that more closely duplicate normal anatomy and function with fewer potentially debilitating side effects. References 1. Fazio VW. Ulcerative colitis: Surgical management. In Berk JE, ed. Bockus gastroenterology. Philadelphia: Saunders, 1985. pp. 2207–2221. 2. Escher JC, Taminiau JA, Nieuwenhuis EE, et al. Treatment of inflammatory bowel disease in childhood: best available evidence. Inflammatory Bowel Diseases 2003; 9(1):34–58. 3. Isaacs KL, Lewis JD, Sandborn WJ, et al. State of the art: IBD therapy and clinical trials in IBD. Inflammatory Bowel Diseases 2005; 11 Suppl 1:S3–12. 4. Hancock L, Windsor AC, Mortensen NJ. Inflammatory bowel disease: the view of the surgeon. Colorectal Disease 2006; 8(Suppl. 1):10–14. 5. Tsujikawa T, Andoh A, Sakaki M, et al. Operative indications for patients with refractory or severe ulcerative colitis. Hepato-Gastroenterology 2005; 52(65):1470–3. 6. Ausch C, Madoff RD, Gnant M, et al. Aetiology and surgical management of toxic megacolon. Colorectal Disease 2005; 8(3):195–201. 7. Gan SI, Beck PL. A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and management. American Journal of Gastroenterology 2003; 98(11):2363–71. 8. Itzkowitz SH, Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroenterology 2004; 126(6):1634–48.
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9. Proctor ML, Langer JC, Gerstle JT, Kim PC. Is laparoscopic subtotal colectomy better than open subtotal colectomy in children? Journal of Pediatric Surgery 2002; 37(5):706–8. 10. Wexner SD, Cera SM. Laparoscopic surgery for ulcerative colitis. Surgical Clinics of North America 2005; 85(1):35–47. 11. Kienle P, Weitz J, Benner A, et al. Laparoscopically assisted colectomy and ileoanal pouch procedure with and without protective ileostomy. Surgical Endoscopy 2003; 17(5):716–20. 12. Rotholtz NA, Pikarsky AJ, Singh JJ, Wexner SD. Adenocarcinoma arising from along the rectal stump after double-stapled ileorectal J-pouch in a patient with ulcerative colitis: the need to perform a distal anastomosis. Report of a case. Diseases of the Colon & Rectum 2001; 44(8):1214–7. 13. O’Riordain MG, Fazio VW, Lavery IC, et al. Incidence and natural history of dysplasia of the anal transitional zone after ileal pouch-anal anastomosis: results of a five-year to ten-year follow-up. Diseases of the Colon & Rectum 2000; 43(12):1660–5. 14. Davis C, Alexander F, Lavery I, Fazio VW. Results of mucosal proctectomy versus extrarectal dissection for ulcerative colitis and familial polyposis in children and young adults. Journal of Pediatric Surgery 1994; 29(2):305–9. 15. Fazio VW, Ziv Y, Church JM, et al. Ileal pouch-anal anastomoses complications and function in 1005 patients. Annals of Surgery 1995; 222(2):120–7. 16. Farouk R, Dozois RR, Pemberton JH, Larson D. Incidence and subsequent impact of pelvic abscess after ileal pouch-anal anastomosis for chronic ulcerative colitis. Diseases of the Colon & Rectum 1998; 41(10):1239–43. 17. Sugerman HJ, Sugerman EL, Meador JG, et al. Ileal pouch anal anastomosis without ileal diversion. Annals of Surgery 2000; 232(4):530–41. 18. Kim NK, Park JS, Park JK, et al. Restorative proctocolectomy: operative safety and functional outcomes. Yonsei Medical Journal 2000; 41(5):634–41. 19. Telander RL, Smith SL, Marcinek HM, et al. Surgical treatment of ulcerative colitis in children. Surgery 1981; 90(4):787–94. 20. Castillo E, Thomassie LM, Whitlow CB, et al. Continent ileostomy: current experience. Diseases of the Colon & Rectum 2005; 48(6):1263–8. 21. Guenaga KF, Matos D, Castro AA, et al. Mechanical bowel preparation for elective colorectal surgery. [update of Cochrane Database Syst Rev. 2003;(2):CD001544; PMID: 12804412]. Cochrane Database of Systematic Reviews 2005(1):CD001544. 22. Chambers WM, Mortensen NJ. Postoperative leakage and abscess formation after colorectal surgery. Best Practice & Research in Clinical Gastroenterology 2004; 18(5):865–80. 23. Thompson-Fawcett MW, Jewell DP, Mortensen NJ. Ileoanal reservoir dysfunction: a problem-solving approach. British Journal of Surgery 1997; 84(10):1351–9. 24. Telander RL, Spencer M, Perrault J, et al. Long-term follow-up of the ileoanal anastomosis in children and young adults. Surgery 1990; 108(4):717–23; discussion 723–5. 25. Fonkalsrud EW, Loar N. Long-term results after colectomy and endorectal ileal pullthrough procedure in children. Annals of Surgery 1992; 215(1):57–62. 26. Fonkalsrud EW. Long-term results after colectomy and ileoanal pull-through procedure in children. Archives of Surgery 1996; 131(8):881–5; discussion 885–6. 27. Fonkalsrud EW, Thakur A, Beanes S. Ileoanal pouch procedures in children. Journal of Pediatric Surgery 2001; 36(11):1689–92. 28. Rintala RJ, Lindahl HG. Proctocolectomy and J-pouch ileo-anal anastomosis in children. Journal of Pediatric Surgery 2002; 37(1):66–70. 29. Wewer V, Hesselfeldt P, Qvist N, et al. J-pouch ileoanal anastomosis in children and adolescents with ulcerative colitis: functional outcome, satisfaction and impact on social life. Journal of Pediatric Gastroenterology & Nutrition 2005; 40(2):189–93. 30. Weinryb RM, Gustavsson JP, Liljeqvist L, et al. A prospective study of the quality of life after pelvic pouch operation. Journal of the American College of Surgeons 1995; 180(5):589–95. 31. Shamberger RC, Masek BJ, Leichtner AM, et al. Quality-of-life assessment after ileoanal pull-through for ulcerative colitis and familial adenomatous polyposis. Journal of Pediatric Surgery 1999; 34(1):163–6. 32. Luukkonen P. Manometric follow-up of anal sphincter function after an ileo-anal pouch procedure. International Journal of Colorectal Disease 1988; 3(1):43–6.
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33. Becker JM, McGrath KM, Meagher MP, et al. Late functional adaptation after colectomy, mucosal proctectomy, and ileal pouch-anal anastomosis. Surgery 1991; 110(4):718–24; discussion 725. 34. Shamberger RC, Lillehei CW, Nurko S, Winter HS. Anorectal function in children after ileoanal pull-through. Journal of Pediatric Surgery 1994; 29(2):329–32; discussion 332–3. 35. Shilyansky J, Lelli JL, Drongowski RA, Coran AG. Efficacy of the straight endorectal pull-through in the management of familial adenomatous polyposis–a 16-year experience. Journal of Pediatric Surgery 1997; 32(8):1139–43. 36. Coran AG. A personal experience with 100 consecutive total colectomies and straight ileoanal endorectal pull-throughs for benign disease of the colon and rectum in children and adults. Annals of Surgery 1990; 212(3):242–7; discussion 247–8. 37. Orkin BA, Telander RL, Wolff BG, et al. The surgical management of children with ulcerative colitis. The old vs. the new. Diseases of the Colon & Rectum 1990; 33(11):947–55. 38. Kohler LW, Pemberton JH, Zinsmeister AR, Kelly KA. Quality of life after proctocolectomy. A comparison of Brooke ileostomy, Kock pouch, and ileal pouch-anal anastomosis. [see comment]. Gastroenterology 1991; 101(3):679–84. 39. Michelassi F, Lee J, Rubin M, et al. Long-term functional results after ileal pouch anal restorative proctocolectomy for ulcerative colitis: a prospective observational study. Annals of Surgery 2003; 238(3):433–41; discussion 442–5. 40. Scotte M, Del Gallo G, Steinmetz L, et al. Ileoanal anastomosis for ulcerative colitis: results of an evolutionary surgical procedure. Hepato-Gastroenterology 1998; 45(24):2123–6. 41. Choen S, Tsunoda A, Nicholls RJ. Prospective randomized trial comparing anal function after hand sewn ileoanal anastomosis with mucosectomy versus stapled ileoanal anastomosis without mucosectomy in restorative proctocolectomy. British Journal of Surgery 1991; 78(4):430–4. 42. Kayaalp C, Nessar G, Akoglu M, Atalay F. Elimination of mucosectomy during restorative proctocolectomy in patients with ulcerative colitis may provide better results in low-volume centers. American Journal of Surgery 2003; 185(3):268–72. 43. Baixauli J, Delaney CP, Wu JS, et al. Functional outcome and quality of life after repeat ileal pouch-anal anastomosis for complications of ileoanal surgery. Diseases of the Colon & Rectum 2004; 47(1):2–11. 44. Bach SP, Mortensen N. Revolution and evolution: 30 years of ileoanal pouch surgery. Inflammatory Bowel Diseases 2006; 12(2):131–145. 45. Heuschen UA, Autschbach F, Allemeyer EH, et al. Long-term follow-up after ileoanal pouch procedure: algorithm for diagnosis, classification, and management of pouchitis. Diseases of the Colon & Rectum 2001; 44(4):487–99. 46. Prudhomme M, Dehni N, Dozois RR, et al. Causes and outcomes of pouch excision after restorative proctocolectomy. British Journal of Surgery 2006; 93(1):82–6. 47. Shen B, Fazio VW, Remzi FH, Lashner BA. Clinical approach to diseases of ileal pouch-anal anastomosis. American Journal of Gastroenterology 2005; 100(12):2796–807. 48. Sandborn WJ, Tremaine WJ, Batts KP, et al. Pouchitis after ileal pouch-anal anastomosis: a Pouchitis Disease Activity Index. Mayo Clinic Proceedings 1994; 69(5):409–15. 49. Shen B, Achkar JP, Connor JT, et al. Modified pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis.[see comment]. Diseases of the Colon & Rectum 2003; 46(6):748–53. 50. Kooros K, Katz AJ. Infliximab therapy in pediatric Crohn pouchitis. Inflammatory Bowel Diseases 2004; 10(4):417–20. 51. Welters CF, Heineman E, Thunnissen FB, et al. Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with an ileal pouch-anal anastomosis. Diseases of the Colon & Rectum 2002; 45(5):621–7. 52. Shen B, Brzezinski A, Fazio VW, et al. Maintenance therapy with a probiotic in antibiotic-dependent pouchitis: experience in clinical practice. Alimentary Pharmacology & Therapeutics 2005; 22(8):721–8. 53. Meier R, Steuerwald M. Place of probiotics. Current Opinion in Critical Care 2005; 11(4):318–25. 54. Fedorak RN, Madsen KL. Probiotics and the management of inflammatory bowel disease. Inflammatory Bowel Diseases 2004; 10(3):286–99. 55. Alexander F, Sarigol S, DiFiore J, et al. Fate of the pouch in 151 pediatric patients after ileal pouch anal anastomosis. Journal of Pediatric Surgery 2003; 38(1):78–82. 56. Wolff BG. Is ileoanal the proper operation for indeterminate colitis: the case for. [see comment]. Inflammatory Bowel Diseases 2002; 8(5):362–5; discussion 368–9.
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57. Bernstein CN. Ulcerative colitis with low-grade dysplasia. Gastroenterology 2004; 127(3):950–6. 58. Ullman TA. Making the grade: should patients with UC and low-grade dysplasia graduate to surgery or be held back? Inflammatory Bowel Diseases 2002; 8(6):430–1. 59. Gorfine SR, Bauer JJ, Harris MT, Kreel I. Dysplasia complicating chronic ulcerative colitis: is immediate colectomy warranted?[see comment]. Diseases of the Colon & Rectum 2000; 43(11):1575–81. 60. Ekbom A. The epidemiology of IBD: a lot of data but little knowledge. How shall we proceed? Inflammatory Bowel Diseases 2004; 10 Suppl 1:S32–4. 61. Laureti S, Ugolini F, D’Errico A, et al. Adenocarcinoma below ileoanal anastomosis for ulcerative colitis: report of a case and review of the literature. Diseases of the Colon & Rectum 2002; 45(3):418–21. 62. Borjesson L, Willen R, Haboubi N, et al. The risk of dysplasia and cancer in the ileal pouch mucosa after restorative proctocolectomy for ulcerative proctocolitis is low: a long-term term follow-up study. Colorectal Disease 2004; 6(6):494–8. 63. Hassan C, Zullo A, Speziale G, et al. Adenocarcinoma of the ileoanal pouch anastomosis: an emerging complication? International Journal of Colorectal Disease 2003; 18(3):276–8. 64. Olsen KO, Joelsson M, Laurberg S, Oresland T. Fertility after ileal pouch-anal anastomosis in women with ulcerative colitis. British Journal of Surgery 1999; 86(4):493–5. 65. Olsen KO, Juul S, Bulow S, et al. Female fecundity before and after operation for familial adenomatous polyposis.[see comment]. British Journal of Surgery 2003; 90(2):227–31. 66. Ording Olsen K, Juul S, Berndtsson I, et al. Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample. [see comment]. Gastroenterology 2002; 122(1):15–9. 67. Gorgun E, Remzi FH, Goldberg JM, et al. Fertility is reduced after restorative proctocolectomy with ileal pouch anal anastomosis: a study of 300 patients.[see comment]. Surgery 2004; 136(4):795–803. 68. Wax JR, Pinette MG, Cartin A, Blackstone J. Female reproductive health after ileal pouch anal anastomosis for ulcerative colitis. Obstetrical & Gynecological Survey 2003; 58(4):270–4. 69. Johns A. Evidence-based prevention of post-operative adhesions. [see comment]. Human Reproduction Update 2001; 7(6):577–9. 70. Farquhar C, Vandekerckhove P, Watson A, et al. Barrier agents for preventing adhesions after surgery for subfertility. Cochrane Database of Systematic Reviews 2000; (2):CD000475. 71. Kapiteijn E, van de Velde CJ. Developments and quality assurance in rectal cancer surgery. European Journal of Cancer 2002; 38(7):919–36. 72. Prystowsky JB, Bordage G, Feinglass JM. Patient outcomes for segmental colon resection according to surgeon’s training, certification, and experience. Surgery 2002; 132(4):663–70; discussion 670–2. 73. McGrath DR, Leong DC, Gibberd R, et al. Surgeon and hospital volume and the management of colorectal cancer patients in Australia. [see comment]. ANZ Journal of Surgery 2005; 75(10):901–10. 74. Tekkis PP, Senagore AJ, Delaney CP, Fazio VW. Evaluation of the learning curve in laparoscopic colorectal surgery: comparison of right-sided and left-sided resections. Annals of Surgery 2005; 242(1):83–91. 75. Tekkis PP, Fazio VW, Lavery IC, et al. Evaluation of the learning curve in ileal pouch-anal anastomosis surgery. Annals of Surgery 2005; 241(2):262–8. 76. McMullen K, Hicks TC, Ray JE, et al. Complications associated with ileal pouch-anal anastomosis. World Journal of Surgery 1991; 15(6):763–6; discussion 766–7.
37 Pouchitis After Ileal Pouch-Anal Anastomosis Christine Carter-Kent and Robert Wyllie∗
Introduction Proctocolectomy with Ileal Pouch-Anal Anastomosis (IPAA) has emerged as the surgical procedure of choice for patients diagnosed with Familial Adenomatous Polyposis Syndrome (FAP) and ulcerative colitis since its introduction in the 1980‘s. In pediatric patients diagnosed with Ulcerative colitis, specific indications for proctocolectomy include severe disease refractory to medications, toxic megacolon, perforation, and intractable bleeding. In addition, findings consistent with dysplasia or malignancy on biopsy specimens are strong indications to proceed with IPAA [1]. These entities, however, are rare in pediatric patients. Patients with indeterminate colitis who undergo IPAA represent a special population. These patients have a complication rate similar to that of ulcerative colitis, unless the diagnosis of Crohn disease is ultimately made [2]. Initially, restorative proctocolectomy was performed using straight ileo-anal anastomosis without construction of a pouch. The results of multiple subsequent studies have shown the superiority of IPAA in comparison to the straight ileo-anal anastomosis. (Telander, Wewer) In the pediatric population, Telander et al. compared 121 children and young adults with either the straight IAA or the J pouch procedure. They found the J pouch to be superior in relation to stool frequency and nighttime stool patterns [3]. The IPAA procedure involves total abdominal colectomy with the upper internal anal sphincter and rectal muscular cuff left intact. A pouch reservoir is then created utilizing the ileum and an anastomotic connection is made to the anus. J-type, W-type, and S-type pouch reservoirs have been fashioned, but the most common procedure involves using the J pouch. Temporary loop ileostomies are performed at the time of the procedure to facilitate healing of the anastomotic connection and closed at a later date, typically 2–3 months. Contraindications to IPAA include both pelvic floor dysfunction and decreased anal sphincter muscle tone [4]. Long term results are excellent with minimal mortality related to the procedure. The majority of patients are satisfied with the IPAA procedure. Maintenance of bowel continence with a satisfactory functional outcome rank high with these patients. However, there can be significant morbidity related to IPAA. Long-term complications include stenosis, infection, pouch dysfunction, and pouchitis.
*Cleveland Clinic Foundation, Chair, Dept of Ped GI and Nutrition, 9500 Euclid Ave, Dept A111, Cleveland, OH 44195-0001, Phone: 216-444-2237, Fax: 216-444-2974
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Definition and Incidence Pouchitis is defined as idiopathic inflammation of the ileal reservoir in patients status-post proctocolectomy with IPAA. Pouchitis is the most common long-term complication of IPAA and is a significant cause of morbidity related to the procedure. Pouchitis was first described in the literature by Kock et al. in 1977. His group described the condition as inflammation in the ileal reservoir constructed after proctocolectomy [5]. Since the initial description, multiple investigators have attempted to characterize pouchitis and delineate the underlying pathophysiology. The diagnosis of pouchitis is based on clinical symptoms, endoscopic findings, and histologic findings. The frequency of pouchitis reported by different groups has varied significantly. However, it is well established that the incidence of pouchitis is higher for Ulcerative colitis patients as compared to FAP patients. Pouchitis in patients with UC varies between 15–53% (6–9). In comparison, pouchitis in FAP patients varies between 3–14% [10]. The overall incidence reported for pouchitis is related to duration of clinical follow-up and the clinical definition used for diagnosis of pouchitis [11]. In adult patients, Simchuk et al. reported that the incidence of pouchitis was 25% for patients followed for less than 6 months, 37% for patients followed for one year, and 50% for patients followed for three years [12]. In pediatric patients, Robb et al. analyzed patients 10 years of age or younger who were diagnosed with pouchitis after IPAA was performed. His group found that 75% of the patients (9/12) were diagnosed with pouchitis with an average of 9 years of post-operative follow-up [13]. Alexander, et al. reported 56% of pediatric patients (less than 21 years of age) with at least one episode of pouchitis with a mean follow-up of approximately seven years post-IPAA [14]. Durno et al. reported 41% incidence of acute pouchitis in pediatric patients in Toronto, Canada [15].
Etiology and Pathogenesis Although there has been much interest in defining and classifying pouchitis, the etiology of pouchitis remains unknown. There are a host of proposed factors that may play a role in the pathogenesis. It is most likely that the development of pouchitis is multi-factorial with several physiological and immunological factors contributing in a susceptible host. Table 37.1. lists the proposed etiological factors that contribute to the development of pouchitis [16]. Alterations in Proinflammatory Cytokines One of the most pursued areas of inflammatory bowel disease research is the influences of variations of gene loci on the development of IBD. As cytokines play a major role in the Table 37.1. Proposed etiological factors of pouchitis. Alterations in proinflammatory Cytokines Bacterial overgrowth Fecal stasis Nutritional Mucosal ischemia Crohn disease, undiagnosed Severity of UC Extra-intestinal manifestations, including primary sclerosing cholangitis Smoking pANCA Adapted from [16]
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inflammatory pathway that lead to disease manifestations, many studies have focused on the role of cytokines such as Interleukin (IL)-1 alpha, beta, and receptor antagonist (ra) in the etiology of IBD. IL-1 alpha and beta are pro-inflammatory cytokines, whereas IL-1ra is the natural inhibitor of these cytokines. Genetic polymorphisms that lead to a reduction in the ratio of IL-1 alpha and beta to IL-1ra will potentially lead to increased and/or chronic inflammation [17]. It is also possible that an imbalance in the ratio of IL-1 alpha and beta to IL-1ra may influence the initiation of inflammation leading to pouchitis in patients status-post IPAA. In 2001, Carter et al. reported that patients that developed pouchitis had a higher IL-1RN*2 carrier rate as compared with patients that did not have the particular allele, 72% versus 45% respectively [6]. IL-1RN*2 represents a polymorphism in the IL-1 gene cluster that has been associated with a change in the ratio of Il-1 alpha and beta to IL-1ra and the development of ulcerative colitis. This finding suggests that ulcerative colitis patients that carry this allele may have an increased tendency of developing pouchitis after IPAA. Fecal Stasis & Bacterial Overgrowth The response of the majority of acute episodes of pouchitis to antibiotic therapy and more recently to administration of probiotics suggests that bacterial populations are important etiological factors in the development of pouchitis. However, to date, no single microbial factor has been identified as the causative factor. In 2004, Gosselink, et al. reported an increase in aerobic bacteria and pathogenic bacteria such as Clostridium perfringens and hemolytic strains of Escherichia coli in stool collected from patients during episodes of acute pouchitis [18]. The significance of these particular pathogens is yet to be determined. Mucosal Ischemia It has been proposed that ischemia plays a role in the etiology of pouchitis. Several studies have examined the relationship between mucosal pH as a marker of ischemia and the development of pouchitis. The results of these studies are mixed and show no definitive relationship. Other studies have investigated the relationship between anastomotic narrowing and ischemia. No direct relationship has been demonstrated between tension at the anastomotic site leading to ischemia and the subsequent development of pouchitis [12]. Crohn Disease Undiagnosed Crohn disease can present clinically as chronic pouchitis following IPAA. In his retrospective study of 151 pediatric patients who underwent IPAA for presumed underlying ulcerative colitis, Alexander et al. reported that 15% of the patients were ultimately diagnosed with Crohn disease [14]. Wewer et al. reported approximately a 6% detection rate for Crohn disease in pediatric patients aged 7–17 years of age status-post IPAA [19]. The most common manifestations of Crohn disease noted for patients status-post IPAA are pouch fistulizing disease and pre-pouch ileitis. Extra-intestinal Manifestations The presence of extra-intestinal manifestations related to inflammatory bowel disease has been studied as predictors of the development and severity of pouchitis. Lohmuller et al. looked at extra-intestinal manifestations such as erythema nodosum, arthritis and uveitis to determine a relationship. Their group found that pouchitis occurred in 39% of patients with pre-operative extra-intestinal manifestations as compared to 26% of ulcerative colitis patients with no preoperative extra-intestinal manifestations. They also found an increased association with pouchitis if post-operative extra-intestinal manifestations were diagnosed [7].
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Multiple groups have specifically analyzed the relationship between primary sclerosing cholangitis and the development of pouchitis. Penna et al. found that pouchitis occurred in 63% of the patients with primary sclerosing cholangitis, while pouchitis only occurred in 32% of the patients without this particular extra-intestinal manifestation. This group also reported an increased frequency of chronic pouchitis in patients with primary sclerosing cholangitis versus patients without this disease, 60% and 15% respectively [8]. In 2005, a study by Gorgun et al. refuted this claim. This group reported a higher overall mortality for patients with primary sclerosing cholangitis status-IPAA, however they did not find a statistically significant relationship between chronic pouchitis and ulcerative colitis in patients with pre-operative primary sclerosing cholangitis [20]. Smoking It has previously been established that cigarette smoking is associated with a reduction in the risk of developing ulcerative colitis. In 1996, Merrett, et al. also described a link between smoking and a reduction in the incidence of pouchitis in patients after IPAA. Their study documented that 18/72 (25%) non-smokers were diagnosed with pouchitis, while 1/17 smokers (5%) were diagnosed with pouchitis. The reason for these findings is unclear, but may be related to the effect of smoking on gut mucosal permeability [21]. Serum Perinuclear Antineutrophil Cytoplasmic Antibody It has been shown that serum perinuclear antineutrophil cytoplasmic antibody (pANCA) is associated with a diagnosis of ulcerative colitis, therefore it is a natural progression to investigate whether serum pANCA has any effect on the diagnosis of pouchitis in patients after IPAA. Retrospective studies have shown mixed results in determining whether there is a direct relationship between pANCA and pouchitis. In 2001, Fleshner et al. studied the relationship between pouchitis and pANCA in a prospective study. They did not find an overall significant difference in the occurrence of pouchitis in the pANCA positive versus pANCA negative groups. They did, however, demonstrate a significant relationship between the development of chronic pouchitis in patients with a high level of pANCA (>100 EU/ml) as compared to patients with a medium level (40–100 EU/ml), low level (<40 EU/ml) or undetectable level of pANCA [9].
Diagnosis The first episode of pouchitis occurs most often in the first 6 months after closure of the loop ileostomy, however it can occur at anytime after IPAA is performed [10]. To accurately make a diagnosis, a combination of clinical symptoms, endoscopic findings and histologic findings need to be obtained. In practice, a presumptive diagnosis of pouchitis is often made on clinical symptoms alone. The proper diagnosis of pouchitis has been a source of debate in the literature. Several groups advocate that diagnosing pouchitis on clinical symptoms alone leads to overdiagnosis of this disease. The clinical presentation of pouchitis typically includes a combination of increased stool frequency, abdominal cramping, hematochezia, bowel incontinence, and/or low grade fever. Endoscopic findings involve assessing the severity of inflammation of the pouch mucosa. Signs of inflammation include erythema, edema, granularity, mucosal ulceration, and friability. The distal and posterior portions of the pouch are most often effected and should routinely be biopsied. In addition, if inflammation of the neo-terminal ileum is visualized, this finding is suggestive of Crohn disease. Cheifetz et al. suggest that single aphtous lesion in the terminal ileum do not confirm the diagnosis, rather the presence of serpiginous ulcers are more suggestive [22]. Histology of the pouch is graded on an ABC scale. Type A mucosa is described as normal
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Table 37.2. Pouchitis Disease Activity Index (PDAI) [25]. Criteria Clinical Stool frequency Usual post-operative stool frequency 1–2 stools/day > post-operative usual 3+ stools/day > post-operative usual Rectal bleeding None or rare Present daily Fecal urgency or abdominal cramping None Occasional Usual Fever (over 37.8C) Absent Present Endoscopic inflammation Edema Granularity Friability Loss of vascular pattern Mucoid exudate Ulceration Acute histologic pattern Polymorphonuclear infiltration Mild Moderate with crypt abscesses Severe with crypt abscesses Ulceration per low-power field (mean) <25% 25–50% >50%
Score
0 1 2 0 1 0 1 2 0 1 1 1 1 1 1 1 1 2 3 1 2 3
Pouchitis defined as a total PDAI score of 7 or above.
mucosa or mild villous atrophy with no or minimal inflammation. Type B mucosa is described as transient atrophy with temporary moderate to severe inflammation followed by normalization of the architecture. Type C mucosa is described as persistent atrophy with severe inflammation [23]. Type B and C mucosa are most often found in pouchitis. When a diagnosis of pouchitis is made, evidence of acute and/or chronic inflammation is typically present on biopsy samples. Chronic lymphocytic infiltrate, crypt hyperplasia, crypt abscesses, and fibromuscular obliteration of the lamina propria are specific findings that aid in the diagnosis [24]. Several scales for grading pouchitis have been developed over the last two decades. The most commonly used and referenced scales include the Pouchitis Disease Activity Index (PDAI) [25], Moskowitz Criteria [26], and The Heidelberg Pouchitis Activity Score [27]. Tables 37.2 and 37.3 detail the PDAI and the Moskowitz Criteria.
Classification The classification of pouchitis can be made based upon several different factors. Severity varies from remission to severely active. Duration varies from acute (less than four weeks) to chronic (more than 4 weeks). Frequency varies from infrequent to continuous. Pouchitis can also be graded according to response to therapy. Response to therapy is described as antibiotic-responsive,
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Table 37.3. Moskowitz criteria [26]. Acute changes Acute inflammatory cell infiltrate None Mild and patchy infiltrate in the surface of the epithelium Moderate with crypt abscesses Severe with crypt abscesses Ulceration None Mild superficial Moderate Extensive Maximum Chronic changes None Mild and patchy Moderate Severe Villous atrophy None Minor abnormality of villous architecture Partial villous atrophy Subtotal villous atrophy Maximum
Score 0 1 2 3 0 1 2 3 6 0 1 2 3 0 1 2 3 6
antibiotic-dependant, or antibiotic-resistant [28]. In addition, it must be considered that not all patients status-post IPAA with symptoms of diarrhea and abdominal pain will truly have pouchitis. Other disease entities that may present similarly to pouchitis include Irritable Pouch Syndrome, cuffitis, stenosis of the pouch, Crohn disease, celiac disease, and infectious bowel disease (most often secondary to Clostridium dificille or Cytomegalovirus).
Treatment There are currently less than 15 randomized, controlled trials that address the treatment of pouchitis. None of these trials have been performed in pediatric patients. Therefore, the majority of treatment regimens for pouchitis are based on empiric data alone. Medical Acute episodes of pouchitis respond to antibiotic therapy 95% of the time. The first-line antibiotics of choice for acute pouchitis are metronidazole and ciprofloxacin. In the past metronidazole alone was considered to be first line therapy. The first controlled studies with this drug were published by Madden et al. in 1994. They performed a double-blind, crossover trail comparing metronidazole with placebo. They reported that patients with pouchitis treated with metronidazole had statistically significant improvement in their stool frequency as compared with placebo [29]. Later studies showed of efficacy of ciprofloxacin. In an unblinded randomized control trial by Shen et al. it was reported that both ciprofloxacin and metronidazole significantly improved PDAI scores. In addition, the ciprofloxacin group experienced significantly larger reductions in PDAI scores and decreased side effects as compared with metronidazole [30]. Both metronidazole and ciprofloxacin are now considered first-line therapy for acute pouchitis.
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The medical treatment of chronic pouchitis is less clear. Other antibiotic combinations such as tetracyline, erythromycin, amoxicillin, and rifaximin have been used in the treatment of chronic pouchitis. In 2004, a study evaluating the effectiveness of combination therapy of rifaximin and ciprofloxacin was published. Eight patients with chronic pouchitis refractory to ciprofloaxcin were treated with rifaximin and ciprofloxacin for two weeks. Eighty eight percent (7/8) of the patients responded to therapy and five went into remission for at least six months [31]. Rifaximin is currently licensed in the US. Additional medications that have been used in the treatment of pouchitis include 5-ASA products (i.e. oral mesalamine, rectal mesalamine suppositories and enemas), topical and oral steroids (i.e. prednisone or budesonide enemas), or bismuth-containing products. The literature on these medications reveals mixed results and inconsistent efficacy. The use of probiotics is proposed to increase the normal, healthy flora of the colon such that concentration of unhealthy microflora are reduced and the incidence and severity of pouchitis is decreased. VSL-3® contains four strains of Lactobacillus, three strains of Bifidobacterium, and one strain of Streptococcus salivarius. In their 2000 randomized control trail, Gionchetti et al. showed that treatment with VSL-3 for nine months following antibiotic treatment compared with antibiotic treatment alone was statistically significantly better in maintaining remission from pouchitis [32]. In 2005, a double-blind placebo controlled trail examined the expression of pro-inflammatory cytokines in patients diagnosed with pouchitis who were treated VSL-3® . The results revealed that the expression of mRNA for the pro-inflammatory cytokines IL-1 beta, IL-8, and IFN-gamma in patients treated with VSL-3 were significantly decreased as compared with placebo. The levels of all of these cytokines were decreased at least two fold [33]. For patients status-post IPAA who are subsequently diagnosed with Crohn disease, Infliximab therapy is an option that has been utilized as part of the treatment regimen. In the adult population, Columbel et al. reported in their 2003 case series that 85% percent of the patients (22/26) experienced clinical response to infliximab. Of these responders, 62% (16/26) has a complete response [34]. There is one case series in the pediatric literature supporting these findings. In this case series four patients with Crohn disease diagnosed after IPAA were studied. The Pediatric Crohn disease Activity Index improved from 32.5–42.5 to 0–10 for these patients after infliximab infusions were initiated [35]. The following medical treatment regimen should be followed for acute and chronic pouchitis. The antibiotic treatment of the first, acute episode of pouchitis should be either metronidazole three times per day for 7–14 days or Ciprofloxacin twice per day for 7–14 days. If a patient is diagnosed with chronic pouchitis, alternative therapies include prolonged antibiotic therapy or combined antibiotic therapy with the addition of probiotics such as VSL-3® . Should this therapy fail, the addition of anti-inflammatory or immunosuppressive therapy is advocated. Figure 37.1. lists a proposed treatment regimen for acute and chronic pouchitis. Surgical If medical management of chronic, severe pouchitis is ineffective, patients status-post IPAA may require takedown of the pouch and creation of an ileostomy. It is a rare occurrence that takedown of pouch is a direct result of pouchitis. This occurs in approximately 1–5% of these patients. Pouch excision is most often related to pouch dysfunction as opposed to chronic pouchitis [8].
Outcome One of the most concerning potential complications of long term inflammation of the surgically created pouch is dysplasia and progression to malignancy. Overall, the incidence of dysplasia in the pouch is more common for patients with FAP than with ulcerative colitis. For patients with
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Metronidazole or Ciprofloxacin
Response
Early Recurrence
No Response
No Recurrence
Other Antibiotics + Probiotics
No Response
Metronidazole or Ciprofloxacin
Early Recurrence
Anti-inflammatory Meds, or Immunosuppresives
No reponse
Prolonged Metronidazole or Cipro + Probiotics
Response
No Response
Response
Surgical Consultation
Figure 37.1. Treatment regimen for pouchitis. Source: (Adapted From Shen 2005 et al. and Mahadevan) [4, 10]
FAP, dysplasia is more often related to the development of adenomas in the pouch. For patients with UC, the diagnosis is related to chronic pouchitis. To date, no evidence of dysplasia has been noted in the biopsy specimens of pediatric patients within five years after the pouch has been created [36]. Ten percent of the patients followed did have severe inflammation and villous atrophy noted in biopsy specimens which is concerning for possible neoplasia in the future. No long-term studies in these patients have been performed to delineate the overall risk of malignancy in this patient population. Gullberg et al. compared the risk of dysplasia in patients status-post IPAA with Type A histology of the pouch (normal mucosa or mild villous atrophy) compared with Type C histology of the pouch (persistent atrophy with severe inflammation). They determined that 5/7 patients with Type C mucosa developed dysplasia while no patients with Type A mucosa developed dysplasia [37]. These findings are consistent with other research and confirm that patients with Type C mucosa are a higher risk of dysplasia and possibly malignant lesions in the pouch. Fifteen cases of adenocarcinoma in the pelvic pouches of adult patients have been described in the literature. Eight of these cases occurred with ulcerative colitis patients and seven occurred with FAP patients [1]. There is currently no nationwide screening program for endoscopic surveillance for dysplasia in place for adults or pediatric patients who are status-post IPAA.
Table 37.4. Classification of pouchitis. Classification Severity
Duration Frequency Response to therapy
Description Remission Mildly active Moderately active Severely active Acute (less than 4 weeks) Chronic (more than 4 weeks) Infrequent (1–2 episodes) Relapsing (more then 3 episodes) Continuous Antibiotic-responsive Antibiotic-dependant Antibiotic-resistant
(Adapted from Shen and Mahadevan) [4, 10]
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Summary Ileal pouch-anal anastomosis is the surgical procedure of choice for patients with FAP or ulcerative colitis. The procedure is generally well tolerated, however pouchitis is the most frequent cause of morbidity. The majority of patients will experience isolated, acute episodes of pouchitis. Five percent of patients with pouchitis will ultimately be diagnosed with chronic disease. Therapeutic guidelines are generally empirically derived. Most patients do respond to antibiotic treatment with ciprofloxacin or metronidazole. Others may be treated with a combination of probiotics, antibiotics, anti-inflammatory medications, and/or immunosuppresive medications. Takedown of the pouch is uncommon and occurs only in a small minority of patients. Dysplasia and malignancy are concerns for patients with chronic pouchitis and severe inflammatory changes. To date dysplasia and malignancy have not been diagnosed in pediatric patients. References 1. Duff SE, O’Dwyer T, Hulten l, Willen R, Haboubi NY. Dysplasia in the Pelvic Pouch. Colorectal Disease 2002; 4: 420–429. 2. Pishori T, Dinnewitzer A, Zmora O, Oberwalder M, Hajjar L, Cotman K, Vernava AM, Efron J, Weiss EG, Nogueras JJ, Wexner SD. Outcome of Patients with Intermediate Colitis Undergoing a Double-Stapled Ileal Pouch-Anal Anastomosis. Diseases of the Colon and Rectum 2004; 47: 717–721. 3. Telander RL, Spencer M, Perrault J, Telander D, Zinsmeister AR. Long Term Follow-up of the Ileaoanal Anastomosis in Children and Young Adults. Surgery 1990; 108: 717–723. 4. Shen B, Lashner BA. Pouchitis: A Spectrum of Diseases. Current Gastroenterology Reports 2005; 7: 404–411. 5. Kock NG, Darle E, Hulten L, Kewenter J, Myrvold H, Philipson B. Ileostomy. Current Problems in Surgery. 1977; 14: 1–52. 6. Carter MJ, DiGiovine FS, Cox A, Goodfellow P, Jones S, Shorthouse AJ, Duff GW, Lobo AJ. The Interleukin 1 Receptor Antagonist Gene Allele 2 as a Predictor of Pouchitis Following Colectomy and IPAA in Ulcerative colitis. Gastroenterology 2001; 112: 805–811. 7. Lohmuller JL, Pemberton JH, Dozois RR, Ilstrup D, Van Heerden J. Pouchitis and Extra-intestinal Manifestations of Inflammatory Bowel Disease After Ileal Pouch-Anal Anastomosis. Annals of Surgery 1991; 211: 622–627. 8. Penna C, Dozois R, Tremaine W, Sandborn W, LaRusso N, Schleck C, Ilstrup D. Pouchitis After Ileal Pouch-Anal Anastomosis for Ulcerative colitis Occurs with Increased Frequency in Patients with Associated Primary Sclerosing Cholangitis. Gut 1996; 38: 234–239. 9. Fleshner PR, Vasiliauskas, Kam LY, Fleshner NE, Gaiennie J, Abreu-Martin MT, Targan SR. High Level Perinuclear Antineutrophil Cytoplasmic Antibody (pANCA) in Ulcerative colitis Patients Before Colectomy Predicts the Development of Chronic Pouchitis after Ileal Pouch-Anal Anastomosis. Gut 2001; 49, 671–677. 10. Mahadevan U, Sandborn J. Diagnosis and Management of Pouchitis. Gastroenterology 2003; 124: 1636–1650 11. Stocchi L, Pemberton JH. Disorders of the Anorectum: Pouch and Pouchitis. Gastroenterology Clinics 2001; 30 12. Simchuk EJ, Thirlby RC. Risk Factors and True Incidence of Pouchitis in Patients after Ileal Pouch-Anal Anastomosis. World Journal of Surgery 2000; 24: 851–856. 13. Robb BW, Gang GI, Hershko DD, Stoops MM, Seeskin CS, Warner BW. Restorative Proctocolectomy with Ileal Pouch-Anal Anastomosis in very Young Patients with Refractory Ulcerative colitis. Journal of Pediatric Surgery 2003; 38: 863–867. 14. Alexander F, Sarigol S, Difiore J, Stallion A, Cotman K, Clark H, Lydzinski B, Fazio V. Fate of the Pouch in 151 Pediatric Patients After Ileal Pouch Anal Anastomosis. Journal of Pediatric Surgery 2003; 38: 78–82. 15. Durno C, Sherman P, Harris K, Smith C, Dupuis A, Shandling B, Wesson D, Filler R, Superina R, Griffiths A. Outcome After Ileoanal Anastomosis in Pediatric Patients with Ulcerative colitis. Journal of Pediatric Gastroenterology and Nutrition 1998; 27: 501–507.
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16. Macafee DL, Abercrombie JF, Maxwell-Armstrong C. Pouchitis. Colorectal Disease 2004; 6: 142–152. 17. Casini-Raggi V, Kam L, Chong YLT, Fioncchi C, Pizzaro TT, Eisenberg SP, Nast CC, Cominelli F. Mucosal Imbalance of IL-1 and IL-1 Receptor Antagonist in Inflammatory Bowel Disease: A Novel Mechanism of Chronic Intestinal Inflammation. Journal of Immunology 1995; 154: 2434–2440. 18. Gosselink MP, Schouten R, Van Leishout LMC, Hop WCJ, Laman JD, Ruseler-van Embden JGH. Eradication of Pathogenic Bacteria and Restoration of Normal Pouch Flora: Comparison of Metronidazole and Ciprofloxacin in the Treatment of Pouchitis. Diseases of the Colon and Rectum 2004; 47: 1519–1525. 19. Wewer V, Hesselfeldt P, Qvist N, Husby S, Paerregaard A. J-pouch Ileal Anastomosis in Children and Adolescents with Ulcerative colitis: Functional Outcome, Satisfaction, and Impact on Social Life. Journal of Pediatric Gastroenterology and Nutrition 2005; 40: 189–193. 20. Gorgun E, Remzi FH, Manilich E, Preen M, Shen B, Fazio VW. Surgical Outcome in Patients with Primary Sclerosing Cholangitis Undergoing Ileal Pouch-Anal Anastomosis: A Case Control Study. Surgery 2005; 138, 631–639. 21. Merrett MN, Mortensen N, Kettlewell M, Jewell DO. Smoking May Prevent Pouchitis in Patients with Restorative Proctocolectomy for Ulcerative colitis. Gut 1996; 38: 362–364. 22. Cheifetz A, Itzkowitz S. The Diagnosis and Treatment of Pouchitis in Inflammatory Bowel Disease. Journal of Clinical Gastroenterology 2004; 38: S44–S50. 23. Veress B, Reinholt FP, Lindquist K, Lofberg R, Liljeqvist L. Longterm Histomorphological Surveillance of the Pelvic Ileal Pouch: Dysplasia Develops in a Subgroup of Patients. Gastroenterology 1995; 109: 1090–1097. 24. Nicholls RJ, Banerjee AK. Pouchitis: Risk Factors, Etiology, and Treatment. World Journal of Surgery 1998; 22: 347–351. 25. Sandborn WJ, Tremaine WJ, Batts K, Pemberton JH, Phillips SF. Pouchitis After Ileal Pouch- Anal Anastomosis: A Pouchitis Disease Actvity Index. Mayo Clinic Proceedings 1994; 69: 409–415. 26. Moskowitz RL, Shepard NA, Nicholls RJ. An Assessment of Inflammation in the Reservoir After Restorative Proctocolectomy with Ileoanal Ileal Reservoir. International Journal of Colorectal Disease 1986; 1: 167–174. 27. Heusechen UA, Autschbach F, Allmeyer EH, Zollinger AM, Heuschen F, Uehlein T, Herfarth C, Stern J. Long Term Follow-up After Ileoanal Pouch Procedure. Dis Colon Rectum 2001; 44: 487–499. 28. Shen B. Diagnosis and Treatment of Patients with Pouchitis. Drugs 2003; 63: 451–461. 29. Madden MV, McIntyre AS, Nicholls RJ. Double-Blind Corssover Trial of Metronidazole versus Placebo in Chronic Unremitting Pouchitis. Digestive Diseases and Sciences 1994; 39: 1193–1196. 30. Shen B, Achkar JP, Lashner BA, Ormsby AH, Remzi FH, Brzezinski A, Bevins CL, Bambrick ML, Seidner DL, Fazio VW. A Randomized Clinical Trial of Ciprofloxacin and Metronidazole to Treat Acute Pouchitis. Inflammatory Bowel Disease 2001; 7: 301–305. 31. Abdelrazeq AS, Kelly SM, Lund JN, Leveson SH. Rifaximin-Ciprofloxacin Combination Therapy is Effective in Chronic Active Refractory Pouchitis. Colorectal Disease 2005; 7: 182–186. 32. Gionchetti P, Rizello F, Venturi A, Brigidi P, Matteuzzi D, Bazzocchi G, Poggiolo G, Miglioli M, Campieri M. Oral Bacteriotherapy as Maintenance Treatment in Patients with Chronic Pouchitis: A Double Blind, Placebo-Controlled Trial. Gastroenterology 2000; 119: 305–309. 33. Lammers KM, Vergopoulos A, babel N, Gionchetti P, Rizzello F, Morselli C, Caramelli E, Fiorentino M, D’Errico A, Volk H, Campieri M. Probiotic Therapy in the Prevention of Pouchitis Onset. Inflammatory Bowel Disease 2005; 11: 447–454. 34. Colombel JF, Ricart E, Loftus E, Tremaine WJ, Young-Fadok T, Dozois EJ, Wolff BG, Devine R, Pemberton JH, Sandborn WJ. Management of Crohn disease of the Ileoanal Pouch with Infliximab. American Journal of Gastroenterology 2003; 98: 2239–2243. 35. Kooros K, Katz AJ. Infliximab Therapy in Pediatric Crohn Pouchitis. Inflammatory Bowel Disease 2004; 10: 417–420. 36. Sarigol S, Wyllie R, Gramlich T, Alexander F, Fazio V, Kay M, Mahajan L. Incidence of Dysplasia in Pelvic Pouches in Pediatric Patients After Ileal Pouch-Anal Anastomosis for Ulcerative colitis. Journal of Pediatric Gastroenterology and Nutrition 1999; 28: 429–434. 37. Gullberg K, Stahlberg D, Liljeqvist L, Tribukait B, Reinholt F, Veress B, Lofberg R. Neoplastic Transformation of the Pelvic Pouch Mucosa in Patients with Ulcerative colitis. Gastroenterology 1997; 112: 1487–1492.
38 Enteral Feeding Devices and Ostomies Susan N. Peck∗
Gastrostomy Children and adolescents with inflammatory bowel disease (IBD) often suffer the consequences of malnutrition and growth failure. Enteral nutrition as a therapy has been discussed prior to this chapter. Enteral access either via nasogastric tube feedings or direct enteral access via a gastrostomy tube (G-tube) is an option for children with inflammatory bowel disease. Direct access to the stomach by gastrostomy was first successfully performed by Jones in 1875. In 1980, Gauderer, Ponsky and Izant described the first nonsurgical placement of a gastrostomy tube when they introduced the endoscopically guided percutaneous gastrostomy tube [1]. In 1981 a percutaneous radiographic gastrostomy tube was placed by Dr. Preshaw [2]. The method of placement vary from open surgical, laparoscopic, percutaneous endoscopic gastrostomy (PEG) or percutaneous radiologic gastrostomy (PRG). The indications for placement are to provide longterm nutrition to patients who cannot orally ingest sufficient calories for appropriate weight gain and growth, and for disease treatment. It is essential that families are well educated regarding the care and maintenance of enteral feeding devices and it is preferable that the success of enteral nutrition via nasogastric tube has been previously documented. The trial of feedings allows the family the opportunity to become familiar with the enteral feeding regimen, the enteral feeding pump and the feeding bag system, and the care that is necessary. For many patients and families nasogastric tube feeding is cosmetically unappealing and is difficult to maintain on a long-term basis. Gastrostomy feeding is appealing for a number of reasons, the tube does not require daily insertion, it is not visible to the outside world, and connection to the gastrostomy tube is quick and easy. Prior to endoscopic or radiologic gastrostomy tube placement an upper gastrointestinal series should be considered in order to assure that the anatomy of the gastrointestinal tract is normal, as well as upper endoscopy to assess for the presence and severity of stomach inflammation which might interfere with the tube site healing. Once the decision has been made to pursue gastrostomy tube placement, it is important that the family be familiar with the type of gastrostomy tube being placed, i.e. PEG vs. low-profile gastrostomy tube, the length of time that the family can expect the initial tube to be in place and who will perform the first change. All of these vary with institutions, and specialties. An example of this is a surgically placed gastrostomy tube that could be a balloon low-profile device such as a MIC-KEY low profile®, a balloon replacement
*Division of GI, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, 34th Street & Civic Ctr. Blvd., Philadelphia, PA 19104, Phone: 215-590-3634, Fax: 215-590-3606, E-mail:
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tube, or a Malecot® tube. A surgically placed G-tube could be changed within 4 to 6 weeks. A percutaneously placed tube, either endoscopic or radiologic, is most likely going to be a tube that extends off the abdomen and is approximately 25–30 cm long; however it could also be a one-step button (Bard®). Most centers would recommend waiting 12 weeks before changing a PEG to a low-profile device in order to maximize healing and decrease risk of gastric dehiscence. The list of commonly used enteral feeding devices is presented in Table 38.1. The personnel involved in the tube replacement procedure also varies based on who placed the original tube and the direct visualization is now recommended either through radiology or a repeat endoscopic procedure. Care of the gastrostomy post placement is simple. The skin around the G-tube should be washed daily with a mild soap and water. Use of hydrogen peroxide should be avoided as it causes unnecessary irritation to the skin. If erythema is present, using a topical antibiotic ointment may be indicated. Covering the skin with gauze should be avoided.
Complications of Gastrostomy/Gastrojejenunostomy Tubes The most commonly encountered complications of enteral devices include infection, leakage, granulation tissue, migration, obstruction, and persistent fistula after removal [3]. Infection Gastrostomy tube infections are more common in the first several weeks following percutaneous placement. It has been estimated that 25 to 33% of patients develop a peristomal infection [4]. Few studies have addressed the issue of peristomal infections in children. The underlying medical condition of the child may influence their risk for infection and hinder wound healing. Antibiotic prophylaxis with placement of percutaneous endoscopic gastrostomies is recommended by the American Society for Gastrointestinal Endoscopy [5, 6]. Infection of the peristomal area can present with a variety of symptoms. Fever, spreading erythema, tenderness, pain, induration, and purulent discharge are typical. However, the yellowbrown crusty discharge that is commonly seen around the gastrostomy site is not a sign of infection, a finding that is confusing to families and caregivers. In case of infection treatment with a topical antibiotic may be all that is needed, however oral antibiotics may be necessary. Most infections respond to a first generation cephalosporin. Abscess formation adjacent to the stoma is another potential complication. These lesions have a rapid onset of a pustule or a red-purple fluid-filled lesion that is tender to the touch. When it ruptures, a punctuate opening is apparent and may drain for several days. Treatment with warm compresses and antibiotic therapy is recommended. Feeding tubes may become colonized with microbial organisms, yeast and fungus. There have been more 100 different microorganisms isolated from gastrostomy tubes with the most common being Candida (Figure 38.1), Pseudomonas, Escherichia coli, Enterobacter cloacae, Streptococci, Lactobacillus, Staphylococcus aureus, and Bacteroides. The significance of gastostomy tube colonization is unclear, however in the face of recurrent infections, culture of the site and treatment with the appropriately sensitive antibiotic is recommended. Tube Migration Migration of the gastrostomy tube with aberrant tract formation has been reported. The buried bumper syndrome (retrograde migration of the gastostomy tube’s internal bumper into the abdominal wall or into the stoma tract) is well described [7]. This occurs when there is traction placed on the external portion of the gastrostomy tube that results in excessive tension on the internal bumper at the time of placement. A false tract may develop as a late complication when
Table 38.1. Examples of available enteral feeding devices. Ross Introducer Gastrostomy Kit With Brown/MUELLER T-Fastener™ SET 18 FR
Balloon Replacement Gastrostomy Tubes
Magna-Port® Gastrostomy Tubes 14 FRTO 26 FR
Balloon Low Profile Tubes
MIC* Percutaneous Endoscopic Gastrostomy Feeding Tube 14 FR Mic* Safety Peg Feeding Tube/Kit, 14 FR O.D., Push (Over-the-Wire) Method MIC* Gastrostomy Feeding Tube 12 FR to 22 FR
MIC-Key* Low-Profile Feeding Tubes 12 FR 0.8 CM Shaft to 24 FR 3.0 CM Shaft Diameter 12 FR, 14 FR, !6 FR, !8 FR, 20 FR, 22 FR and 24 FR. 16FR has the maximum shaft length of 5.0cm
Corpak (Viasys)
Bard
Corflo Max-Peg System 12 FR, 16 FR and 20 FR
Bard® Peg Feeding Devices Gauderer Genie™ System 20 FR
Gastrostomy Tubes
Bard® TRI-Funnel Replacement Gastrostomy Tube 12 FR to 24 FR
5 CC Balloons –12 FR, 14 FR, 16 FR and 18 FR 20 CC Balloons – 16 FR, 18 FR, 20 FR, 22 FR and 24 FR Corflo-Cubby Low Profile Dual Port Wizard® Low-Profile Gastrostomy 12 FR, 14 FR, Gastrostomy Device 16, 18, 16 FR, 18 FR, 20 FR and 24 20 and 24 FR With 10 CC FR and 20 CC Balloons
Shaft Lengths - 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0 and 4.5 CM, Except the 12 FR Tubes. (Continued)
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Table 38.1. (Continued) Ross
Kimberly Clark
Corpak (Viasys)
Bard® button replacement gastrostomy devices 18 fr, 24 fr, 28 fr
Mushroom low profile tube (button) Gastro-jejunal tubes
Mic* transgastric-jejunal Corflo® -ultra jejunostomy tube feeding tube-endoscopic/radiology placement kit, 16 fr 8 fr and 10 fr sizes for use with Mic-key* low-profile 20 fr pegs transgastric-jejunal feeding tube 16 fr Mic* gastro-enteric feeding 6 fr for use with 16 fr pegs tube, 16 fr, 18 fr, 20 fr, 22 fr ponsky™ non-balloon replacement gastrostomy tubes 16 fr, 20 fr
Non- balloon replacement gastrostomy tubes Jejunal feeding tubes
Bard
Mic-key* low-profile jejunal feeding tube, 14 fr o.d., 0.8cm stoma length, 5 cc balloon
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Yeast infection
Figure 38.1. Fungal tube site infection.
the shaft length of the low-profile gastrostomy tube is not resized in a growing child. Failure to remeasure the shaft length may result in a too short tube causing the balloon or internal bumper to move up into the tract. Leakage and focal abdominal discomfort may result. Long-term migration of the balloon in to the tract may result in the development of a false tract or dilatation of the gastric opening. This allows for drainage of gastric contents onto the skin resulting in peristomal skin excoriation and breakdown. It is important to remeasure the stomal tract correctly and accurately. It is best to measure with the patient in both a supine and sitting position. If the measure significally differ in either position, the tract length should be the average between the two measurements. It is recommended that tracts be remeasured annually. Leakage Chronic leakage is a worrisome complication (Figure 38.2). Leakage of gastric contents will result in peristomal skin breakdown and the subsequent pain and potential infection. The first goal is always to stop the leakage. Remeasuring the shaft length and ensuring the proper fit of the gastrostomy tube is the first step. Ensuring that there is adequate water in the balloon is important. While most manufacturers recommend that the balloon be inflated with 6 cc of water, most can accommodate up to 10 cc safely. It is important to be cognizant of the size of the child and their gastric volume, to avoid exceeding gastric capacity. If the leakage is from an enlarged stoma tract, increasing the diameter of the gastrostomy tube (for example going from a 14 French to a 16 French) may be necessary. However, continuing to increase the size of the tube should be avoided when possible. Removing the gastrostomy tube for a couple of hours and allowing the stoma to “shrink” may be helpful. Many patients benefit from changing to a different appliance if leakage is a chronic issue. If all interventions fail, surgical revision may be necessary. Wound management of the eroded gastrostomy tube site is a challenge. The guidance of a wound and ostomy nurse may be necessary. Skin barriers are helpful in preventing ongoing damage from gastric secretions. Antacids have been used on the peristomal skin to neutralize and protect from gastric secretions. Skin barriers such as zinc oxide and other diaper rash agents may provide comfort to the patient and protect the skin from further breakdown. There are numerous
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Eroded skin
Figure 38.2. Skin irritation from tube leakage.
wound dressings that support wound healing. Absorbent hydrogels have been effective when used around gastrostomy tubes. Fistula Formation A persistent gastrocutaneous fistula is one that does not close spontaneously in 4 to 6 weeks after the gastrostomy tube has been removed. Approximately 25% of all children who had an endoscopically placed gastrostomy tube will suffer this complication [8]. The longer the gastrostomy tube is in place the less likely the fistula will heal spontaneously. A variety of techniques for promoting closure have been reported in the literature but all with limited success. Tract cauterization and use of fibrin glue have been reported in adults [9]. Surgical consultation and closure is usually recommended if the tract has not closed within four to six weeks. Gastrocolonic fistulas may develop at any time after the placement of the gastrostomy. Fecal drainage from the stoma, foul breath or leakage of formula or medications from the rectum should raise the suspicion of a gastrocolonic fistula. Surigcal closure of the fistula with a replacement of the gastrostomy tube is necessary. Granulation Tissue Granulation tissue is a frequent complication of gastrostomy tube (Figure 38.3). For some patients it is a minor complication but in others it results in unsightly tissue that is painful, oozing secretions, often times bleeding and may lead to other issues such as leakage and erosion of the surrounding skin. Granulation tissue is a proliferation of capillaries that forms around the external stoma and occasionally within the gastric opening. Current treatment options are limited. Stomadhesive powder, silver nitrate and topical corticosteroids are currently used to treat granulation tissue [10]. Cauterization of granulation tissue with silver nitrate has been utilized for years. It can result in significant complications if applied improperly. Burns to the surrounding skin is not uncommon. Cauterization can be painful and may need to be repeated to eliminate the granulation tissue. It is important to protect the healthy peristomal skin with a skin barrier, or surgical lubricating jelly. When the granulation tissue is cauterized, it changes color from pink to gray. Repeat cauterization
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Granulation tissue
Figure 38.3. Granulation tissue.
should occur when the tissue becomes pink again, usually in two to three days, until the tissues resolves. There is little data to support the use of corticosteroid creams in the treatment of granulation tissue, however, dermatologists have used topical steroids in the treatment of postoperative granulation tissue for several years [11]. It is thought that the topical steroids have an antiangiogenic effect on the granulation tissue similar to that of systemic steroids in the treatment of large capillary hemangiomas. Anecdotal reports on the successful use of triamcinolone cream in the treatment of granulation tissue are available. The usual dose is 0.1% triamcinolone cream twice daily for two weeks has met with some success. Prolapsed gastric tissue is often confused with granulation tissue. The tissue with gastric prolapse is a deeper red and more granular in appearance. Cautery with silver nitrate has no effect on this tissue, which is typically intermittent. Tube Obstruction Obstructed tubes are an issue primarily with gastrojejunal devices. Migration or dislodgement of these tubes is common in children with gastrointestinal dysmotility. To prevent tube clogging, frequent flushing is recommended, before and after bolus feeding or medication administration and every tow to four hours during continuous feedings. Families should be instructed on how to administer medication and which medications are more likely to cause tube obstruction. Water is recommended with a volume large enough to clear the tube, approximately 10 cc with each flush. Use of pancreatic enzyme mixed with sodium bicarbonate might help relieve tube obstruction.
Ostomy Education and Management Patients with inflammatory bowel disease modify many aspects of their lives to gain control of their disease. Diets are changed, activities impacted, and relationships are affected. Patients who undergo a bowel resection with an ostomy placement gain control that had previously been lost. For the majority of children and adolescents with inflammatory bowel, having a surgical intervention that results in an ostomy is associated with fear. For many patients, surgery is recommended either emergently or urgently due to a complication of the disease. It is important
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that the patient and family be well prepared. Stressing the positives of surgery is important. Many have never heard the words stoma or ostomy and the information they have may be incorrect. It is important that the patient and the family understand that living with an ostomy requires a lifestyle adjustment, and that new skills will be acquired and mastered. From a healthcare provider perspective, patient/family education prior to the surgery and preoperative marking of the stoma site are essential. The placement of the stoma is important for successful secure pouching and optimal patient satisfaction and outcomes. It is important to stress that ostomies do not smell, they are not visible under clothing and that sports participation is possible. Swimming, scuba and sky diving, and even professional football are possible with an ostomy. Adolescents fear intimacy with a stoma. This too needs to be addressed up front. If the healthcare professional is uncomfortable with the topic, then arranging a consultation with another provider or an enterostomal nurse who can address these issues is important prior to surgery. Family education and support is important. Piwonka and Merion reported that a person who has support throughout the surgical process did better than the patient who is alone during stoma surgery [12]. The preoperative discussion should include what the stoma will look like, how it functions, how it is managed, what the appliance or pouching system will look like. Have the pouching system available so that the patient and family can visualize how the stoma is fitted and how the pouch is emptied. Encourage the patient to wear a pouch prior to surgery so they are familiar with the sensation of the pouch on their abdomen and to be familiar with what to expect after surgery. Stoma site selection is a key predictor for successful stoma management [13]. A nurse certified in ostomy care should be involved preoperatively. The patient’s abdomen should be evaluated in several positions to determine that the location of the stoma, to guarantee that the seal of the pouching system will remain secure, that the peristomal skin is protected and fashion needs maintained [14, 15]. The most common problem encountered in ostomy management is leakage from around the pouching system. It is important to be able to maintain the seal on the pouching system for a predictable period of time, for most patients five to seven days, minimum of three days. Leakage results in denuded peristomal skin, and more importantly, loss of confidence and frustration for the patient. It is important for the patient to be able to predict the timing for changing the pouching system, thus allowing them to change it on a scheduled day and avoid the worry that the system will fail in the interval. Recognizing and treating peristomal issues will minimize long-term complications. One of the more common problems encountered is contact dermatitis. Contact dermatitis is treated by removing the offending product and then using a topical anti-inflammatory and replacing the product. Poor wound healing is the cause of muco-cutaneous separation. The separated area is filled with a skin barrier powder and then covered with a solid skin barrier to protect and promote healing. Periostomal abscesses should be treated with systemic antibiotics and topically with an absorptive foam product. Candidaisis or the peristomal area is best treated with a topical antifungal powder. Pyoderma gangrenosum may occur at the stoma of patients with IBD. Classically, a full thickness ulcer develops in the peristomal area with a halo of purple discoloration. The ulcers are extremely painful. If the ulcer is large, it may interfere with the pouch seal resulting in leakage and further skin breakdown. Treatment of peristomal pyoderma gangrenosum is difficult and varies. Topical and systemic corticosteroids may be necessary. Immunomodulator therapy and biologic agents have also been used. Absorptive dressings will collect the moisture and exudates. Preparing a patient and family for living with an ostomy, whether temporary or permanent, is a planned approach. It should provide them with education regarding the stoma, the skills necessary to care for the stoma and emotional support.
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References 1. Gauderer MW, Ponsky JL, Izant RJ, Jr. Gastrostomy without laparotomy: a percutaneous endoscopic technique. J Pediatr Surg 1980; 15:872–5. 2. Preshaw RM. A percutaneous method for inserting a feeding gastrostomy tube. Surg Gynecol Obstet 1981; 152:658–60. 3. Khattak IU, Kimber C, Kiely EM, Spitz L. Percutaneous endoscopic gastrostomy in paediatric practice: complications and outcome. J Pediatr Surg 1998; 33:67–72. 4. Friedman JN, Ahmed S, Connolly B, Chait P, Mahant S. Complications associated with image-guided gastrostomy and gastrojejunostomy tubes in children. Pediatrics 2004; 114:458–61. 5. Antibiotic prophylaxis for gastrointestinal endoscopy. American Society for Gastrointestinal Endoscopy. Gastrointest Endosc 1995; 42:630–5. 6. Gossner L, Keymling J, Hahn EG, Ell C. Antibiotic prophylaxis in percutaneous endoscopic gastrostomy (PEG): a prospective randomized clinical trial. Endoscopy 1999; 31:119–24. 7. Klein S, Heare BR, Soloway RD. The “buried bumper syndrome”: a complication of percutaneous endoscopic gastrostomy. Am J Gastroenterol 1990; 85:448–51. 8. El-Rifai N, Michaud L, Mention K, et al. Persistence of gastrocutaneous fistula after removal of gastrostomy tubes in children: prevalence and associated factors. Endoscopy 2004; 36:700–4. 9. Gonzalez-Ojeda A, Avalos-Gonzalez J, Mucino-Hernandez MI, et al. Fibrin glue as adjuvant treatment for gastrocutaneous fistula after gastrostomy tube removal. Endoscopy 2004; 36:337–41. 10. Goldberg E, Kaye R, Yaworski J, Liacouras C. Gastrostomy tubes: facts, fallacies, fistulas, and false tracts. Gastroenterol Nurs 2005; 28:485–93; quiz 493–4. 11. Mandrea E. Topical diflorasone ointment for treatment of recalcitrant, excessive granulation tissue. Dermatol Surg 1998; 24:1409–10. 12. Piwonka MA, Merino JM. A multidimensional modeling of predictors influencing the adjustment to a colostomy. J Wound Ostomy Continence Nurs 1999; 26:298–305. 13. Bass EM, Del Pino A, Tan A, Pearl RK, Orsay CP, Abcarian H. Does preoperative stoma marking and education by the enterostomal therapist affect outcome? Dis Colon Rectum 1997; 40:440–2. 14. Erwin-Toth P, Barrett P. Stoma site marking: a primer. Ostomy Wound Manage 1997; 43:18–22, 24–5. 15. Erwin-Toth P. Ostomy pearls: a concise guide to stoma siting, pouching systems, patient education and more. Adv Skin Wound Care 2003; 16:146–52.
Section 6 Research
39 Clinical Indices for Pediatric Inflammatory Bowel Disease Research Angela Noble∗ and Dan Turner
Introduction Clinical research in pediatric inflammatory bowel disease (IBD) has been increasing over the last 20 years. It has been recognized that the interpretation of clinical studies in children with IBD requires the use of outcomes that reflect pediatric specific qualities of the disease. Subsequently, different clinical indices have been developed for clinical research in children with IBD. To fully appreciate the role of these instruments, an understanding of their components and their performance in children with IBD is paramount.
Assessment of Instruments Used in Clinical Research Disease activity is a concept for which no gold standard exists. Even in ulcerative colitis (UC), where colonoscopic appearance is readily available and important in evaluating disease activity, it is still not regarded as the gold standard because the degree of inflammation is subjective and mucosal healing lags after clinical improvement. Therefore, disease activity is best measured using multi-item indices which often incorporate clinical symptoms, laboratory parameters, and endoscopy findings. According to accepted standards of health indices development [1], the introduction of a new measure for use in clinical research should follow a multi-step process of item generation, reduction, grading, weighting and evaluation [2, 3]. A list of all potentially useful items is generated by a panel of experts and then reduced to include only the most relevant items. These items are then evaluated for their ability to explain the desired attribute (e.g. disease activity or quality of life); each item is graded and may be given a weight according to its ability to correctly categorize the response options (e.g. remission versus active disease). The final product, the clinical index, is then evaluated to define cut-off scores that correspond to clinically important disease states such as remission and mild to severe disease activity. For clinical indices that will
*Clinical Instructor in Pediatrics, Department of Gastroenterology, Hepatology and Nutrition, St. Justine Hospital, University of Montreal, 3175 Cote Sainte Catherine, Montreal, Canada, Phone: 514-345-493, Ext 6666, Fax: 514-345-4999, Email:
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be used to determine changes in disease activity over time (evaluative measures), a definition of “response” (i.e. the minimal important difference) is also required. Once the instrument has been developed, it must be evaluated for validity, reliability, responsiveness and feasibility [4–6]. Briefly, validity is the degree to which the instrument measures the concept that it purports to measure [7]. The reliability of an instrument relates to its stability on repeated measures or the amount of inherent error of the measure, both random and systematic [8]. Responsiveness refers to the instrument’s ability to correctly identify change over time in the concept being measured. It is not merely sensitivity to change but rather the ability of the instrument to detect changed from unchanged patients. A highly responsive index is invaluable in clinical trials, as it allows performing the trial with a smaller sample size [9–12]. Finally, feasibility encompasses both respondent and administrative burden. Respondent burden represents the participant’s contribution to the completion of the instrument and the administrative burden is the researcher’s involvement. An instrument is feasible if the participant and researcher report that the instrument is completed within reasonable limits of participant discomfort and both participant and researcher time constraints. This evaluative process is illustrated in Table 39.1, using a theoretical instrument aimed to measure disease activity in pediatric IBD. The examples Table 39.1. Evaluation example of a hypothetical IBD disease activity index. Term Validity Face and content validity
Criterion validity Construct validity
Concurrent validity Convergent validity Extreme group validity
Reliability Inter-observer reliability Test-retest reliability Responsiveness
Definition Most experts in the field will judge the index as sensible and that the included items are the important ones Determines the relationship between the measure and a gold standard A mini-theory to explain whether a measure acts the way it is expected based on the concept it represents The relationship of the index with other measures that reflect the same attribute The relationship between the new index and an established one Whether the measure differentiates extreme sides of the disease spectrum
Whether a score is reproducible between different raters at the same time Whether a score is reproducible at different times, when the patient remains stable The ability of an instrument to accurately detect change in disease activity over time, when it occurs
DAI disease activity index, IBD inflammatory bowel disease
Example from DAI [1] A group of experts in pediatric IBD approves the completeness and sensibility of the DAI Not applicable to IBD
The DAI is highly correlated with endoscopy score, histology score and physician global assessment The DAI is appropriately correlated with a previously established adult activity index The DAI differentiated well IBD children, sent home without change in therapy from children admitted to the hospital Two independent physicians scored the DAI concurrently on the same individuals with similar results The DAI remained unchanged on repeated visits of patients whose disease activity was judged to be unchanged The DAI dropped significantly over time in a group of IBD children treated with steroids for active disease, and not significantly when no therapy was given
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provided in the table are a few of many methods available; a complete description of the available techniques used at each step is beyond the scope of this chapter.
Outcomes for Clinical Research in Paediatric Inflammatory Bowel Disease Crohn Disease Activity Indices One of the first Crohn disease (CD) activity indices developed in adults was the Crohn disease Activity Index (CDAI) published in 1976 by Best and colleagues [13]. This index includes clinical symptoms, IBD related complications, physical examination findings, laboratory tests, weight, and use of medications to treat diarrhea. The initial study determined score cut-offs indicative of disease remission and activity and also determined responsiveness to change in disease activity status (Table A-1). Since its publication, it has been used extensively and is currently the primary outcome used in most clinical trials in adult Crohn disease. Despite its widespread use, the CDAI has been criticised for its potentially poor inter-observer agreement [14, 15] and moderate respondent and administrative burden. The instrument entails a prospective 7-day diary of clinical symptoms prior to the physician visit (for the patient) and a complicated calculation for the final CDAI score (for the investigator). Given these limitations, simpler disease activity indices have been developed, the most commonly used being the Harvey Bradshaw Index (HBI). Harvey and Bradshaw developed this index to include only clinical symptoms and physical exam findings [16]. The respondent burden is significantly lower than the CDAI as there is no need for a symptom diary or blood work. In addition, since this is an additive scale, the final score can be easily calculated (Table A-1). The Crohn disease activity indices developed in adults are not felt to adequately represent the pediatric population, primarily because they lack a measure of growth which is an important parameter in childhood IBD. In addition, the CDAI attributes 30 points to treatment with antidiarrheal medications, not commonly prescribed in pediatric IBD. The CDAI was therefore modified for use in pediatric clinical trials: the use of anti-diarrheals was replaced with number of days unable to participate in normal activities and standard weight was replaced by ideal weight (Table A-2). The modified CDAI and the HBI have been used in pediatric clinical trials in the absence of an evaluation of their validity, reliability, and responsiveness in children [17, 18]. A group of pediatric gastroenterologists proposed a Pediatric Crohn disease Activity Index (PCDAI) [19]. The PCDAI was designed to incorporate clinical variables, similar to those found in the modified CDAI and HBI, in addition to measures of growth and laboratory parameters. The final instrument contains patient symptoms (based on a 7-day recall), physical exam findings, laboratory parameters, and growth measures (Table A-3). Unlike the CDAI that was weighted using mathematical modelling, the development process of the PCDAI was entirely judgmental by experts in the field. PCDAI scores range from 0 to 100 with higher scores reflecting more severe disease. This instrument has been evaluated in four cohorts of children with CD [19–22] (Table 39.2). The demographic characteristics and distribution of disease found in these cohorts were similar to previously described pediatric CD populations. However, the distribution of disease activity was skewed towards no to mild disease so discrimination between moderate and severe disease activity was not possible. In a head to head comparison, Otley et al. [20] showed that the PCDAI was highly correlated with physician global assessment (r = 0.86) higher than the CDAI (r = 0.77), the modified CDAI (r = 0.76) and the HBI (r = 0.72). Inter-observer reliability was demonstrated by concurrent calculation of the PCDAI by two independent gastroenterologists. However, more data on reliability, especially test-retest is required. Responsiveness to change in disease activity was demonstrated and the minimal clinically important change, to define “response”, was found to be at least 12.5 points [21]. The optimal PCDAI score representative of
Table 39.2. Validity, reliability, and responsiveness of pediatric crohn disease activity index. Instrument PCDAI Hyams et al [19]
Otley et al [20]
Study population
Validity
Reliability
Responsiveness
n = 131 prospective cohort
PCDAI to HBImod r = 0.81 PCDAI to PGA r = 0.80 Score cut offs No disease 0 − 10 69% Mild 11 − 30 correct Moderate/Severe > 30 classification
Interobserver r = 0.86
N/A
n = 81 prospective cohort
PCDAI to CDAI r = 0.86 PCDAI to PGA r = 0.86 PCDAI to HBI r = 0.84 Receiver operating curves to select versus mild disease: Sensitivity ≤ 10 0.75 < 15 0.83
N/A
Correlation of the difference PCDAI score, between the two visits was highly correlated with the difference in the CDAI in 17 patients. No other responsiveness measures are provided and time of follow-up visit not specified
PCDAI cut offs for no Specificity 0.905 0.905
Hyams et al [22]
n = 181 from Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry
Validation of previously defined score cut offs: Sensitivity Specificity No disease vs mild: < 10 0.81 0.68 Mod/severe vs mild: > 30 0.71 0.83
N/A
Clinically significant change in PCDAI predictive of change in PGA = 12.5 points (sensitivity 0.87, specificity 0.73)
Kundhal et al [21]
n = 25 & 63 (from 2 prospective cohorts)
N/A
N/A
Minimal clinically significant change in PCDAI predictive of PGA at 1 month follow-up = 12.5 points (sensitivity 0.83, specificity 0.92) High effect size statistics in 15 patients who responded to therapy (SES=1.78, SRM=1.41)
Abbreviated PCDAI Loonen et al [23]
Shepanski et al [24]
n = 71 (previously reported in Otley et al 1999)
Area under the curve to differentiate quiescent from active patient judged by PGA: PCDAI 0.96 abPCDAI 0.94 abPCDAI + labs 0.96 Abbreviated PCDAI < 10 points for disease remission (sensitivity 0.84, specificity 0.88)
N/A
N/A
n = 40
abPCDAI to PCDAI abPCDAI to IMPACT PCDAI to IMPACT
N/A
N/A
r = 0.85 r = –0.58 (n = 29) r = –0.55 (n = 29)
CDAI Crohn’s disease Activity Index; HBI Harvey-Bradshaw Index; PCDAI Pediatric Crohn’s disease Activity Index; abPCDAI abbreviated PCDAI; PGA Physician Global Assessment
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disease remission has been open to some discussion. The initial study found that a PCDAI score of less than or equal to 10 points discriminated active from quiescent disease. Recent studies, however, have found that PCDAI scores of less than 10 and 15 points were more sensitive and specific than a score of less than or equal to 10 points for disease remission (Hyams et al. [22] and Otley et al. [20] respectively). Until more clinical experience is available with the PCDAI, a conservative approach is to define active disease as a minimum PCDAI score of greater than 15 or more points for recruitment of children into clinical trials and a PCDAI of less than 10 points as disease remission following the trial intervention. No formal assessment of the feasibility of the PCDAI is reported although the authors comment that the instrument was not difficult to administer. The respondent burden appears reasonable as instrument completion requires a physician assessment and laboratory tests that are routinely ordered as part of standard medical care. The PCDAI is expected to replace the CDAI in pediatric IBD clinical trials as a valid and reliable measure of long-term disease activity outcomes. The growth parameters of the PCDAI are pediatric specific and contribute 20 points to the total PCDAI score. The weight variable requires an accurate weight reading at an interval of a minimum of 4 months. Points are allocated to involuntary stable weight or weight loss, the weight loss being quantified as a percentage (current weight – previous weight/ previous weight). The height variable requires an accurate height measurement with a properly calibrated stadiometer and an experienced operator. At diagnosis, points are allocated to the number of channels crossed (downward) determined by plotting the current and past heights on a sex appropriate growth chart. The height variable on follow-up visits employs height velocity [25, 26]. Height velocity, by consensus, is measured over a minimum period of 6 to 12 months: Height velocity =
2nd height − baseline cm Time year
(1)
To compare children of different ages and gender, the height velocity is converted to a Z-score: Z-score =
Observed height velocity – Mean height velocity for age and sex (cm/yr) Standard deviation of the mean height velocity (for age and sex)
(2)
The Z-score corresponds to the standard deviation (SD) of the child’s height velocity. Points are allocated to the number of standard deviations below normal, defined as greater than or equal to –1 SD. A possible limitation of the PCDAI is its responsiveness to short term change. The growth items, as noted in the previous paragraph, contribute 20 points to the overall score. These items are measured over a minimum period of 4 and 6 months for the weight and height respectively. Clinical trials that evaluate induction of remission typically follow the cohort for 4 to 12 weeks. A child with growth delay could potentially have a PCDAI score that remains unchanged at the 10 to 20 point level regardless of his or her short-term response to the trial intervention. To alleviate this problem and assess the contribution of the laboratory items, two groups evaluated an abbreviated PCDAI (Table 39.2) [23, 24]. The abbreviated PCDAI (abPCDAI) removed the height parameter and 3 laboratory items from the original PCDAI (Table A-4). The validation of the abPCDAI in the initial study relied primarily on its ability to differentiate patients with quiescent versus active disease, similar to the PCDAI [23]. The second study showed that the abPCDAI was highly correlated with the full index (r = 0.85), but there was no comparison to other CD activity assessments [24]. In the same study, a moderate correlation of the abbreviated PCDAI with the pediatric IBD quality of life instrument, Impact-III was demonstrated (r = –0.55) [24]. The exclusion of the lab items from the abbreviated PCDAI makes it attractive for short-term follow-up visits that may not require laboratory testing as part of routine medical care. However, more studies of the performance of the abbreviated PCDAI are required before recommendation can be made for its routine use in clinical trials with short-term follow-up.
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Perianal Crohn Disease Perianal Crohn disease encompasses perianal skin tags, fissures, enterocutaneous fistulas, and abscesses. It affects up to one third of the CD population and it may be the only manifestation of the disease [27, 28]. Numerous clinical trials have been devised, primarily in adult populations, to determine the optimal management of this challenging condition. There are two disease activity measures currently used in clinical trials to follow perianal CD activity: the Perianal Disease Activity Index (PDAI) and the Fistula Drainage Assessment (Table B-1). The PDAI was developed and validated by Irvine and colleagues [29]. It contains five items, each scored 0 to 4, with higher scores representing more severe disease. In the validation cohort, it had moderate correlation with both physician and patient assessment of perianal disease activity (r = 0.72 and 0.66 respectively). As expected, it correlated poorly with the CDAI and HBI (r = 0.23 and 0.21 respectively) implying that perianal disease can present in the absence of other CD symptoms. The PDAI scores were reproducible in patients with stable disease over 4 to 8 weeks, implying test-retest reliability. Although the PDAI changed in patients who improved or deteriorated on repeat visits, robust and accepted responsiveness statistics were not presented. The second instrument, the Fistula Drainage Assessment, was introduced as part of a clinical trial of infliximab therapy for perianal CD [30]. This instrument simply defines response as a 50% decrease in draining fistulas and complete response as fistula closure or the absence of any draining fistulas. In that study, the Fistula Drainage Assessment was significantly lower in the treatment versus the control group, similar to the PDAI calculated concurrently. These results have been replicated in other clinical trials [31–33]. Since reliability of this subjective index was never formally assessed, it is recommended that two independent physicians score the index in future clinical trials. Moreover, in view of the questionable validity and responsiveness of these indices, and since no other similar measure is available, both should be calculated in clinical trials, until more data is available. There is no unique perianal disease activity index for children with perianal CD. The use of the PCDAI is not recommended for assessing perianal disease as it contributes only 10 points to the overall score. At present, the use of the Fistula Drainage Assessment definitions appears to be the preferred perianal outcome in pediatric clinical trials, as an anchor for physician assessment of disease activity. In order for the PDAI to be considered in children, the sexual dysfunction component should be modified to reflect more age appropriate issues such as participation in school and other social activities. Obviously, this modification requires appropriate validation and assessment of reliability and responsiveness, before being used in pediatric studies. Ulcerative Colitis Disease Activity Indices The earliest classification of UC disease activity was a qualitative scale published by Truelove and Witts in 1955 (Table C-1) [34]. This index defined remission, mild and severe disease. A score between mild and severe was considered as moderate. Because of this simple gradation and poor definition of moderate severity, significant ambiguity exists in defining change in disease activity with this index. Arbitrary quantitative indices have since been introduced, including the PowellTuck Index [35], the Mayo-Clinic score [36], Rachmilewitz Index [37], and Lichtiger Score [38] (Table C-2). The first three include an endoscopic evaluation of the rectosigmoid as part of the global assessment. None have been formally evaluated with respect to criterion validity, reliability or responsiveness. Their validation has therefore been a side product of clinical trials in which they have been used and developed. Seo and colleagues recently developed and evaluated an UC disease activity index [39, 40], weighted against the Truelove and Witts classification (Table C-2). The initial development process was biased towards severe disease since the investigators used a retrospective cohort of hospitalized patients. It is not surprising, therefore, that the index is heavily weighted toward three (of five) laboratory items which may be more important in severe disease.
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This index has not gained wide use despite its multi-step development. Walmsley and colleagues developed a Simple Clinical Colitis Activity Index that removed all laboratory parameters [41]. It correlated highly with both the Powell-Tuck Index and Seo index. However, this index is not commonly used, perhaps because it was aimed only for initial assessment by non-specialist physicians as a guide for the need to seek further medical advice (Table C-2). Recently, the Endoscopic Clinical Correlation Index (ECCI) was developed prospectively in 137 adults with UC undergoing full colonoscopy [42] (Table C-2). Items were chosen based on their ability to predict endoscopic outcome. The final index is composed of four items: nocturnal diarrhea, abdominal pain, albumin and rectal bleeding. The ECCI highly correlated with the endoscopy colitis score (r = 0.81) slightly higher than the Seo, Truelove and Witts, Powell-Tuck and Walmsley’s simple colitis index. However, these correlations were obtained from the derivation cohort only and not from a separate validation cohort. Moreover, the reliability and responsiveness of the index were not assessed. To date, this index has not been used in any clinical study, and more performance evaluation is required. Unlike Crohn disease, UC has a more homogenous presentation and it is believed that patients in remission have a normal, or near normal, endoscopic appearance. Nonetheless, endoscopic assessment cannot be considered a gold standard. The macroscopic assessment of the degree of inflammation is subjective and endoscopic healing tends to lag behind symptom improvement in UC [43, 44]. A very recent and comprehensive position paper on the selection of outcomes in adult UC clinical trials recommended that the primary endpoint for therapeutic trials should be induction of remission (and exacerbation in maintenance studies), confirmed by an endoscopic assessment of the intestinal mucosa [45]. Whether clinical symptoms and endoscopic appearance should be incorporated in a single composite score remains a matter of debate. At present, the most commonly used index, the Mayo-Clinic score, incorporates both clinical and endoscopic evaluations. Until recently, two indices have been available for pediatric use, the Lloyd-Still index and the Colitis Symptom Score. The Lloyd-Still index does not discriminate between CD and UC despite the major differences between these two disease entities [46]. In addition, it requires a radiological and endoscopic assessment at each evaluation and, therefore, is not practical. The Colitis Symptom Score was developed as part of a study to assess mucosal healing in children. It also requires an endoscopic assessment at each evaluation [47]. The validity, reliability, and responsiveness of these instruments have never been formally evaluated and neither have gained wide spread use in pediatric UC clinical trials. In children, the need for repeat endoscopic assessment can deter patients from participating in clinical trials and therefore, a non-invasive measure is preferred. In keeping with this, pediatric gastroenterologists participating in the 2004 Crohn and Colitis Foundation of America, Pediatric IBD Clinical Trials Workshop reviewed the existing measures of UC activity and concluded that a novel instrument for use in pediatric patients should be developed. As a result, the Pediatric UC Activity Index (PUCAI) was very recently introduced (Table C-3) [48]. The index was developed by a combined judgemental, using a Delphi group of 36 experts in pediatric IBD, and mathematical approach on a prospective cohort of 157 children with UC. Items were weighted using regression modelling with physician global assessment as the dependent variable. Six clinical items were retained in the final model, of which “rectal bleeding” obtained the highest weighting. The PUCAI was validated on a separate prospective cohort of 48 children undergoing full colonoscopy, wherein it showed very good to excellent correlation with PGA (r = 0.91), colonoscopic appearance (r = 0.77) and the adult invasive reference index, the Mayo Clinic Score (r = 0.95). Correlations were higher than two non-invasive adult indices, the Seo and Lichtiger indices, calculated concurrently. Inter-observer and test-retest reliability were excellent (ICC = 0.95). The PUCAI differentiated well the categories of disease activity of none, mild, moderate and severe judged by a physician’s global assessment (areas under the ROC curves of
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>0.97). Responsiveness was shown to be high at repeated visits of 74 children. Remission was defined as a PUCAI score of <10, and the minimal clinically important difference as a change of at least 20 points (area under the ROC curve of 0.97). The laboratory items did not improve the validity or responsiveness of the PUCAI and thus were removed, making it attractive for pediatric use. The encouraging results obtained from the development cohorts are yet to be replicated in cohort studies and clinical trials.
Gastrointestinal Endoscopy Indices Crohn Disease Assessment of gastrointestinal mucosal disease is important in CD research as mucosal healing has been associated with better long term outcomes [49]. Two groups have developed standardized approaches to endoscopy findings in Crohn disease. The “Groupe d’etudes therapeutiques des affections inflammatoires du tube digestif” designed the Crohn disease endoscopic index of severity (CDEIS) by incorporating endoscopic findings, previously shown to have high interrater reliability [50], into a regression model using the physician global assessment of endoscopy severity as the dependent variable [51] (Table D-1). The index was found to have high inter-rater reliability (r = 0.96), and was highly correlated with the physician endoscopy assessment in an independent cohort with Crohn disease (r = 0.81). It has subsequently been used in multiple clinical trials evaluating endoscopic endpoints [52–54]. However, it has been criticized for its complexity. Thus, Daperno and colleagues developed the Simplified Endoscopic Activity Score for Crohn disease (SES-CD) [55] (Table D-2). The SES-CD had high inter-rater reliability (ICC = 0.98) and was highly correlated with the CDEIS (r = 0.92). The CDEIS was similarly found to have high inter-rater reliability (ICC = 0.91) in their study. Lower correlations were found between both the SES-CD and CDEIS and other parameters of disease activity including the CDAI (0.39 and 0.36 respectively) and C-reactive protein (r = 0.47 and 0.45 respectively) confirming that in Crohn disease, mucosal findings do not necessarily reflect a patient’s current clinical status. There is no standardized endoscopic instrument for pediatric CD. However, there is no evidence that endoscopic characteristics differ in children. Although the CDEIS is the most widely employed instrument in adult clinical trials, the SES-CD seems to be a valid alternative to its more complicated counterpart. The use of either instrument in pediatric studies should be supplemented with a physician global endoscopy assessment until further assessment in pediatric CD is available. Postoperative Crohn Disease Endoscopic Assessment After intestinal resection, recurrence of CD is almost inevitable when patients are followed-up long-term, and it usually occurs at the site of the surgical anastomosis [56]. Endoscopic recurrence precedes clinical recurrence; at 1-year follow-up, 70% of patients had endoscopic recurrence but only 20% were symptomatic [57]. Therefore, endoscopy is an important outcome in clinical trials assessing postoperative interventions in Crohn disease. Rutgeerts and colleagues [57] proposed a scoring system for recurrent endoscopic disease at the surgical anastomosis based on their clinical experience (Table D-3). The Rutgeerts endoscopic scoring system has been incorporated into a number of clinical trials and although it is quite subjective, higher Rutgeerts scores consistently predict a more severe clinical course [57–59]. However, as the reliability of this index has never been formally assessed, it would be prudent for two independent physicians to score the index in future clinical trials, until more data is available.
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Ulcerative Colitis Colonoscopic assessment in UC seems to be more important than in CD for assessing disease activity. The involved mucosa is readily visualized, and, albeit not perfect, it is believed that endoscopic remission follows clinical remission more closely than in CD. Therefore, endoscopic assessment is part of most adult UC clinical trials. Surprisingly, however, none of the existing endoscopic scoring systems in UC (Truelove and Witts assessment [34], endoscopic assessment as part of Powell-Tuck index [35], Baron’s classification [60], endoscopic assessment as part of Rachmilewitz index [37], sigmoidoscopic index [61], and endoscopic assessment as part of the Mayo score [62]) were derived under stringent criteria for indices development. Similarly in children, no endoscopic index has been rigorously developed and evaluated. The lack of an evaluated measure is concerning in view of the potential low reliability of some endoscopic assessments. Baron and colleagues found only 66% agreement on a subset of endoscopic findings in adults with proctocolitis [60]. Specifically, spontaneous bleeding, friability, and the presence of ulcers were found to have greater than 66% agreement only if classified as present or absent. If characteristics of these variables, for example the extent of friability, were added to the endoscopic assessment then the agreement was poor on all items. Recently, moderate to good agreement (k > 0.39) was observed among four experienced colonoscopists for 10 of 14 signs or patterns of mucosal appearance in ulcerative colitis [63]. The agreement was poor, however for mild and moderate disease activity. Therefore, inter-observer variability of endoscopy findings in ulcerative colitis requires further evaluation. Although there are no standardized endoscopic assessment instruments available for ulcerative colitis, repeat endoscopic assessment is standard practice in adult UC clinical trials [64]. A similar standard may not be feasible in pediatric trials. Children may require general anasthesia for the procedure raising ethical concerns about the risk of participating in the study. Repeat endoscopy may also deter families from participating in trials. Therefore, unlike in the adult population, repeat endoscopic assessment may not be essential in pediatric UC clinical trials.
Quality of Life Instruments Both adults and children diagnosed with IBD are at increased risk of emotional problems and decreased social functioning [65, 66]. Thus, quality of life (QOL) assessment has been increasingly recognized as an important and independent clinical outcome in IBD research. There are two types amongst children of quality of life instruments, generic and disease specific. The choice of instrument depends on the clinical question. Generic QOL instruments are preferred when comparing QOL amongst children suffering from different diseases. However, for assessing only IBD populations, a disease specific quality of life instrument should be used. A thorough discussion of QOL instruments available for pediatric IBD research is found in Chapter 14.
Summary Various instruments are available to measure clinical outcomes in pediatric inflammatory bowel disease (Table 39.3). Valid pediatric clinical indices and quality of life measures exist for both UC and CD. Endoscopic scores, however, have not yet been evaluated in children. The evaluation of health related indices is an ongoing process and therefore, the development of new indices and the re-evaluation of the performance of existing indices will continue to be explored in different clinical and research settings.
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Table 39.3. Clinical indices for research in pediatric inflammatory bowel disease. Clinical trial outcome Disease activity index Perianal disease activity index Endoscopic scores Quality of life instruments Generic Disease specific
Instrument Crohn disease
Ulcerative colitis
Physician global assessment PCDAI Abbreviated PCDAI (short-term) Fistula Drainage Assessment
Physician global assessment PUCAI
CDEIS (assessed only in adults) SES-CD (assessed only in adults)
Numerous non-validated indices
Multiple (e.g. PedsQL, Child QOL questionnaire) IMPACT-III
Multiple (e.g. PedsQL, Child QOL questionnaire) IMPACT-III
N/A
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40. Seo M, Okada M, Yao T, Okabe N, Maeda K, Oh K. Evaluation of disease activity in patients with moderately active ulcerative colitis: comparisons between a new activity index and Truelove and Witts’ classification. Am J Gastroenterol 1995;90:1759–63. 41. Walmsley RS, Ayres RC, Pounder RE, Allan RN. A simple clinical colitis activity index. Gut 1998;43:29–32. 42. Azzolini F, Pagnini C, Camellini L, Scarcelli A, Merighi A, Primerano AM, Bertani A, Antonioli A, Manenti F, Rigo GP. Proposal of a new clinical index predictive of endoscopic severity in ulcerative colitis. Dig Dis Sci 2005;50:246–51. 43. Beattie RM, Nicholls SW, Domizio P, Williams CB, Walker-Smith JA. Endoscopic assessment of the colonic response to corticosteroids in children with ulcerative colitis. J Pediatr Gastroenterol Nutr 1996;22:373–9. 44. Irvine E. Assessing outcomes in clinical trials. In: Satsangi J, ed. Inflammatory bowel disease. Philadelphia: Churchill Livingstone, 2003:319–33. 45. D’Haens GS, WJ; Feagan, BG, Geboes, K, Hanauer, SB, Irvine, EJ, Lemann, M, Marteau, P, Rutgeerts, P, Scholmerich, J, Sutherland, LR. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007; 132:763–86. 46. Lloyd-Still JD, Green OC. A clinical scoring system for chronic inflammatory bowel disease in children. Dig Dis Sci 1979;24:620–4. 47. Beattie RM, Nicholls SW, Domizio P, Williams CB, Walker-Smith JA. Endoscopic assessment of the colonic response to corticosteroids in children with ulcerative colitis. J Pediatr Gastroenterol Nutr 1996;22:373–9. 48. Turner D, Otley A, deBruijne J, Mack, D, Uusoue, K, Zachos, M, Mamula, P, Hyams, J, Griffiths, A.M. Development of a pediatric ulcerative colitis activity index (PUCAI). J Pediatr Gastroenterol Nutr 2006;43:E47. 49. Travis SP, Stange EF, Lemann M, Oresland T, Chowers Y, Forbes A, D’Haens G, Kitis G, Cortot A, Prantera C, Marteau P, Colombel JF, Gionchetti P, Bouhnik Y, Tiret E, Kroesen J, Starlinger M, Mortensen NJ. European evidence based consensus on the diagnosis and management of Crohn disease: current management. Gut 2006;55 Suppl 1:i16–35. 50. Reproducibility of colonoscopic findings in Crohn disease: a prospective multicenter study of interobserver variation. Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Dig Dis Sci 1987;32:1370–9. 51. Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn disease: a prospective multicentre study. Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989;30:983–9. 52. Rutgeerts P, Diamond RH, Bala M, Olson A, Lichtenstein GR, Bao W, Patel K, Wolf DC, Safdi M, Colombel JF, Lashner B, Hanauer SB. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn disease. Gastrointest Endosc 2006;63:433–42; quiz 464. 53. D’Haens G, Van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F, Braakman T, Schaible T, Geboes K, Rutgeerts P. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn disease: A European multicenter trial. Gastroenterology 1999;116:1029–34. 54. Bauditz J, Haemling J, Ortner M, Lochs H, Raedler A, Schreiber S. Treatment with tumour necrosis factor inhibitor oxpentifylline does not improve corticosteroid dependent chronic active Crohn disease. Gut 1997;40:470–4. 55. Daperno M, D’Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, Sostegni R, Rocca R, Pera A, Gevers A, Mary JY, Colombel JF, Rutgeerts P. Development and validation of a new, simplified endoscopic activity score for Crohn disease: The SES-CD. Gastrointest Endosc 2004;60:505–12. 56. Rutgeerts P, Geboes K, Vantrappen G, Kerremans R, Coenegrachts JL, Coremans G. Natural history of recurrent Crohn disease at the ileocolonic anastomosis after curative surgery. Gut 1984;25:665–72. 57. Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn disease. Gastroenterology 1990;99:956–63. 58. Rutgeerts P, Van Assche G, Vermeire S, D’Haens G, Baert F, Noman M, Aerden I, De Hertogh G, Geboes K, Hiele M, D’Hoore A, Penninckx F. Ornidazole for prophylaxis of postoperative Crohn disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2005;128: 856–61.
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59. Hanauer SB, Korelitz BI, Rutgeerts P, Peppercorn MA, Thisted RA, Cohen RD, Present DH. Postoperative maintenance of Crohn disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology 2004;127:723–9. 60. Baron JH, Connell AM, Lennard-Jones JE. Variation between observers in describing mucosal appearances in proctocolitis. Br Med J 1964;1:89–92. 61. Hanauer S, Schwartz J, Robinson M, Roufail W, Arora S, Cello J, Safdi M. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Pentasa Study Group. Am J Gastroenterol 1993;88:1188–97. 62. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76. 63. Orlandi F, Brunelli E, Feliciangeli G, Svegliati-Baroni G, Di Sario A, Benedetti A, Guidarelli C, Macarri G. Observer agreement in endoscopic assessment of ulcerative colitis. Ital J Gastroenterol Hepatol 1998;30:539–41. 64. Sands BE, Abreu MT, Ferry GD, Griffiths AM, Hanauer SB, Isaacs KL, Lewis JD, Sandborn WJ, Steinhart AH. Design issues and outcomes in IBD clinical trials. Inflamm Bowel Dis 2005;11 Suppl 1:S22–8. 65. Mackner LM, Crandall WV, Szigethy EM. Psychosocial functioning in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2006;12:239–44. 66. Sainsbury A, Heatley RV. Review article: Psychosocial factors in the quality of life of patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005;21:499–508. 67. Sandler RS, Jordan MC, Kupper LL. Development of a Crohnindex for survey research. J Clin Epidemiol 1988;41:451–8. 68. Griffiths AM, Otley AR, Hyams J, Quiros AR, Grand RJ, Bousvaros A, Feagan BG, Ferry GR. A review of activity indices and end points for clinical trials in children with Crohn disease. Inflamm Bowel Dis 2005;11:185–96.
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Appendix A
Table A-1: Crohn disease Activity Index (CDAI) & Harvey Bradshaw Index (HBI) Instrument items
CDAI [13]
HBI [16]
Clinical signs & symptoms Stools Abdominal pain General well-being No. of complications
No. of liquid stools/day (× 2) 0–3 (× 5) 0–4 (× 7) 1/item (6 categories) (× 20)
No. of liquid stools/day 0–3 0–4 1/item (8 categories)
Physical exam Abdominal mass Abdominal tenderness Weight
0–2 (× 10) – 1 – (wt/standard wt) × 100
0–3 – –
Laboratory variables
Hct (×6): 47 – Hct (male) 42 – Hct (female)
–
Other
Use of anti-diarrheals: 0–1 (× 30)
–
Score cut-off for disease activity
Remission < 150 Mild 150–300 Moderate 300–450 Severe > 450
Remission ≤ 4 Relapse > 4
Validity
Correlation with PGA (r = 0.7) [67]
Correlation with CDAI (r = 0.93)
Reliability
ICC 0.66[5]
ICC 0.55 [5]
Responsiveness
Decrease of 70–100 points 25% improvement from baseline
Responsive in relapsed patients [5]
Comments
Clinical symptoms based on 7 day recall
Clinical symptoms based on previous 24 hours
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Table A-2: Modified Crohn disease Activity Index [68] Variable Description No. of liquid or soft stools (each day × 7 days) Abdominal pain None 0 Mild 1 Moderate 2 Severe 3 General well-being Generally well 0 Slightly under par 1 Poor 2 Very poor 3 Terrible 4 Number of listed complications (1 for each) Arthritis or arthalgia Iritis or uveitis Erythema nodosum, pyoderma gangrenosum, or aphthous stomatitis Anal fissure, fistula, or abscess Other fistula Fever > 37.8° C (100° F) Number of infirm days of 7 days* Abdominal mass No 0 Questionable 1 Yes 2 Hematocrit Normal for age/sex - Hct(%) Body weight (1 – weight/ideal body weight) × 100 *days unable to attend school or participate in normal activities as a result of Crohn disease (Modifications in bold print)
Multiplier ×2 ×5
×7
× 20
×5 × 10
×6 ×1
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Table A-3: Pediatric Crohn disease Activity Index [19] History (Recall, 1 week) Abdominal Pain 0 = None
Score 5 = Mild: Brief, does not interfere with activities
10 = Moderate/Severe: Daily, longer lasting, affects activities, nocturnal
Patient Functioning, General Well-Being 0 = No limitation of 5 = Occasional difficulty in activities, well maintaining age appropriate activities, below par
10 = Frequent limitation of activity, very poor
Stools (per day) 0 = 0–1 liquid stools, no blood
10 = Gross bleeding, or ≥ 6 liquid, or nocturnal diarrhea
5 = Up to 2 semi-formed with small blood, or 2–5 liquid
Score
Score
Laboratory Hematocrit (HCT) < 10 years : 0 = > 33%
Score 2.5 = 28–32% 5 = < 28%
11–19 years (Female): 0 = ≥ 34%
2.5 = 29–33% 5 = < 29%
11–14 years (Male): 0 = ≥ 35% 2.5 = 30–34% 5 = < 30% 15–19 years (Male): 0 = ≥ 37% 2.5 = 32–36% 5 = < 32
Erythrocyte Sedimentation Rate (ESR) 0 = < 20 mm/hr 2.5 = 20–50 mm/hr 5 = > 50 mm/hr Albumin 0 = ≥ 3.5 g/dL
Score
5 = 3.1–3.4 g/dL
10 = ≤ 3.0 g/dL
0 = < 1 channel decrease
5 = ≥ 1 < 2 channel decrease
10 = > 2 channel decrease
Height at follow up 0 = Height velocity ≥ –1SD
5 = Height velocity < –1SD, > –2SD
10 = Height velocity ≤ –2SD
Abdomen 0 = No tenderness, no mass
5 = Tenderness, or mass without tenderness
10 = Tenderness, involuntary guarding, definite mass
Perirectal Disease 0 = None, asymptomatic tags
5 = 1–2 indolent fistula, scant drainage, no tenderness
10 = Active fistula, drainage, tenderness, or abscess
Score
Examination
Score
Score
Score
Extra-intestinal Manifestations (fever ≥ 38.5 °C for 3 days over past week, definite arthritis, uveitis, E. nodosum, P. gangrenosum) 0 = None 5 = One 10 = ≥ Two Total Score:
Score
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Table A-4: Modified Pediatric Crohn disease Activity Index [24] History (Recall, 1 week) Abdominal Pain 0 = None
Score 5 = Mild: Brief, does not interfere with activities
Patient Functioning, General Well-Being 0 = No limitation of 5 = Occasional difficulty activities, well in maintaining age appropriate activities, below par Stools (per day) 0 = 0-1 liquid stools, no 5 = Up to 2 semi-formed blood with small blood, or 2–5 liquid
10 = Moderate/Severe: Daily, longer lasting, affects activities, nocturnal Score 10 = Frequent limitation of activity, very poor
Score 10 = Gross bleeding, or ≥ 6 liquid, or nocturnal diarrhea
Examination Weight 0 = Weight gain or voluntary weight stable/loss Abdomen 0 = No tenderness, no mass Perirectal Disease 0 = None, asymptomatic tags
Score 5 = Involuntary weight stable, weight loss 1–9%
10 = Weight loss ≥ 10%
Score Score 5 = Tenderness, or mass without tenderness
10 = Tenderness, involuntary guarding, definite mass
5 = 1–2 indolent fistula, 10 = Active fistula, scant drainage, no drainage, tenderness, or tenderness abscess Extra-intestinal Manifestations (fever ≥ 38.5°C for 3 days over past week, definite arthritis, uveitis, E. nodosum, P. gangrenosum) 0 = None 5 = One 10 = ≥ Two Total Score:
Score
Score
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Appendix B
Table B-1: Perianal Crohn disease activity index [29] Discharge 0 No discharge 1 Minimal mucous discharge 2 Moderate mucous or purulent discharge 3 Substantial discharge 4 Gross fecal soiling Pain/restriction of activities 0 No activity restriction 1 Mild discomfort, no restriction 2 Moderate discomfort, some limitation activities 3 Marked discomfort, marked limitation 4 severe pain, severe limitation Restriction of sexual activity 0 No restriction sexual activity 1 Slight restriction sexual activity 2 Moderate limitation sexual activity 3 Marked limitation sexual activity 4 Unable to engage in sexual activity Type of perianal disease 0 No perianal disease/skin tags 1 Anal fissure or mucosal tear 2 < 3 perianal fistulae 3 >= 3 perianal fistulae 4 Anal sphincter ulceration or fistulae with significant undermining of skin Degree of induration 0 No induration 1 Minimal induration 2 Moderate induration 3 Substantial induration 4 Gross fluctuance/abscess Total score = sum of total score per category
Table B-2: Fistula Drainage Assessment [30] Definition Remission Response
Fistula closure or absence of any draining fistulas 50% decrease in draining fistulas
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Appendix C
Table C-1: Truelove and Witts Score [34] Disease activity
Criteria
Remission
1–2 stools/day without blood No fever No tachycardia Haemoglobin normal or returning to normal ESR normal or returning to normal Gaining weight (To be in remission, must exhibit all 6 features)
Mild
≤ 4 stools/day with no more than small amounts of macroscopic blood No fever No tachycardia Anaemia not severe ESR ≤30
Moderate
Intermediate between severe and mild
Severe
≥ 6 stools/day with macroscopic blood Fever > 37.5°C (mean evening temperature) or ≥ 37.8°C 2 days out of 4 Tachycardia (mean HR > 90/minute) Anaemia (Hgb 75% or less; allowance made for recent transfusion) ESR > 30
Table C-2: Ulcerative colitis disease activity indices (Adult)
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Table C-3: Pediatric Ulcerative Colitis Activity Index(PUCAI© ) ITEM
POINTS
1. Abdominal pain: No pain Pain can be ignored Pain cannot be ignored
0 5 10
2. Rectal bleeding None Small amount only, in less than 50% of stools Small amount with most stools Large amount (>50% of the stool content)
0 10 20 30
3. Stool consistency of most stools Formed Partially formed Completely unformed
0 5 10
4. Number of stools per 24 hours 0–2 3–5 6–8 >8
0 5 10 15
5. Nocturnal stools (any episode causing wakening) No Yes
0 10
6. Activity level No limitation of activity Occasional limitation of activity Severe restricted activity
0 5 10
SUM OF PUCAI (0-85)
PUCAI© user guide Most items contained in the PUCAI© can be scored using the instructions provided within the instrument. The following issues require additional clarification:
Time period for evaluation • Answers should reflect a daily average of the last two days. • However, if clinical conditions are changing rapidly (e.g. during intense intravenous therapy), the most recent 24 hours should be considered. • For patients undergoing colonoscopy, answers should reflect the two days before bowel cleanout was started.
Rectal bleeding • “Large amount” should be selected if large amount of blood is present in most stools.
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Number of stools per 24 hours • Clustered several small stools over a very short period of time that could be related to tenesmus or incomplete evacuation, should be considered as ONE stool.
Activity level • Occasional limitation of activity=could attend school or equivalent, but reduced activity (e.g. attends school but does not play at breaks). • Severe restricted activity=could not attend school or equivalent activity.
PUCAI© definitions of disease activity, remission, and response to therapy∗ • Remission: total score less than 10 points. • Mild disease activity: total score between 10 and 34 points, inclusive. • Moderate disease activity: total score between 35 and 64 points, inclusive. • Severe disease activity: total score of 65 points or greater. • Response (minimal clinically significant change in score over time): a change in score of at least 20 points.
∗
Based on analysis of data generated from during development process, 2006
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Appendix D Table D-1: Crohn disease endoscopic index of severity [51] Rectum
Sigmoid & left colon
Transverse colon
Right colon
Ileum
Total
Deep ulceration (12 present, 0 absent)
1
Superficial ulceration (6 present, 0 absent)
2
Surface involved by the disease (/10cm)*
3
Ulcerated surface (/10cm)*
4
*Analogue scales converted to numeric values Total A = Total 1 + Total 2 + Total 3 + Total 4 No. of segments explored (1-5) CDEIS = Total A + 3 (ulcerated stenosis present) + 3(nonulcerated stenosis present) (Adapted from Daperno and colleagues [55])
Table D-2: Simple Endoscopic Score for Crohn disease [55] Score per segment Variable Size of ulcers
0 None
1 Aphthous ulcers (0.1–0.5cm*)
2 Large ulcers (0.5–2cm*)
3 Very large ulcers(> 2cm*)
Ulcerated surface
None
< 10%
10–30%
> 30%
Affected surface
Unaffected segment None
< 50%
50–75%
> 75%
Single, can be passed
Multiple, can be passed
Cannot be passed
Presence of narrowing
* diameter SES-CD = Total score from each segment (rectum, sigmoid & left colon, transverse colon, right colon, ileum)
Table D-3: Rutgeerts Score for postoperative endoscopic disease recurrence [57] Grade 0 1 2 3 4
Endoscopic finding No lesions in the distal ileum ≤ 5 apthous lesions > 5 apthous lesions with normal mucosa between the lesions or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis Diffuse apthous ileitis with diffusely inflamed mucosa Diffuse inflammation with already larger ulcers, nodules, and/or narrowing
40 Clinical Trials (Clinical Perspective) Salvatore Cucchiara* and Osvaldo Borrelli
Introduction Inflammatory bowel disease (IBD) refers to a chronic relapsing disorder causing inflammation of the intestine and developing during childhood or adolescence in up to 25% of patients [1]. It includes two classical conditions, ulcerative colitis (UC) and Crohn disease (CD). However, there is a subgroup of patients with IBD that cannot be easily characterized as either UC or CD based on classical diagnostic criteria and referred to as indeterminate colitis (IC). The latter seems to be a distinct patient population with IBD, with the disease prevalence higher in children than that observed in adults [2]. Despite recent dramatic developments in our understanding of IBD pathogenesis, several problems remain in regards to the medical management: IBD is a disorder difficult to treat and we are still far from a curative strategy; furthermore, treatment of IBD in childhood has several unique characteristics. Due to the relative paucity of randomized controlled trials (RCTs) in children, most therapeutic pediatric strategies are extrapolated from trials performed in adults, both for the doses of the drugs administered and for the duration of treatment, without the necessary knowledge of the pediatric pharmacokinetics.
Markers and Indexes of Disease Activity Table 40.1. summarizes the current expectations for IBD therapy: the latter are shared by physicians treating both adults and children with IBD; however, in children a unique goal of treatment is the promotion of growth and development. The importance of the growth as a marker of the adequacy of control of intestinal inflammation is widely agreed so that linear growth should be included as an outcome in pediatric clinical trials [3]; indeed, persistence of delay in longitudinal growth is commonly thought to be a sensitive marker of underlying active inflammatory process in the gut [4]. The percentage of IBD children with growth delay varies with the adopted criteria for defining growth impairment and with the nature of the population under study (tertiary referral center versus population based). It has not uncommonly been observed that impairment of linear growth can occur prior to the diagnosis, as well as during the subsequent years and that height at maturity has often been compromised [1]. Among the various factors involved into the pathogenesis of growth impairment in children with IBD the direct growth-inhibiting effect of pro-inflammatory cytokines released from inflamed ∗
Division of Pediatric and Liver Unit, Head, Pediatric Inflammatory Bowel Disease Center, Director, University Hospital Umberto I, University of Rome “La Sapienza”, Viale Regina Elena 324 – 00161 Rome, Italy, Phone: +390649979326, Fax: +390649979325, E-mail:
[email protected]
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Table 40.1. Current expectations for IBD therapy. SHORT-TERM • Induce clinical remission • Maintain clinical remission • Improve patient’s quality of life LONG-TERM • Heal mucosa • Decrease hospitalization/surgery and overall costs • Reduce disease-related and therapy-related complications • Promote growth and pubertal development
intestine has recently emerged and is now the focus of new therapeutic strategies such as the biologic drugs [5]. Despite height velocity commonly considered to be the most sensitive traditional variable to measure growth pattern, there are problems in the interpretation of height velocity data: reproducible serial measurements of the height are essential with a well calibrated wall mounted stadiometer; height velocity should be calculated over intervals of no less than six months and must be evaluated in the context of maturity, gender, and age; height velocity should be converted to a standard deviation score (Z score) for height velocity according to chronological age if maturity is normal, or according to bone age if maturity is delayed or advanced. Cross-sectional studies have shown a good correlation between markers of bone and collagen turnover that reflect the childhood growth curve [6]; however, due to the “pulse” (not linear) nature of the normal growth, collagen metabolism measurements at a single point in time do not necessarily reflect growth pattern over a follow up period of six to 12 months in a clinical trial or a cohort study. In general, when growth pattern is considered in pediatric IBD, it is recommended that height velocity must be included in therapeutic trials of IBD children with a duration of six months or older (as it occurs in the maintenance remission trial or in the prevention of postoperative recurrence trial); adolescents in the post-pubertal phase can be excluded from this aspect of outcome evaluation. In order to compare children with different ages and stages of pubertal development, the measured height velocity should be given as the Z score; finally, height velocity should not be considered in acute disease treatment trials, but a post-study follow up height velocity calculation (i.e. every six months) should be accomplished. There are no single clinical or laboratory variable that constantly and accurately reflects the underlying intestinal inflammation or the overall IBD disease. Furthermore, a lack of correlation between objective features such as radiological features, endoscopy, histology and subjective description of symptoms and signs has often been observed [7]. Ideally, an instrument useful to measure activity of IBD should be reproducible, valid, responsive to change of the disease course, easy to administer and based on accepted standard of reporting. Multi-item measurements of disease activity have been developed in order to allow uniformity between observers when assessing patients and stratifying them into groups with different degrees of disease activity. In patients with CD, the most commonly used instruments to measure activity are the CD activity index (CDAI) [8], that is a widely accepted tool for adult trials, and the pediatric CD activity index (PCDAI), that was developed and validated by pediatric IBD experts at several North American centers [9] (Table 40.2). Both instruments have similar domains, however, the CDAI, although not developed among children has until now been employed in several pediatric trials in order to measure disease activity in children. There are some concerns regarding the use of CDAI in children: the requirement of a 7-day diary that affects feasibility, the documented poor reliability in studies among adults, the absence of growth parameters as scoring items, the concern that pediatric subjects may underreport and underestimate symptoms and signs, and, mostly, lack of clear cutoff scores to correctly classify pediatric patients
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Table 40.2. Score for pediatric crohn disease activity index. 1. Abdominal pain rating - none - mild - brief (no interference with activities) - moderate/severe-daily, longer lasting, affects activities, nocturnal 2. Stools (per day) - 0–1 liquid, no blood - up to 2 semi-formed with small blood, or 2–5 liquid - gross bleeding, or ≥ 6 liquid, or nocturnal diarrhea 3. Patient functioning, general well-being - no limitation of activities, well - occasional difficulty in maintaining age appropriate activities, below par - frequent limitation of activity, very poor LABORATORY 4. HCT Female< 10 years: ≥ 33 = 0 p Male 11–14 yrs ≥ 33 = 0 p 28–32 = 2.5 p 30–34 = 2.5 p < 28 = 5 p < 30 = 5 p Female 11–19 yrs ≥ 34 = 0 p Male 15–19 yrs ≥ 37 = 0 p 29–33 = 2.5 p 32–36 = 2.5 p < 29 = 5 p < 32 = 5 p 5. ESR (mm/hr) < 20 = 0 p 20–50 = 2.5 p > 50 = 5 p 6. Albumin (g/L) ≥ 3.5 = 0 p 3.1–3.4 = 2.5 p ≤ 3.0= 5 p PHYSICAL EXAMINATION 7. Weight - Weight gain or voluntary weight stable/loss - Involuntary weight stable, weight loss 1–9% - Weight loss ≥ 10% 8. Height At Diagnosis Follow-up < 1 channel decrease = 0 p Height velocity ≥ - 1 SD 1, < 2 channel decrease = 5 p Height velocity < - 1 SD, > -2 SD ≥ 2 channel decrease = 10 p Height velocity ≤ - 2 SD 9. Abdomen - no tenderness, no mass - tenderness, or mass without tenderness - tenderness, involuntary guarding, definite mass 10. Perirectal disease - none, asymptomatic tags - 1–2 indolent fistula, scant drainage, no tenderness - active fistula, drainage, tenderness or abscess 11. Extra-intestinal manifestations (Fever ≥ 38.5 for 3 days over past week, definite arthritis, uveitis, E. nodosum, P. gangrenosum) - none - one ≥ two Total Score
Pediatric Crohn Disease Activity Index (PCDAI)
Score =0p =5p = 10 p =0p =5p = 10 p =0p =5p = 10 p
=0p =5p = 10 p =0p =5p = 10 p =0p =5p = 10 p =0p =5p = 10 p
=0p =5p = 10 p
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and to define criteria for response in children. Recently, a CDAI version with pediatric changes (and with a modified CDAI score) has been reported: however, it still requires validation (Table 40.3) [3]. In comparison with the CDAI, the PCDAI decreases the emphasis on subjective items while taking into account height velocity and adding laboratory parameters such as erythrocyte sedimentation rate and serum albumin level. Despite the inclusion of a variable such as linear growth would not be expected to change during an interval of a few weeks, the PCDAI has been demonstrated to be responsive to changes in disease activity over a time interval such as that of an acute treatment trial [10]. Thus, the use of this tool in acute treatment trials of pediatric IBD is encouraged. However, until now the CDAI, although not developed for pediatric patients, has been the most frequently index used for pediatric trials. In the original multicenter validation study of PCDAI, it was shown that a PCDAI cut score of ≤ 10 was able to classify “correctly” 69% of patients based on physician global assessment (PGA) of inactive versus active disease [9]. In another study performed at a single center, a PCDAI value ≤ 10 was able to discriminate clinical remission from a mildly active disease in 54 patients, giving a sensitivity of 75% and a specificity of 90%, while a PCDAI value < 15 had a sensitivity of 83% with a specificity remaining at a value of 90% [11]. In a multicenter prospectively conducted evaluation of the PCDAI, physicians were allowed to view laboratory parameters of disease activity before providing a PGA of the disease status. Interestingly, the specificity of a PCDAI cut score as low as < 10 was only 68% (with a specificity of 81%) in a group of 95 patients, judged to have inactive or mildly active disease at either 30 days or 3 months following the first diagnosis and treatment [12]. Available data suggest that a PCDAI cut score of < 10 is a realistic target for at least long-term therapeutic trials in children. The same value seems to be a realistic compromise for defining clinical remission in short-term pediatric clinical trials [13]. There are few data from which to determine the minimal change in the PCDAI score reflecting a clinically significant response to the therapy. Recently, it has been suggested from a consensus paper that a PCDAI decrease of at least 12.5 points can be an appropriate change reflecting a “moderate improvement” as determined by a physician assessment [13]. Greater decreases in PCDAI have greater specificity but will determine drop-off in sensitivity.
Table 40.3. Crohn disease activity index with pediatric modifications. Variable 1 2 3 4 5 6 7 8
Variable Description
Multiplier
Number of liquid or soft stools (each day for 7 days) Abdominal pain, sum of 7 daily ratings (0 = none, 1 = mild, 2 = moderate, 3 = very poor, 4 = terrible) General well-being, sum of 7 daily ratings (0 = generally well, 1 = slightly under par, 2 = poor, 3 = very poor, 4 = terrible) Number of listed complications (arthritis or arthralgia, iritis or uveitis, erythema nodosum or pyoderma gangrenosum or aphthous stomatitis, anal fissure or fistula or abscess, other fistula, fever > 37.8 °C) Number of infirm days of 7 days (i.e. days unable to attend school or participate in normal activities as a result of Crohn disease) Abdominal mass (0 = no, 2 = questionable, 5 = definite) Hematocrit(normal hematocrit for age and sex* - observed hematocrit) Body weight 1 - (body weight/ideal body weight**) x 100 (add or subtract according to sign)
×2 ×5 ×7 × 20 ×5 × 10 ×6 ×1
* lower limit of the normal hematocrit values for age and sex should be used (< 10 years: 34; 11–14 years, male: 35; 11–19 years, female: 34; 15–19 years, male: 47) ** ideal weight for height is measured as follows: after determining the percentile for height, the ideal weight is the weight that plots for the same percentile for the child’s age
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Differently from CD, no pediatric indexes for disease activity have been developed for UC: however, the development of a specific pediatric activity index for UC is currently under investigation. This index includes several clinical and laboratory items such as stool number, consistency and blood, abdominal pain, activity level, nocturnal diarrhea, serum albumin and CRP, and will be validated with both PGA and colonoscopic appearance. Table 40.4 lists the most frequently used indexes in UC and the items included in each of them. The first index to score disease activity in UC, the Truelove-Witts score, was mainly used to characterize a severe relapse and has been frequently applied in clinical trials (Table 40.5) [14]. The disadvantage of the index is the difficulty in classifying a number of patients to the appropriate disease category and in quantifying changes in disease activity over time. Whereas the Powell-Tuck index, consisting of ten items, is hardly applicable due to its complexity and low feasibility [15], other scores were based on increased emphasis on endoscopic features: Rachmilewitz developed an endoscopic index, scoring for granularity, vascular pattern, vulnerability and mucosal damage [16]. This score is numerical and has been used in adult clinical trials. The Baron scale, distinguishing three grades of activity, is the most commonly used score to assess the degree of endoscopic activity [17]. To combine the advantages of the clinical Truelove score and the endoscopic Baron scale, the Mayo score has been developed and is currently the favorite score in clinical studies in adults [18]. Clinical indexes of IBD are subjective and correlate poorly with endoscopic inflammation that can continue despite the absence of clinical features. The presence of chronic inflammatory lesions of the intestinal mucosa not only causes classic gastrointestinal symptoms such as diarrhea, pain, and poor health status, but also nutritional burdens. Mucosal ulcerations may cause loss of proteins, electrolytes, fluid, and iron; furthermore, important systemic and extraintestinal complications, such as growth failure or arthropathy, are due to the delivery of pro-inflammatory cytokines from the inflamed tissue [19]. Thus, treatment of IBD should be aimed both at relieving symptoms and at healing mucosal lesions, in an attempt to restore an adequate nutritional status and minimize systemic effects of the disease [20]. There is a growing view that in IBD, particularly in CD, the concept of clinical remission must be challenged, whereas the primary objective of the therapy should be mucosal remission. It has also been suggested that persistence of subclinical mucosal inflammation may be associated with higher degrees of subsequent relapses [21]. Nevertheless, the effects of anti-inflammatory therapy on endoscopic and histological lesions, mainly in CD, have not been addressed systematically in children. Recently, the therapeutic impact on IBD has dramatically changed since there is evidence that the biological therapy, largely represented by anti-TNF antibodies, is able to induce a rapid symptomatic relief that is paralleled by a mucosal healing as well [22].
Table 40.4. Most frequently used indices in ulcerative colitis. Items Bowel frequency Blood in stools Well-being Abdominal pain Stool consistency Nausea Weight loss Extraintestinal signs Fever Erythrocyte sedimentation rate Physician’s global assessment Sigmoidoscopy
Powell-Tuck
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Table 40.5. Severity categories of ulcerative colitis (Truelove-Witts) (adult patients). MILD Diarrhea < 4 times/day, non bloody No fever Pulse rate < 90 beats/min Erythrocyte sedimentation rate < 30 mm/h MODERATE Intermediate between mild and severe SEVERE Diarrhea > 4 times/day, bloody Hemoglobin 75% or below Evening temperature > 37.5 °C Pulse rate > 90 beats/min Erythrocyte sedimentation rate > 30 mm/h
Quality of Life In addition to improvement in clinical, laboratory and endoscopic variables, it is important to define if the treatment of IBD in childhood truly affects the “well being” of the subjects. There is a growing consensus that evaluation of biological data and endoscopic inflammation might not be sufficient to assess exhaustively the health status of the patients with IBD and that measures of quality of life and psychological factors should be obtained to better cure and follow patients with such chronic disorders. Health-related quality of life (HRQOL) can be measured in a generic and in a disease-specific fashion. The generic measures of HRQOL make different kinds of patients comparable to the normal healthy population since they include items and domains that belong to different diseases and populations. These measures are insensitive to follow the clinical changes of a specific clinical condition. Thus, adoption of a disease-specific questionnaire allows to detect clinically meaningful changes of a particular patient group, since it includes items and domains specific to the disease under evaluation. A disease-specific HRQOL questionnaire for use in children with IBD, called “IMPACT”, has been developed and validated by a Canadian multidisciplinary research group [23, 24]. It was designed for use in older children (≥ 9 years of age) and in adolescents with an established IBD. It includes 33 items categorized in 6 domains (body image, emotional impairment, social-functional impairment, test/treatment, systemic impairment, bowel symptoms). The original IMPACT questionnaire has been translated in different languages and administered to different patient populations and new versions have been proposed. The last version (IMPACT III), that includes 35 questions and a 5-point Likert scale for response options, is best suited to international multicenter trials, due to its easiness of translating and scoring. It is recommended that this specific-disease questionnaire should incorporate a generic HRQOL measure for comparison between the patient group and different chronic disorders (i.e. IBD versus chronic arthropathies). A critical factor when assessing the effect of different therapies in children with IBD is the ability to compare new drugs to standard therapies in a meaningful way. Only randomized controlled trials (RCTs) provide gold standard evidence on the efficacy of pharmacologic and non pharmacologic treatment of IBD. An ideal clinical trial should deal with well defined primary research questions in well defined study population, and should produce data that are relevant both statistically and clinically. Steps that characterize RCTs are: definition of the population investigated; randomized assignment to the treatment regimen; standardized intervention; welldefined interventions; clear definition of the primary (and secondary) outcomes. Moreover, a well
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defined patient population derives from clear outlined inclusion and exclusion criteria. If broad inclusion criteria are used recruitment of patients is easier, however, there will be a risk of lack of noticeable overall treatment effect, since less responsive subgroup could be included. On the other hand, if narrow inclusion criteria are used, the population recruited will be homogeneous and patients are likely to exhibit similar response, however, the results may not be universally applicable to large population with the disease investigated. The design of the trials should be sufficiently linear to fulfill the trial’s questions; on the other hand it must not be so weighty that physicians cannot reach outcomes of the study. A simple RCT evaluates two different treatments of comparable groups of patients, whereas more complicated trials are due to different factors such as intervention in parallel or sequential, inclusion of several categories of patients as defined by the kind of disease (i.e. CD, UC or indeterminate colitis), the type of treatment (evaluation for induction of remission or for maintenance of the latter). Due to the complexity of IBD, trials are often designed to include different subgroups of patient populations (i.e. CD with mucosal disease or with fistulizing disease or with an intermingled condition); furthermore, results of the trials in IBD patients can be commonly hard to be interpreted due to the fact that too many questions are often addressed in a single study. The pediatric literature on therapeutic management of IBD is frustrating, because the majority of published papers deal with retrospective and often uncontrolled studies, with small size patient population. As a consequence, clinical use of drugs in IBD children is guided by extrapolation from the numerous and extensively RCT in adults; thus, children are going to receive drugs without a complete knowledge of dosing and side effects specific to the pediatric age. It is possible that pediatricians have an emotional reluctance to employ new pharmacological agents in children before they have successfully and safely used in adults; furthermore, the pharmaceutical industry does not promote studies in children and infants due to concerns about safety and economic reasons because children are only a small portion of the potential market for a new drug. Because a considerable placebo response has been described in adult studies, partly reflecting spontaneous healing, more sound evidence is now awaited from pharmacokinetic studies and from well designed and controlled clinical trials in children. On the other hand, legal impediments to the conduction of pharmacologic studies in pediatric age are going to be removed. On December 1998, the Department of Health and Human Services of FDA has issued a guidance document containing comments and suggestions for pediatric pharmacokinetic studies for drugs and biological products and encouraging drug testing in children. On July 2000, the European Agency for the Evaluation of Medicinal Products (EMEA) has published a document for guidance on clinical investigation of medicinal products in the pediatric age. The Agency claims that during the clinical development of a drug the timing of pediatric studies will depend on the medicinal product, the type of disease being treated, safety considerations and the efficacy and safety of alternative treatments. More recently, the FDA has announced that pediatric studies are not necessarily required for all new medications, whereas it will still provide market exclusivity for those firms performing adequate pediatric studies. However, it is still emphasized that pharmaceutical industry should focus on pediatric pharmacokinetic studies for those medications with a strong potential impact in children.
Summary Pediatric patients with IBD are increasingly candidates for future clinical trials. Until now, very few RCTs have been conducted in pediatric populations with IBD. The main challenge will be the use of new therapies for treating active disease and inducing remission as well as for maintaining remission. However, accurate choice of the patient phenotype to be enrolled in the clinical trials is crucial both for reaching meaningful results and conclusions. Due to heterogeneous nature of
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IBD, homogeneous populations of patients should be studied and compared even if this could prolong patient recruitment time and make more complex the screening process. The principal variables that should be taken into account when patients with IBD are evaluated for clinical trial are: disease type; severity; topographic distribution; complications (i.e. presence of fistulas in CD); weight and linear growth pattern; serological markers for activity, nutrition and absorption; genotype. The latter will be increasingly included among the features capable to influence the outcome of different treatment as more insights into genotype-phenotype correlations will be gained and other genes of susceptibility for IBD will be described. Future pediatric topics to be investigated through RCTs are summarized as follows: • use of biologic therapy in “early” IBD as first-line treatment, to assess if a timely and vigorous cytokine targeting can alter the course of the disease; • early introduction of immunomodulators (in addition to the traditional therapy), both in UC and CD, to assess if this strategy can prolong the duration of remission and reduce the rate of relapses; • introduction of mucosal healing as main target in therapeutic trial since this goal is increasingly recognized as capable to influence the course of the disease. References 1. Griffiths AM. Specificities of inflammatory bowel disease. Best Pract & Res Clin Gastroenterol 2004;18:509–523. 2. Carvalho RS, Abandom V, Dilworth HP, et al. Indeterminate colitis: a significant subgroup of pediatric IBD. Inflamm Bowel Dis 2006;12:258–262. 3. Griffiths AM, Otley AR, Hyams J. et al. A review of activity indices and end points for clinical trials in children with Crohn disease. Inflamm Bowel Dis 2005;11:185–196. 4. Sands BE, Abreu MT, Ferry G et al. Design issues and outcomes in IBD clinical trials. Inflamm Bowel Dis 2005;11:S22–S28. 5. Pappa HM, Semrin G, Walker TR, Grand RJ. Pediatric inflammatory bowel disease. Curr Opin Gastroenterol 2004;20:333–340. 6. Crofton PM, Kelnar CJH. Bone and collagen markers in pediatric practice. Int J Clin Pract 1998;52: 557–565. 7. Kim SC, Ferry GD. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterology 2004;126:1550–1560. 8. Best W, Becktel J, Singleton J et al. Development of a Crohn disease activity index. Gastroenterology 1976;70:439–444. 9. Hyams J, Ferry G, Mandel F, et al. Development and validation of a pediatric Crohn disease activity index. J Pediatr Gastroenterol Nutr 1991;12:439–447. 10. Kundhal PS, Critch JN, Zachos M, et al. Pediatric Crohn disease activity index: responsive to short-term change. J Pediatr Gastroenterol Nutr 2003;36:83–89. 11. Otley A, Loonen H, Parekh N, et al. Assessing activity of pediatric Crohn disease: which index to use? Gastroenterology 1999;116:527–531. 12. Hyams J, Markowitz J, Otley A, et al. Evaluation of the pediatric Crohn disease activity index: usefulness in the practice setting. J Pediatr Gastroenterol Nutr 2004;39 (Suppl):0712. 13. Hyams J, Markowitz J, Otley A, et al. Evaluation of the pediatric Crohn disease activity index: a prospective multicenter experience. J Pediatr Gastroenterol Nutr 2005;41:416–421. 14. Truelove SC, Witts LJ. Cortisone in ulcerative colitis. Final report on a therapeutic trial. BMJ 1955;2:1041–8. 15. Powell-Tuck J, Bown RL, Lennard-Jones JE. A comparison of oral prednisone given as single or multiple daily doses for active ulcerative colitis. Scand J Gastroenterol 1978;13:833–7. 16. Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in treatment of active ulcerative colitis: a randomised trial. BMJ 1989;298:82–6. 17. Baron JH, Conell AM, Lennard-Jones JE. Variation between observers in describing mucosal appearance in proctocolitis. BMJ 1964;1:89–92.
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18. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderate active ulcerative colitis. A randomised study. N Engl J Med 1987;317:1625–9. 19. D’Haens G, Hlavaty T. Advances in medical therapy for Crohn disease. Curr Gastroenterol Rep 2004;6:496–505. 20. Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterol Clin North Am 2003;32:867–995. 21. Arnott ID, Watts D, Ghosh S. Review article: is clinical remission the optimum therapeutic goal in the treatment of Crohn disease? Aliment Pharmacol Ther 2002;16:857–67. 22. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn disease. Gastrointest Endosc 2006;63:433–442. 23. Griffiths AM, Nicholas D, Smith C, et al. Development of a quality-of-life index for pediatric inflammatory bowel disease: dealing with differences related to age and IBD type. J Pediatr Gastroenterol Nutr 1999;28:S46–S52. 24. Otley A, Smith C, Nicholas D, et al. The IMPACT questionnaire: a valid measure of health-related quality of life in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2002;35:557–563.
41 Clinical Trials (Industry Perspective) Allan David Olson*
Introduction Development of a medication for a new indication is a high cost, high risk, and complicated collaboration between government agencies, academic researchers and industry. A drug is defined by the Federal Drug Administration (FDA) as any substance or combination of substances presented for treating or preventing disease. Though the drug development process has become better defined over the past several decades as regulatory agencies have both increased the guidance for drug development and worked to “harmonize” the drug approval processes across countries, the cost and complexity of the drug development process has also increased. In this chapter I will review the process of drug development, emphasizing the key players and key regulations, which ensure clinical trials are carried out ethically, while minimizing the risks to the subjects in the trials. I will review key features of clinical trial development and execution. I will also examine the economic drivers for drug development and will review the history and impact of the key regulatory agencies, and of the pediatric rule(s) on clinical trial design and execution. Finally, I will review current trends in clinical research, and will examine what these trends will likely mean for future clinical research in pediatric patients. The “Guide to Clinical Trials” by Bert Spilker [1] remains a classic and one of the most complete textbooks on the drug development process with detailed descriptions of trial design and implementation. Several guides to clinical research have been recently published [2–5] which review clinical research from the prospective of the principle investigator and the site coordinator. Furthermore, a recent series of articles, published as the supplement to the Inflammatory Bowel Diseases in Nov.1995, form a concise review of the drug development process [6–9]. I will refer to specific articles from this supplement where appropriate and I recommend the supplement for any reader who wishes to review the drug development process in more detail.
Key Players in the Drug Development Process The key participants in drug development include regulatory agencies, industrial sponsors and contract research organizations (CROs). Regulatory Agencies: The Federal Drug Administration (FDA), the Committee for Human Medicinal Products (CHMP) and its advisory body the European Agency for Evaluation of Medicinal Products (EMEA), and the Ministry of Health, Labour and Welfare (MHLW) which ∗ Allan David Olson, MD, MS, MBA, Director, Alza Inc, 3210 Merry Field Row, San Diego, CA, 92121, Phone 858-784-3012, E-mail:
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regulate drug approvals in the United States (US), the European Union (EU) and Japan respectively, have defined the drug development process with their regulations. Together these three agencies regulate the approval and sale of all medications in the three countries which together account for more than 3/4 of the world-wide drug market [10]. In April 1990, these three agencies formed the International Committee for Harmonization (ICH) [11] with the goal of decreasing costs and delays in drug approvals by creating a common approach and common requirements for drug development. [12]. International Committee for Harmonization (ICH) Guidelines: The ICH guidelines developed by representatives from US, EU, and Japan were designed to guide development of experimental agents, to reduce the costs of the drug approval process world-wide, and expedite the availability of new drugs to consumers. Principles of ICH and good clinical practice (GCP) are based on ethical principles including those outlined in the Declaration of Helsinki [13] and include efforts to balance the risks and inconveniences against the anticipated benefit for the subjects. Pharmaceutical and Biotech Industries: The pharmaceutical and biotech industries are responsible for the process of identifying agents that will eventually become marketed drugs or biological agents. Drug development is divided into two processes; research and development. Research is defined as the laboratory activities designed to identify promising targets, to discover agents effective against the targets and to optimize the properties of the agents through chemical and structural modification. Development consists of two phases, preclinical development and clinical development designed to establish the safety and efficacy of the candidate agent. Principle Investigator (PI): The PI is responsible for the conduct of the trial. The key responsibilities of the PI are listed in the Form 1572, as outlined in Table 41.1 and will be discussed in more detail below [14]. National Institutes of Health (NIH): The NIH, founded in 1887, serves as the focal point for federal funding of medical research in the United States. The NIH has the goal of acquiring the knowledge required to prevent, detect, diagnose and treat disease and disability. The NIH accomplishes this goal through research in its laboratories, support of research in academic and research institutions and hospitals, through grants, and through the training of scientists, researchers and physicians through grants. The NIH is currently the greatest contributor to medical research and a major player in drug development. The NIH is also the sponsor and administrator of the clinicaltrials.gov website a location where ongoing trials are posted. Institutional Review Board (IRB) and Ethics Committee: The IRB within the US and the ethics committee outside the US are charged with insuring that research is conducted in a safe, scientifically sound, and ethical manner. The IRBs are established and governed by regulations Table 41.1. Investigator responsibilities as outlined in section 9 of the FDA 1572 “SMALL PRINT”. • Supervise: all aspects of the trial are ultimately the responsible of the investigator • Maintain Records: meticulous record keeping is critically important • Adhere to the protocol: deviations from the protocol should not be implemented without the notification and consent of the sponsor • Learn the investigator brochure: provides a summary of all known information about the compound under study • Let the FDA inspect: to determine whether the study has been conducted according to GCP • RePort adverse events: the investigator is obligated to report all AEs regardless of the perceived relation to the study drug • Retain records; case report forms and all regulatory documents • Inform subjects: of all aspects of the trial before enrollment in comprehensive language and notify of all changes • Notify the IRB • Train staff
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outlined in the United States Code of Federal Regulations (CFR) [12], which is administered by the Office of Human Research Protections (OHRP). These regulations are based on the ethical principles set forth in the Belmont Report [15] that include: respect for the research participant, beneficence for society at large, and justice with equal access to participation and equal treatment of subjects in a research study. Also outlined in these regulations are requirements for the informed consent that are listed in Table 41.2. Sponsor: The sponsor is a company or organization providing resources that enable the trial to proceed. A sponsor’s contribution will range from providing the agent to be studied, to providing full financial and logistic support for the development program. Contract Research Organizations (CRO): A CRO is an organization hired to assist with implementation of the clinical trial by the sponsor. The CRO’s roles and responsibilities vary but often include responsibility for negotiation of the contracts with the sites, for negotiating the exact language of the informed consent form (ICF), for monitoring of sites, and for data collection. In some cases, the CRO will hold and lock the database and are responsible for data analysis. Data Monitoring Committee (DMC): A DMC may serve many roles; the DMC can function solely as a Data and Safety Monitoring Boards (DSMB) or be involved in endpoint analysis and in trial modification. Key questions you should ask your self are: Would a DMC help mitigate risk to subjects? Would a DMC help maintain study integrity? If yes, a DMC is indicated.
Drug Development Process Recent reviews have emphasized the large number of chemical compounds that must be examined as potential drugs during the development of each successfully approved agent. It has been estimated, that up to 10,000 compounds are examined for each therapeutic agent approved. The drug development process is also time consuming with drug development taking up to 16 years from the identification of a likely target to approval of a drug effective against the target [16]. The development of every new drug begins with an idea. Often this idea or insight comes from a clinical observation, such as the recognition of a drug’s “side effect” during drug development for another indication, such as the observation of hair growth in subjects receiving a drug for hypertension. The idea or insight also often comes from advances in our understanding of disease pathophysiology. For example, the basic research that established the critical role of cytokines in inflammation, and the clinical research that confirmed that cytokines were elevated in inflammatory bowel disease (IBD), led to selection of tumor necrosis factor alpha as a target and to the development of anti-TNF agents for treatment of IBD. The idea or insight leads to selection of a target, and the development of an agent effective against the target.
Table 41.2. Informed consent requirements. Language • Should not contain language that waives or seems to waive the subject’s legal rights or liability for negligence • Should include all information about the trial including that it was approved by the IRB • Should be non-technical, understandable in lay language, and written at a seventh grade reading level • Should be written in the primary language of the subject Consent Process • Should be voluntary • Should allow the subject ample time and opportunity to ask questions • Should avoid coercive or undue influence on a subject to participate or continue participating • Should maintain the confidentiality of the information provided by the subject
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Figure 41.1. The drug development process. Adapted from Pharmaceutical Industry Profile 2005. Washington, DC: PhRMA; March 2005.
Drug development is generally divided into four stages: drug discovery, preclinical studies, clinical studies and regulatory review. As outlined in Figure 41.1 nearly half of the time invested in drug development time is spent in the drug discovery and preclinical stages (6.5 years), with the remainder spent in clinical trials (7 years) and in review by the regulatory agencies (1.5 years). During the first stage, drug discovery, compounds are evaluated for their effectiveness against identified targets using in vitro assay systems and when available animal models. Once a promising candidate has been identified, that candidate is further examined in the preclinical stage with toxicology studies to evaluate the potential of the drug for mutagenicity/genotoxicity, teratogenicity and carcinogenicity. Pharmacological studies in animals are also undertaken in the preclinical stage to establish the pharmacokinetic (PK) parameters that define the absorption, distribution, metabolism, and excretion of the agent. This preclinical toxicology data is combined with a clinical development plan to form an independent new drug application (IND). The IND is submitted to the FDA at the end of preclinical studies and prior to the first in human phase I trial. The IND provides the FDA with data required to ensure the potential safety of the candidate compound and provides the basis for clinical studies. The FDA must approve the IND prior to trials in man. The clinical study stage is divided into four phases. • In phase 1 trials: healthy volunteers are given the agent to confirm the PK parameters in man, while evaluating the safety of first single doses and then multiple doses of the agent. Generally restricted to a limited number of subjects (20–80), phase 1 trials often require hospitalization to enable the blood sampling required for the PK analysis. • In phase 2 trials: initial efficacy and safety data is collected in subjects with the disease under study. Generally multiple doses will be used during these studies and larger numbers of subjects are enrolled (250–400). Once the phase 2 studies have established the safety and efficacy of the drug, a full development decision is made, a post phase two meeting is scheduled with the FDA, and trials are designed for Phase 3 to establish the efficacy and safety of the drug using dose regimens planned for the clinical use. • In phase 3 trials: well-defined selection criteria are used (inclusion and exclusion criterion) and multiple trials are conducted to establish the efficacy and safety of the drug understudy. Phase 3 trials require a larger numbers of subjects (1000–5000) utilizing dose regimens proven
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to be effective in the phase 2 trials. The FDA generally requires independent confirmation of efficacy with two adequately powered and controlled trials. • In phase 4 trials: the drug has been approved and the studies are undertaken to further define the drug’s efficacy, safety, and pharmacology. The new drug application (NDA) describes all data collected on a product and includes the chemistry, manufacturing process and quality control, animal toxicology, pharmacokinetics in animals and in man, and the clinical trial evidence on efficacy and safety. The results of phase 1–3 studies form the basis of a drug application (NDA). Only after review and approval of the NDA by the regulatory authority and receipt of a signed approval action letter can a drug be marketed.
Key Clinical Trial Design Features The patient population to be studied in each trial must be carefully chosen to adequately define the study population to minimize variability while studying a population, which allow physicians to generalize to the patients in their practice. The study design chosen must match the hypothesis and the objective of the study. As an example, a classic design when the objective is to establish that an agent is effective in inducing response and remission would compare an active agent to a placebo in a population with active disease. In contrast, when the objective is to establish that the agent maintains remission, a study, which randomizes subjects in remission to placebo or active agent and then arranges to follow the subjects long enough to ensure exacerbation of disease to occur would be a good choice. The choice of endpoint and the timing of the endpoint measure are key aspects of the trial. The endpoint should be validated and if possible have a clear history as accepted by regulatory authorities and opinion leaders. The choice of the timing of the endpoint measure is also critical; too early and the drug will not have time to induce response, too late and placebo response may mask a true effect of the active agent. The dose and dosing regimen must be chosen to ensure adequate serum levels of the active agent. This is generally based on preclinical PK and is confirmed by phase 1 PK.
The Regulatory Agencies and the Regulatory Process Since 1938, when the Food, Drug and Cosmetic Act was passed, all new drugs brought to market in the US have required the approval of the FDA through the new drug application process (NDA) [17]. Though initially this review was restricted to ensuring the safety of new drugs, the NDA process was modified in 1962 with the Kefauver-Harris Amendments to the 1938 Act to add efficacy for intended use and confirmation that the benefits of the drug outweigh its know risks to the review of the NDA [12, 15, 17]. The FDA Modernization Act reduced review times, allowed for electronic submissions and proposed the first “pediatric rule” which mandated assessments of new drugs and biologic products. Though this first “pediatric rule” was overturned in a federal district court, in Dec. 2003, the Pediatric Research Equity Act (PREA) required pediatric studies for all new drug applications (NDAs) and biologics license applications (BLAs) re-established the pediatric rule. In 2002, the Best Pharmaceuticals for Children Act (BPAC) established a voluntary program that awards a six-month exclusivity incentive to sponsors of marketed products that conducted pediatric studies in response to a written request from the FDA. The BPCA was the result of a partnership between the FDA and the NIH to promote pediatric studies for off-patent products.
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In the EU, the Committee for Human Medicinal Products (CHMP), which represents each European Union member state, is responsible for approval or rejection of drugs proposed as potential medications. The CHMP receives support and advice from the European Agency for Evaluation of Medicinal Products (EMEA) and is based in London. A draft proposal is currently under review, which will regulate pediatric studies for marketed agents.
Good Clinical Practice Good Clinical Practice (GCP) is a collection of regulations (including state and local laws), guidelines (including ICH guidelines) and standard operating procedures (SOPs) that define the responsibilities of sponsor, investigator and institutions, which are designed to protect the rights and safety of study subjects. GCP also ensures that the trial is conducted in a way which ensures the credibility and accuracy of the data. A key component of GCP is the responsibility of the investigator to communicate to both patients and IRB or ethics committees all trial information. During this process the regulatory agencies, the IRBs and ethics committees work to ensure the safe and ethical execution of the trial. Each group works to maximize patient understanding of all known risks of the treatment, to ensure an informed consent and to maximize the patient’s safety by ensuring timely reporting of unexpected serious adverse events. The investigator brochure (IB) is a summary of all preclinical and clinical data available on the compound under study in a clinical trial. The principal investigator should be aware of the data outlined in the IB. The IB generally defines the expected adverse events (AEs) that can be expected from the drug. The clinical trial protocol is both a legal document and the master plan for the execution of the trial. The protocol serves the PI, and the study coordinator as their guide to trial execution. The IRB uses the protocol as the definitive description of the procedures and interventions that patients will face during the trial. The clinical protocol and the informed consent form must be reviewed and approved by the IRB or ethics committee prior to recruitment of subjects into the trial. The informed consent is a key component of the trial process and the consent form (ICF) serves several critical roles. The consent form is both the key document that outlines to the patient and their family what will occur during the trial and what are the risks of the trial and it serves as the legal confirmation that the subjects in the trial have granted an informed consent to participate in the trial (Table 41.1). The informed consent form must be reviewed and approved by the IRB/ethics committee and must conform to both local guidelines and key universal requirements; see Table 41.2. Informed consent by parents and guardians is required prior to any activities or procedures that are done as part of a clinical trial. The signature of the subject (or in the case of pediatric trials of the parent or guardian) on the consent form indicates that the subject both understands the risks of the trial and accepts these risks. It is expected that the pediatric subject will also indicate their understanding of the trial and their agreement with participating in the trial by signing an assent form. The institutional review board (IRB) in the US and ethics committees outside the US must review and approve clinical protocols, consent forms and information sheets prior to trial initiation at each site. The IRBs in the US and ethics committees outside the US are sponsored by universities and hospitals and clinic systems. Physicians who are in private practice and are not affiliated with an institution with an IRB may have the trial documents reviewed by a central IRB. The investigator’s responsibilities in the trial are outlined in Section 9 of Form 1572 [2]. This form when signed by the principle investigator serves as an agreement between the principle investigator and the federal government. The principle investigator (PI) commits to ensure that he has appropriate education, experience and training to assume the responsibilities of the trial, that he
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is familiar with the test agent or article, that he will comply with GCP and applicable regulations, that he will permit monitoring and auditing by both the sponsor and regulatory agencies, that he will maintain lists of qualified persons who have trial responsibilities and that the resources exist to properly conduct the trial. The details of this “small print” are outlined in Table 41.1. The principle investigator and the sub-investigators are responsible for the medical care of the trial subjects both during and after their participation in the trial. Following consent of the subject, medical care during the trial should be coordinated with the patient’s primary care physician. A key responsibility of the PI is identification and reporting AEs and SAEs that occur during the trial. An adverse events (AE) is defined, by the Good Clinical Practice Consolidated Guideline, as any untoward event in a clinical investigation subject who has been administered a pharmaceutical product. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the product. All AEs must be reported cumulatively to the FDA and IRB at designated intervals. A serious adverse event (SAE) is an untoward adverse event which is serious in nature, unexpected, and related to the medicinal product. An event is defined by regulatory definition as “serious” if it results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital anomaly birth defect, requires medical intervention to prevent any of these outcomes or is in the physician’s judgment considered to be serious. Key in this definition of an SAE is that the event is unexpected, is any event not observed or documented in the Investigator Brochure (IB), and that it is related to the experimental agent (that must be assumed if it can not be ruled out). Expedited reporting is required for all SAEs that occur in a study conducted under an IND. The SAEs are reported using either FDA medwatch form or a CIOMS reporting form developed by the CHMP. To ensure that the trial has been carried out as described in the protocol, the sponsor or their representative (usually a CRO) and /or the regulatory agencies, such as the FDA in the US, will audit sites. Site audits are generally scheduled several days to several weeks prior to the visit. Sites with higher enrollment rates are generally chosen for audits, since they have made a greater contribution to the trials outcome.
Practicing Physicians and Conduct of Clinical Trials Commitment to participate in clinical trials by the practicing clinician is often driven by a desire to provide new therapeutic options to their patients. Though participation in a clinical trial can be rewarding to both the principle investigator and his patients, participation in any clinical trial requires that the investigator have sufficient time to commit to the conduct of the trial, have a qualified staff to implement the trial, have adequate motivation to conduct the trial and have a sufficient number of patients motivated to participate in the clinical trial, and who can meet the inclusion and exclusion criterion. All principal investigators should carefully consider both the quality and feasibility of doing the clinical trial prior to committing to participate in the clinical trial. The clinical trial should be designed to ask and answer an important question that interests the investigator. An adequate number of subjects should be participating in a trial to ensure that the question can be answered (i.e. the trial should have adequate power to answer the question). Any patient inconvenience or discomfort resulting from procedures or tests required during the trial should be reasonable and acceptable to the patients eligible for the trial. If the patient will be randomized between different treatments, the investigator should ensure that each choice is reasonable for the subject in view of the potential risks and benefits and their medical condition. It is ideal if there is equipoise between the different choices. Equipose exists when the investigators does not know which of the two choices is the better choice and believes each are equivalent choices.
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An initial inquiry from a sponsor or CRO is generally followed by a site qualifying visit prior to acceptance of the site as a participating site in the trial. After initiation of a contract between the sponsor and the site, and following review and approval of the protocol and informed consent by the local IRB/ethics committee, the site will have a site initiation visit. During the site initiation visits, the full set of trail procedures will be reviewed and any questions from site personnel will be answered. The process of randomization after using the interactive voice recognition system (IVRS system) will be reviewed at that time. Identification of patients and recruitment into a clinical trial is critical for a successful clinical trial. Retention in clinical trials is also essential if the clinical questions proposed in the protocol are to be answered. Compliance with trial procedures and treatment is also important if the impact of treatment is to be accurately assessed. Once initiated, the site will screen patients at screening visits at which time an informed consent is obtained. As noted, the informed consent must be reviewed with the patient and signed prior to trial participation. A baseline visit initiates the patient into the trial, and subsequent trial visits occur with a final trial visit and concluding with follow-up safety visits. Data management with the help of clinical trial management initiates and manages the data cleaning process, during which sites are asked to clarify, confirm or correct data from the trial database in response to data clarification forms. Once all data corrections have been completed, the database will be locked and the data presented. Investigators must retain trial records for potential future review as outlined in the protocol. Several key documents that must be completed prior to trial initiation including contracts, and the 1275 form. Contracts are prepared between the sponsor (generally the pharmaceutical company) and the principle investigator and between the sponsor and the organization or hospital in which the trial will be carried out. Form 1275 is a contract between the principle investigator and the federal government, which requires the investigator to ensure that the trial will be implemented as indicated by the protocol in accordance with good clinical practice (GCP). Form 1275 must be signed prior to site initiation. The consent form and protocol must be reviewed and approved by IRB prior to trial initiation at the site. The randomization process must also be established and tested prior to site initiation. It has become increasingly common for industry-sponsored trials to utilize interactive voice recognition systems (IVRS) to enable randomization of subjects. In the IVRS, structured questions can be answered by phone and a centralized computer driven process will properly stratify and randomize the subject to the appropriate treatment group.
Economics of Drug Development The drug development process is driven by both medical need and business opportunity. The three largest markets for pharmaceuticals are the US, the EU and Japan. The regulatory requirements in these three countries largely define the regulatory requirement for drug development. The US alone, with 300 million people, accounts for the 46% of global pharmaceutical sales, hence the economic impact of the US market is an important factor in drug development. The European Union (EU), which on May 1, 2004 added 10 new countries now represents 25 countries and 475 million people. Patents (granted by the patent office) are designed to provide the discoverer a period of market exclusivity. Drugs are patented at discovery for 17 years from date issued for patents licensed prior to 8 June 1995 and 20 years from the date of filing for those issued after 8 June 1995. Patents may be extended for up to 5 years maximum if there are delays in approval. Maximum patent extension is for 14 years from the date the NDA is approved. Drug development is a high-risk undertaking that requires many million of dollars in order to develop a drug for a new indication. Development is rarely successful and when successful the company has just 20 years on patent to recoup the development costs and make a profit. In
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addition the approval of a new agent requires multiple studies (generally 3–6) with substantial costs (20–60 million dollars).
Unique Issues in Pediatric Research: Dosing and Consent/Assent Pediatric subjects have been specifically identified by the regulations as a vulnerable population that must be carefully protected. This has led to special regulations for informed consent in the pediatric population and to pediatric oriented IRBs and ethics committees. Appropriate formulations must be available to allow delivery of a safe and efficacious dose to pediatric patients of all ages and sizes. The large variation in weight, and body surface area in the pediatric age group generally require dosing by body weight. An alternative can be differing doses for different age groups. Liquid formulations are particularly flexible in providing for dosing per kilogram. Since pediatric patients by law may not consent for trial participation, informed consent must be obtained from parents or legal guardians prior to initiation of trial procedures. Assent should be obtained from pediatrics patients who are capable of understanding the trial activities and their consequences. This is particularly important in the adolescent and pre-adolescent populations to ensure their understanding of the protocol procedures and to confirm that they agree to participate in the trial.
Impact of the Pediatric Rule(s) Legislation and rules implemented over the past nine years have substantially increased the number of drugs that have received approval for pediatric indications with more than 100 label changes resulting from this legislation. As an incentive to encourage clinical trials in pediatric patients, a provision of the Food and Drug Administration Modernization ACT of 1997 that amended the current Food, Drug & Cosmetic ACT, allowed a drug’s original sponsor an additional 6 month period of market exclusivity for new or already marketed drugs in exchange for performance of pediatric studies. Also in 1997, the FDA proposed the first pediatric rule that mandated pediatric assessments of new drugs and biological products [18]. This rule was overturned in October 2002, in a federal district court. A modified pediatric rule, the Pediatric Drug Equity Act (PREA), went into law in 2003 and is retroactive to April 1999, and requires pediatric studies for all new drug applications (NDAs) and biologic licensing applications (BLAs). These rules provide the FDA with both the ability to reward companies for pediatric studies and to mandate studies.
Summary Substantial progress has been made in clinical research in pediatric patients with an increase in clinical trials in children in response to the pediatric rules, which has resulted in better information on efficacy and optimum dosing for children. In addition, this activity has fostered development of a clinical trial infrastructure for clinical studies in children. The future of clinical research in pediatric subjects appears both promising and challenging. A rewarding challenge awaits clinical researchers working with children. References 1. Spilker B. Guide to Clinical Trials. New York, NY: Raven Press, 1991. 2. Miskin BM, Neuer A. How to Grow your Investigative Site: A Guide to Operating and Expanding a Successful Clinical Research Center. CenterWatch. Stamford, CT: Thomson Healthcare, 2002.
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3. Good PI. A Manager’s Guide to the Design and Conduct of Clinical Trials. New York, NY: Wiley-Liss, 2002. 4. Norris, D. Clinical Research Coordinator Handbook. 3rd ed. Meford, NJ: Plexus Publishing, 2004. 5. The Center for Clinical Research Practice. GCP Education, training, and SOP templates. http://www.ccrp.com 6. Feigin RD, Prospects for the future of child health through research. JAMA 2005; 294:1373–9. 7. Shah S, whittle Al, Wilfond B, Gensler , Wendler D. How do institutional review boards apply the federal risk and benefit standards for pediatric research? JAMA 2004; 291:476–482. 8. Wendler D, Belsky L, Thompson KM, Emanuel EJ. Quantifying the federal minimal risk standard: Implications for pediatric research without a prospect of direct benefit. JAMA, 2005; 294: 826–832. 9. Sugarman J. Determining the appropriateness of including children in clinical research: how thick is the ice? JAMA, 2004; 291:494–6. 10. IMS Health, IMS MIDAS®, 2Q2006. 11. International Conference on Harmonisation (ICH) Guideline for Industry Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, March 1995 and 21 CRF312 Investigational New Drug Application (IND) [FDA IND Regulations]: http://www.fda.gov/cder/ guidance/959fnl.pdf. 12. The Code of Federal Regulations. GCP/ICH Guidelines. Washington, DC: GMP Publications; 2004. 13. Declaration of Helsinki www.wma.net/e/policy/b3.htm. 14. Jensen, Erich. Read the SMALL PRINT of the 1572. Presentation at the University of Michigan Center for the Advancement of Clinical Research, Ann Arbor, Michigan. October 20,2003; www.wlap.org/wlrepository/umich/cacr/cre/20031020/real/f001.htm. 15. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects in Research. April 18, 1979. 16. Pharmaceutical Industry Profile 2005. Washington, DC: Pharmaceutical Research and Manufacturers of America; March 2004. 17. A History of the FDA and Drug Regulation in the United States. http:// www.fda.gov/centennial/ history/history.html. 18. Milne C-P. Pediatric Research: Coming of Age in the New Millennium. American Journal of Therapeutics, 1999:263–282.
Glossary of acronyms ADME: AE: BLA: CFR: CDP: CHMP: CRF: CRO: DCF: DMC: DSMB: eCTD: EDC: EMEA: e-signature: FDA:
Absorption, distribution, metabolism, and excretion Adverse event Biologic license application Code of Federal Regulation Clinical development plan Committee for Human Medicinal Products Case report form Contract research organization Data clarification form Data monitoring committee Data safety monitoring board Electronic common technical document Electronic data capture European Agency for Evaluation of Medicinal Products electronic signature Federal drug administration
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FDC: GCP: GLP: GMP: HIPAA: IB: IC: ICF: ICH: IEC: IND: IRB: IVRS: MAA: NDA: NIH: NME: OHRP: PDUFA: PI: RCT: RFA: RFP: SAE: SMO: SOP: TPP:
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Federal Drug and Cosmetic Act Good clinical practice Good laboratory practice Good Manufacturing Practice Health Insurance Portability and Accountability Act of 1996 Investigator brochure Informed consent Informed consent form International Conference on Harmonization Internal ethics committee Investigational New Drug Institutional review board Interactive voice recognition system Marketing application authorization New drug application National Institute of Health New molecular entity Office of Human Research Protection Prescription Drug User Fee Act Principal Investigator Randomized clinical trial Request for application Request for proposals Serious adverse advent Site management organization Standard operating procedures Target product profile
Websites Belmont Report. http://ohsr.od.nih.gov/guidelines/Belmont.htmlClinitrials.gov FDA Handbook on Drug Development. http://www.fda.gov/cder/handbook/ FDA Inspections. http://www.wlap.org/file-archive/cacr/1 FDA Enforcement Actions. http://www.fda.gov/oc/gcp/clinenforce.html GCP Consolidated Guideline. http://www.fda.gov/cder/guidance/959fnl.pdf Guideline IBD Act. http://www.ccfa.org/advocacy/whatistheibdact HIPAA (Clinical Research and the Privacy Rule). http//privacyruleandresearch.nih.gov/ pdf/clin_research.pdf HIPAA (Myths and Facts about the Privacy Act).
[email protected] MedWatch. http://www.fda.gov/medwatch/ NIH Roadmap. www.nihroadmap.nih.gov NIH website. http://www.nih.gov OHRP website. http://www.hhs.gov/ohrp/
Section 7 Special Considerations
42 Psychological Aspects of Pediatric Inflammatory Bowel Disease Laura M. Mackner and Wallace V. Crandall
Introduction Inflammatory bowel disease (IBD) presents many potential challenges to psychological adjustment. The disease course is unpredictable, treatment can be frustrating, and the symptoms can be embarrassing and socially-limiting. Children with IBD can be reluctant to talk about their symptoms and their frequent visits to the bathroom can be embarrassing. They may even fear becoming the target of “bathroom humor” among their peers. They may limit their activities to those with ready access to a bathroom, or they may need to unexpectedly cancel planned activities. Short stature and delayed puberty can also contribute to feeling different from peers, and this may be particularly detrimental for boys since larger and more developed boys are often favored in social and athletic settings. Furthermore, corticosteroid medication is associated with emotional lability [1], and it may also indirectly impact psychosocial functioning via appearancealtering side effects. IBD clearly has the potential to affect psychosocial functioning. The purpose of this chapter is to review psychological aspects of pediatric IBD in the areas of behavioral/emotional functioning, social functioning, family functioning, self-esteem and body image, stress and coping, academic functioning and eating problems. Psychotherapy research in pediatric IBD will be reviewed, and resources and recommendations regarding psychosocial functioning will be provided.
Behavioral/Emotional Functioning Two primary methods of assessment exist for examining behavioral/emotional functioning: structured interviews and normed questionnaires. Validated structured interviews have been developed that lead to the diagnosis of psychiatric disorders. Training is required in order to adequately conduct these interviews, and reliability checks should be conducted among interviewers for reliable administration. Norm-based questionnaires typically measure specific symptoms such as depression symptoms and can be completed by children themselves, or by parents and/or teachers who respond in reference to the child. Since these measures are age- and gender-normed, raw scores are usually converted to a standardized score, a T score, for more meaningful comparisons. During development of these questionnaires, cutoff scores are derived that best discriminate children in the normative sample who were referred for mental health services from non-referred children. Thus, a T score above the cutoff indicates a clinically significant problem. Some of the early work utilizing structured interviews is limited by small samples sizes (≤ 20 participants) and inadequate description of interviewer training or reliability checks. Among
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studies with better methodology, rates of current depressive disorders range from 10% to approximately 20% [2, 3], and this rate was not significantly higher than the rate in children with cystic fibrosis (CF) in the one study that utilized a comparison group [2]. Lifetime prevalence of depressive disorders was significantly higher in the IBD group (25%) than the CF group (12%) [2]. For anxiety disorders, rates of current diagnoses range from 4% in a heterogeneous sample to 28% in a newly diagnosed sample [2, 4]. Lifetime prevalence was 11% and not significantly different from a CF comparison group [2]. Studies using smaller samples and less reliable methodology reported rates of disorders (primarily depressive and anxiety disorders) from 59–73% [5–10]. This rate was significantly higher than that of healthy children but similar to other chronic illness groups [5, 7, 11]. Several studies have examined specific behavioral and emotional symptoms using parent-report and child self-report questionnaires. Not all studies reported the T scores that are necessary to determine clinical significance, but among the six that did, all reported mean scores within the Average range [10, 12–16]. With the exception of one study [13], most reported that children with IBD had significantly more behavioral and emotional symptoms overall and/or significantly more depressive symptoms than healthy children [5, 7, 8, 11, 14, 16]. Children with functional GI disorders had significantly more symptoms [12], but there were few differences between the IBD and other chronic illness groups [7, 8]. To sum, rates of psychiatric disorders in children with IBD vary a great deal, and many studies are limited by small sample sizes. The studies with larger samples reported lower rates (4–28%) than studies with small samples and less optimal methodology (59–73%). Children with IBD were more likely to meet criteria for a psychiatric diagnosis than healthy children, but rates were similar to those of children with other chronic illnesses. Studies using specific behavioral and emotional questionnaires consistently demonstrated mean scores in the Average range. Children with IBD had fewer symptoms than children with functional GI disorders, a similar number of symptoms to children with other chronic conditions, but more symptoms than healthy children. Both the studies of psychiatric disorders and those examining specific symptoms consistently reported problems primarily in the areas of depression and anxiety. Taken together, these results suggest that children with IBD may be at greater risk for more difficulties than healthy children, particularly in the areas of depression and anxiety, but the difficulties do not reach clinical significance in most children. See Table 42.1 for the primary symptoms of common depressive and anxiety disorders [17].
Table 42.1. Primary symptoms of depressive and anxiety disorders.[17] Major Depressive Disorder A. At least 5 of the following symptoms during a 2-week period; at least one of the symptoms is either 1 or 2: 1. depressed mood most of the day, nearly every day. In children, can be irritable mood. 2. markedly diminished interest or pleasure in almost all activities most of the day, nearly every day 3. significant weight loss when not dieting or weight gain (e.g., change of > 5% of body weight in a month), or decrease or increase in appetite nearly every day. In children, consider failure to make expected weight gains. 4. insomnia or hypersomnia nearly every day 5. psychomotor agitation or retardation nearly every day that is observable by others, not merely subjective feelings 6. feelings of worthlessness or excessive/inappropriate guilt nearly every day 7. diminished ability to think or concentrate, or indecisiveness nearly every day 8. recurrent thoughts of death or suicidal ideation without a plan, or suicide attempt or specific plan for committing suicide
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Dysthymic Disorder A. Depressed mood for most of the day, for more days than not. In children and adolescents, mood can be irritable and duration must be at least 1 year. B. While depressed, presence of at least two of the following: 1. 2. 3. 4. 5. 6.
poor appetite or overeating insomnia or hypersomnia low energy or fatigue low self-esteem poor concentration or difficulty making decisions feelings of hopelessness
C. During the 1 year period, the person has never been without the symptoms in A and B for more than 2 months at a time. Generalized Anxiety Disorder A. Excessive anxiety and worry about a number of events or activities, occurring more days than not for at least 6 months. B. Difficulty to controlling the worry C. The anxiety and worry are associated with at least 3 or the following symptoms on more days than not for the past 6 months (Only one item is required for children). 1. 2. 3. 4. 5. 6.
restlessness or feeling keyed up or on edge being easily fatigued difficulty concentrating or mind going blank irritability muscle tension sleep disturbance (difficulty falling or staying asleep or restless unsatisfying sleep)
Social Phobia A. A marked and persistent fear of a social or performance situation in which the person is exposed to unfamiliar people or to possible scrutiny by others. The individual fears that he or she will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing. B. Exposure to the feared social situation almost invariably provokes anxiety. C. The feared situations are avoided or else endured with intense anxiety or distress. D. In individuals under 18 years, the duration is at least 6 months. Panic Attack A. A discrete period of intense fear or discomfort, in which at least 4 of the following symptoms developed abruptly and reached a peak within 10 minutes: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
palpitations, pounding heart, or accelerated heart rate sweating trembling or shaking sensations of shortness of breath or smothering feeling of choking chest pain or discomfort nausea or abdominal distress feeling dizzy, lightheaded or faint feelings of unreality or being detached from oneself fear of losing control or going crazy (Continued)
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Table 42.1. (Continued) 11. fear of dying 12. paresthesias 13. chills or hot flushes Note: For all disorders, the symptoms must cause clinically significant distress or impairment in important areas of functioning, and the symptoms must not be due to a medical condition or effects of a substance (e.g., medication).
The relationships between behavioral/emotional problems and factors such as disease severity and other psychosocial characteristics have been investigated in several studies. It seems logical that a child with more severe disease may have more emotional difficulties such as depression or anxiety symptoms. However, four studies have reported no significant relationship between behavioral/emotional functioning and disease factors such as validated disease activity scores, growth delay, and/or frequency of relapse [9, 13, 14, 15]. Three studies found significant relationships with only some disease severity indicators and/or with only specific symptoms of depression [3, 15, 16]. For example, one study [3] found significant differences in depressive symptoms between the moderate/severe disease activity versus remission groups, but not between these categories and the mild disease group. Additionally, these results were found for boys but not girls, and disease severity was correlated with only three items on the depression questionnaire, namely anhedonia, decreased appetite, and fatigue. Another study found that emotional symptoms were significantly associated with subjective reports of increased disease severity, but they were not associated with objective findings (laboratory values) [15]. Additionally, one small study reported that diagnosis of depression was significantly associated with less severe illness [4]. It is not surprising that disease severity has not been consistently associated with behavioral/emotional symptoms in IBD. Research in other pediatric chronic illnesses has repeatedly shown that psychosocial factors such as family functioning and stress coping strategies are better predictors of behavioral/emotional functioning than illness factors [18]. For example, a child with good family supports and stress coping skills may be less likely to develop emotional problems when faced with severe IBD than a child without these resources. Conversely, a child with poor coping skills may have difficulty with behavioral/emotional functioning even in the context of mild IBD. Other factors associated with increased behavioral/emotional symptoms, specifically depressive symptoms, include more stressful life events, maternal depression, family dysfunction, and steroid treatment [3, 4, 19, 20]. Two studies investigating the effects of steroids on mood and memory in children with IBD found that subjects on steroids had significantly more problems with verbal memory, working memory, and depression compared to youth not on steroids [19, 20]. Mixed results have been found for the relationship between age at diagnosis and behavioral/emotional symptoms [3, 14]. Contributions of other psychosocial factors to behavioral/emotional functioning have not been well studied.
Social Functioning IBD has the potential to significantly disrupt social functioning, particularly involvement in social activities such as spending the night with a friend, hanging out at the mall, and participating in many sports. Belonging to a particular social group becomes very important during adolescence, and acceptance by peers is an important part of adolescent self-identity [21, 22]. In questionnaire studies of social functioning, parents reported that children with IBD had significantly worse social functioning than healthy children [8, 13, 14], and significantly more parents of children with
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IBD reported clinically significant problems in social functioning (22%) than parents of healthy children (2%) [14, 23]. There were no significant differences in one study of child-reported social functioning [13]. However, 31% to 50% of children reported that IBD restricts their social activities in quality of life studies [24, 25], and children with IBD have been found to have fewer close friends and to have participated in fewer organized activities than healthy children [14]. Diagnosis of IBD during adolescence rather than childhood has been associated with significantly worse social functioning, and these problems were clinically significant in 35% of those diagnosed during adolescence, compared to 5% of those diagnosed in childhood [14].
Family Functioning Having a child with a chronic illness affects the whole family, so family functioning and the behavioral/emotional functioning of parents and siblings have been investigated in families with a child with IBD. Mixed results have been reported when examining overall family functioning among those with a child with IBD compared to healthy families [8, 14]. Family dysfunction was significantly related to more severe disease, increased pain/fatigue, more bowel movements, and a greater number of behavioral/emotional symptoms [26, 27, 28]. Rates of depression in mothers of children with IBD were similar to mothers of children with CF (10% current diagnosis; 51% lifetime history) [29]. A small study examining specific symptoms found that mothers of children with IBD reported significantly more behavioral/emotional symptoms than mothers of healthy children [8], but T scores were not reported, which limits conclusions about clinical significance. Mixed results have been found for the relationship between maternal symptoms and child behavioral/emotional functioning [8, 27]. Finally, one study investigated behavioral and emotional functioning in healthy siblings of children with IBD. Siblings of children with Crohn’s disease scored significantly above the normative mean on a questionnaire, whereas the mean score of siblings of children with ulcerative colitis fell at the normative mean. No siblings of healthy children were included [30]. To sum, conflicting results have been found in the research comparing overall family functioning in those with a child with IBD and those with healthy children. Among those with a child with IBD, family dysfunction may be related to increased disease severity. Parents of children with IBD may be more likely to have behavioral/emotional difficulties than those of healthy children but rates are similar to other chronic illnesses. The limited research in parent and sibling functioning prevents further conclusions in these areas.
Body Image and Self-esteem In the area of body image, concerns about poor growth and appearance have been cited frequently in QOL studies [31, 32, 33, 34, 35], although QOL measures are not validated specifically for assessing body image, and comparison groups were not included. Using a normed questionnaire assessing self-esteem about physical appearance, one study found mean T scores in the Average range and no significant differences between children with IBD and healthy children [13]. Five studies have investigated general self-esteem among children with IBD. Both studies utilizing normed questionnaires reported mean T scores in the Average range [12, 13]. Two out of the three studies with comparison groups found that children with IBD had significantly lower selfesteem than healthy children [7, 8, 13, 36]. Thus, similar to the findings in behavioral/emotional functioning, children with IBD may be at risk for low self-esteem, but the difficulties do not reach clinical significance in most children.
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Stress and Coping Although stressful life events and coping strategies have been studied among adults with IBD [37], these areas have received little attention in pediatric IBD. In a review of the adult literature, it was concluded that both stressful life events and daily hassles are associated with symptom exacerbation although this remains controversial. Among adults, problem-solving coping strategies and social support are associated with lowered psychological distress and better health outcomes. Avoidant coping strategies and lower perceived personal control are associated with poorer health status. Surprisingly, children with IBD have reported significantly fewer stressful life events than healthy children [38]. Two studies reported that children with IBD use less effective coping strategies, such as avoidant coping strategies [38, 39], but another study found no differences in the coping strategies or social support of healthy children and those with IBD [13]. In addition, coping involving a more passive, depressive style was associated with worse quality of life in adolescents with IBD compared to using a more positive, active coping style [39]. Finally, a small study reported that children with IBD were significantly more likely to have an external locus of control (i.e., believing events are out of your control rather than affected by your efforts) than healthy children, and having a stronger external locus of control was associated with worse disease severity [6]. The role of stress in symptom exacerbation has not been investigated in children.
Eating Problems Children with other chronic illnesses such as type 1 diabetes are at increased risk for eating disorders, and it has been suggested that children with IBD may be at risk as well [40]. However, research examining eating disorders among children with IBD is currently limited to case reports [41, 42, 43]. In a similar area, one study reported that children with IBD had significantly more problematic eating behaviors than healthy children, and gender differences were found in the relationships between body image, weight and eating problems. For girls, body image was a significant predictor of problematic eating behaviors, but weight was not. For boys, the opposite was found: weight was significantly associated with eating problems but body image was not [44].
Education School attendance and academic achievement are important areas of psychosocial functioning for children and two potential areas of concern for children with chronic illnesses. In a small sample of children with moderate to severe IBD, 44% reported more than 20 days absent from school. None of the children had to repeat a school year [24]. In another study with children with moderate to severe IBD, 60% of children averaged 3 months of absences during the previous year, and 80% felt that they had underachieved due to ill health, although no objective measures of academic achievement were reported [25]. Both studies relied on child report of absences with no external validation. A study utilizing report cards obtained from schools and a healthy comparison group reported that children with IBD had significantly more absences than healthy children, but there were no differences in GPA, or rates of grade retention or special education services[45]. Retrospective studies of adults with IBD have reported that their levels of educational attainment did not differ from the general population or healthy comparison groups [46, 47, 48, 49].
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Psychotherapy and Other Resources A pilot study has examined cognitive behavioral therapy for depression in adolescents with IBD [50]. Each adolescent participated in at least 12 individual and 3 family sessions addressing illness problem-solving, pain management, identifying and modifying negative cognitions, social problem-solving, and increasing positive solo and social activities. After treatment, depression symptoms decreased significantly, and social functioning and perceptions of health significantly improved. The improvements in depression symptoms and health perceptions were maintained at 6 and 12 months after treatment; social functioning results were not reported [43]. For any child with IBD, psychotherapy is warranted whenever behavioral or emotional problems cause significant distress and/or significantly interfere with functioning in any area such as school, social interactions, or family relationships. In addition to the symptoms in Table 42.1, specific signs include lowered grades, significant school absences, social withdrawal, lack of enjoyment in social or recreational activities, increased arguments with parents and/or siblings, and significant family stressors in addition to IBD. Mental health professionals who specialize in health psychology can help children cope with the disease as well as with issues such as pain management (including biofeedback), distress with medical procedures, medication adherence, pill swallowing training, and school attendance if excessive absences are a problem.Support groups, camps, and websites can also provide resources as well as supportive peers who may have similar concerns. In fact, a recent study found that attending an IBD camp was related to significant improvement in quality of life [51]. The Crohn’s and Colitis Foundation of America (CCFA; www.ccfa.org) provides camps and support groups for children with IBD. Two websites provide information and message boards for children and adolescents with IBD: www.kidsibd.org is supported by the Children’s Digestive Health and Nutrition Foundation (CDHNF) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), and www.ucandcrohns.org is supported by CCFA.
Summary Children with IBD appear to be at risk for more difficulties in psychosocial functioning than healthy children, although only a subset have clinically significant problems. The difficulty experienced by children with IBD is generally similar to that experienced in other chronic health conditions. Depressive and anxiety disorders are most common. Disease severity has not been consistently associated with behavioral/emotional functioning, and this may be due to differences in coping strategies and family/social supports. Children with IBD also appear to be at risk for difficulties in social functioning and self-esteem, with a subset having clinically significant problems. Onset of IBD during adolescence may be particularly detrimental to social functioning. Mixed results have been found in the areas of family dysfunction and body image, and limited research exists in the areas of stress and coping, education, and eating problems. Psychotherapy has been shown to be effective in treating depression in adolescents with IBD, and mental health professionals have expertise in many areas that can benefit children with IBD. Camps, support groups, and websites are additional resources for improved psychosocial functioning. References 1. Drigan R, Spirito A, Gelber RD. Behavioral effects of corticosteroids in children with acute lymphoblastic leukemia. Med Pediatr Oncol 1992;20(1):13–21. 2. Burke P, Meyer V, Kocoshis S, et al. Depression and anxiety in pediatric inflammatory bowel disease and cystic fibrosis. J Am Acad Child Adolesc Psychiatry 1989;28(6):948–51. 3. Szigethy E, Levy-Warren A, Whitton S, et al. Depressive symptoms and inflammatory bowel disease in children and adolescents: A cross-sectional study. J Pediatr Gastroenterol Nutr 2004;39(4):395–403.
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4. Burke PM, Neigut D, Kocoshis S, Chandra R, Sauer J. Correlates of depression in new onset pediatric inflammatory bowel disease. Child Psychiatric and Human Development 1994;24(4):275–83. 5. Engstrom I. Parental distress and social interaction in families with children with inflammatory bowel disease. J Am Acad Child Adolesc Psychiatry 1991;30(6):904–12. 6. Engstrom I. Family interaction and locus of control in children and adolescents with inflammatory bowel disease. J Am Acad Child Adolesc Psychiatry 1991;30(6):913–20. 7. Engstrom I. Mental health and psychological functioning in children and adolescents with inflammatory bowel disease: A comparison with children having other chronic illnesses and with healthy children. J Child Psychol Psychiatry 1992;33(3):563–82. 8. Engstrom I. Inflammatory bowel disease in children and adolescents: Mental health and family functioning. J Pediatr Gastroenterol Nutr 1999;28(4):S28–S33. 9. Steinhausen HC, Kies H. Comparative studies of ulcerative colitis and Crohn’s disease in children and adolescents. J Child Psychol Psychiatry 1982;23(1):33–42. 10. Szajnberg N, Krall V, Davis P, Treem W, Hyams J. Psychopathology and relationship measures in children with inflammatory bowel disease and their parents. Child Psychiatry Hum Dev 1993;23(3):215–32. 11. Engstrom I, Lindquist BL. Inflammatory bowel disease in children and adolescents: a somatic and psychiatric investigation. Acta Paediatrica Scandinavica 1991;80(6–7):640–7. 12. Gold N, Issenman R, Roberts J, Watt S. Well-adjusted children: An alternate view of children with inflammatory bowel disease and functional gastrointestinal complaints. Inflamm Bowel Dis 2000;6(1):1–7. 13. Mackner LM, Crandall WV. Long-term psychosocial outcomes reported by children and adolescents with inflammatory bowel disease. Am J Gastroenterol 2005;100(6):1386–92. 14. Mackner LM, Crandall WV. Brief report: Psychosocial adjustment in adolescents with inflammatory bowel disease. J Pediatr Psychol 2006;31(3):281–5. 15. Ondersma SJ, Lumley MA, Corlis ME, Tojek TM, Tolia V. Adolescents with inflammatory bowel disease: The roles of negative affectivity and hostility in subjective versus objective health. J Pediatr Psychol 1997;22(5):723–38. 16. Wood B, Watkins JB, Boyle JT, Nogueira J, Zimand E, Carroll L. Psychological functioning in children with Crohn’s disease and ulcerative colitis: Implications for models of psychobiological interaction. J Am Acad Child Adolesc Psychiatry 1987;26(5):774–81. 17. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed.). In: 1994; Washington, DC: Author; 1994. 18. Thompson RJ, Gustafson KE. Adaptation to chronic childhood illness. Washington, DC: American Psychological Association; 1996. 19. Mackner LM, Crandall WV. Steroid treatment impairs memory in pediatric inflammatory bowel disease. Gastroenterology 2005;128(Suppl 2):A166–A7. 20. Mrakotsky C, Bousvaros A, Chriki L, et al. Impact of acute steroid treatment on memory, executive function, and mood in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2005;42:540–1. 21. Brown BB. Peer groups and peer cultures. In: Feldman SS, Elliott GR, eds. At the Threshold: The Developing Adolescent. Cambridge, MA: Harvard University Press; 1990:171–96. 22. Harter S, Bresnick S, Bouchey HA, Whitesell NR. The development of multiple role-related selves during adolescence. Dev Psychopathol 1997;9(4):835–53. 23. Mackner LM, Crandall WV, Szigethy EM. Psychosocial functioning in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2006;12:239–44. 24. Moody G, Eaden JA, Mayberry JF. Social implications of childhood Crohn’s disease. J Pediatr Gastroenterol Nutr 1999;28(4):S43–S5. 25. Rabbett H, Elbadri A, Thwaites R, et al. Quality of life in children with Crohn’s disease. J Pediatr Gastroenterol Nutr 1996;23(5):S28–S33. 26. Burke P, Kocoshis SA, Chandra R, Whiteway M, Sauer J. Determinants of depression in recent onset pediatric inflammatory bowel disease. J Am Acad Child Adolesc Psychiatry 1990;29(4):608–10. 27. Tojek TM, Lumley MA, Corlis M, Ondersma S, Tolia V. Maternal correlates of health status in adolescents with inflammatory bowel disease. J Psychosom Res 2002;52(3):173–9.
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28. Wood B, Watkins JB, Boyle JT, Nogueira J, Zimand E, Carroll L. The “Psychosomatic Family” Model: An empirical and theoretical analysis. Family Process 1989;28:399–417. 29. Burke PM, Kocoshis S, Neigut D, Sauer J, Chandra R, Orenstein D. Maternal psychiatric disorders in pediatric inflammatory bowel disease and cystic firbrosis. Child Psychiatry Hum Dev 1994;25(1):45–52. 30. Wood B, Boyle JT, Watkins JB, Nogueira J, Zimand E, Carroll L. Sibling psychological status and style as related to the disease of their chronically ill brothers and sisters: Implications for models of biopsychosocial interaction. J Dev Behav Pediatr 1988;9(2):66–72. 31. Akobeng AK, Suresh-Babu MV, Firth D, Miller V, Mir P, Thomas AG. Quality of life in children with Crohn’s disease: A pilot study. J Pediatr Gastroenterol Nutr 1999;28(4):S37–S9. 32. Griffiths AM, Nicholas D, Smith C, et al. Development of a quality-of-life index for pediatric inflammatory bowel disease: Dealing with differences related to age and IBD type. J Pediatr Gastroenterol Nutr 1999;28(4):S46–S52. 33. Loonen HJ, Derkx BH, Koopman HM, Heymans HS. Are parents able to rate the symptoms and quality of life of their offspring with IBD? Inflamm Bowel Dis 2002;8(4):270–6. 34. Loonen HJ, Grootenhuis MA, Last BF, de Haan RJ, Bouquet J, Derkx BH. Measuring quality of life in children with inflammatory bowel disease: the impact-II (NL). Qual Life Res 2002;11(1):47–56. 35. Richardson G, Griffiths AM, Miller V, Thomas AG. Quality of life in inflammatory bowel disease: a cross-cultural comparison of English and Canadian children. J Pediatr Gastroenterol Nutr 2001;32(5):573–8. 36. Raymer D, Weininger O, Hamilton JR. Psychological problems in children with abdominal pain. Lancet 1984;1(8374):439–40. 37. Drossman DA. Psychosocial factors in ulcerative colitis and Crohn’s disease. In: Kirsner JB, ed. Inflammatory bowel disease. London: W. B. Saunders Co; 2000:342–57. 38. Gitlin K, Markowitz J, Pelcovitz D, Strohmayer A, Dorstein L, Klein S. Stress mediators in children with inflammatory bowel disease. In: Johnson JH, Johnson SB, eds. Advances in Child Health Psychology. Gainesville: University of Florida Press; 1991:54–62. 39. van der Zaag-Loonen HJ, Grootenhuis MA, Last BF, Derkx HH. Coping strategies and quality of life of adolescents with inflammatory bowel disease. Qual Life Res 2004;13(5):1011–9. 40. Nielsen S. Eating disorders in females with type 1 diabetes: An update of a meta-analysis. Eur Eat Disord Rev 2002;10(4):241–54. 41. Bayle FJ, Bouvard MP. Anorexia nervosa and Crohn’s disease dual diagnosis: a case study. Eur Psychiatry 2003;18(8):421–2. 42. Gryboski JD. Eating disorders in inflammatory bowel disease. Am J Gastroenterol 1993;88(2):293–6. 43. Szigethy E, Carpenter J, Baum E, et al. Case study: longitudinal treatment of adolescents with depression and inflammatory bowel disease. J Amer Acad Child Adolesc Psychiatry 2006;45(4):369–400. 44. Mackner LM, Crandall WV. Gender differences in weight and body image contribute to problematic eating behaviors in inflammatory bowel disease compared to healthy children. J Pediatr Gastroenterol Nutr 2003;37:375. 45. Mackner LM, Crandall WV. Psychosocial outcomes in mild pediatric inflammatory bowel disease. Gastroenterol Clin North Am 2003;124(suppl. 1):A212–A3. 46. Ferguson A, Sedgwick DM, Drummond J. Morbidity of juvenile onset inflammatory bowel disease: Effects on education and employment in early adult life. Gut 1994;35(5):665–8. 47. Mayberry MK, Probert C, Srivastava E, Rhodes J, Mayberry JF. Perceived discrimination in education and employment by people with Crohn’s disease: A case control study of educational achievement and employment. Gut 1992;33:312–4. 48. Bernstein CN, Kraut A, Blanchard JF, Rawsthorne P, Yu N, Walld R. The relationship between inflammatory bowel disease and socioeconomic variables. Am J Gastroenterol 2001;96(7):2117–25. 49. Longobardi T, Jacobs P, Bernstein CN. Work losses related to inflammatory bowel disease in the United States: results from the National Health Interview Survey. Am J Gastroenterol 2003;98(5):1064–72. 50. Szigethy E, Whitton SW, Levy-Warren A, DeMaso DR, Weisz J, Beardslee WR. Cognitive-behavioral therapy for depression in adolescents with inflammatory bowel disease: a pilot study. J Am Acad Child Adolesc Psychiatry 2004;43(12):1469–77. 51. Shepanski MA, Hurd LB, Culton K, Markowitz JE, Mamula P, Baldassano RN. Health-related quality of life improves in children and adolescents with Inflammatory Bowel Disease after attending a camp sponsored by the Crohn’s and Colitis Foundation of America. Inflamm Bowel Dis 2005;11(2):164–70.
43 Measurement of Quality of Life in Pediatric Inflammatory Bowel Disease Anthony Otley*
Introduction The burden of disease imposed on children and youth by Crohn disease (CD) and ulcerative colitis (UC) may be considerable, as manifested by clinical parameters such as symptoms, number of hospitalizations, growth retardation, and frequent need for surgery [1–5]. However, much less has been documented concerning the psychosocial burden of inflammatory bowel disease (IBD) on young patients [6–8]. One means of assessing the psychosocial burden is through evaluation of health-related quality of life (HRQOL). The purpose of this chapter is to provide the reader with an understanding of the concept of HRQOL, the approaches to its measurement in children, and more specifically in pediatric patients with IBD. Finally the gaps in knowledge of HRQOL in pediatric IBD and the future directions for research in this area will be discussed.
Quality of Life: Concepts/Definitions In 1948 the World Health Organization defined health as being not only the absence of disease and infirmity but also the presence of physical, mental and social well-being [9]. Since that time quality of life (QOL) issues have been increasingly recognized as important parameters in determining health status. A single definition of quality of life is difficult to find [10, 11]. Without a clear definition multiple interpretations of what quality of life “is” have evolved. This has lead to development of a number of different measures which assess varying aspects of quality of life. This failure to achieve a unifying definition has hampered the ability to make comparisons between quality of life outcomes. Most recent definitions include the concept of the multidimensional nature of quality of life, and incorporate domains of social, physical and emotional functioning of the individual [12]. With HRQOL one is attempting to ascertain the impact of the disease, concentrating on the health-related aspects of quality of life. Quality of life outcomes have been conceptualized by viewing the domains in two dimensions: objective assessments of functioning or health status (the y axis in Figure 43.1), and more subjective perceptions of health (the x axis) [13]. While the objective assessment is integral ∗
Division of Gastroenterology, Department of Pediatrics, Associate Professor, Dalhousie University, Izaak Walton Killam Health Centre, 5850 University Avenue, Halifax, Nova Scotia CANADA B3J 3G9, Phone: 902-470-8746, Fax: 902-470-7249, E-mail:
[email protected]
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Anthony Otley Measurement Scales Z Work Daily role Personal relations Positive affect Negative affect Behavior Symptoms
High
Physical
High
Quality of Life Q (X,Y)
Health Domains Low Low
Low
Objective Health Status
Disability
Psychological
Social
Functioning
Y
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Subjective Perceptions X
Figure 43.1. Conceptual Scheme of the Domains and Variables Involved in a Quality-of-Life Assessment. The x axis represents subjective perceptions of health, the y axis objective health status, the coordinates Q(X,Y) the actual quality of life, and Z the measurement of the actual quality of life associated with a specific component (i.e. positive affect) or domain (i.e. the psychological domain). Reprinted from Current Concepts: Assessment of Quality-of-Life Outcomes by Testa, Simonson from The New England Journal of Medicine, 1996, March; 334: 835–840 by permission of Mass Medical Society, all rights reserved.
for describing an individual’s degree of health, the individual’s subjective perceptions and expectations modify the objective assessment into the real quality of life experienced (or Q, as expressed in Figure 43.1 by the intersection of the x and y coordinates). Because perceptions and expectations may vary from individual to individual, two people with the same health status may have very different qualities of life [13]. Why Measure Health-related Quality of Life? Over the past several decades a dramatic increase in the employment of quality of life outcome measures has been evident in the adult and pediatric clinical trials literature. In part this is a result of the trend to expand the traditionally selected, “objective” outcome measures of morbidity (i.e. days hospitalized, number of infections) and/or mortality, to include assessment of the emotional and functional status of participants. The single-minded focus on mortality and morbidity as outcomes in health is being steadily superseded by broader considerations of quality of life. One of the first stages in evaluating a new measure is to determine the “phenomenon of interest,” to define the conceptual framework underlying the measure [14]. In IBD the primary outcome measure traditionally selected for use in clinical trials has been a multi-item disease activity index [15], such as the pediatric Crohn disease activity index (PCDAI) [16, 17]. For the disease activity measures, the concept is to use the degree of intestinal inflammatory activity as a surrogate measure of the patient’s health status. This framework is based heavily on physician perceptions, with little input about the patient’s perception of the disease on their health status [15]. Quality of life measures try to address this deficiency. Because existing measures of disease activity are not sensitive enough to assess the full impact of the disorder, HRQOL measures have been developed to do this [18].
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Approaches to Health-related Quality of Life Measurement The ideal assessment of HRQOL would involve lengthy, detailed interviews between the patient and an independent interviewer, an impractical procedure in day-to-day clinical care. A selfadministered questionnaire, that is easy to understand and complete, and that covers all the important aspects of the patient’s HRQOL, is a more attractive means of assessing HRQOL. The questionnaire should include all relevant elements, or “domains”, of HRQOL. These domains may cover physical, functional, emotional and cognitive well-being and, in case of disease, diseaserelated aspects. Each domain consists of a number of “dimensions”, or questions. A balance needs to be struck between including a sufficient number of dimensions so that a complete assessment of HRQOL can be made, but not to create too lengthy a questionnaire so that it becomes burdensome for the patient to complete. There are two basic types of HRQOL measures, generic and disease-specific. A generic measure is designed to measure all aspects of health and its related quality of life, and can include items and domains that are broadly applicable to various diseases and populations. Although diseasespecific questionnaires include some of these same issues, they also address issues specific to the particular disease. Disease-specific questionnaires are more sensitive to disease related changes in patients’ health status than generic questionnaires. Generic measures can take several forms, from instruments with: global assessments using single indicators (for example, “What is the quality of your life on a scale of 1 to 10?”); utilities (for example, Standard Gamble, Time Trade-Off); or multi-item measures which give a health profile, such as the Medical Outcomes Study Short-Form 36 (SF-36) [19]. One of the advantages of a generic measure is its generalizability. Generic measures permit comparisons between “healthy populations” and different disease groups, interventions, and demographic and cultural groups [20, 21]. Generic questionnaires, such as the SF-36 for adults [20, 22] or the Child Health Questionnaire for children [23], have been applied to groups with no defined illness, allowing normative values to be generated for these healthy populations. When such normative data is available it offers the potential to make comparisons as to burden of illness between populations affected with and without chronic illness [24]. The chief disadvantage to generic measures is their insensitivity to important clinical change. This stems from their inherent lack of specificity; a result of the inclusion of many items which may not be relevant to the individual patient with an isolated disease. This can be addressed by the use of a disease-specific measure that focuses on concerns relevant to a particular patient group. “Specificity” is achieved by the inclusion of dimensions and domains which are targeted to the disease in question. For example, in the Pediatric Asthma Quality of Life Questionnaire, a measure developed by Juniper et al. [25], the symptoms domain includes questions such as “How much did tightness in your chest bother you during the past week?” and “How often did your asthma wake you up during the night during the past week?”. This specificity makes the questionnaire more sensitive to important clinical change in asthma, which is an important criterion when choosing an outcome measure in a clinical trial. In the adult literature, disease-specific questionnaires have been developed for a number of diseases, including IBD [26], rheumatoid arthritis [27], breast cancer [28, 29], and asthma [30, 31]. In comparison very few disease-specific questionnaires have been developed for use in the pediatric population [30, 32–35]. Any measurement tool should be tested prior to use to ensure it fulfils the fundamental psychometric characteristics of a good measure. A HRQOL questionnaire would be one example of a measurement tool. The psychometric characteristics to be assessed include sensibility, reliability, validity and responsiveness to change (Table 43.1). Sensibility is a measurement characteristic with many aspects, and for a questionnaire should include assessment of feasibility for both the person administering and completing the questionnaire (i.e. time to complete and mark, readability), as well as a critical review of the appropriateness of items included or omitted. Reliability looks at whether a measure has reproducibility, i.e. if the same result is obtained when
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Table 43.1. The four fundamental measurement characteristics to be assessed of any measure. Measurement characteristic
Definition
Examples of what to look for
Sensibility
Do the components of the instrument make sense AND is it feasible to administer and complete?
• Readibility statistics • Number of questions left blank • Inappropriate inclusions or important omissions of items
Reliability
Are similar scores obtained on subsequent assessments if no change in disease status has occurred? (test-retest reliability)
Validity
Is the instrument measuring what it was intended to measure?
Responsiveness
Does the instrument score change with a change in disease status?
• Test-retest reliability most commonly reported (either as Intraclass correlation coefficient or Kappa value) • Instruments with good reliability require smaller sample sizes • Criterion validity testing when a gold standard exists to compare to • Construct validity testing when no gold standard exists, and hypotheses are generated and tested on how the instrument would be expected to function • No one accepted way to evaluate • Want to know over what time period an instrument is responsive (i.e. short-term, 4 weeks, or longer term, 6 months)
the same (unchanged) entity is measured again [17]. For example, assuming that HRQOL is influenced by disease activity or medication use, one would expect a reliable HRQOL questionnaire to show very similar scores when given to a patient at time one and again at time two if no interval change in disease activity or medication has occurred. Validity is concerned with whether a questionnaire actually measures what it is intended to measure. Ideally one would like to measure the validity of a HRQOL measure comparing it with a gold standard. Unfortunately, HRQOL is a concept for which no gold standard exists. Thus a process of construct validity testing must be carried out. This involves generating hypotheses, called constructs, and studying whether the measure acts as one would expect. The final characteristic, responsiveness to change, relates to the ability of the questionnaire to detect change over time, characteristics important for use in clinical settings. The smaller the change in disease status that can be detected with a questionnaire, the more responsive the questionnaire. This latter characteristic is especially important in determining the sample size for studies in which HRQOL is a main outcome.
Health-related Quality of Life Assessment in Pediatrics Making quality of life assessments in a pediatric population requires the awareness of several key methodological issues: whether to ask children directly [36, 37]; and how to allow for varying developmental level and age [10, 38]. It is not always possible to obtain the child’s assessment of their quality of life, whether due to age, developmental or disability limits to comprehension. In these instances a proxy is sought. The proxy reporter of the child’s quality of life is most often their
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parent/caregiver, but in some cases may be another individual such as a teacher or physician [37]. Research has shown, however, that proxies tend to have a low to modest agreement with the child’s reported quality of life self-assessment [39]. The degree of agreement seems to relate to the objectiveness of the dimension of quality of life being assessed. Pantell et al. showed that parents and teachers agreed fairly well in reporting on child functioning but markedly less well for recent functional status, certain types of subjective feelings in regard to illness, information needs, emotional states, and family functioning [40]. Agreement among raters may differ as a result of factors such as child sex, age, and condition [41]. Other issues relate to the wide developmental spectrum seen across the pediatric age group. The quality of a child’s self-report is highly dependent on their expressive and receptive language abilities [10]. As well, differences in time perception and memory related to their developmental stage will affect a child’s ability to respond to questions based upon experiences during a specific time period [37]. Within a given culture developmental tasks can vary by age such that some quality of life items may be appropriate for a specific age range, but not for another. For example, perceptions on relationships with the opposite sex will vary with age. Other issues likely related to developmental age include: position bias, the tendency to choose the first answer; acquiescence response bias, the tendency to agree with the interviewer; and limited understanding of negatively worded items [42]. Realizing there are low agreements for proxy ratings in some areas of response, it is unclear to what extent differences in response pattern are due to limitations in abstract reasoning or true differences in perspective or opinion.
Health-related Quality of Life Assessment in Inflammatory Bowel Disease: Adult IBD Perspective Measurement of HRQOL in IBD has received a lot of attention over the post several decades, with the result that there are now validated outcome measures that have been used in clinical trials or cross-sectional studies (Table 43.2). Early attempts at assessing HRQOL in IBD, however, were hampered by a number of methodological issues: healthy or medical comparison groups were not used; studies were done by retrospective analyses [43, 44]; non-standardized instruments [44–47] and unskilled interviewers were used to obtain the data, and insensitive outcome factors (i.e. ability to work) [43, 47, 48] were used as measures of HRQOL. The main disease-specific HRQOL instrument used currently is the Inflammatory Bowel Disease Questionnaire (IBDQ) which was developed for IBD patients and to be used in clinical trials [26, 49, 50]. It is a 32 item questionnaire, consisting of 30 items chosen most frequently and rated most important by adult IBD patients, and two items added based on feedback obtained by clinicians who had practices heavily weighted with IBD patients. The four domains covered in IBDQ include: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). Responses are based on a 7-point Likert scale in which 1 represents worst function, and with 7 indicating best function. Thus the higher the score the better the quality of life. The questionnaire can be self-administered [51, 52] and takes approximately 15 minutes to complete. The IBDQ has undergone extensive testing of its measurement characteristics, including several randomized controlled trials [49, 53, 54] and cross-sectional studies [55]. From a large multi-centred Canadian trial of maintenance therapy, an intraclass correlation coefficient of 0.70 was calculated for test-retest reliability in 280 patients with stable disease over an 8 week period [49]. Responsiveness testing using a modified responsiveness index developed by Guyatt et al. indicated that all IBDQ indices reflected deterioration for those patients whose condition worsened during the study [56]. Construct validity testing in the original publication of the measure, and with subsequent use of the IBDQ in trials, has shown it to be a valid measure of HRQOL in adult patients with IBD. It has been shown to have strong
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Table 43.2. Health-related quality of life measures for inflammatory bowel disease. Name ADULT Inflammatory Bowel Disease Questionnaire (IBDQ) 32-item Likert Scale Interview format Modified IBDQ 36-item Likert Scale Self-administered Cleveland Clinic Questionnaire 47-item Likert Scale Interview format
Scales
Comments
Bowel Symptoms, Systemic Symptoms, Social Function, Emotional Function
Well standardized; designed for clinical trials; developed on “sick” patients – GI referrals and inpatients
Bowel Symptoms, Systemic Symptoms, Social Function, Emotional Function, Functional Impairment Functional/Economic, Social/ Recreational, Affect/Life in general, Medical/Symptoms
Derived from IBDQ; developed on “well” patients – local chapter of NFIC Correlates with SIP; developed on UC/CD surgical/ nonsurgical groups; quality of life index distinguishes groups
Rating Form of IBD Patient Concerns (RFPIC) 25-item Visual Analogue Scale Self-administered
Impact of disease, Sexual intimacy, Complications, Body Stigma
UC/CD Health Status Scales 9 or 10-item Likert Scale Physician/patient scoring
Ulcerative colitis, Crohn’s disease
Standardized to health care use, function, psychological distress in CCFA national sample
30 generic questions, 5 disease specific (more detail not specified)
Only 16 patient pilot study reported to dateChild does not have to read
Physical, emotional and social
Reported in abstract form, with validation and reliability data
Bowel, emotional, functional, tests/treatments, systemic, body image
Three versions (IMPACT-I, II, and III). Developed using several pediatric IBD cohorts; in use in clinical trials
PEDIATRIC Computer-based animated questionnaire 35-item visual scale Children ages 5–11 yrs PEDIBDQ 45-item Likert scale Children ages 8–18 yrs IMPACT 35-item Likert scale Self-administered Children ages 10–17 yrs
Correlates with SIP and SCL–90; developed on “well” patients – CCFA national sample
Abbreviations used: Crohn’s and Colitis Foundation of America (CCFA); Crohn’s disease (CD); Crohn’s disease activity index (CDAI); Gastrointestinal (GI); National Foundation for Ileitis and Colitis (NFIC); Pediatric Inflammatory Bowel Disease Questionnaire (PEDIBDQ); Symptom Checklist-90 (SCL-90); Sickness Impact Profile (SIP); ulcerative colitis (UC). Adapted from Drossman [57]
correlation with patient, relative, and physician global ratings and discriminate between the groups of patients who did or did not require surgery [49]. Some researchers have expressed concern about the use of a single measure to describe the HRQOL for IBD, because of the frequently disparate natures of its component diseases, Crohn disease and ulcerative colitis [57]. For example, because Crohn disease can affect variable locations in the bowel the range of symptoms can also vary greatly, with differences exacerbated by relapsing and remitting disease activity. This is compared with ulcerative colitis in which the bowel disease is limited to the colon. Given these
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differences some researchers have suggested that a different or separate approach to HRQOL evaluation for these two diseases may be required. This issue was apparently not addressed in the development of the IBDQ [26, 49]. If HRQOL is to be considered as an outcome measure in a multinational trial, translation of the questionnaire to the mother tongue of the studied patient population is required to reliably compare data across populations. Translation alone, without consideration of cultural differences, may not be sufficient. Cultural differences with respect to disease perception and illness experience are becoming more apparent with the increasing immigrant population residing in western countries [58]. The exclusion from a study of a group or population, based on culture or language, could lead to a systematic bias in studies of health care utilization or quality of life [59]. Given the increasing number of cross-culturally adapted versions of the IBDQ [60–66] and the development [67] and subsequent validation [68, 69] of the 10-item Short Inflammatory Bowel Disease Questionnaire (SIBDQ), it seems unlikely that other HRQOL measures for adult IBD patients will be developed, unless it is to target specific subgroups missed in the IBDQ item generation such as patients with ileostomy.
Health-related Quality of Life Assessment in Pediatric Inflammatory Bowel Disease As is the case with pediatric quality of life assessment in general, consideration of quality of life issues in pediatric IBD has lagged behind that of the adult IBD cohort. The earliest semblances of quality of life inquiry were from a number of centres which reported the results of long-term follow-up or cross-sectional assessments of their pediatric IBD populations [2, 3, 70–76]. In many instances, rather than actually describing the quality of life, they were describing the functional status of the patients [70–72, 75, 76]. Goel et al. [70] and Lindquist et al. [72] did not use a formal measure to describe quality of life, but rather, in their description of the current status [70] or clinical course [72] of the patients, included limitations on social activities, school attendance or occupation as descriptors. Farmer and Michener [73, 74] developed a simple measure which provided three categories of quality of life: “Good – meaning ability to function in a nearly normal manner with minimal interference from the illness and its sequelae; Poor – indicated severe effect on life style, requiring medication and often frequent hospitalization; Fair – suboptimal but adequate functioning, i.e., chronic illness and partial disability.” Patients were categorized based on interviews by trained personnel. The researchers acknowledged that their view of quality of life was a composite of several elements of the patient’s life and that patients might experience varying degrees of quality of life over a long period of time. Patients were asked to consider the cumulative effect of the illness and treatment and to describe their current state of health. Farmer and Michener’s long-term follow-up study of 522 patients (followed from 1955 to 1974) with onset of CD under age 21 found that approximately two thirds of patients considered their functioning to be in the fair level, with only 6% rating their functioning as poor [73, 74]. Given the marked changes in management over the past five decades, it is unclear what relevance quality of life outcomes in such a cohort would have compared to a similar present day cohort. More recently researchers have sought to assess quality of life in pediatric IBD using measures with domains which encompass a broader concept of quality of life [77–80]. MacPhee et al. [80] completed an assessment of thirty pediatric IBD patients using a number of generic psychological and quality of life questionnaires. Their study emphasized social supports, and coping strategies. They used the Quality of Life for Adolescents and Parents questionnaire [81], a generic measure which gives a total satisfaction score with health status and similar scores for subscales. Thomas et al. [77, 78] describe the early stages of development of a disease–specific quality of life questionnaire which they used to assess quality of life in their pediatric Crohn disease cohort.
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Focus group meetings were held with pediatric patients of ages from 8 to 17 years (two groups, 8 to 12 years and 12 to 17 years of age) to learn how their disease and its treatment affected their lives at school, at home, and with friends. An 88-item questionnaire was constructed based on the areas identified in the focus groups. The questionnaire contained six domains of HRQOL including symptoms and treatment, social life, emotional state, family life, education, and future aspects. No data on validity, reliability or sensibility was provided for this questionnaire [77, 78]. The questionnaire was used in one pilot study involving 16 children from one academic IBD program in England. Acknowledging the limitations of a small sample size, they found that CD appeared to most adversely affect the HRQOL of children as manifested through school absenteeism, fatigue limiting sports activities and difficulties in taking holidays. Moody et al. [79] studied quality of life in pediatric Crohn disease using a questionnaire they developed in conjunction with a British national lay committee of Crohn in Childhood Research Association (CICRA) members. Limited information is provided on the questionnaire’s development, and it’s length and exact format is unclear from the published report [79]. Results from sixty-four valid questionnaires were received in a pilot study. The mean age of the children in this study was 14.1 ± 2.8 years (range 6–17 years). In this cohort 60% of the children reported prolonged absences from school, with a mean 3 ± 2.8 months’ absence in the previous 12 months. Eighty percent of those who had taken examinations felt that their marks had suffered due to ill health. Seventy percent of patients with CD were unable to participate in sports on a regular basis, 60% did not feel comfortable leaving their homes, and 50% did not feel they could play outside with their friends, because of the illness. Forty percent of children also reported concerns about taking holidays and being able to have sleep-overs at friends’ homes. This study would suggest that CD has a major impact on the QOL of pediatric patients. However, caution should be exercised in making these conclusions as there are several limitations of the published study. It is not clear if the questionnaire underwent any validity testing to ensure it was measuring what it intended to measure. Given the study design, in which a general mailing was sent to members of a society, there may be a strong response bias in favour of those whose QOL is poor. As well, the authors do not tell us the number of questionnaires distributed, nor do they clarify the response rate. Preliminary development of the Pediatric Inflammatory Bowel Disease Questionnaire (PEDIBDQ) for children and teens [82, 83], and a computer-based animated program to assess HRQOL for young children 5 to 11 years of age [84] have been reported in abstract or manuscript form. Further work has not been reported using these questionnaires, however. In the mid 1990s, researchers at the Hospital for Sick Children in Toronto, Canada began work on a diseasespecific measure, the IMPACT questionnaire [85], which today is the most commonly employed disease-specific measure for assessing HRQOL in the pediatric IBD population.
IMPACT The Development of the IMPACT Questionnaire There are three English iterations of the IMPACT questionnaire at present, and work is actively underway on translation of IMPACT-III into other languages. Work on IMPACT began in the mid 1990s because at that time there was no published disease-specific HRQOL instrument available for pediatric patients with IBD. Generic pediatric HRQOL questionnaires, such as the Child Health Questionnaire [23, 86], were felt to be insensitive to the disease-specific issues of IBD. Concerns about wording issues, including inappropriate omissions and inclusions for a pediatric target audience, led researchers at the Hospital for Sick Children to seek a pediatric-derived instrument over the adult-derived IBDQ [35]. For example, one question in the IBDQ [49] pertains to limitation of sexual activity by IBD, an issue which was felt to be of limited relevance in a
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pediatric cohort, except perhaps for the older adolescent. Issues not covered by the IBDQ which were felt to be of likely relevance to a pediatric cohort included growth concerns and limitations on school and extracurricular activities. Defining how a new HRQOL tool will be used is important in guiding the development process, as this helps to ensure that the end product is addressing the underlying need. The IMPACT developers sought to create a questionnaire which would serve both as a descriptive and evaluative tool. As a descriptive tool, the measure would facilitate recognition in individual patients of disparity between apparent IBD activity and severity, organic disease-related phenomena, which the physician is accustomed to assessing, and emotional or functional disability. As an evaluative tool it was to be incorporated as an outcome measure in clinical trials to assess change in HRQOL over time. In the development of IMPACT, there was a focus on children aged 10 to 17 years. Younger patients were excluded because of concern that systematic exploration of quality of life among very young children would require significantly modified methods. Items to be included in the final questionnaire were generated chiefly from interviews of pediatric patients with IBD. Items universally of greatest importance for all IBD patients were included, as well as some items rated as very important by one subgroup of patients (CD or UC), even if not by others [85]. The original IMPACT [35], or IMPACT-I as it is currently known, consisted of 33 questions, and responses were given using a visual analogue scale. Each question was scored out of seven, so that the final total score would be similar to what was seen with the adult IBDQ. Thus, the range of scores possible for IMPACT-I was 0 to 231. During the cross-cultural adaptation and translation process of IMPACT-I into the Dutch language, a modified version was developed [87]. This version, IMPACT-II, eliminated or modified four questions, and added a new question, resulting in a 35 item questionnaire with simplified wording of the response options for the visual analogue scale. IMPACT-II was available in both English [88] and Dutch [87] language versions. Some researchers preferred a Likert response scale, and IMPACT-III [89] was created, which is identical to IMPACT-II save for the 5 point Likert response scales and anchors (Figure 43.2). IMPACT-III is available in Canada/US and UK English versions, as well as European French and Dutch versions. IMPACT-III is the questionnaire used for ongoing cross-cultural adaptation. Through cohort studies, and more recently in randomized controlled trials [89–91], IMPACT has demonstrated itself to be a valid measure of disease-specific HRQOL in pediatric IBD patients 10 years of age and over. From this work, while disease activity or disease severity are two factors which have been identified as strongly correlated with HRQOL, regression modeling clearly shows that they can only explain a small part of the HRQOL “puzzle” [35, 88]. As well work to date has not shown any influence of disease type (CD or UC) or gender in influencing the performance of IMPACT. With age there remains less clarity. The original validation did not shown any significant differences in perceived HRQOL across the age group studied. Research has shown that the perceived HRQOL as assessed by IMPACT is most influenced by the current health status rather than that suffered over the previous twelve months [35]. That the
Question 10.
Never
How often have you been bothered by diarrhea (loose or frequent bowel movements) in the past two weeks?
Rarely
Sometimes
Often
Very often
Figure 43.2. Sample IMPACT-III question As opposed to IMPACT versions I and II which used visual analogue response scales, IMPACT-III uses a 5 point Likert response scale.
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IMPACT questionnaire is greatly influenced by the patient’s current health status is an important feature for its use in clinical trials. If IMPACT scores continued to be influenced more by the patient’s health status over the preceding year than by their current disease status, short-term responsiveness to change in clinical status would be compromised. To date the IMPACT questionnaire has been used to evaluate HRQOL in pediatric IBD patients in a number of research studies, involving a variety of study designs (Table 43.3). These studies provide a preliminary picture of what the HRQOL is in this population, and increasingly the data obtained from such studies will allow clinicians and researchers to develop an improved understanding of the factors which both positively and negatively influence HRQOL in older children and teenagers with IBD. Description of the Instrument (IMPACT-III) The IMPACT-III questionnaire takes about 10 to 15 minutes to complete and contains 35 questions encompassing six domains: bowel (7 concerns), body image (3 concerns), functional/social impairment (12 concerns), emotional impairment (7 concerns), tests/treatments (3 concerns), and systemic impairment (3 concerns) (Table 43.4). Each question is scored on a five point scale (Figure 43.2). Individual questions within IMPACT are equally weighted; hence the scores range from a maximum of 175 to a minimum of 35, with higher scores representing better quality of life. Table 43.3. Clinical trials and other studies utilizing IMPACT to assess health-related quality of life in pediatric IBD. First author and year
IMPACT version studied
Key Findings
Afzal et al. [92] 2004
IMPACT-II
Shepanski et al. [93] 2005
IMPACT-II
Otley et al. [88] 2006
IMPACT-II
Otley et al. [90] 2006
IMPACT-III
Otley et al. [89] 2006
IMPACT-III
Hyams et al. [91] 2006
IMPACT-III
Open-label trial of enteral nutrition in CD. Improved HRQOL mirrored attainment of clinical remission, but not improved mucosal inflammation Prospective cohort study. Improved HRQOL noted after attendance at pediatric IBD camp Prospective cohort study. Improved HRQOL noted from time of diagnosis to 12 months, also evaluated factors influencing HRQOL scores Improved HRQOL in patients receiving infliximab in RCT. Improvement was noted by first HRQOL follow-up at 10 weeks. RCT of Infliximab, with secondary analysis of data. Demonstrates IMPACT-III is a valid disease-specific HRQOL questionnaire for pediatric IBD. As well it is reliable and responsive to change. Preliminary cut-scores of ≥ 143 to denote clinical remission RCT of natalizumab in CD. No significant change in HRQOL total score, despite improved disease activity
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Table 43.4. IMPACT-III: 35 questions sorted by six domains. Domain IBD symptoms
Question • • • • • • •
Stomach aches Not being able to eat what you want because of disease Diarrhea Worried about blood with bowel movement Being sick Afraid about not making to the bathroom in time Having to pass gas
Systemic symptoms
• How much energy • How did you feel • How tired did you feel
Emotional functioning
• • • • • • •
Worried about having a flare-up Worried about having a chronic condition Worries about health in future Thinking it is unfair to have this disease Being angry to have this disease Being ashamed Being happy
Social functioning
• • • • • • • • • • • •
The influence of the disease upon the family Having to miss out on hobbies Having rules imposed because of the disease Having fun Is it harder to make friends Worries not to be able to go out on dates Teased or bullied because of the disease or treatment Difficulties to travel or go on holiday Try and keep your disease a secret Able to talk to anyone about worries Able to play sports as much as you would like Able to go to school
Body Image
• How do you feel about height • How do you feel about weight • How do you feel about the way you look
Treatment/interventions
• How do you feel about taking medicines • How do you feel about investigations • Worries about ever having an operation
Readability statistics for the IMPACT-III are excellent with a Flesch-Kincaid Grade level of 4.8, a Flesch Reading ease of 74.3, and 1% passive sentences. This suggests a very appropriate level of wording given the target population of ages 10 and above. Practical Issues for Use of IMPACT Administration and Instructions to Respondents The person administering IMPACT III should verbally review the written instructions provided on the initial page of the questionnaire with the child completing the questionnaire. It is important that the responses are the child’s, and parents should be specifically asked not to help their child with the answers. It is, therefore, helpful to have an assistant nearby to answer questions that the respondent might have, so that the parent(s) will not have to aid them. It should be made clear that if the child feels that the issue raised by a particular question is not a problem for them (i.e.
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questions mentions blood in stool, but they have never had blood in stool) then the child should mark it as “best quality of life” response. This will help decrease the number of questions left blank. Scoring By convention, the higher the score the better the quality of life. For IMPACT III the “good” QOL anchors are always presented on the left, with the “poor” QOL anchors on the right. There are five Likert response options per question. For scoring purposes, from left to right, they can be numbered 5 through 1. To obtain a total score, responses from all 35 questions are summed. Domain scores can be obtained by summing the responses for each question within a domain (Table 43.4). Interpretation of HRQOL scores is another important area to consider. In IBD, the HRQOL outcomes from either IBDQ or IMPACT, have usually been reported as the mean total score for study participants at various study timepoints. Other ways of reporting HRQOL outcomes would be to focus on the mean scores of a domain (i.e. the bowel domain) for study participants at various study timepoints. The latter may be optimal when a specific intervention would be expected to have a predominant influence on a specific domain.
Deficiencies in Current Knowledge and Areas for Future Research Evaluation of HRQOL in pediatric IBD remains in its infancy. Although we have a tool with which to assess disease-specific HRQOL in this population, a number of unanswered questions remain. While some factors, such as disease activity and severity, are known to negatively influence HRQOL, further research is needed to elaborate other key factors which may influence HRQOL. By gaining an understanding of factors which influence HRQOL we can then work on developing specific interventions to target these factors, with the goal to improve HRQOL in these patients. As IMPACT is increasingly used in clinical and research settings an improved understanding of HRQOL in patients with pediatric IBD should result. Also important, however, is understanding how these patients fare when compared to children with other chronic illnesses. This latter work will need to be done utilizing generic HRQOL measures. IMPACT is a tool to evaluate HRQOL in pediatric patients aged 10 to 17 years inclusive. The researchers who developed the questionnaire were concerned that issues of importance to younger patients with IBD may be different than the older cohort which were involved in the development of IMPACT. Also a self-administered questionnaire for these patients less than 10 years of age would be problematic given the developmental and comprehension concerns in the younger age range [11]. It is most likely that younger patients would require assistance in completing the questionnaire and/or a different method of delivery [11], such as computer-based questionnaire with video and/or audio components [84]. This is an area which requires further consideration, but it will be necessary to determine whether the relatively small population of patients with IBD who are less than 10 years of age can justify the development of a tool specifically for this age group. During the development of IMPACT, patients with ostomies or proctitis were not included. Therefore, the applicability of IMPACT to this cohort of patients has not been established. There may be HRQOL issues unique to this population not addressed by the IMPACT. As well, IMPACT development involved participants who had been diagnosed with IBD for at least six months. The researchers wished to have a body of “lived experiences and concerns” and it is not clear whether when the diagnosis is more recent, if the perception of issues influencing HRQOL are the same as those when there has been more disease experience. A further gap in assessment of HRQOL in pediatric IBD is the lack of ability to make comparisons across different cultures and/or languages. This stems from the limited cross-culturally adapted versions of IMPACT-III. Other IBD outcome measures such as the commonly utilized
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disease activity measures can be utilized irrespective of culture or language. They collect fundamental information which are not limited by ethnicity or language. This is not true for quality of life assessments. Language translation, as well as cultural adaptation, may be required before these measures can be broadly applied. It will be important for this process to occur so that IMPACT can be fully utilized and accepted as the HRQOL outcome measure of choice for use in pediatric IBD populations. Cross-cultural adaptation of IMPACT is ongoing with Dutch, European French and UK English versions currently available. For use in clinical trials as a key outcome measure researchers and clinicians will need to determine the minimum clinically important difference (MCID) in IMPACT score. The MCID refers to the smallest amount of benefit that patients can perceive and value. The MCID is an important characteristic and when this is understood aids in the determination of sample size. For example, if a small MCID is determined, this limits the sample size that would be required, as compared to the scenario in which a large MCID is observed, and in which a very large sample size would be needed to show the difference (if such a difference existed). References 1. Ferguson, A., D.M. Sedgwick, and J. Drummond, Morbidity of juvenile onset inflammatory bowel disease: Effects on education and employment in early adult life. Gut, 1994. 35: pp. 665–668. 2. Gryboski, J., Ulcerative colitis in children 10 years or younger. J Pediatr Gastroenterol Nutr, 1993. 17: pp. 24–31. 3. Gryboski, J.D., Crohn disease in children 10 years old and younger: comparison with ulcerative colitis. J Pediatr Gastroenterol Nutr, 1994. 18: pp. 174–182. 4. Barton, J.R., S. Gillon, and A. Ferguson, Incidence of inflammatory bowel disease in scottish children between 1968 and 1983; marginal fall in ulcerative colitis, three-fold rise in crohn disease. Gut, 1989. 30: pp. 618–622. 5. Mir-Madjlessi, S.H., W.M. Michener, and R.G. Farmer, Course and prognosis of idiopathic ulcerative proctosigmoiditis in young patients. J Pediatr Gastroenterol Nutr, 1986. 5(4): pp. 570–575. 6. Mackner, L.M., and W.V. Crandall, Long-term psychosocial outcomes reported by children and adolescents with inflammatory bowel disease. Am J Gastroenterol, 2005. 100(6): pp. 1386–92. 7. Mackner, L.M., and W.V. Crandall, Oral medication adherence in pediatric inflammatory bowel disease. Inflamm Bowel Dis, 2005. 11(11): pp. 1006–12. 8. Mackner, L.M., W.V. Crandall, and E.M. Szigethy, Psychosocial functioning in pediatric inflammatory bowel disease. Inflamm Bowel Dis, 2006. 12(3): pp. 239–44. 9. Constitution of the World Health Organization, in World Health Organization. Handbook of Basic Documents. 1952, Palais des Nations: Geneva. pp. 3–20. 10. Eiser, C., and R. Morse, Quality-of-life measures in chronic diseases of childhood. Health Technology Assessment, 2001. 5(4): pp. 1–168. 11. Eiser, C., Children’s quality of life measures. Archives of Disease in Childhood, 1997. 77: pp. 347–354. 12. Jenney, M.E.M., and S. Campbell, Measuring quality of life. Archives of Disease in Childhood, 1997. 77: pp. 347–354. 13. Testa, M.A., and D.C. Simonson, Assessment of quality-of-life outcomes. New Engl J Med, 1996. 334(13): pp. 835–840. 14. Streiner, D.L., and G.R. Norman, Health measurement scales: A practical guide to their development and use. 2nd ed. Basic Concepts. 1995, New York: Oxford University Press Inc. 4–14. 15. Otley, A.R., et al., Assessing disease activity in pediatric crohn disease: which index to use? Gastroenterology, 1999. 116: pp. 527–531. 16. Hyams, J.S., et al., Development and validation of a pediatric crohn disease activity index. J Pediatr Gastroenterol Nutr, 1991. 12: pp. 439–447. 17. Hyams, J.S., et al., Relationship of common laboratory parameters to the activity of crohn disease in children. J Pediatr Gastroenterol Nutr, 1992. 14: pp. 216–222. 18. Ferry, G., Quality of life in inflammatory bowel disease: Background and definitions. J Pediatr Gastroenterol Nutr, 1999. 28(4): pp. S15–S18. 19. Yacavone, R.F., et al., Quality of life measurement in gastroenterology: What is available? Am J Gastroenterol, 2001. 96(2): pp. 285–297.
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70. Goel, K.M., and R.A. Shanks, Long-term prognosis of children with ulcerative colitis. Arch Dis Childhood, 1973. 48: pp. 337–342. 71. Cooke, W.T., et al., Crohn disease: Course, treatment and long term prognosis. Q J Med, 1980. 49(195): pp. 363–384. 72. Lindquist, B.L., G. Jarnerot, and G. Wickbom, Clinical and epidemiological aspects of crohn disease in children and adolescents. Scand J Gastroenterol, 1984. 19: pp. 502–506. 73. Farmer, R.G., and W.M. Michener, Prognosis of crohn disease with onset in childhood or adolescence. Dig Dis Sci, 1979. 24(10): pp. 752–757. 74. Michener, W.M., R.G. Farmer, and E.A. Mortimer, Long-term prognosis of ulcerative colitis with onset in childhood and adolescence. J Clin Gastroenterol, 1979. 1: pp. 301–305. 75. Mayberry, J.F., Impact of inflammatory bowel disease on educational achievements and work prospects. J Pediatr Gastroenterol Nutr, 1999. 28(4): pp. S34–S36. 76. Engstrom, I., Inflammatory bowel disease in children and adolescents: Mental health and family functioning. J Pediatr Gastroenterol Nutr, 1999. 28(4): pp. S28–S33. 77. Akobeng, A.K., et al., Quality of life in children with crohn disease: A pilot study. J Pediatr Gastroenterol Nutr, 1999. 28(4): pp. S37–S39. 78. Rabbett, H., et al., Quality of life in children with crohn disease. J Pediatr Gastroenterol Nutr, 1996. 23: pp. 528–533. 79. Moody, G., J.A. Eaden, and J.F. Mayberry, Social implications of childhood crohn disease. J Pediatr Gastroenterol Nutr, 1999. 28(4): pp. S43–S45. 80. MacPhee, M., E.J. Hoffenberg, and A. Feranchak, Quality-of-life factors in adolescent inflammatory bowel disease. Inflammatory Bowel Dis, 1998. 4(1): pp. 6–11. 81. Olson, D., and H. Barnes, Quality of life questionnaire. 1982, University of Minnesota Press: St. Paul, MN. 82. Forget, S., et al., Validation of a disease specific health-related quality of life (HRQOL) Instrument for Pediatric Inflamm Bowel Dis (IBD). Gastroenterology, 1998. 114(4 (Part 2)): p. A978. 83. Forget, S., et al., Health-related quality of life in pediatric inflammatory bowel disease: A comparison of parent and child reports. Gastroenterology, 1998. 114(4 (Part 2)): p. A977. 84. Buller, H., Assessment of quality of life in the younger child: The use of an animated computer program. J Pediatr Gastroenterol Nutr, 1999. 28(4): pp. S53–S55. 85. Griffiths, A.M., et al., Development of a quality-of-life index for pediatric inflammatory bowel disease: Dealing with differences related to age and IBD type. J Pediatr Gastroenterol Nutr, 1999. 28: pp. S46–S52. 86. Piers, E.V., and D.B. Harris, The Piers-Harris children’s self-concept scale. 1996, Western Psychological Services: Los Angeles, CA. 87. Loonen, H.J., et al., Quality of life in paediatric inflammatory bowel disease measured by a generic and a disease-specific questionnaire. Acta Paediatr, 2002. 91(3): pp. 348–54. 88. Otley, A.R., et al., Health-related quality of life in the first year after a diagnosis of pediatric inflammatory bowel disease. Inflamm Bowel Dis, 2006. 12(8): pp. 684–91. 89. Otley, A., et al., IMPACT-III is a valid, reliable and responsive measure of health-related quality of life in pediatric Crohn disease. J Pediatr Gastroenterol Nutr, 2006. Abstract accepted for presentation at conference. 90. Otley, A., et al., The effects of infliximab therapy on health-related quality of life in pediatric crohn disease. J Pediatr Gastroenterol Nutr, 2006. Abstract accepted for presentation at conference. 91. Hyams, J., et al., Safety, tolerability, and efficacy of natalizumab in adolescents with crohn disease. To be submitted - should be available later in 2006. 92. Afzal, N.A., et al., Improvement in quality of life of children with acute Crohn disease does not parallel mucosal healing after treatment with exclusive enteral nutrition. Aliment Pharmacol Ther, 2004. 20(2): pp. 167–72. 93. Shepanski, M.A., et al., Health-related quality of life improves in children and adolescents with inflammatory bowel disease after attending a camp sponsored by the Crohn and Colitis Foundation of America. Inflamm Bowel Dis, 2005. 11(2): pp. 164–70.
44 Irritable Bowel Syndrome and Functional Gastrointestinal Disorders in Pediatric Inflammatory Bowel Disease Manu R. Sood
Introduction Irritable bowel syndrome (IBS) is characterized by altered bowel habits and abdominal pain in the absence of detectable structural abnormality. There are no clear diagnostic markers for this illness and all definitions are based on clinical symptoms. Getting an accurate history from a child can be difficult and therefore until recently IBS was not considered a clinical entity in children. Many pediatricians still view IBS as nothing more than a somatic manifestation of psychological stress. Availability of better techniques to study bowel motility and sensory function along with advancements in functional brain imaging techniques have improved our understanding of the pathophysiology of IBS. It is thought that the generation of IBS symptoms may result from the convergence of multiple factors including a genetic predisposition, an infectious or inflammatory injury to the gastrointestinal (GI) tract leading to altered sensory perception by the brain, and an underlying bowel dysmotility. Functional gastrointestinal symptoms can co-exist in patients with inflammatory bowel disease (IBD). It can be difficult to differentiate these symptoms from those associated with the relapse of the underlying disease process. Emerging data suggest that there may be an overlap in the symptoms and etiopathogenesis of IBS and IBD. In this chapter I will discuss how to make a symptom based diagnosis of IBS, review the pathophysiology and management of IBS. I will also discuss the enteric nervous system changes and the prevalence of functional GI symptoms in IBD.
Epidemiology A large proportion/majority of children with IBS are still categorized under a broad umbrella of recurrent abdominal pain, and the prevalence of IBS in children is under recognized. In one
*Manu R Sood, M.D., Children’s Hospital of Wisconsin, Pediatric GI and Nutrition, 9000 W Wisconsin Avenue Milwaukee, WI 53226, Phone: 414-2 66-3690, Fax: 414-266-3676, E-mail:
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study of 171 subjects with recurrent abdominal pain, 68% fulfilled the clinical criteria for the diagnosis of IBS [1]. Community based studies from North America and China suggest that 8%–17% of school children have IBS-like symptoms [2, 3]. Subcategorizing children presenting with functional abdominal pain into IBS, dyspepsia and recurrent abdominal pain is important because it helps to narrow down the differential diagnosis, reduces the number of unnecessary investigations and better targets the therapy to the child’s symptoms.
Clinical Features A good clinical history is vitally important in making a symptom based diagnosis of IBS and in differentiating it from organic diseases which can mimic IBS symptoms (Table 44.1). To standardize the diagnosis of IBS, symptom based criteria have been developed and amended by the Pediatric Rome Committee (Table 44.2) [4]. Specific alarm symptoms, which alert the clinicians to the increased likelihood of an underlying organic disease can help in the management and planning of investigative work up. One major drawback of the Rome criteria is that there are very few good validation studies in children and most of the data has been extrapolated from adult studies. Abdominal pain or discomfort is a prerequisite clinical symptom of IBS. The pain is highly variable in intensity and location, but usually restricted to the lower abdomen. It can be episodic and cramping, or superimposed on a background of constant ache. It is usually relieved by the passage of stool or flatus and exacerbated by meals. The pain does not interrupt sleep. Up to 50% of adults with IBS also have upper gastrointestinal symptoms such as nausea, vomiting or epigastric pain. Altered bowel habit is one of the most consistent symptoms and can include constipation, diarrhea or both. To begin with the constipation can be episodic but usually becomes continuous and refractory to treatment with laxatives. Stool is hard and narrow in caliber. It can be associated with the feeling of incomplete evacuation; the child can spend a long time sitting on the toilet straining unsuccessfully to have a bowel movement. Most patients with diarrhea predominant IBS pass a small volume of liquid stool at frequent intervals. It can be accompanied with the passage of mucus but not blood. Nocturnal diarrhea is uncommon. Some patients will have periods of constipation alternating with diarrhea. Abdominal bloating, belching and flatulence are also common.
Table 44.1. Diseases which can mimic irritable bowel syndrome symptoms. Diarrhea predominant IBS • GI infections • Inflammatory bowel disease • Celiac disease • Carbohydrate malabsorption (lactose, sucrose, fructose, sorbitol) • Lymphocytic and collagenous colitis • Food intolerance Constipation predominant IBS • Celiac disease • Hypothyroidism • Anal sphincter/pelvic floor abnormality • Tethered spinal cord • Colon motility disorder • Neoplastic disorders (rare in children)
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Table 44.2. Rome III criteria for the diagnosis of irritable bowel syndrome [4]. The criteria should be fulfilled at least once per week for at least 2 months before diagnosis. Must include all of the following 1. Abdominal discomfort (an uncomfortable sensation not described as pain) or pain associated with 2 or more of the following at least 25% of the time: a. Improved with defecation b. Onset associated with change in frequency of stool c. Onset associated with a change in form (appearance) of the stool 2. No evidence of an inflammatory, anatomic metabolic, or neoplastic process that explains the subjects symptoms
Pathophysiology Our understanding of IBS pathogenesis is based mainly on adult data. Changes in GI sensory perception, central neuronal dysfunction, abnormal motility, stress, psychological abnormalities and luminal factors have all been implicated. The enteric nervous system consists of two distinct nerve plexuses which are interconnected and they also receive sensory input from the bowel lumen through the sensory receptors. The enteric nervous system communicates with the brain through neural pathways as well as by immune and endocrine mechanisms. The pain signals are transmitted from the primary sensory afferent neurons with cell bodies in the dorsal root ganglia to the dorsal horn of the spinal cord. Spinal pathways run to the thalamus and relay messages to the limbic system and the sensory cortex. The combined functioning of the GI motor, sensory and CNS activity is termed as the brain gut axis. Abnormalities along the brain gut axis such as altered peripheral sensory perception, hypersensitivity of sensory neurons in the dorsal horn and increased activation of brain regions associated with visceral pain sensation have been reported in IBS [5]. Sensory sensitization and hyperalgesia: Peripheral sensitization of nerves within the GI tract follows the release of inflammatory mediators after a transient inflammatory or injurious event [6]. Fibroblasts and mast cells release nerve growth factor which increases transcription of the neuropeptides, substance P and calcitonin generelated peptide. This initiates nerve activation and the release of yet more substance P. Previously silent nocioceptors are recruited and contribute to the development of hyperalgesia (an exaggerated pain response to a sensory stimulus) and allodynia (painful response to a physiologically painless stimulus). Visceral hyperalgesia has been reported in children with abdominal pain and IBS [7, 8]. Following rectal balloon distension stimulus, children with IBS perceived pain with smaller volumes of rectal distension compared to healthy subjects. Visceral hyperalgesia could result from sensitization of primary sensory afferent fibers innervating the gut or the neurons receiving input from visceral afferents along the brain-gut axis [5]. In adults functional magnetic resonance imaging studies and a study of evoked potentials following electric stimulation of the rectum, have shown increased brain activation in IBS subjects compared to controls [5]. Hypersensitivity of the brain gut axis has also been documented using a subliminal rectal stimulus i.e. a stimulus below an individual’s perception threshold, therefore eliminating the emotional and cognitive components sensory perception [9]. Animal studies suggest that visceral sensitization can be sustained by increased sensitivity of N-methyl- D-aspartate receptors expressed in dorsal horn neurons to synaptically released glutamate [10]. Diet may also affect visceral sensory perceptionlipids are known to lower the threshold for abdominal discomfort and pain and, increase the area of referred pain in IBS patients [11].
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Low grade inflammation Bowel infection can lead to persistent low grade inflammation and IBS like symptoms in 7% to 31% of adults [12–15]. The symptoms in post-infectious IBS are thought to be generated and mediated by immune mechanisms. Increased intraepithelial and lamina propria lymphocytic infiltration, together with an increase in enteroendocrine cells have been reported in bowel biopsies obtained from post infectious IBS patients [15]. These changes can persist for up to 12 months and are associated with increased mucosal permeability [12, 15]. It had been a matter of on going debate whether a mild mucosal inflammation can cause GI symptoms. In patients with lymphocytic colitis, increase in intraepithelial lymphocytes is associated with abdominal pain and diarrhea [16]. Recent studies have shown that inflammation in deeper bowel layers can be present in the absence of mucosal changes. Intra and peri-ganglionic infiltration with lymphocytes in the myenteric plexus [17] and mast cells present near the enteric nerves can produce IBS symptoms [18]. It appears that increased inflammatory cells in the mucosa and deeper bowel layer contribute to IBS symptoms. These changes are milder than those seen in IBD, but sufficient to cause GI symptoms. Altered Motility Abnormal rectal, colon and small bowel motility has been implicated in IBS pathophysiology. Interpretation of colon motility studies in adults with IBS is hampered by a relatively primitive understanding of normal colon motility and its intrinsic variability. Abnormalities in colon motility and abnormalities in response to food and stress have been reported in patients with IBS [19]. Abnormalities in small bowel motility such as repetitive bursts of contractions or clusters, prominent high amplitude waves in the terminal ileum and an exaggerated jejunal motor response to a meal have also been reported in adults with IBS [19, 20]. There is also a suggestion that IBS patients handle small bowel gas differently and there is slow transit of gas directly infused into the small bowel in adults with IBS [19]. Abdominal bloating and flatulence can also result from higher colonic fermentation in IBS [19, 21]. Some patients without evidence of small bowel bacterial overgrowth can benefit from treatment with unabsorbable antibiotics [22], which raises the question of a qualitative change in bowel bacterial flora in IBS. Biochemical Changes Serotonin (5-hydroxytryptamine: 5HT) is secreted in copious amounts by the gut enteroendocrine cells and serves as a critical messenger for GI fluid secretion and motility. It activates at least five different receptor types, with the 5-HT3 and 5-HT4 receptors being the most extensively studied in IBS [23]. The transporter of 5-HT (SERT), mediates the reuptake of 5-HT by the neurons and crypt epithelial cells and terminates its action. Plasma 5-HT concentration is elevated in IBS patients [24] and the proportion of 5-HT secreting enteroendocrine cells is elevated in the GI tract in post infectious IBS patients [12]. Symptom relief by serotonergic agents including 5HT3 antagonists and 5HT4 agonists provides additional support for a possible role of 5-HT in IBS pathophysiology [25]. Genetics Familial aggregation and twin studies suggest that there may be a genetic predisposition to developing IBS [26, 27]. Family members of IBS patients are more likely to have the condition, compared to their spouse controls. Twin studies have shown that the concordance rate for IBS is higher in monozygotic compared to dizygotic twins [28], suggesting a genetic predisposition to developing IBS. However, IBS in the parents was an independent risk factor for developing IBS, suggesting that social learning was as important as hereditary factors in IBS [28].
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Interleukin 10 (IL-10) is an anti-inflammatory cytokine and fewer IBS patients have the high IL-10 producing (G/G) genotype compared to healthy controls [26]. Four different studies have explored the association of serotonin reuptake transporter gene (SERT) polymorphism in IBS [26], SERT is important for terminating the GI activity of 5-HT. The wild type l/l polymorphism results in normal function, whereas the presence of the short allele (s/l or s/s) results in impaired SERT function. As a group, SERT polymorphism was similar in healthy subjects and IBS patients, but some differences were observed in subgroups of IBS patients, and these differences could be population specific. Psychological Factors Contrary to the generally held belief, community based studies in adults have shown that IBS patients are indistinguishable from the rest of the population in psychological terms [29]. Higher psychological co-morbidities though exist in a subset of IBS patients who seek medical help [29]. Research in psychosomatic medicine has shown that there may be an association between depression and the activation of the immune system and elevated C-reactive protein [30]. Therefore, psychological factors may alter individual immune response. Depression in adults is associated with the development of post-infectious IBS [31] and has also been linked to the number of relapses of colitis [32] and disease activity [33] in IBD patients. In children social learning of illness behavior can also contribute to the development of functional GI disorders; children of mothers with IBS are more likely to seek medical help for functional symptoms in their children [34]. Enteric Nervous System, Functional & Motility Abnormalities in Inflammatory Bowel Disease Bowel injury and inflammation can induce functional and structural changes in the enteric neurons and muscles. Increased numbers of ganglion cells, axonal degeneration and a reduced number of interstitial cells of Cajal have been reported in IBD [35]. In Crohn disease there is increase in substance P and its receptors in the GI tract [35]. The bowel innervation shifts from a predominantly cholinergic to a substance P predominant innervation in ulcerative colitis (UC) [35]. These changes can cause alteration in bowel sensory perception in subjects with IBD. Patients with active UC show a decreased threshold for painful and non-painful rectal distension stimulus [36]. The sensory hypersensitivity can be widespread and a lower pain threshold to esophageal distension has been reported in adults with UC [37]. In contrast, patients with isolated ileal Crohn disease have an increased pain threshold following rectal distension [38]. It appears that the development of visceral hyperalgesia in IBD may depend on the disease activity, type of inflammation and region of the GI tract involved. There is a considerable overlap between IBS and IBD symptoms (Figure 44.1). Adults who develop IBD may have a prodrome of IBS like symptoms; which can be as long as 7 years [39].
IBD
IBS
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IBD
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Figure 44.1. a showing overlap between IBD and IBS symptoms and, 1b presence of functional symptoms in a subset of IBD patients.
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Remission with placebo therapy (%)
Pooled estimate of placebo remission rate 35 30 25 20 15 10 5 0 < 2 months 2 to 4 months > 4 months Study duration
Figure 44.2. Data from meta-analysis of 23 studies that used CDAI to measure disease activity in Crohn disease. The pooled estimate of remission with placebo therapy increased with study duration.
Some of these patients have GI inflammation not severe enough to make a diagnosis of IBD, but sufficient to cause IBS like symptoms at their initial assessment. Up to 57% of adults with Crohn disease and 32% with UC have symptoms like pain and bloating when in clinical, laboratory and endoscopic disease remission [40]. Since, a few inflammatory cells located strategically near the enteric nerves or myenteric ganglion cells can alter bowel function in IBS. Similar changes could be responsible for the functional symptoms in Crohn disease patients. Chronic inflammation can also induce phenotypic and physiological changes in the bowel neuromuscular apparatus and these may lead to an altered bowel sensory and motor function and persistent symptoms despite treatment of bowel inflammation [35]. Evaluation of placebo response in Crohn disease provides indirect evidence to the existence of functional GI disorders in these patients. Placebo therapy can alter the natural course of Crohn disease. A meta-analysis of 23 adult studies using CDAI to measure disease activity, reported that the pooled median remission rate with placebo was 19% (range 0%–50%) [41]. The significant predictors of a placebo response were the study duration and number of clinic visits. The placebo effect increased with the increasing study duration (Figure 44.2), suggesting that frequent contact with medical professionals can relieve symptoms in some patients with Crohn disease. A high CDAI and CRP at recruitment showed a negative correlation with the placebo response, suggesting that patients with a low or normal CRP and a comparatively mild clinical disease activity were more likely to respond to a placebo. The obvious question is, did some of these patients with Crohn disease have functional GI symptoms to begin with and were therefore more likely to respond to a placebo.
Diagnosis The diagnosis of IBS is based on clinical symptoms and signs (Figure 44.3). IBS symptoms commonly overlap with those of IBD, enteric infections and malabsorption disorders, and investigations to exclude these disorders may be required in patients who have alarm features. In the absence of alarm symptoms abnormalities of complete blood count, blood chemistry, erythrocyte sedimentation rate and C-reactive protein are rare. Celiac disease can mimic IBS symptoms. Adult studies suggest that 5%–17% of celiac disease patients have IBS like symptoms and in one study of 1032 adults with celiac disease 37% were diagnosed with IBS prior to celiac disease [42]. More than 90% of these adults have improvement in IBS like symptoms on gluten free diet.
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Child with suspected IBS
Assess for Alarm features Nocturnal pain Unintentional weight loss Persistent vomiting Arthritis Blood in the stool Growth delay Fever Delayed puberty Family history of IBD Peri-rectal disease Alarm features present Directed diagnostic testing *
Alarm features absent • Make a confident diagnosis of IBS • Explain illness pathophysiology • Initiate behavioral modification therapy & treatment based on predominant symptom
No improvement Reassess symptoms in 4-6 weeks Improvement Continue current management * Predominant symptoms diarrhea & abdominal pain CBC, ESR, CRP, Albumin, IgA and TTG Stool occult blood Test for Lactose intolerance EGD & Colonoscopy Consider UGI and follow through * Predominant symptoms constipation & abdominal pain CBC, IgA and TTG Stool occult blood Consider sitz marker study, anorectal manometry & spine MRI for tethered cord Colonoscopy if blood in the stool
Figure 44.3. Algorithm for management of children presenting with symptoms consistent with the diagnosis of IBS.
Lactose intolerance occurs in 15%–25% of adults with IBS. However, it is yet to be determined if lactose exclusion results in resolution of IBS symptoms in these patients. In children presenting with abdominal pain and diarrhea one must be vigilant regarding celiac disease before diagnosing lactose intolerance.
Treatment Establishing an effective clinical relationship is probably the most cost-effective and beneficial treatment for IBS. One must acknowledge the presence of pain, adopt an empathic and nonjudgmental point of view, educate and reassure the child and the parents by explaining the source of symptoms in the absence of an identifiable cause. Setting reasonable goals and helping
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the patients take responsibility with some lifestyle and dietary changes may induce symptom resolution [43]. It should also be made clear that the improvement will be slow and the focus should be on normalization of psychosocial functioning, rather than trying to identify the cause for the symptoms. Cognitive behavioral therapy, family intervention and guided imagery, a form of relaxed and focused concentration have been successfully used in treating abdominal pain in children. Adult studies have shown that attention management techniques such as hypnosis and mindfulness meditation can also be useful to treat IBS symptoms. Dietary triggers such as caffeine, fatty meals and carbonated soft drinks should be eliminated. A lactose free diet can help patients with IBS symptoms associated with lactose intolerance. Increasing dietary intake of fiber can help patients with constipation predominant IBS, but metabolism of the bulking agents by gut bacteria can produce bowel gas, which can worsen symptoms of bloating and flatulence. A meta-analysis in adults with IBS suggested that soluble fiber sources such as psyllium, isphagula and calcium polycarbophil may be more effective in improving global IBS symptoms [44] compared to insoluble fiber. Polyethylene glycol 3350 and milk of magnesia can be used as an alternative stool softener in patients with bloating and flatulence. The author avoids using stimulant laxatives in constipation predominant IBS patients, as these can increase abdominal pain and cramping. Loperamide can be useful to reduce the stool frequency in diarrhea predominant IBS patients. Patients with bloating and flatulence may benefit from treatment with an oral antibiotic for small bowel bacterial overgrowth. The role of probiotic is controversial and one randomized placebo study in children has shown that lactobacillus GG does not improve IBS symptoms. Menthol, the active ingredient in peppermint oil inhibits smooth muscle contractions by blocking calcium channels. Enteric-coated peppermint oil capsules can help relieve abdominal pain [45]. Peppermint oil can cause rectal burning, esophageal pain and allergic reactions [45]. There are no controlled studies in children showing the efficacy of anticholinergics in IBS and adult trials have also produced conflicting results. In general, the anticholinergic effect in adults with IBS is comparable to a placebo [45]. The author does not prescribe antispasmodics, but if a patient is already using them and finds them useful then the author does not discontinue the medication. Tricyclic antidepressants (TCAs) are superior to placebo in treating IBS symptoms in adults [45]. TCAs act primarily through noradrenergic and serotonergic pathways, and have antimuscarinic and antihistaminic properties as well. TCA’s facilitate descending inhibitory pain pathways and alter gastrointestinal physiology to improve IBS symptoms. Amitriptyline has sedative properties which can be used to improve sleep quality when given at bed time. The usual dose of Amitriptyline is 0.2 mg/kg once at bedtime but higher dose can be tried if there is no improvement in 2–3 weeks. It tends to cause constipation, which is beneficial in patients with D-IBS. In patients without diarrhea, imipramine may be a better choice because of lesser anticholinergic effects. If the sedative properties are undesirable, desipramine can be used. TCAs can cause cardiac dysarrhythmia, in patients with prolonged QT syndrome, therefore an electrocardiogram prior to starting the therapy is advisable. Tegaserod, a partial 5-HT4 receptor agonist stimulates the peristaltic reflex, improves gastric emptying, and accelerates intestinal and colonic transit. It also stimulates chloride secretion in the intestinal tract and reduces visceral sensation. In a meta-analysis, it was shown to improve the global assessment score for IBS symptoms including abdominal pain, and is approved for the treatment of constipation predominant IBS in women [45]. Recently, a study in adolescents with constipation predominant IBS reported improvement in abdominal pain in combination with a stool softener [25]. The onset of action is fairly rapid and if no response is observed in two weeks, prolonging therapy is unlikely to be beneficial. The dose used in adolescents was 6 mg twice a day. The reported side effects include diarrhea, headaches and flatulence and the drug should be discontinued if diarrhea occurs. The drug has been with drawn from the market because of concerns regarding cardiac side effects.
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“Irritable” Pouch Syndrome Total proctocolectomy with ileal pouch anal anastomosis is the treatment of choice for patients with fulminant colitis or ulcerative colitis refractory to medical management. The most common long term complication in 24% to 46% of these patients is pouchitis [46]. The most frequently reported symptoms of pouchitis are increased stool frequency, fecal urgency, abdominal cramping, and rectal bleeding [46]. Patients who have symptoms in the absence of macroscopic or microscopic inflammation of the pouch probably have a functional disorder similar to IBS. In one adult study of 61 symptomatic patients with ileal pouch anal anastomosis for ulcerative colitis, 42.6% had no macroscopic or microscopic inflammation of the pouch [46]. Almost half of the patients with symptoms but no pouch disease responded to treatment with antidiarrheal, anticholinergic and antidepressants, similar to what has been used in treating patients with IBS.
Summary The onset of IBS symptoms most likely represents the convergence of genetic and psychosocial factors, perhaps triggered by some external stimulus such as a dramatic life event or an enteric infection or inflammatory condition. Dysmotility, hypersensitivity and disturbed brain perception may be the consequence of these events rather than the primary abnormality. Persistent low grade bowel inflammation may be responsible for IBS symptoms following a bacterial GI infection. In some patients IBS symptoms may predate the development IBD, and a subset of IBD patients can have “functional” GI symptoms. Altered bowel sensory and motor function due to inflammation induced changes in the bowel neuromuscular apparatus may be responsible for “functional” GI symptoms in IBD. In due course we may realize that immune dysregulation plays a central role in the pathogenesis of both IBS and IBD and they are the two ends of a spectrum of GI inflammatory disorders. Most patients with IBS have mild disease and require education, reassurance and life style changes. A smaller proportion with moderate to severe symptoms can benefit from cognitive behavioral therapy and treatment with pharmacological agents. References 1. Hyams JS, Treem WR, Justinich CJ, et al. Characterization of symptoms in children with recurrent abdominal pain: resemblance to irritable bowel syndrome. J Pediatr Gastroenterol Nutr. 1995;20(2): 209–14. 2. Dong L, Dingguo L, Xiaoxing X, Hanming L. An epidemiologic study of irritable bowel syndrome in adolescents and children in China: A school-based study. Pediatr. 2005;116(3):e393–6, 3. Hyams JS, Burke G, Davis PM, et al. Abdominal pain and irritable bowel syndrome in adolescents: A community-based study. J Pediatr. 1996;129(2):220–6. 4. Rasquin A, Di Lorenzo C, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130(5):1527–37. 5. Hobson AR, Aziz Q. Brain imaging and functional gastrointestinal disorders: has it helped our understanding? Gut. 2004;53(8):1198–206. 6. Price DD, Zhou Q, Moshiree B, et al. Peripheral and central contributions to hyperalgesia in irritable bowel syndrome. J Pain. 2006;7(8):529–35. 7. Van Ginkel R, Voskuijl WP, Benninga MA, et al. Alterations in rectal sensitivity and motility in childhood irritable bowel syndrome. Gastroenterology. 2001;120(1):31–8. 8. Di Lorenzo C, Youssef NN, Sigurdsson L, et al. Visceral hyperalgesia in children with functional abdominal pain. J Pediatr. 2001;139(6):838–43. 9. Lawal A, Kern M, Sidhu H, Hofmann C, Shaker R. Novel evidence for hypersensitivity of visceral sensory neural circuitry in irritable bowel syndrome patients. Gastroenterology. 2006;130(1):26–33.
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10. Delvaux M. Role of visceral sensitivity in the pathophysiology of irritable bowel syndrome. Gut. 2002;51(1):67–71. 11. Lea R, Whorwell PJ. The role of food intolerance in irritable bowel syndrome. Gastroenterol Clin North Am. 2005;34(2):247–55. 12. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47(6):804–11. 13. Gwee KA, Collins SM, Read NW, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003;52(4):523–6. 14. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ. 1997;15;314(7083):779–82. 15. Bercik P, Verdu EF, Collins SM. Is irritable bowel syndrome a low-grade inflammatory bowel disease? Gastroenterol Clin North Am. 2005;34(2):235–45. 16. Pardi DS, Microscopic colitis: An update. Inflamm Bowel Dis. 2004;10(6):860–70. 17. Hans Törnblom, Greger Lindberg, Björn Nyberg, Béla Veress Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology. 2002;123(6):1972–9. 18. Tornblom H, Lindberg G, Nyberg B, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004;126(3): 693–702. 19. Quigley EMM. Disturbances of motility and visceral hypersensitivity in irritable bowel syndrome: Biological markers or epiphenomena. Gastroenterol Clin N Am 2005;34:221–33. 20. Kellow JE, Gill RC, Wingate DL. Prolonged ambulant recordings of small bowel motility demonstrate abnormalities in the irritable bowel syndrome. Gastroenterology. 1990;98:1208–18. 21. Haderstorfer B, Psycholgin D, Whitehead WE, Schuster MM. Intestinal gas production from bacterial fermentation of undigested carbohydrate in irritable bowel syndrome. Am J Gastroenterol. 1989;84(4):375–8. 22. Pimentel M, Chatterjee S, Chow EJ, et al. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006 Oct 17;145(8):557–63. 23. Tonini M, Pace F. Drugs acting on serotonin receptors for the treatment of functional GI disorders. Dig Dis. 2006;24(1–2):59–69. 24. Mawe GM, Coates MD, Moses PL. Review article: intestinal serotonin signaling in irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23(8):1067–76. 25. Khoshoo V, Armstead C, Landry L. Effect of a laxative with and without tegaserod in adolescents with constipation predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23(1): 191–6. 26. Park MI, Camilleri M. Genetics and genotypes in irritable bowel syndrome: implications for diagnosis and treatment. Gastroenterol Clin North Am. 2005;34(2):305–17. 27. Morris-Yates A, Talley NJ, Boyce PM, et al. Evidence of a genetic contribution to functional bowel disorder. Am J Gastroenterol. 1998;93(8):1311–7. 28. Levy RL, Jones KR, Whitehead WE, et al. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology. 2001 Oct;121(4):799–804. 29. Palsson OS, Drossman DA. Psychiatric and psychological dysfunction in irritable bowel syndrome and the role of psychological treatments. Gastroenterol Clin North Am. 2005;34(2):281–303. 30. De Berardis D, Campanella D, Gambi F, et al. The role of C-reactive protein in mood disorders. Int J Immunopathol Pharmacol. 2006;19(4):721–5. 31. Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology. 2003;125(6):1651–9. 32. Mittermaier C, Dejaco C, Waldhoer T, et al. Impact of depressive mood on relapse in patients with inflammatory bowel disease: a prospective 18-month follow-up study. Psychosom Med. 2004;66(1): 79–84. 33. Mardini HE, Kip KE, Wilson JW. Crohn disease: a two-year prospective study of the association between psychological distress and disease activity. Dig Dis Sci. 2004;49(3):492–7.
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34. Levy RL, Whitehead WE, Walker LS, et al. Increased somatic complaints and health-care utilization in children: effects of parent IBS status and parent response to gastrointestinal symptoms. Am J Gastroenterol. 2004;99(12):2442–51. 35. Bercik P, Verdu EF, Collins SM. Is irritable bowel syndrome a low-grade inflammatory bowel disease? Gastroenterol Clin North Am. 2005;34(2):235–45. 36. Farthing MJ, Lennard-Jones JE. Sensibility of the rectum to distension and the anorectal distension reflex in ulcerative colitis. Gut. 1978;19(1):64–9. 37. Farthing MJ, Lennard-Jones JE, Galeazzi F, et al. Esophageal hyperalgesia in patients with ulcerative colitis: role of experimental stress. Am J Gastroenterol. 2001;96(9):2590–5. 38. Bernstein CN, Niazi N, Robert M, Mertz H, et al. Rectal afferent function in patients with inflammatory and functional intestinal disorders. Pain. 1996;66(2–3):151–61. 39. Pimentel M, Chang M, Chow EJ, et al. Identification of a prodromal period in Crohn disease but not ulcerative colitis. Am J Gastroenterol. 2000;95(12):3458–62. 40. Simren M, Axelsson J, Gillberg R, et al. Quality of life in inflammatory bowel disease in remission: the impact of IBS-like symptoms and associated psychological factors. Am J Gastroenterol. 2002;97(2): 389–96. 41. Su C. Outcomes of placebo therapy in inflammatory bowel disease Inflamm Bowel Dis 2006;12: 328–333. 42. Zipser RD, Patel S, Yahya KZ, et al. Presentations of adult celiac disease in a nationwide patient support group. Dig Dis Sci. 2003;48(4):761–4. 43. Miranda A, Sood M. Treatment options for chronic abdominal pain in children and adolescents. Curr Treat Options Gastroenterol. 2006;9(5):409–15. 44. Quartero AO, Meineche-Schmidt V, Muris J, et al. Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2005.18;(2):CD003460. 45. Schoenfeld P. Efficacy of current drug therapies in irritable bowel syndrome: what works and does not work. Gastroenterol Clin North Am. 2005;34(2):319–35. 46. Shen B, Fazio VW, Remzi FH, Lashner BA. Clinical approach to diseases of ileal pouch-anal anastomosis. Am J Gastroenterol. 2005;100(12):2796–807.
45 Inflammatory Bowel Disease in Pregnancy Sunanda Kane
Introduction While the incidence of ulcerative colitis has remained stable, the incidence of Crohn disease has increased over the past few decades [1]. It is not clear whether this is due to improved diagnostic techniques, an increase in smoking habits by young female patients [patients with CD tend to be smokers compared to people without CD [2]] or other factors not yet identified. However, the consequence of this trend is a growing population of patients in their child-bearing years. Having intercourse, age of sexual debut, and pregnancy rates does not differ among adolescents with and without disability based on a study by Suris et al [3]. Disability, defined “as a long-term reduction in ability to conduct social role activities, such as school or play, because of a chronic physical or mental condition [4]” does not interfere with sexuality of an adolescent [5]. Thus, adolescent patients with inflammatory bowel disease (IBD) may be sexually active and are at risk for pregnancy. This chapter will review how pregnancy affects the adolescent with IBD both in terms of disease and management options, and how inflammatory bowel disease and its therapies may affect a pregnancy.
Onset and Diagnosis During Pregnancy An early clinical series suggested that the prognosis was poor for those female patients with ulcerative colitis diagnosed during pregnancy [6]. Since that time, epidemiological data has failed to show a worse disease course than any other time [7]. There has been no large study involving de novo diagnosis of Crohn disease during pregnancy; no conclusion about its severity under these physiological conditions can be drawn.
Contraception The management of contraception in those female patients with IBD who do not wish to become pregnant differs from that in normal female patients. The most important goal still remains the selection of the most reliable method of birth control. Barrier methods of contraception are
*Sunanda Kane, M.D., Mayo Clinic, 200 First Street SW, Rochester MN 55905, Phone: 507 284-0959, Fax: 507 266-0335, E-mail:
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acceptable but are not as effective as alternatives. The use of intrauterine devices is not usually recommended, as any complaint of abdominal pain could potentially delay the correct diagnosis of active IBD versus pelvic inflammatory disease. However, no strict contraindication exists to preclude their use in the appropriate patient. The data regarding the safety of oral contraceptives (OCs) in IBD are conflicting. Early studies suggested an increased risk (Odds Ratios ranging from 1.2–6) for the development of Crohn disease and ulcerative colitis with OC use. Several of these studies did not however, account for tobacco use [8, 9, 10, 11, 12, 13]. Two other case-control studies failed to find any association with disease onset [9, 10]. Reports from Europe, where contraceptives contain a higher estrogen content, continue to show modest increases in risk for the development of Crohn disease after adjusting for cigarette use (Odds Ratios 1.2–2.0) [11, 12, 13]. Other data suggest that OC use may exacerbate disease activity. Two small prospective studies have found an increased risk of disease recurrence after induction of remission in Crohn disease with OC use [12]. Timmer found a hazard ratio of 3 (1.5–5.9) for increased disease activity following medical induction of remission. No information is available for a possible similar risk in ulcerative colitis. At this time, no standard guidelines exist for OC use, as there are many preparations available. The variable amounts of progesterone and estrogen are the factors that determine the side effect profile. The choice of which OC preparation to use has to be individualized, taking into consideration other factors including patient history, parity and personal preferences. It does appear prudent to try a formulation that contains the lowest amount of estrogen possible or the progesterone only formulations, given the additional risk factors of smoking and predilection towards thromboembolic events in patients with IBD. Hormonal contraception in the transdermal formulation may be considered both because it avoids the addition of another oral pill for the adolescent patient as well as its delivery despite possible decrease in absorption during active flares in a patient with IBD. There are no data yet regarding the recently marketed NuVa® ring.
Fertility Adolescents with chronic conditions are just as likely to have sexual intercourse as their peers [3]. Even though adolescents may not be trying to get pregnant, the rising age of marriage and decreasing age of first intercourse combined with the inconsistent use of contraception has led to the continued trends of teenage motherhood [13]. Overall, the fertility rates for female patients with ulcerative colitis are essentially the same as those of the normal population [14]. Early studies suggesting lower fertility rates had not taken into account an increased voluntary childlessness rate in female patients with IBD. Active Crohn disease, however, can reduce fertility in several ways, depending upon the location of inflammation. Active inflammation in the colon as well as terminal ileal disease has been shown to decrease fertility [15, 16]. Active ileal inflammation can cause inflammation or scarring of the fallopian tubes and ovaries because of their proximity to the terminal ileum in the lower abdomen. Female patients with perianal disease may have secondary dyspareunia and decreased libido contributing to lower fertility rates. The systemic effects of Crohn disease including fever, pain, diarrhea, and sub-optimal malnutrition have also been implicated in decreased fertility. Female patients who have had any surgical resection are at risk for adhesions, which can also impair tubal function. Fear of pregnancy may also play a role in the reported reduced fertility seen in female patients with CD. None of the medications used to treat IBD has an adverse effect on female fertility, but it is important to remember that sulfasalazine therapy reduces sperm motility and count in males [17, 18, 19, 20]. These effects are not dose related and do not respond to supplemental folic acid. The overall reproductive capacity of men with IBD has not been found to be decreased,
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although male patients with CD have been noted to have small families [18]. A recent sperm analysis study has failed to show significant differences on count or morphology in men with exposure to 6-mercaptopurine (6-MP) compared to established WHO criteria [19].
Effect of IBD on Pregnancy Open discussions between patient and physician are the best way to ensure a successful pregnancy outcome. If a woman is doing well and in remission, there is every reason to expect the pregnancy to proceed smoothly. While there is no minimum required time period for quiescent disease prior to a planned conception, at least three months is recommended. If active disease is present, it is likely to continue through pregnancy and will place the pregnancy at greater risk for a complication. [20] This risk appears to be higher in CD than in UC. Female patients with inactive IBD at the time of conception appear no more likely to experience spontaneous abortion, still birth, or children born with a congenital abnormality [21]. Some work has suggested that babies born to female patients with IBD, regardless of disease activity, are of smaller birth weight [22]. This appears to be particularly in those female patients with Crohn disease [16, 22]. Female patients with active disease run a greater risk for premature birth [23]. One study in UC showed an increased when the first hospitalization for UC occurred during pregnancy [24]. Others have shown an increased rate for preterm births [25] and small size for gestational age [26]. The presence of IBD does not appear to have an impact on maternal complications related to pregnancy, including hypertension or proteinuria [27].
Effect of Pregnancy on IBD For female patients with quiescent UC at the time of conception, the rate of relapse is approximately the same in pregnant versus non-pregnant patients [15]. This is in contrast to the presence of active disease at the time of conception, which is associated with continued or worsening disease activity in approximately 70% of female patients. Comparable observations are seen in Crohn disease [28]. The older literature suggested a trend for disease to flare in the first trimester, but this was documented prior to the accepted practice of maintenance therapy, continued even during pregnancy. Occasionally, pregnancy will induce an improvement in disease activity or clinical remission, usually in the first trimester [29]. In addition, some patients will have symptomatic disease only when pregnant, with quiescence between pregnancies and exacerbations during subsequent pregnancies. A single study suggested that psychological factors play a role in disease course [30]. Investigators found that 38% of unwanted pregnancies were associated with an increased activity of the disease compared with only 12% among female patients with planned pregnancies. The clinical course or outcome of previous pregnancies cannot predict either the clinical course of IBD or the outcome of pregnancy. The activity of IBD at conception remains the primary predictor of the course of pregnancy. One study has suggested that the course of the disease, either UC or CD, correlates with HLA maternal-fetal disparity [31]. Fifty mother-child pairs were studied for maternal disease course in relation to the amount of shared HLA alleles. Those pregnancies in which the mother had disparity at both the DR and DQ alleles tend to see an improvement in disease scores over time compared to those female patients who shared more alleles with the fetus. Subsequent pregnancies in the same female patients showed the same effect. There are data suggesting that a history of child bearing changes the natural history of Crohn disease [32]. Female patients having been pregnant had fewer resections or longer intervals between resections as compared to female patients who had not had children but otherwise similar
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disease. One theory proposed is the inhibition of macrophage function by relaxin. Relaxin is a hormone produced exclusively during pregnancy which may result in less fibrosis and stricture formation by this inhibition of macrophages. This study was small and has yet to be replicated.
Management of IBD During Pregnancy Clinical Assessment The main priority is to establish and maintain remission before the patient conceives. One of the problems in Crohn disease is the accurate definition of disease activity. In CD, a patient may feel fine even though she has an elevated C-reactive protein, an abnormal colonoscopy and/or x-ray. In addition, many pregnant female patients will have intermittent abdominal discomfort related to changes in bowel habits or gastroesophageal reflux that commonly occur during pregnancy. In addition, abdominal pain in the pregnant IBD patient could be related to cholelithiasis, pancreatitis, toxemia or a problem with the pregnancy itself. Clinically, these processes can be distinguished from a flare of IBD by a careful history, examination and laboratory evaluation. It is important to remember that during pregnancy hemoglobin and albumin levels decrease by 1 g/dl, sedimentation rate increased two- to three-fold, and there is a 1.5-fold rise in serum alkaline phosphatase. Because of these normal physiologic changes, disease assessment during pregnancy should rely more on clinical symptoms than laboratory parameters. It is also important to keep in mind that a growing uterus changes normal anatomy, with the terminal ileum and appendix higher in the right upper quadrant. In terms of radiographic testing, ultrasound exams are safe, as is magnetic resonance imaging [33] but are rarely used for clinical assessment. Clearly, it is best to avoid exposure of the fetus to radiation from abdominal x-rays, especially early in the pregnancy. However, the absolute risk to the fetus of abdominal radiography is minimal, and clinical necessity should guide the decision making [34]. There is no evidence that if indicated, that a sigmoidoscopy will induce premature labor [35, 36]. Most patients can be evaluated with sigmoidoscopy without full colonoscopy. However, if full colonoscopy is necessary if diagnosis needs to be established or extent and severity of disease specifically needs to be ascertained, close fetal monitoring may be warranted.
Medical Therapies The key principle to management is to remember that the greatest risk to pregnancy is active disease, not active therapy [37]. Since there are limited definitive data available on the safety of IBD medications in pregnancy, the focus therefore should be on establishing remission before conception and maintaining remission during pregnancy. The two fundamental issues regarding medical therapy in the pregnant IBD patient are regarding the outcome of the pregnancy whether the mother is taking medications for her IBD compared to those who are not, and second, are the medications used to treat the pregnant patient safe and effective. Early studies suggested that the rates of prematurity, spontaneous abortions, and fetal malformations among mothers with IBD undergoing medical treatment were increased [23, 38]. However, most investigators have shown that medical therapy, when analyzed as an independent variable, has no effect on pregnancy outcome [25, 38, 39]. As previously discussed, it is evident that disease activity, not medication, most strongly effects pregnancy outcome. Those patients who have been reported to have adverse birth outcomes tend to occur more often in the setting of active disease. Table 45.1 outlines the relative safety profiles of those medications used in IBD.
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Table 45.1. Safety of IBD Medications During Pregnancy. Safe to Use When Indicated Oral, topical mesalamine Sulfasalazine Corticosteroids Total parenteral nutrition Loperamide
Limited Data
Contraindicated
Olsalazine Azathioprine 6-MP Cyclosporine Metronidazole* Ciprofloxacin* Infliximab
Methotrexate Thalidomide Diphenoxylate
*probably safe after first trimester
Safe to use in pregnancy Sulfasalazine Oral mesalamine Topical mesalamine Corticosteroids
When maternal health mandates
Limited data to support use
6-MP Azathioprine Metronidazole Ciprofloxacin
Cyclosporine
Contraindicated in pregnancy Methotrexate Thalidomide
Anti-diarrheals Symptomatic therapies used in IBD include the anti-diarrheals and anti-spasmodics, as well as pain medications. Loperamide use has not been associated with an increased rate of first trimester fetal malformations, spontaneous abortion, low birth weight or premature delivery [40] and is considered safe. One has to keep in mind however that increased stool frequency may be a sign of increased activity and loperamide use should be monitored. Diphenoxylate with atropine is teratogenic in animals, and fetal malformations have been observed in infants exposed during the first trimester [41]. Anti-spasmodics and anticholinergics have been associated with non-life threatening fetal malformations and are best avoided during pregnancy [41]. Codeine has been used for many years during pregnancy without reports of associated fetal abnormalities. Drug dependence and withdrawal in the newborn can occur, but fortunately is rare. Aminosalicylates Aminosalicylates are first-line medications for mild to moderate IBD. While the exact mechanism is unknown, it is thought that the effects result from topical action on the GI mucosa rather than through systemic action [42, 43]. Sulfasalazine has been used for over 50 years in the treatment of IBD. Sulfasalazine is the combination of sulfapyridine and 5-ASA, which is eventually cleaved by enteric bacteria, allowing the main anti-inflammatory effects to take place in the colon. The majority of the side effects of sulfasalazine are due to sulfapyridine causing such effects as bone marrow suppression, megaloblastic anemia, hemoslytic anemia, sperm abnormalities, pancreatitis and nephrotoxicity [43]. Sulfasalazine crosses the placenta and can displace unconjugated bilirubin from binding sites on plasma albumin with the theoretical risk of causing kernicterus in the fetus [44]. Both sulfasalazine and its metabolite sulfapyridine cross the placenta with fetal serum levels equivalent to maternal levels [45]. Multiple studies have shown that despite this phenomenon, there appears to be no increased incidence of abnormal birth outcomes [25, 46, 47, 48]. One study of 1,400 patients did report that the rate of congenital malformations among the offspring
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of male IBD patients taking sulfasalazine was greater compared with the offspring of untreated IBD patients, the rate of congenital abnormalities was nearly identical to that in the normal population [46]. Sulfasalazine has been shown to inhibit folate acid metabolism, which can cause neural tube defects in the fetus [49, 50]. While the risk of fetal abnormalities has not been shown to increase with sulfasalazine and its derivatives, pregnant female patients taking sulfasalazine should still supplement their diet with 2 mg of folate daily. Mesalamine is a sulfa-free aminosalicylate that is also effective in mild-moderate IBD and is widely used for acute and long-term management of IBD [51]. 5-Aminosalicylic acid (5-ASA) and its metabolite acetyl-5-aminosalicyclic acid are found in both maternal and fetal plasma in female patients taking mesalamine. The use of this therapy is considered first-line for IBD, and its safety during pregnancy has been demonstrated in a number of trials [52, 53, 54, 55]. In a post-marketing study of controlled-release mesalamine capsules, female patients treated with 1.5–4 g/day in 76 pregnancies in 55 female patients. Three fetal malformations occurred, not an increased number over the general population. One of the only prospective controlled data available on pregnancy and therapy comes from Diav-Citrin and colleagues. They conducted a prospective controlled cohort study of 165 female patients exposed to mesalamine during pregnancy, 146 of them having exposure in the first trimester. Pregnancy outcomes were matched with a control group. The mean daily dose was 2 g, with 20% of female patients taking between 2.4–3.2 g/day and another 20% taking greater than 3.2 g/day. There was no increase in major malformations for the mesalamine treated female patients compared with controls. There was a statistically significant increase in pre-term deliveries (13% vs. 5%) and a decrease in mean birth weight (3.2 kg vs. 3.4 kg). Female patients with active IBD during pregnancy had significantly lower birth weight compared with female patients with inactive disease. No significant differences in the rates of live births, miscarriages, terminations, or fetal distress were detected between the two groups. There is a single case report of renal interstitial damage in a child born to a woman taking mesalamine [53]. This finding has not been confirmed in any other studies. A study looking at topical use of 5-ASA agents during pregnancy failed to find any increase in adverse birth outcomes related to its use during pregnancy [52]. Norgard et al. published a population-based longitudinal study examining all prescriptions for oral 5-ASAs in the 3 months prior to and during pregnancy (N = 148) versus all pregnant female patients without such a prescription history, (N = 19,418), which included female patients with IBD who remained untreated [54]. The odds ratios for malformations, stillbirth, preterm birth, and low birth weight in female patients who received prescriptions for all 5-ASA drugs were 1.9 (95% confidence interval 0.7–5.4), 6.4 (1.7–24.9), 1.9 (0.9–3.9), and 1.2 (0.4–3.3), respectively, with the increased risk of stillbirth and preterm birth found only in patients with ulcerative colitis. The investigators also found it difficult to determine whether outcomes were related to disease activity versus drug effect, but in general found there to be no significant risk for fetal malformations with 5-ASA use Olsalazine, another 5 ASA compound that has recently fallen out of favor, comes as an FDA class C rating based on the paucity of prospective safety data with this agent. Antibiotics Currently, the most frequently used antibiotics in IBD include metronidazole and ciprofloxacin. Animal studies have not shown any evidence of teratogenicity or increased fetal loss with metronidazole. Short courses of metronidazole during the first trimester of pregnancy for Trichomonas vaginalis has been shown to be well-tolerated and safe [55, 56]. The most recent study of 228 female patients exposed to metronidazole during pregnancy followed female patients prospectively through their pregnancy [55]. Eighty-six percent of female patients were exposed during the first trimester. The malformation rate was 1.6% in the treatment group, and 1.4% in the control group. Female patients with IBD require the use of metronidazole for longer periods of time, and
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there are limited data regarding prolonged use of this medication. Typically, it is recommended that metronidazole be used only in the second and third trimester. In animal studies, no teratogenicity has been seen with ciprofloxacin, although musculoskeletal abnormalities have been identified in immature animals [57]. Moskovitz et al found that in 27 patients who were receiving 1 gram/day, even in the first trimester, its use appeared to be safe, while ciprofloxacin at doses of 1 gram/ day also appeared safe (18 patients) [58]. Two studies investigated the effects of fluoroquinolones in the first trimester and did not show an increased risk of congenital malformations, prematurity or low birth weight [59, 60]. While these data are comforting, this information applies to the non-IBD population, where antibiotics are used short-term. While these agents are more commonly used for longer durations in IBD, the use of these two antibiotics during pregnancy should currently be restricted to short-term courses. Corticosteroids In moderate to severe disease, corticosteroids are the mainstay of treatment. As shown in studies for rheumatological conditions as well as for IBD, corticosteroids during pregnancy have largely been regarded as safe [38, 61]. Corticosteroids cross the placental barrier but the fetal: maternal serum concentration of the steroids varies between different corticosteroid preparations. Prednisolone and prednisone are more efficiently metabolized by the placenta than dexamethasone or betamethasone and fetal levels of this steroid are approximately eight to ten-fold lower than that of the maternal circulation [62]. While steroids are known to be rapidly metabolized to inactive metabolites in the fetus, there remains some concern for adrenal suppression in newborns born to mothers taking corticosteroids [58]. Since corticosteroids are conjugated more rapidly to biologically less active sulfates in the fetus than the adult, a suppressive fetal blood concentration is not often reached with therapeutic doses used during pregnancy [28]. Among female patients with IBD, corticosteroids have not been found to be harmful to the fetus [61, 63]. Mogadam et al. also studied the effects of steroid use in 185 out of 531 pregnancies in female patients with IBD and did not find a statistically significant increased incidence of prematurity, spontaneous abortions, still-birth or development defects in the ulcerative colitis subgroup (4.6% in the treated group vs. 2.2% in the untreated group; P>0.10) [28]. In the Crohn disease subgroup, patients did significantly worse in the treated group compared to the untreated group (13.5% vs. 1.9%, P<0.1). Patients with CD may have more severe disease and require more medical intervention to control the activity of the disease and it is possible that the severity of the illness in Crohn disease itself may have caused these patients to not fare as well as the ulcerative colitis patients. More prospective studies are necessary to look into these differences.
Immunomodulators Clearly as more and more patients with IBD are treated with immunosuppressants there is a growing need for information on their effects on the pregnant patient and growing fetus. There is a large body of literature on the use of these agents among pregnant transplant recipients and those patients with autoimmune diseases [64, 65]. It is generally believed by the most experienced IBD clinicians that immunosuppressives such as 6-MP, azathioprine and even cyclosporine can be used safely during pregnancy if the mother’s health mandates therapy, based on the evidence from these other conditions. Thiopurines are used for steroid-sparing and steroid-dependent inflammatory bowel disease. Azathioprine (AZA) is a prodrug of 6-mercaptopurine (6-MP) and does cross the placental barrier but the immunomodulatory effects of azathioprine do not affect the fetus due to the fetus’ lack of inosinate pyrophosphorylase, which converts azathioprine into the active metabolites of 6-MP and
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S-methyl-4-nitro-5-thioimidazole [66, 67]. Placental concentrations of azathioprine range from 64–93% of the maternal blood level, while 6-MP and AZA levels in the fetal blood run about 1–5% and 1.2%,respectively [68]. Despite this, based on animal studies showing an increased risk of teratogenicity at doses significantly higher than what is used in clinical practice, thiopurines have been considered category D medications [51, 69]. Several human studies have suggested that AZA and 6-MP may, in fact, be safe during pregnancy. Present et al first reported on the outcomes of 13 pregnancies born to female patients with IBD who had been taking 6-MP who had been part of a large retrospective cohort [70]. The study is limited since only 3 female patients were taking 6-MP at the time of conception, but none of the children appeared to have congenital abnormalities. Literature from the renal transpant population suggests that the use of azathioprine in pregnancy does not increase the risk of fetal abnormalities, with few reports of premature birth, fetal intrauterine growth retardation, lower birth weight, lymphopenia or pancytopenia [71, 72]. A large Danish cohort study used a population-based prescription registry to examine the risk of congential malformation and perinatal mortality among patients taking azathioprine or mercaptopurine during pregnancy [73]. Nine pregnancies exposed to 6-MP in the first trimester and 10 pregnancies exposed throughout the pregnancy were compared to nineteen thousand four hundred eighteen pregnancies without 6-MP exposure. Fifty-five percent of the exposed female patients had a history of IBD and 45% had other autoimmune diseases. The adjusted odds ratios for congenital malformations, perinatal mortality and preterm birth, and low birth weight were 6.7% (95% CI 1.4–32.4), 20.0 (95% CI, 2.5–161.4), 6.6% (95% CI, 1.7–25.9) and 3.8 (95% CI, 0.4–33.3) in female patients treated with 6-MP or AZA. The conclusion of the investigators was that a causal relationship between drug use and outcome could not be established. Francella et al., in a retrospective cohort study, investigated the possible toxicity of 6-MP from a review of records of 485 patients who had received the drug [74]. Of the 462 female patients who were contacted, 155 had conceived at least 1 pregnancy after developing IBD. Pregnancies were analyzed based on whether the patients had taken 6-MP before or at the time of conception compared with those IBD patients who had their pregnancies before taking 6-MP. There was no statistically significant increase in spontaneous abortion rates or major congenital malformations among patients taking 6-MP compared to control subjects [RR 0.85 (95% CI, 0.47–1.55), p = 0.59]. The authors concluded that the use of 6-MP or AZA and its beneficial effect on maternal health outweighed any risk to the fetus and that it was not unreasonable to continue its use throughout pregnancy. In IBD, methotrexate is used in the management of steroid-dependent or steroid-resistant Crohn disease as an alternative to azathioprine and 6-MP. Methotrexate is a known abortifacent, showing increased risk of spontaneous abortions in various studies, currently used therapeutically at high doses in tubal pregnancies [75]. As a folic acid antagonist, it is a mutagenic agent known to cause neural tube defects and palatal defects. Therefore, methotrexate is a Category X medication. Patients who are started on methotrexate should be strongly advised to use reliable contraception. If termination of a pregnancy is not possible, high doses of folic acid therapy are recommended to prevent CNS abnormalities, including anencephaly, meningomyelocele and hydrocephaly [51]. The optimum management includes careful counseling and effective contraception prior to any initiation with MTX therapy. Biologic Agents Infliximab is the first biologic agent FDA-approved for the treatment of inflammatory and fistulizing Crohn disease. [47, 76] The safety of infliximab prior to and during pregnancy has not yet been completely defined. Infliximab is an anti-tumor necrosing factor antibody that is used for the treatment of inflammatory and fistulizing Crohn disease. The safety literature on infliximab use is still limited but
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one study by Katz et al. suggests that infliximab exposure for CD or RA during pregnancy does not lead to a statistically significant increase in adverse outcomes compared to that of the general population, using the National Center for Health Statistics database between 1976–1996 for comparison [77]. Of 96 female patients who were studied, live births, (67%, 95% CI: 56.3–76.0 vs. 67%) miscarriages, (17%, 95% CI: 8.2–23.2 vs. 15%) and therapeutic terminations (16%, 95% CI: 11.5–28.0 vs. 19%) were not statistically different from that of the general population. In Katz’ review, 8 of 14 miscarriages in female patients who were exposed to infliximab occurred at or before 10 weeks. It is thought that these miscarriages early in pregnancy were related more to disease activity than infliximab use. Maternal IgG is transported across the placenta as early as the late first trimester, but efficiency of transport is poor so that total fetal IgG levels are low until the late second or early third trimester, suggesting that it is not the infliximab exposure that would be contributing to this early miscarriage rate observation. While this study suggests safety of infliximab use in pregnancy, this study relied largely on self-reported data, which is subject to inherent biases. Furthermore, the study did not have a control group and relied on other studies for comparison. There is one case report from Italy which reports a patient continued on infliximab throughout pregnancy tolerated the treatment and had a fetal outcome without adverse events [78]. Larger controlled prospective analyses will be needed to further validate the safety of this drug. Other Immunomodulating Agents Cyclosporine is used only for refractory ulcerative colitis, due to its known significant side effect profile. Cyclosporine’s inhibition of interleukin-2 and its effect on cell proliferation and cell turnover makes its use in pregnancy concerning. While cyclosporine is known to cross the placenta, the concentration of the drug in the newborn falls rapidly within days after birth [79]. At a dose of 10 mg/kg/ day, it has not been shown to cause any fetal toxicity in rats [80]. In the renal transplant literature, cyclosporine has been associated with premature births and growth retardation, but overall, cyclosporine has not been associated with poor pregnancy outcomes or severe adverse effects to the fetus [51]. One case report in 1995 describes the successful use of cyclosporine to avoid the risk of colectomy in a pregnant patient in her 29th week of pregnancy. This woman was effectively treated with cyclosporine resulting in the delivery of a healthy baby boy at 34 weeks [81]. A retrospective review of pregnant female patients hospitalized with severe ulcerative colitis found that female patients treated with cyclosporine in addition to corticosteroids had no more of an increased risk for adverse birth outcomes than those female patients treated with steroids alone [82]. While these are encouraging, more long-term studies are required to investigate the effects of cyclosporine in the pregnant IBD population. Recently, a variety of other therapies have been used to treat refractory IBD. Thalidomide has been found to have some efficacy in the treatment of Crohn disease [83, 84]. Thalidomide however, is a potent teratogenetic and should not be given to female patients of child-bearing age except those who have undergone careful counseling and strict adherence to contraceptive use. Its availability is restricted and only available to those female patients with negative serum pregnancy tests done on a monthly basis. Some of the newer immunomodulators used in refractory Crohn disease include etanercept[85], tacrolimus[86], and mycophenolate mofetil [87]. Again, the safety data during pregnancy comes from the transplant populations. The experience with tacrolimus has been overall favorable, with no evident increase in adverse outcomes based on case reports and National Transplant Registry data [88, 89, 90]. National Registry data followed 100 female patients status post solid organ transplant and reported 4 neonatal malformations in 68 live births. The use of mycophenolate in CD has been recent, and to date there are no data regarding any pregnancies occurring with its use. Etanercept, while recently shown in a controlled trial to
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lack efficacy in Crohn disease, is still used for individual patients. Sills reported a single woman with rheumatoid arthritis who successfully carried to term a healthy single pregnancy while on etanercept therapy [91]. Nutritional Therapies Given the poor nutrition that often accompanies IBD, it stands to reason that both total parenteral (TPN) and enteral supplementation have been used to support the pregnant IBD patient [92, 93, 94]. Despite the theoretical concern about fat embolization to the placenta, pregnant patients receiving TPN with intravenous lipids have done well. The infants born to those mothers have been healthy and examination of the placenta has failed to show any signs of fat emboli. Elemental diets have also been used safely during pregnancy both as primary therapy for active CD as well as a source of supplemental nutrition. Because the nutritional needs of the pregnant IBD patient are quite different from the non-pregnant IBD patient, close monitoring along with a nutritional expert is necessary.
Breastfeeding The advantages of breastfeeding in pregnancy are well known but the effects of IBD medications on breastfeeding still remain unclear. The breastfeeding initiation rates among adolescent mothers are approximately 35–40% [95] and are significantly less than the national rate, which is 60%. In a study by Kane et al, only 44% (54/122) of female patients with IBD had breastfed their infants, the majority of whom had UC [96]. Medications most often discontinued included mesalamine, 6-MP, and azathioprine. No patients were taking infliximab during their pregnancy in this study. Of the 54 female patients who breastfed, 23 female patients (43%) experienced a postpartum flare. The unadjusted OR for disease activity in breastfeeding female patients was 2.2 in (95% CI 1.2–3.9; p = 0.004). When stratified by disease type, the unadjusted OR was 0.89 for UC (95% CI 0.29–2.7; p < 0.005) and 3.8 for CD (95% CI 1.9-7.4; P < 0.005). This increased disease activity in female patients with Crohn disease versus ulcerative colitis could also be a function of decreased medication use in this population. More studies are needed to investigate the effects of drug metabolism on breast milk to potentially allay the fears of nursing female patients with IBD. Table 45.2 summarizes the safety data regarding medications and their use during breastfeeding. The medications known to be safe for breastfeeding (i.e. acceptable milk:serum ratios) include sulfasalazine, the mesalamine preparations (Asacol® , Pentasa® , Rowasa® ) and steroids. Mothers planning on nursing should discontinue the use of cyclosporine, metronidazole, ciprofloxacin and methotrexate. In addition, the anti-diarrheals loperamide and diphenoxylate should be discontinued. Salazopyrine and other forms of 5-ASA are excreted into the breast milk with milk concentrations that are about 40–50% of the maternal serum levels with outcomes study suggesting its safety during breastfeeding [51]. There is one case report of diarrhea in a nursing infant of a mother who used mesalamine suppositories 6 wks after childbirth with four additional challenges of breastfeeding following suppository administration leading to similar results [97]. In a case series, low concentrations of mesalamine and its metabolite were found in the breast milk of two female patients taking mesalamine at 1gram orally three times daily. Milk to plasma ratios at day 7 and 11 postpartum were 0.17 and 0.09, respectively. The mesalamine metabolite ratios were 16.5 and 6.8, respectively. The estimated intake of mesalamine and metabolites per day by the infant was 0.065 mg (0.015 mg/kg) and 10 mg (2.3 mg/kg), respectively, which are considered to be negligible amounts [98].
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Table 45.2. Safety of IBD Medications During Breastfeeding. Safe to Use When Indicated Oral Mesalamine Topical Mesalamine Sulfasalazine Corticosteroids
Safe to use while breastfeeding Sulfasalazine Mesalamine Corticosteroids (up to 20 mg/day)
Very Limited Data Olsalazine Azathioprine 6-MP Infliximab
Limited data, currently not recommended Cyclosporine Infliximab 6-MP Azathioprine
Contraindicated Methotrexate Thalidomide Cyclosporine Ciprofloxacin Metronidazole Loperamide Diphenoxylate Contraindicated Methotrexate Metronidazole Ciprofloxacin
Data pertaining to the antimetabolites, AZA and 6-MP, are sparse. Low concentrations of AZA have been found in breast milk according to Dubinsky but due to the general lack of data, it is not recommended to breast feed while on these medication due to unknown immunosuppressive effects and long-term potential for cancer [99]. Cyclosporine, has also been relatively contraindicated due to theoretical immunosuppression in the infant. However, a study by Nyberg et al. of transplant patients showed that breast fed infants of mothers on cyclosporine received <300 mcg/ day of cyclosporine.100 Blood cyclosporine levels ranged from 55 to 130 ng/ml in mothers (12-hr trough), with a range of 50 to 227 ng/ml in breast milk, and were below the detection limit of 30 ng/ml in all infants. A case report of a 35 year old woman who exclusively breast-fed her infant during the first 10.5 months of life while she was being treated with cyclosporine revealed mean breast milk/maternal blood level ratio of 84%, with undetectable levels in the infant.101 Approximately 5–25% of the maternal serum concentration of corticosteroids reaches breast milk and the amount received by the infant is considered minimal [51]. The commonly used corticosteroids, prednisone and prednisolone, result in low breast milk concentrations with doses of <20 mg of corticosteroids deemed to be safe to use during nursing.102,103 Some suggest that breastfeeding is safer if delayed for 4 hours after ingestion of steroids.51,104 Other medications, such as metronidazole, ciprofloxacin and methotrexate should be discontinued in nursing mothers given their high concentrations in breast milk.
Mode of Delivery The mode of delivery often becomes an obstetrical decision. Adolescents have lower Cesarean section rates than adult women [105]. The indications for Cesarean section for obstetrical reasons are not different in female patients with IBD. The presence of UC does not have a significant impact on the method of delivery, nor is it an indication for a section per se. However, active perianal disease in Crohn disease may worsen after a vaginal delivery. One retrospective a study of female patients with CD found that 18% of those without previous perianal disease developed such disease after delivery, usually involving an extensive episiotomy [106]. General guidelines include a planned C-section for any woman with known perianal or rectal Crohn disease, or if the birth appears to be more complicated than initially presumed.
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Surgery and Pregnancy In the pregnant IBD patient, elective surgical procedures are uncommon, but those that are performed in the second trimester do not appear to carry a significant increase in perinatal morality in female patients without IBD [107]. The indications for surgery during pregnancy are identical to that of non-pregnant patients. These include obstruction, perforation, abscess and hemorrhage. The approach of continuing medical therapy may only further increase the risk to both mother and fetus [108]. In the ill pregnant IBD patient, the greater risk to the child is continued maternal illness rather than surgical intervention [109]. In general, doing what is best for the mother results in what is ultimately best for the fetus. Numerous case reports but only one small case series make up the literature documenting successful surgical intervention for treatment of severe colitis in the pregnant patient [68, 108, 110, 111, 112]. Anderson reported on the outcomes of four pregnant female patients who experience disease activity between the 28th and 37th week of gestation [110]. Three patients were treated medically and allowed to progress to labor. Two babies were stillborn and one child was healthy. All three mothers required colectomy in the weeks after delivery. The fourth patient relapsed at 28 weeks’ gestation, had surgery for toxic megacolon at 31 weeks, and deliver at 34 weeks. In patients with Crohn disease, Hill and colleagues described three pregnant patients with intraperitoneal sepsis, requiring surgery [113]. All three female patients recovered and delivered healthy infants. Most reports suggest proceeding to surgery when indicated. A variety of procedures have been performed, including protocolectomy, subtotal colectomy with ileostomy, hemicolectomy or segmental resection, and combined subtotal colectomy and cesarean section. Two general points should be made: 1) primary anastomosis carries a greater risk of postoperative complication rate, and thus a temporary ileostomy is generally preferred, and 2) if the fetus is significantly mature, then cesarean section along with bowel resection is indicated. In female patients who have a total proctocolectomy with ileal pouch-anal anastomosis (IPAA) prior to pregnancy, there is controversy regarding post-operative fertility and sexual function. One study suggests that these are maintained [114] but most recent studies [115] suggest a significant decrease in fertility following this type of surgery. There has been debate whether female patients who have had IPAA should be allowed to deliver vaginally, or whether cesarean section should be planned. One study suggests normal delivery is possible [114]. In another study of 43 pregnancies in female patients status post IPAA, pregnancy was well tolerated, with a complication rate lower than in female patients who had had an ileostomy [116]. Although more cesarean sections were performed in female patients with IPAA, the explanation was likely due to the uncertainty about the pouch function. An extended follow up of female patients with an IPAA who delivered vaginally showed no adverse long-term effects on pouch function. During actual pregnancy, however, female patients with IPAA did note an increase in stool frequency, incontinence, and pad usage, with symptoms resolving after delivery. The authors suggest that the type of delivery in patients with an IPAA be dictated by obstetrical considerations. Other surgeons feel that the risk to permanent pouch failure is higher with a vaginal delivery, and recommend any patient with surgery for UC undergo cesarean section. Pregnancy has not been shown to complicate stoma function. Female patients may experience some prolapse due to abdominal pressure, but no increased risk to the pregnancy is encountered.
Transition of Care The time to transition care from a pediatric gastroenterologist to an adult gastroenterologist should be an individualized decision. Factors such as autonomy level, activity of disease, transitioning in other phases of life all should be taken into account. When the adolescent patient becomes
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pregnant may be a time to consider transitioning care to the adult provider depending on the experience and comfort level in dealing with pregnancy in a patient with IBD of the pediatric and adult gastroenterologists [117].
Summary Points • Adolescents with IBD are at risk of pregnancy • Fertility is affected in post-surgical UC, and in active CD • There is no increase in adverse outcomes with quiescent IBD • Active disease at conception increases the risk for adverse outcomes • The majority of medications for IBD are safe in pregnancy and breastfeeding—active disease is more deleterious than active therapy References 1. Gasche C, Scholmerich J, Brynskov J, et al. A simple classification of Crohn disease: Report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000; 6:8–15. 2. Silverstein MD, Lashner BA, Hanauer SB, Evans AA, Kirsner JB. Cigarette smoking in Crohn disease. Am J Gastroenterol 1989; 84:31–3. 3. Suris JC, Resnick MD, Cassuto N, Blum RW. Sexual behavior of adolescents with chronic disease and disability. J Adolesc Health. 1996;19(2):153–6. 4. Newacheck P, Halfon N. Prevalence and impact of disabling chronic conditions in childhood. Am J Public Health.1998; 88:610–617 5. Gittes EB, Strickland JL. Contraceptive Choices for Chronically Ill Adolescents. Adolesc Med. 2005; 16: 635–644. 6. Banks B, Korelitz BI, Zetzel L. The course of non-specific ulcerative colitis: A review of twenty years of experience and late results. Gastroenterol 1957; 32:983–1012. 7. Willoughby CP, Truelove SC. Ulcerative colitis and pregnancy. Gut 1980; 21:469–74. 8. Boyko EJ, Theis MK, Vaughan TL, Nicol-Blades B. Increased risk of inflammatory bowel disease associated with oral contraceptive use. Am J Epidemiol 1994; 140:268–78. 9. Lashner BA, Kane SV, Hanauer SB. Lack of association between oral contraceptive use and Crohn disease: a community-based matched case-control study. Gastroenterol 1989; 97:1442–7. 10. Lashner BA, Kane SV, Hanauer SB. Lack of association between oral contraceptive use and ulcerative colitis. Gastroenterol 1990; 99:1032–6. 11. Alic M. Epidemiology supports oral contraceptives as a risk factor in Crohn disease [letter; comment]. Gut 2000; 46:140. 12. Cottone M, Camma, C, Orlando, A, et al. Oral contraceptive and recurrence in crohn disease. Gastroenterol 1999; 116:A693. 13. Coley RL, Chase-Lansdale PL. Adolescent pregnancy and parenthood: Recent evidence and future direction. Am Psychol 1998; 53: 152–166. 14. Woolfson K, Cohen Z, McLeod RS. Crohn disease and pregnancy. Dis Colon Rectum 1990; 33:869–73. 15. Mayberry JF, Weterman IT. European survey of fertility and pregnancy in women with Crohn disease: a case control study by European collaborative group. Gut 1986; 27:821–5. 16. Fonager K, Sorensen HT, Olsen J, Dahlerup JF, Rasmussen SN. Pregnancy outcome for women with Crohn disease: a follow-up study based on linkage between national registries. Am J Gastroenterol 1998; 93:2426–30. 17. Birnie GG, McLeod TI, Watkinson G. Incidence of sulphasalazine-induced male infertility. Gut 1981; 22:452–5. 18. Burnell D, Mayberry J, Calcraft BJ, Morris JS, Rhodes J. Male fertility in Crohn disease. Postgrad Med J 1986; 62:269–72. 19. Dejaco C, Mittemaier C, Reinisch W, et al. Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterol 2001; 121:1048–53.
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73. Norgard B, Pedersen L, Sorensen HT, et al. Azathioprine, mercaptopurine and birth outcome: a population-based cohort study. Aliment Pharmacol Ther. 2003; 17:827–834. 74. Francella A, Dyan A, Present DH, et al. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology. 2003; 124:9–17. 75. Goldenberg M, Bider D, Oelsner G, et al. Methotrexate therapy of tubal pregnancy. Hum Reprod. 1993 ; 8:660–666. 76. Srinivasan R. Infliximab treatment and pregnancy outcome in active Crohn disease. Am J Gastroenterol 2001; 96:2274–5. 77. Katz JA, Antoni C, Lichenstein GR, et al. Outcome of pregnancy in female patients receiving infliximab for the treatment of Crohn disease and rheumatoid arthritis. Am J Gastroenterol. 2004; 99:2385–2392. 78. Tursi A. Effect of intentional infliximab use throughout pregnancy in inducing and maintaining remission in Crohn disease. Dig Liver Dis. 2006; 38:439–40. 79. Kane S. Inflammatory bowel disease in pregnancy. Gastroenterol Clin North Am. 2003; 32:323–340. 80. Ramsey-Goldman R, Schilling E. Immunosuppressive drug use during pregnancy. Rheum Dis Clin North Am. 1997; 23:149–167. 81. Bertschinger P, Himmelmann A, Follath F, et al. Cyclosporine treatment of severe ulcerative colitis during pregnancy. Am J Gastroenterol. 1995; 90:330. 82. Kornbluth A and Reddy D. Management and outcome of severe colitis in pregnancy. Am J Gastroenterol. 2002; 97:P705. 83. Ehrenpreis ED, Kane SV, Cohen LB, Cohen RD, Hanauer SB. Thalidomide therapy for patients with refractory Crohn disease: an open-label trial. Gastroenterol 1999; 117:1271–7. 84. Vasiliauskas EA, Kam LY, Abreu-Martin MT, et al. An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn disease. Gastroenterology 1999; 117:1278–87. 85. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn disease: A randomized, doubleblind placebo-controlled trial. Gastroenterol 2001; 121:1088–94. 86. Sandborn WJ. Preliminary report on the use of oral tacrolimus (FK506) in the treatment of compicated proximal small bowel and fistulizing Crohn disease. Am J Gastroenterol 1997; 92:876–9. 87. Neurath MF, Wanitschke R, Peters M. Randomized trial of mycophenolate versus azathioprine for treatment of chronic active Crohn disease. Gut 1999. 44:625–28. 88. Kainz A, Harabacz I, Cowlrick IS, Gadgil S, Hagiwara D. Analysis of 100 pregnancy outcomes in female patients treated systemically with tacrolimus. Transpl Int 2000; 13:S299–300. 89. Kozlowski RD, Steinbrunner JV, MacKenzie AH, Clough JD, Wilke WS, Segal AM. Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 1990; 88:589–92. 90. Pergola PE, Kancharla A, Riley DJ. Kidney transplantation during the first trimester of pregnancy: immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. Transplantation 2001; 71:994–7. 91. Sills ES, Perloe M, Tucker MJ, Kaplan CR, Palermo GD. Successful ovulation induction, conception, and normal delivery after chronic therapy with etanercept: a recombinant fusion anti-cytokine treatment for rheumatoid arthritis. Am J Reprod Immunol 2001; 46:366–8. 92. Jacobson L, Clapp, DH. Total parenteral nutrition in pregnancy complicated by Crohn disease. JPEN 1987; 11:93–96. 93. Nugent F, Rajala, M, O’Shea, RA, et al. Total parenteral nutrition in pregnancy: conception to delivery. JPEN 1987; 11:424–27. 94. Subhani JM, Hamiliton MI. Review article: The management of inflammatory bowel disease during pregnancy. Aliment Pharmacol Ther 1998; 12:1039–53. 95. Park YK, Meier ER, Song WO.Characteristics of teenage mothers and predictors of breastfeeding initiation in the Michigan WIC Program in 1995. Women, Infants, and Children. J Hum Lact. 2003; 19:50–6. 96. Juhasz ES, Fozard B, Dozois RR, Ilstrup DM, Nelson H. Ileal pouch-anal anastomosis function following childbirth. An extended evaluation. Dis Colon Rectum 1995; 38:159–65. 97. Nelis GF. Diarrhoea due to 5-aminosalicyclic acid in breast milk. Lancet 1989;1:383. 98. Klotz U, Harings-Kaim A. Negligible excretion of 5-aminosalicylic acid in breast milk. Lancet. 1993; 342:618–619.
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99. Dubinsky MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol. 2004; 2:731–743. 100. Nyberg G, Haljamae U, Kjemeller I, et al. Breast-feeding during treatment with cyclosporine. Transplantation. 1998; 65:253–255. 101. Munoz-Flores-Thiagarajan KD, Easterling T, Bond EF, et al. Breast-feeding by a cyclosporine-treated mother. Obstet Gynecol. 2001; 97:816–818. 102. Beitins IZ, Bayard F, Migeon CJ, et al. The transplacental passage of prednisone and prednisolone in pregnancy near term. J Pediatr. 1972; 81:936–945. 103. Ost L, Wettrell G, Rane A, et al. Prednisolone excretion in human milk. J Pediatr. 1985; 106: 1008–1011. 104. Kane S. Breastfeeding and IBD: Safety and Management Issues. Inflamm Bowel Dis Monit. 2004; 6:50–52. 105. Gibert WM, Jandial D, Field NT, et al. Birth outcomes in teenage pregnancies. J Matern Fetal and Neonatal Med 2004; 16: 265–270. 106. Ilnyckyj A, Blanchard JF,Rawsthorne P, Bernstein CN. Perianal Crohn Disease and pregnancy: Role of the mode of delivery. Am J Gastroenterol 1999; 94:3274–78. 107. Levine W, Diamond B. Surgical procedures during pregnancy. Am J Obstet Gynecol 1961; 81: 1046–52. 108. Kelly M, Hunt TM, Wicks ACB, et al. Fulminant ulcerative colitis and parturition: a need to alter current management? Br J Obstet Gnecol 1994; 101:166–67. 109. Subhani JM, Hamiliton MI. Review article: The management of inflammatory bowel disease during pregnancy. Aliment Pharmacol Ther 1998; 12:1039–53. 110. Anderson JB, Turner GM, Williamson RC. Fulminant ulcerative colitis in late pregnancy and the puerperium. J R Soc Med 1987; 80:492–4. 111. Boulton R, Hamilton M, Lewis A, Walker P, Pounder R. Fulminant ulcerative colitis in pregnancy. Am J Gastroenterol 1994; 89:931–3. 112. Greenfield C, Pounder RE, Craft IL, Lewis AA. Severe ulcerative colitis during successful pregnancy. Postgrad Med J 1983; 59:459–61. 113. Hill J, Clark A, Scott NA. Surgical treatment of acute manifestations of Crohn disease during pregnancy. J R Soc Med 1997; 90:64–6. 114. Metcalf A, Dozois RR, Baert RW, et al. Pregnancy following ileal pouch-anal anastomosis. Dis Colon Rectum 1985; 28:859–61. 115. Olsen KO JS, Berndtsson I, Oresland T, Laurberg S. Ulcerative colitis: female fecundity before diagnosis, during disease, and after surgery compared with a population sample. Gastroenterol 2002; 122:15–19. 116. Juhasz ES, Fozard B, Dozois RR, Ilstrup DM, Nelson H. Ileal pouch-anal anastomosis function following childbirth. An extended evaluation. Dis Colon Rectum 1995; 38:159–65. 117. Baldassano R, Ferry G, Griffiths, A. Transition of the patient With Inflammatory Bowel Disease from pediatric to adult care: Recommendations of the North American society for pediatric gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2002;34: 245–248.
46 Malignant Tumors Arising in Inflammatory Bowel Disease Thomas A. Ullman
Introduction Inflammatory bowel disease (IBD) patients have an increased risk for colorectal cancer (CRC). While not always appreciated, this is true not just for patients with ulcerative colitis (UC), but also patients with Crohn disease, particularly those with Crohn colitis. While our understanding of the clinical and molecular basis for this association has improved since the first case descriptions and series were reported nearly a century ago, our means of prevention and treatment, primarily colonoscopic surveillance and prophylactic surgery, remain modest at best. Colorectal cancer still accounts for a large proportion of the premature mortality in both UC and Crohn disease (CD). This chapter will review the pathogenesis and clinical epidemiology of colorectal cancer in inflammatory bowel disease (IBD), as well as the theoretical and literature-based strategies for CRC prevention. Additionally, the available evidence on the association between Crohn ileitis and small intestinal cancer will be presented.
Pathogenesis and Molecular Basis of Cancer in IBD Drawing lessons from the molecular changes that account for colon carcinogenesis in familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), now Lynch syndrome, the genetic and molecular basis of colon carcinogenesis have become better understood in recent years. These lessons have been directly applicable to events involved in the development of sporadic colorectal neoplasia, whose pathways mirror those of the familial cancer syndromes. It is currently believed that the vast majority (80–85%) of sporadic CRC’s arise from a pathway that involves chromosomal instability resulting in abnormal segregation of chromosomes, aneuploidy, and altered expression of tumor suppressor genes (primarily APC and p53) and oncogenes (mainly k-ras) (Figure 46.1). In this pathway, loss of APC function occurs as an initiating or “gatekeeper” event for subsequent molecular alterations that culminate in the development of the adenoma. Loss of p53 gene function occurs later in the sequence, typically at the transition of the adenoma to carcinoma. The remaining 15% of sporadic CRC’s arise through a so-called mutator pathway that involves loss of function of DNA base mismatch repair (MMR)
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SPORADIC COLON CANCER Aneuploidy; Aneuploidy; MSI APC Normal mucosa
k-ras Early adenoma
DCC/18q genes Intermediate adenoma
p53
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COLITISCOLITIS-ASSOCIATED COLON CANCER Aneuploidy; Aneuploidy; MSI
Negative dysplasia
APC
k-ras
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LowLow-grade dysplasia
HighHigh-grade dysplasia
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Figure 46.1. Timing in molecular alterations in Sporadic Colorectal Cancer and Colitis-Associated Colorectal Cancer (From Gastroenterology, 2004) [3].
genes, mainly hMLH1 and hMSH2. In this pathway, loss of MMR gene function results in a phenotype termed microsatellite instability (MSI). Sporadic CRC’s that demonstrate MSI are often diploid (as opposed to the aneuploid state of chromosomal instability pathway-related tumors), tend to occur in the proximal colon, and frequently display rather unique histological features such as a medullary or solid growth pattern, signet ring cell histology, a plethora of tumor infiltrating lymphocytes, and an adjacent inflammatory reaction often referred to as a “Crohn-like reaction”. Another distinguishing feature of MSI-positive sporadic CRCs is the better survival of patients with those tumors compared to ones without MSI [1]. IBD-associated CRC’s share several features in common with sporadic CRC. First, they both arise from a precursor dysplastic lesion. In the case of sporadic CRC, the dysplastic precursor is a discrete, polypoid growth called an adenoma, which typically progresses to cancer by enlarging in size, assuming greater degrees of dysplasia, and often assuming an increasing proportion of villous histology. In chronic colitis, while dysplasia is often polypoid, it may be flat or only slightly raised. Regardless of its growth pattern, colitis-related dysplasia progresses through increasing levels of abnormal development in its path to CRC. Second, stage-based survival of patients with CRC is similar in the two settings. Third, the types of molecular alterations that contribute to the pathogenesis of sporadic CRC are the same ones found in colitis-associated neoplasms [2]. While the similarities, between colitis-associated neoplasia and sporadic colorectal neoplasia are notable, they differ in several important ways. First, colitis-associated cancers affect individuals at a much younger age. Second, colitis-associated neoplasia, by definition, arises in the setting of longstanding chronic inflammation, whereas sporadic neoplasms occur in the absence of an inflammatory background. Oxidative stress or other insults may lead to earlier or more frequent genetic changes to the colon, but the precise mechanisms by which chronic inflammation leads to neoplasia remain elusive. Third, dysplasias and even cancers in colitis are often multifocal, suggesting more of a precancerous “field change” of the colitic mucosa compared to the colons of patients with sporadic adenomas and colon cancer; the clinical consequence of this difference accounts for the different surgical approach: colitis-associated neoplasms are usually treated with total proctocolectomy, whereas sporadic adenomas and cancers are treated with polypectomy or segmental
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resection of affected colon. Fourth, although the two settings of colorectal neoplasia might share the several types of molecular changes, the frequency and timing with which these molecular alterations occur is different (Figure 46.1) [3]. For example, APC mutations are considered to be common and initiating events in sporadic colon carcinogenesis, whereas this molecular alteration is much less frequent and usually occurs late in the colitis-associated dysplasia-carcinoma sequence. Also, in colitis patients, p53 mutations occur early and have even been detected in mucosa that is non-dysplastic or indefinite for dysplasia [4]. Likewise, MSI has been detected in non-dysplastic mucosa from patients with ulcerative colitis, even those patients with disease of relatively short duration, but not from healthy controls or patients with other types of benign inflammatory colitis [5, 6].
Colorectal Cancer in Ulcerative Colitis: Epidemiology and Clinical Practice Epidemiology Crohn and Rosenberg first described rectal cancer complicating UC more than 80 years ago. In their manuscript, they suggested that the malignancy was a complication of the disease [7]. Three years after Crohn and Rosenberg, Bargen, at the Mayo Clinic, reported a series of 17 patients with both chronic colitis and colorectal cancer [8]. Other cases and series followed, and the crude frequency calculations from these studies served as “evidence” supporting a link between UC to CRC. With the application of modern epidemiologic methods, true incidence calculations, cumulative incidence calculations, and standardized incidence rates confirmed the association between UC and CRC. Cumulative incidence rates have largely become the standard by which the time-dependent risk of cancer develops in colitis. Similarly, standardized incidence rates decribe the estimate of the relative risk for developing colon cancer for a segment of a colitis population (such as colitis patients with universal disease) as compared to the general population. While initial series using this more accurate epidemiologic terminology came from large referral centers in which “incident” cases were referred for evaluation and management due to a suspicion for or even the actual presence of CRC, the use of more appropriate terminology was an advance over the previously used crude rates [9, 11, 13]. Due to these now obvious referral biases, however, these first “modern” studies overestimated the true risk of CRC in UC. Subsequent studies from population-based data sources used more realistic calculations for determining the incidence of CRC in UC. Without referral and other selection biases, the cancer incidence calculated in these manuscripts was substantially lower than previously reported [12–16]. These studies, however, may have underestimated the true risk of cancer in longstanding UC, as they included many patients with UC who had undergone previous colectomy in the denominator of the incidence calculations. In a meta-analysis of the risk of CRC in ulcerative colitis in which 116 studies were included, Eaden and colleagues found the overall prevalence of CRC to be 3.7% and an overall incidence rate of 3 cases per 1000 person years duration (95% confidence interval ranging from 2 to 4 cases per 1000 person years duration). The rate increased with each decade of disease, leading to a calculated incidence of 12 per 1000 person years in the third decade of colitis [17]. These data corresponded to a cumulative incidence of CRC of 2% at 10 years, 8% at 20 years, and 18% at 30 years disease duration [17]. It is worth noting, however, that referral centers accounted for 64% of the studies included in Eaden’s study; only 13 population-based reports were located by the Medline search performed as part of the meta-analysis [17]. Based on these and older data, typical estimates of CRC incidence usually range between 0.5–1% per year after 10 years of colitis. More recent studies, however, have raised the possibility that prior studies have overestimated the incidence and risk for CRC in this population. In more recent publications from Denmark [18], Hungary [19], Canada [20], and Olmstead County, Minnesota (with its relatively small
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population) [21] have suggested a CRC in UC incidence of between 1 in 500 to 1 in 1600 per year, far lower than the 1 in 300 rate calculated in Eaden’s meta-analysis [17]. These have corresponded to relative risk calculations ranging from 1.1 to 2.7 times the general population. While some have argued that these more “modern” calculations support a declining incidence over calendar time, as seen by Rutter and colleagues [22], no definitive analysis has been performed to support this hypothesis. To what extent such reductions in incidence (if they exist) are a function of colonoscopic surveillance (see below), chemoprevention with mesalamine-based agents or other medicines (also below), or other factors remains unknown. Risk Factors A number of clinical variables have been demonstrated to modify the risk for colorectal cancer in UC patients. These variables include duration of UC, anatomic extent of disease, age at UC diagnosis, concomitant primary sclerosing cholangitis (PSC), a family history of colorectal cancer, and inflammatory activity. The use of certain medications may lessen the risk of developing CRC, but the impact of these potentially chemopreventive agents is modest. Table 46.1. classifies these different risk modifiers. Duration of Ulcerative Colitis A number of investigators have demonstrated that the duration of ulcerative colitis correlates with the risk of cancer [9, 23–25]. Duration of disease, however, can be a rather subjective measurement. Most studies have used the date of UC diagnosis as the point at which the clock starts, but others have argued that the time of symptom onset is a better measure of disease duration. Whichever point is chosen, a number of distortions can be imagined that would impact the findings in any individual study. If date of diagnosis is used as a starting point, then patients with longstanding, subclinical disease would appear to have relatively shorter duration of disease, and such subjects would contribute less to any calculation of the effect of disease duration. Conversely, by using date of first symptoms, subjects who were without colitis might mistakenly contribute years of disease-free time to calculations of duration. This distinction in the definition of disease duration may be particularly problematic for patients with primary sclerosing cholangitis (PSC) who frequently have clinically quiescent colitis. Without unanimity in definition, there is variability in the estimate of this factor’s effect on subsequent CRC development. In Eaden’s meta-analysis, the effect of duration was made clear as the passage of each successive decade resulted in an increase Table 46.1. Risk Modifiers of Colorectal Cancer in Ulcerative Colitis. Accepted Risk Modifiers Disease duration Extent of disease PSC Age of onset Family history of carcinoma Probable Risk Modifiers Inflammation Possible Risk Modifiers Sulfasalazine/5-ASA Folic acid Ursodeoxycholic acid Unlikely Risk Modifier Glucocorticoid use 6-MP/AZA use PSC-primary sclerosing cholangitis
Longer duration increases risk Greater extent increases risk Presence of PSC increases risk Early age of onset increases risk Positive family history increases risk Increased inflammation increases risk Use reduces risk Supplementation reduces risk Use reduces risk in UC patients with PSC
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in incidence. Incidence was calculated to be 2 per 1000 patient years (95% C.I. 1–4/1000) at 10 years and 11 per 1000 (95% C.I. 4–28/1000) at 30 years; the rate at 20 years was intermediate [17]. As the overall curve for cumulative CRC risk starts to meaningfully exceed that of the general population by eight to ten years, most clinicians will initiate surveillance colonoscopy once this threshold has been reached. Because many of the studies that were entered in to Eaden’s metaanalysis antedated the widespread application of colonoscopic dysplasia surveillance, it remains unclear whether duration of colitis exerts a seeming exponential effect, as Eaden found, or a linear effect, which might result if highest-risk patients are serially removed from the denominator via colectomy from surveillance-identified dysplasia. Anatomic Extent of Ulcerative Colitis The length of involved colon also correlates with cancer risk: the greater the surface area of colitis, the greater the cancer risk. Defining the anatomic extent of ulcerative colitis, as with duration of disease, can vary from study to study. In initial reports documenting this independent risk factor, anatomic extent was defined by a barium enema at diagnosis. Flexible endoscopy long ago replaced barium radiography for diagnosing colitis and its extent, but there is no consensus as to whether naked eye findings at colonoscopy or microscopic extent determined histologically should be the gold standard for measuring extent. Additionally, definitions of “pancolitis,” “universal colitis,” and “extensive colitis” vary within studies, although they are all typically used to describe disease proximal to the splenic flexure. Another feature that invites confusion into the definition of anatomic extent is the timing of the measurement. As extent can change over time [26], should we take the extent at diagnosis or at some point in follow-up? Like other questions surrounding the issue of extent, this question has been left unresolved, although the majority of studies have used the terms “extent” and “extent at diagnosis” interchangeably. Extent at follow-up has not been well studied as an independent risk factor. A population-based investigation of a cohort of more than 3,000 patients with UC defined extent of UC by barium enema exam at diagnosis, and demonstrated an impressive gradient of risk as one moves from proctitis (standardized incidence ratio of 1.7, 95% confidence interval 0.8–3.2) to left-sided colitis (SIR = 2.8, 95% C.I. 1.6–4.4) to pancolitis (SIR = 14.8, 95% C.I. 11.4 to 18.9) [13]. Devroede [9], Greenstein, [25] Gyde, [24] Katzka, [27] Mir-Madjlessi, [28] and Gilat [14] all reported similar gradients in their studies. This finding was confirmed, though not directly studied, in Eaden’s meta-analysis [17]. In terms of “how” extent should be defined, it is worth noting that a group from University of California San Francisco found CRC in areas proximal to the endoscopically perceived margin of colitis that turned out to have microscopic disease in that region [29]. On this basis, clinicians should consider the most proximal extent of disease microscopically as the proximal extent of disease, and plan any prevention strategy accordingly. Age of Ulcerative Colitis Onset Age of colitis onset, as a variable independent of disease duration, has been implicated in some studies to modify the risk of colitic cancer. This hypothesis, however, remains in question. Reporting one of the highest published cumulative rates of CRC in colitis, Devroede and colleagues found that at 35 years of follow-up, 43% of subjects with documented UC prior to age 15 had developed CRC [9]. This study, however, reflected pediatric patients seen at a large referral-center; additionally, the number of patients available to analyze after 35 years of follow-up was quite small, with the error surrounding this point estimate correspondingly quite broad. While some investigators have failed to demonstrate a link between age of colitis onset and the subsequent development of CRC [14, 27], others have confirmed the direction if not the magnitude of Devroede’s findings [13, 24]. In the previously mentioned study by Ekbom, for example, the
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authors found that the relative risk of cancer in colitis decreased with advancing age—younger patients have a higher risk [13]. This overall gradient was confirmed by Eaden, who found that cumulative rates of CRC were greater than the pooled estimates for CRC among adult colitic patients, though this difference did not meet conventional thresholds for statistical significance [17]. Although neither the precise nature nor the precise magnitude of CRC risk for younger patients with UC has been determined, extra caution should be applied to pediatric patients given both the suggestion of an increased risk from the medical literature and the obvious increased lifetime risk given a longer life expectancy.
Primary Sclerosing Cholangitis Primary sclerosing cholangitis is a chronic cholestatic liver disease in which there is progressive inflammatory fibrosis of the biliary tree. It is an infrequent complication of IBD, affecting 2–8% of patients with ulcerative colitis. However, among patients with PSC, 62–72% have underlying IBD. Since the intersection of CRC and PSC would be expected to occur in small absolute numbers in patients with UC, it is largely through case-control studies and referral center-based cohort studies that the majority of data have been generated to support an association between PSC and CRC in UC. Although a positive association has not always been noted [30–32], most studies do support such an association, with derived odds ratios from these “positive” studies ranging from 9 to 16 [33–37]. In a population-based study from Sweden, Kornfeld and colleagues found a substantially elevated cumulative incidence of CRC in UC/PSC patients: 33% at 20 years [38]. As noted above, since colitis activity in PSC is often mild or even subclinical, PSC patients in these studies might well have had a longer duration of disease than was appreciated, making it difficult to tease out the precise, independent contribution of PSC to the development of CRC.
Family History of Colorectal Cancer Family history of CRC has long been recognized as a risk factor for the development of sporadic colorectal cancer. This risk increases according to the number of relatives affected with CRC [39]. In UC, only a few clinical studies have been performed to investigate the independent contribution of a positive family history for colorectal cancer. An early study from Lashner’s group at the University of Chicago supported family history of CRC as a potential risk factor for CRC in colitis, although the association did not reach statistical significance [40]. A second report from the Cleveland Clinic documented a lower rate of positive family history of CRC among UC patients with cancer or dysplasia compared to UC controls without colonic neoplasia, though this finding, too, failed to exclude the null hypothesis [41]. Both of these studies, however, were designed to test hypotheses concerning the association between folic acid supplementation and colorectal cancer in colitis. Testing for family history as a risk factor was performed as part of a secondary analysis, and these studies did not specify the rigor with which a family history was obtained. More recently, a handful of studies have suggested an increased risk for CRC in UC when a positive family history of CRC was documented. Nuako and colleagues at the Mayo Clinic were the first to clearly demonstrate this increased risk, calculating an odds ratio of 2.3 (95% CI 1.1–5.1) in their case-control study [42]. In a population-based study from Scandinavia, Askling and colleagues found a similar elevated risk of 2.5 (95% C.I. 1.4–4.4) [43], while Eaden (in the U.K.) found an even greater risk (OR 5.0, 95% CI 1.1–22.8) in a multivariable model using case-control derived data [44]. Whatever the absolute magnitude, it appears quite likely that a positive family history confers an increased risk of CRC in UC.
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Inflammation Curiously, although inflammation has been assumed to be a key factor contributing to higher risk of colonic neoplasia in UC, few studies have examined this issue. One well conducted retrospective case-control study recently reported that histologic inflammation was indeed associated with an increased risk of neoplastic progression based on a retrospective case-control analysis of patients followed at a specialized center [45]. A retrospective cohort study from Mount Sinai, New York has also demonstrated a link between histologic inflammation on dysplasia and cancer risk, with a 2-fold risk increase for each unit of inflammation derived from a 4-point scale [46]. Pharmacotherapy and Chemoprevention As with sporadic colorectal cancer and interest in cyclooxygenase inhibiting compounds, investigators, clinicians, and patients are actively seeking medications that might decrease the risk of developing CRC in UC. Retrospective studies have been performed examining a number of potential chemopreventive agents with mixed results. As is often the case in retrospectively performed studies of medication use, the dose and duration of use that defines exposure can be arbitrarily chosen. Nevertheless, a number of studies have been performed looking at different hypothesized chemopreventive medication with exposure defined in a number of different ways. Sulfasalazine Sulfasalazine and the newer 5-amino-salicylic acid (5-ASA) products have been investigated for their chemopreventive effect, mainly by post-hoc secondary analyses, yielding conflicting results. In a study designed to investigate the effect of supplemental folic acid on CRC risk, sulfasalazine use was found to have a positive (i.e. predisposing) effect on the development of CRC (slightly but not significantly higher rates of CRC in the exposed group); sulfasalazine allergic patients, however, were noted to have a substantially lower risk of developing CRC [40]. Subsequently, Pinczowski and Eaden were able to demonstrate a protective effect for sufasalazine or mesalazine [44, 47], when dose and duration were considered. Tung [48] failed to demonstrate a meaningful protective effect, but this study was limited to high-risk PSC patients. A number of additional studies with a variety of definitions for exposure have now been performed with conflicting results. Some have shown benefit with exposure to mesalamine-based agents [49, 50], while others have been less optimistic [51, 52]. A meta-analysis has reviewed a number of these studies, but its conclusion that mesalamine is chemopreventive must be taken with some caution owing to the heterogeneity of the included studies as well as the different designs that were used (case-control, retrospective cohort, secondary analyses) [53]. Given the lack of unanimity of these studies, it remains in question whether mesalamine-based medications constitute truly chemopreventive agents. Given their utility at preventing flares in patients in remission, however, their use should be advocated in all UC patients. Folic Acid Folic acid, which has been demonstrated to have a protective effect in sporadic colorectal cancer was twice studied by Lashner, once at the University of Chicago [40] and again at the Cleveland Clinic [41]. In neither study was a significant protective effect noted, although the point estimates of risk (0.38 and 0.45) suggested the possibility of a chemopreventive effect. Given the low cost and the low risk of adverse events at conventional doses of 400 ug per day and 1 mg per day, the administration of folic acid as a chemopreventive drug should be strongly considered for all at risk patients.
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Ursodeoxycholic Acid Ursodeoxycholic acid, an exogenous bile acid used in the treatment of PSC, has also been studied. In UC-PSC patients, an impressive chemopreventive effect has been demonstrated, with a 40 percent difference in neoplasia noted between the ursodeoxycholic acid treated group (32%) and the untreated group (72%) [48]. This was additionally demonstrated in a randomized clinical trial of ursodeoxycholic acid in which a 74% reduction in dysplasia or CRC was noted [54]. Whether this chemopreventive effect can be demonstrated in patients with UC or Crohn colitis who do not have PSC remains unknown, although it is under investigation. Methods to Reduce Risk/Mortality Until we discover or develop a meaningful chemopreventive agent and effective strategies to identify a minimal risk sub-group, only two acceptable forms of CRC prophylaxis exist: surgery and dysplasia surveillance. In dysplasia surveillance, high-risk patients are identified by the identification of neoplasia (either dysplasia or cancer) at colonoscopy and are subsequently referred to surgery, while cancer and dysplasia-free patients continue with periodic colonoscopy. The presumption is that only the highest risk patients will undergo a colectomy, and lower risk patients will be able to maintain a higher quality of life with their colons intact. A third option, watch and wait, with colonoscopy performed only for symptoms, is available, but due to the available evidence that symptomatic cancers are associated with a worse survival than asymptomatic ones [55, 56] never used in clinical practice. Surgery Without question, the most effective method for minimizing CRC risk in UC patients is to perform a total proctocolectomy. This nearly eliminates the risk of colon or rectal cancer, and, while cancers have been reported in case reports and series in patients who have undergone either handsewn or stapled anastomoses, the risk of such an event is quite small. In the pre-endoscopic era, this strategy of cancer prevention was often advocated for patients with longstanding colitis, and should still be considered, particularly for patients with medically refractory or difficult disease. As surgery is not without its potential complications and change in quality-of-life, however, and as the absolute risk of developing a lethal colon cancer may not be sufficiently high to warrant such a radical approach in all colitis patients, surgical prophylaxis in asymptomatic patients with longstanding colitis is now viewed with skepticism by both patients and clinicians. At present, surgical options (for colorectal cancer prophylaxis or as primary treatment for colitis-related dysplasia or cancer) include total proctocolectomy with creation of an ileal pouch-anal anastomosis (often referred to as a restorative proctocolectomy) or total proctocolectomy with end-ileostomy. Subtotal colectomy with ileorectal anastomosis is to be avoided, although there are no studies comparing this procedure to either of the other conventional choices. Pouch surgery is generally reserved for younger patients, as it requires sufficient anal sphincter tone. Following pouch surgery, patients may expect to have five or more bowel movements per day due to pouch size and ileal flow. Possible complications include sexual and bladder dysfunction, incontinence, pouchitis (which usually responds to short courses of antibiotics but may become chronic and refractory), fistula formation, stricture formation, anastomotic leakage, and pouch failure. The overall failure rate (the proportion of patients eventually converted to end-ileostomy) is approximately 5% [57]. It should also be noted that the malignant potential of ileal pouch mucosa in colitis patients remains unknown. Initial reports of pouch dysplasia have been reported, and there have been reports of cancer in the cuff of rectal mucosa to which the pouch is anastomosed [58, 59]. While cancer risk following proctocolectomy with Brooke ileostomy is close to nil, the loss of anorectal function and attendant stoma make this option less appealing to most patients who would
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otherwise be candidates for pouch surgery. Potential complications of total proctocolectomy with end-ileostomy include sexual and bladder dysfunction, stomal fistula, peristomal hernia, and small bowel obstruction [57]. Dysplasia Surveillance As it results in too many colectomies in patients who would otherwise be unaffected by CRC, prophylactic total proctocolectomy is seldom performed. Even if limited to the high risk groups of patients with longstanding and extensive UC, with or without PSC or a family history of CRC, a large number of colectomies would be performed in patients who would never develop CRC. What is needed is a tissue marker that better determines the highest risk patients, those with an imminent risk of colorectal cancer. While imperfect on many levels, mucosal dysplasia serves as such a marker. In 1967 Morson and Pang first reported the association between mucosal dysplasia and CRC in patients with UC [60]. In their seminal report they noted that rectal dysplasia, then termed “precancer” and identified by blind rectal biopsy of colitis mucosa, heralded the presence of an invasive adenocarcinoma elsewhere in the colon. If appropriately discriminating, mucosal dysplasia, it was hypothesized, could be used as a diagnostic test to identify the highest risk patients to whom surgery would be offered. Subsequent studies revealed that, although by no means a perfect test, dysplasia was discriminating enough to be tested in clinical practice. Retrospective studies confirmed Morson and Pang’s findings, noting the presence of dysplasia either adjacent to or remote from cancer in colitis [61– 63]. Additionally, cancer foci were discovered in colons resected for the indication of dysplasia [64]. These data as along with the advent of flexible fiberoptic instruments with their ability to deliver multiple mucosal samples to the pathologist’s microscope, led to the development of protocol-based surveillance programs. Unfortunately, no randomized, controlled trials of surveillance were performed. (This may have been a function of difficulty in defining suitable control patients: would patients allow themselves to be randomized to a “no surgery” or “no endoscopy” arm of a surveillance study? Or to a “prophylactic surgery” arm?) Nevertheless, based on the clinical characteristics of dysplasia and the results of numerous surveillance programs, as well as the very limited acceptability of other prevention strategies, namely surgery for all longstanding colitis or waiting for cancer symptoms, periodic colonoscopy with biopsy for dysplasia became an accepted form of cancer prevention in UC. In addition to its widespread use in clinical practice, it has been advocated in guidelines statements for colon cancer prevention [65] and ulcerative colitis care [66]. Single-armed surveillance programs have demonstrated the feasibility, though not the efficacy, of conventional surveillance [15, 64, 67–77]. When “control” arms were used in these studies, they included patients in whom surveillance at another institution or referral to the institution for malignancy could be considered as “no surveillance.” Nevertheless, the finding that cancers found during surveillance were more often at earlier stages than cancers found in a “watch and wait” strategy contributed to the acceptance of dysplasia surveillance as a form of cancer prevention [55, 56]. Other key features about surveillance programs worth noting include the presence of advanced stage cancers despite inclusion in a surveillance program (some due to patient drop-out and some due to progression while under surveillance); [74, 77, 78] the variable intervals used for surveillance; variable rates of patient drop-out; and the substantially varied rates of dysplasia incidence across studies. For surveillance to be effective, it should reduce CRC mortality in IBD patients. In the absence of prospective controlled studies, a well-designed population-based case-control study sheds light on this issue. Karlen and colleagues compared the exposure to colonoscopy among cases with CRC deaths and alive controls matched for age, gender, disease duration and disease extent [79]. Their point estimate of cancer mortality reduction from either one or only two previous colonoscopic exams was a three-fold decrease. Although the odds ratio
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of 0.3 did not reach statistical significance, (95% CI: 0.1 to 1.3), this is certainly a clinically impressive result. A recent case-control study from the Mayo Clinic confirmed these findings, and even crossed the threshold of statistical significance with an odds ratio of 0.4 for 1–2 surveillance examination (95% CI: 0.2 to 0.7) [80]. While these data were not population-based in their orientation, they nevertheless support the notion that surveillance is likely effective. Additional support comes from decision analysis models [81, 82, 83] that demonstrate improved outcomes for a population in surveillance compared to no surveillance. As with all such modeled data, there are many assumptions that lack real-world support, such as a lack of drop-out while under surveillance and an orderly progression from no dysplasia to low-grade dysplasia to high-grade dysplasia to colorectal cancer [81, 84, 85]. Cost effectiveness analyses have similarly predicted that surveillance was a superior strategy to no surveillance (although prophylactic colectomy, while unacceptable to patients, was the preferred strategy vis-à-vis life-years saved over time). What then might limit the effectiveness of dysplasia surveillance in UC in practice? One factor may be difficulties in histologic interpretation among pathologists. Indeed this was thought to be so substantial a problem after the initial reports of surveillance studies that in 1983, an international group of experts convened to establish true definitions for the evaluation of dysplasia surveillance specimens: no dysplasia, indefinite for dysplasia (with three subtypes), low-grade dysplasia, high-grade dysplasia and colorectal cancer [86]. Unfortunately, despite these codified definitions, substantial rates of disagreement, even among expert GI pathologists, have been noted [86–89]. Rates of disagreement among community pathologists, not surprisingly, have been substantial, too [87]. In these studies, crude rates of agreement have been as low as 40% and as high as 72%, with best agreement when no dysplasia was present; kappa values, which can account for chance agreement were fair to good. Clearly, this system needs less subjectivity and overall improvement. Lack of perfection from practicing pathologists is not the only reason for surveillance not to reach its potential. Gastroenterologists also fall short of ideal practices. One variable that contributes to lack of uniform clinician practices stems from the uncertainty that surrounds the predictive value of dysplasia. While there is near-universal agreement that patients found to have high-grade dysplasia should undergo colectomy due to rates of concurrent adenocarcinoma near 50% [62], considerable controversy surrounds the management of low-grade dysplasia. Adding to the controversy is the fact that LGD can be flat or polypoid, unifocal or multifocal, or not repeatedly found on sequential colonoscopic exams. Few studies have directly addressed these variables in patients with LGD. How to best manage LGD depends in large part on how likely patients with this finding are to either already harbor or progress to more advanced neoplasia (HGD or cancer). More specifically, the essential unanswered question is whether failure to perform a colectomy in patients with LGD results in a poor outcome. In a landmark study from St. Marks Hospital in which the Inflammatory Bowel Disease Morphology Study Group’s 1983 definitions were used [86], the rate of progression to advanced dysplasia from LGD was 54% at five years [90]. In the same year as the St. Mark’s publication, a systematic review of surveillance programs by Bernstein and colleagues noted a 19% rate of cancer at “immediate colectomy” following the discovery of LGD. These results were confirmed by studies from the Mayo Clinic [91] and Mount Sinai in New York [78], in which the rates of progression for flat LGD were 33% (95% CI 9 to 56%) and 53% (95% CI ) respectively. Furthermore, in the Mount Sinai study, 19% of patients who underwent colectomy within 6 months of their initial flat LGD finding were found to have CRC in their resection specimens. Of those who progressed, cases of node positive cancer without intervening HGD were found. Neither the number of biopsies positive for LGD nor any other clinical variable were found to be predictive of subsequent progression, with unifocal flat LGD carrying a 5-year rate of progression of 53% [78]. Investigators from the University of Washington where an aggressive biopsy protocol is followed [92] and from The Karolinska
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Institute, Sweden [93], however, discovered less frequent progression and no cancers. Not all investigators have discovered the same high-risk for LGD as that noted by St. Mark’s, Mayo Clinic, and Mount Sinai in New York. A group from Karolinska in Sweden noticed a near-total lack of progression following discovery of LGD, but this group’s pathologists did not use the full panoply of IBD Morphology Study Group definitions, as readings of “indefinite” for dysplasia were not allowed. Additionally, a number of patients were included whose discovery of LGD occurred prior to establishment of the Riddell criteria [94]. Additionally, the Leeds, U.K. group led by Lim found little progression from LGD, leading him and his co-authors to conclude that continued surveillance with satisfactory biopsy practices was a safe alternative to surgery [95]. While the variable rates of progression (perhaps secondary to variable biopsy practices, observer variation in the interpretation of dysplasia, or imperfect follow-up), make it difficult to draw absolute conclusions for the management of patients with flat LGD, early colectomy for LGD that is histologically confirmed by two expert pathologists should be strongly considered at the least. For patients who defer or refuse colectomy for LGD, gastroenterologists must make certain that patients return for follow-up examinations and that surveillance is appropriately performed with an adequate number of biopsies taken to exclude dysplasia. It should be noted that a negative exam following LGD can occur for a number of reasons: 1) the previous examination was a false positive due to pathologic interpretation error; 2) the present examination is a false negative due to sampling or interpretation error; or 3) both exams were accurate. Not finding dysplasia on a repeat colonoscopy following one that detected LGD is no reassurance that dysplasia has regressed or will not “recur.” [77] It was estimated that to exclude dysplasia with 95% confidence, 56 biopsies must be performed, and to exclude 90% confidence, 33 biopsies should be taken [96]. This number of biopsies is rarely performed even in academic centers [97, 98]. Eaden noted that 57% of U.K gastroenterologists take fewer than 10 biopsies in a surveillance exam based on their response to a questionnaire [97]. In a study examining actual gastroenterologists’ practices, Ullman and colleagues found that the mean number of evaluable biopsies in patients with LGD was only 17.5 [78]. Such undersampling represents another limitation for dysplasia surveillance among gastroenterologists. Whether such practices truly limit the effectiveness of surveillance remains unknown. The appropriate management of polypoid LGD, like that of flat LGD, is equally challenging. Polypoid dysplastic lesions in UC were labeled DALMs, (dysplasia-associated lesions or masses), by Blackstone and colleagues in 1981 [68]. In this study, in which the pond was effectively stocked with patients referred for a suspicion of CRC and many lesions were noted to be > 2 cm in diameter, DALMs were noted to harbor a 58% (7 of 12) risk of cancer [68]. Despite the impressive cancer risk of DALMs in the Blackstone report, astute clinicians hypothesized that smaller, adenoma-like lesions might present a lesser risk. Two simultaneously published studies reported on their experience of treating smaller, sessile lesions with endoscopic resection (without surgery). Rubin and colleagues from Mount Sinai, New York followed 48 patients with ulcerative or Crohn colitis in whom dysplastic polyps were detected at colonoscopy [99]. In those patients in whom polyps were endoscopically resected and the remaining colon was dysplasia-free, no patients progressed to colorectal cancer after a mean follow-up of 4.1 years [99]. In Engelsgjerd’s study from the Brigham and Women’s Hospital in Boston, none of 24 colitis patients with adenoma-like polyps treated with polypectomy developed adenocarcinoma after a mean follow-up of 42.4 months [100]. Odze reported on the continued follow-up of the Brigham group 5 years later, and only one case of CRC developed, this in a patient 7.5 years after her initial polypoid lesion had been resected [101]. Similar results were noted in a recent publication by Rutter and colleagues [22]. he need for complete resection of polypoid lesions was underlined in a publication by Vieth, in which 10 of 60 patients in whom residual neoplasia was left behind progressed to CRC [102]. These data seem to indicate the relative safety of endoscopic polypectomy in colitis provided the lesions are small, completely resected, and that the rest of the surveillance run is
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dysplasia-free. When removing a suspicious polyp in a colitic colon, it is important to separately biopsy the mucosa immediately adjacent to the polyp base because if the polyp resides in a bed of dysplasia, colectomy is warranted. The colitic colon with numerous inflammatory pseudopolyps presents another challenge to the endoscopist. It is wise to remove any polyp that has unusual features. Molecular studies using global gene expression arrays suggest that DALMs can be distinguished from apparently sporadic adenomas [103] holding promise for managing these difficult lesions. Finding a dysplastic lesion in a sea of inflammatory polyps, however, poses a substantial challenge to the endoscopist. It is not surprising that a recent publication found that the presence of inflammatory pseudopolyps carries a substantial (2.5-fold) risk for subsequent colorectal cancer [80]. In addition to a lack of certainty among experts as to how to manage flat, low-grade dysplasia and polypoid dysplasia, other impediments to the success of surveillance exist within the GI community. Poor understanding of dysplasia and surveillance practices exist among trained gastroenterologists [97, 98, 104]. Indeed, only 19% of respondents correctly identified dysplasia as neoplastic tissue in Bernstein’s two-decade old questionnaire study [104]. Whether gastroenterologists’ understanding has improved since that time remains uncertain. Patient factors have also limited the effectiveness colonoscopic surveillance in colitis. Patient drop-out or non-compliance with surveillance programs has been demonstrated to be a substantial source of colorectal cancer mortality [56, 72, 74, 77]. Despite the limitations of surveillance based on the difficulties of dysplasia interpretation, poor agreement on dysplasia management, suboptimal surveillance performance, and risks of patient drop-out, no other acceptable method for cancer prevention in colitis exists. As such, dysplasia surveillance will remain with us until a superior substitute is found. Current recommendations for how surveillance should be performed has been published in a number of different formats [3, 105, 106]. All of these publications agree that 4-quadrant biopsies, with each quartet of biopsies in a separate jar, should be taken every 10 cm, with suspicious lesions labeled and placed in a separate jar; examinations should be performed every 1–2 years for patients with disease involving 1/3 or more of their colon after 8 years of disease. Surveillance should begin at diagnosis for all patients with UC and PSC. Alternatives to Surveillance Augmentation of white light surveillance has been proposed using chromoendoscopy using the dye stains methylene blue or indigo carmine to better highlight subtle and “flat” lesions. These procedures have demonstrated higher detection rates for dysplasia in head-to-head comparisons [107] with conventional dysplasia surveillance and in back-to-back surveillance in which each patient serves as his/her own control [108]. Whether the introduction and application of chromoendoscopic surveillance will alter outcome for colitis patients remains untested. Other types of advanced endoscopy have been proposed as well, including narrow band imaging and various forms of spectroscopy. To date, none have been subjected to a trial. Molecular markers, whether from serum, RNA or stool, may also hold promise for complementing or replacing dysplasia surveillance, but as yet, they have not been incorporated into surveillance protocols.
Colorectal Cancer in Crohn Disease Like UC, colitis in Crohn disease carries a risk for colorectal cancer greater than that of the general population. This was not always appreciated, however, as initial reports noted only a small, and sometimes not statistically significant, increase in colorectal cancer among patients with Crohn disease [110]. A number of factors likely contributed to the dilution of the true effect of Crohn disease on colorectal carcinogenesis. First, patients with disease limited to the small bowel
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were included in some calculations of incidence. Second, patients who had undergone surgery, particularly colectomy, were often included. And finally, a number of investigators performed their analyses without taking into account the duration of disease, or more importantly, the extent of colonic involvement for this often segmental disease. Together, these factors resulted in a longheld belief that Crohn disease carried a lower risk for colon cancer than ulcerative colitis. Other studies [111–114] and even re-analysis of original data in which only subjects with longstanding and anatomically substantial Crohn colitis were examined [115] demonstrated that Crohn colitis harbored a CRC risk increase similar to that of ulcerative colitis and that both greater duration of colitis and greater length of involved colon increased the risk. As with UC, earlier disease onset resulted in even greater increases in relative risk of CRC, likely as a function decreased risk in the rate of sporadic CRC used in the denominator of these calculations. Population-based studies from separate continents have demonstrated a clear increase in CRC rates not only when limited to cases of Crohn colitis, but even when all patients with Crohn disease are considered [20, 116]. A recent meta-analysis by Canavan and colleagues calculated a pooled estimate of CRC relative risk to be 2.5 (95% CI: 1.3 to 4.7) for all patients with Crohn disease, culled from 12 published manuscripts; for patients with colonic disease (in the 4 reports where it was available), the pooled RR was 4.5 (95% CI: 1.3 to 14.9) [117]. Clearly patients with Crohn have a higher risk than the general population. Similarities between CRC in Crohn and UC and Rationale Behind Recommendation for Surveillance In addition to the greater rate and earlier appearance of CRC in Crohn colitis when compared to the general population, investigators have noted other important similarities between Crohn-related CRC and UC-related CRC [118]. These include: • A higher proportion of mucinous and signet-ring histology • A greater proportion of synchronous lesions compared to sporadic CRC • Similar survival rates once detected (also true of sporadic CRC) • Presence of tumor in areas of macroscopic disease (although this point remains in question for Crohn disease) • Presence of dysplasia adjacent to and distant from tumor suggesting a field effect This latter feature has led a number of experts to recommend a strategy of serial surveillance colonoscopy for patients with longstanding, extensive Crohn colitis as is performed and recommended for UC patients. To date, only one single-practice-based retrospective Crohn surveillance program has been reported in the literature [119]. In this study, Friedman and colleagues demonstrated both the feasibility and practicality of surveillance in Crohn patients with colitis affecting at least 1/3 of their colon for a minimum of 8 years. The authors detected dysplasia or cancer in 16% of their 259 patients over a 16-year period, in which 663 examinations were performed; there were no cancer deaths [119]. As this is the only available study describing a surveillance program in Crohn disease, and there is no available control arm (i.e. no surveillance) against which to compare mortality rates, the efficacy of surveillance in Crohn disease is not yet established. Nevertheless, it has been recommended that all patients with extensive Crohn colitis (greater than one-third of colon involved) undergo periodic surveillance or be recommended prophylactic surgery after 8 years of disease, as is done with extensive ulcerative colitis. Guidelines have suggested that practices used in surveillance should be similar to those demonstrated to be able to rule out dysplasia in ulcerative colitis [3]. The effects of agents thought to be chemopreventive in UC are untested in Crohn disease.
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Table 46.2. Small Intestinal Cancer and Crohn Disease. Year
Author
Subjects
Cases
Risk/Odds
95% CI
1992 1993 1994 2001
Ekbom [116] Munkholm [110] Persson [123] Bernstein [20]
1655 373 1251 2857
1 2 4 5
3.4 50 15.6 17.4
01−186 371−659 47−401 42−729
95% CI=95 percent confidence interval
Crohn Disease and Adenocarcinoma of the Small Intestine As with colonic adenocarcinoma in Crohn colitis, an increased risk of small intestine adenocarcinoma has been demonstrated in patients with small bowel Crohn. Unlike colorectal cancer, the second most common lethal malignancy in the U.S., adenocarcinoma of the small intestine is uncommon. Even when evaluated in population-based reports, absolute numbers are quite small, with the largest such series having only 5 patients with small bowel adenocarcinoma [20]. A summary of these studies is presented in Table 46.2. Since the absolute rates for these cancers is so small, and the best means of prevention is uncertain if a pre-clinical, precancerous finding were detected, it would be impractical to perform screening and surveillance in all patients with small bowel Crohn disease. When there is a change in clinical symptoms or a change in barium exams, however, the possibility of a small bowel malignancy should be entertained, particularly in a patient with longstanding disease.
Other Malignancies Following case reports and series of extraintestinal malignancies, investigators questioned whether certain neoplasms might be related to either the presence or treatment of IBD. Greenstein and colleagues performed one of the first studies in which relative risks were calculated [120]. Using patients hospitalized for IBD at a tertiary care hospital, the authors determined that there was an increased incidence of leukemias, lymphomas, and squamous cell cancers when compared to published population-based controls [120]. Given the source of their sampling, a likelihood of selection and detection biases must be considered. Other referral-based studies examining this issue have demonstrated increased incidence of leukemias [121, 122] as well as bile duct [28], and endometrial cancers [28]. Despite the large number of Crohn and ulcerative colitis patients, low absolute numbers of extraintestinal malignancies with broad confidence intervals have resulted in claims of “significance,” when one less case would have resulted in “no significance.” Ultimately, population-based analyses of cancer incidence in IBD have replaced the center-specific studies with their inherent biases. One such population-based study came from Ekbom and colleagues who determined that in a cohort from Uppsala, Sweden there was no increase in the incidence of leukemias, lymphomas, bile duct cancers or uterine cancers [116]. However, an increase was noted in connective tissue cancers and squamous cell cancers of the skin, as well as brain cancers among patients with extensive ulcerative colitis [116]. It is worth noting, however, that no adjustments were made for the multiple comparisons in Ekbom’s studies. Other population-based studies have also failed to detect an increased number of extraintestinal malignancies. These include another Swedish study in which Crohn patients from Stockholm county were analyzed [123]—only a slight increase in bladder cancer was found and no increase in leukemias, lymphomas, bile duct cancers or endometrial cancers was demonstrated—and one from North America [20]. In this latter population-based study from Manitoba, Canada that included over 6000 IBD subjects, Bernstein and colleagues found an increase in liver and biliary tumors in both Crohn and ulcerative colitis
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(with only five such cases) and a small increase in lymphomas only among men with Crohn disease. As increased rates of lymphoma and other hematologic malignancies have been raised as possible adverse effects of either azathioprine or 6-mercaptopurine use in other conditions [124–126] and rates of these malignancies have been calculated in series from large referral practices and centers [127, 128], it is notable that Bernstein and colleagues demonstrated no relation to an increased risk of hematologic malignancies and purine analogue use, the first population-based data set to do so [20]. More recently, rare lymphomas (hepatosplenic T-cell lymphomas), particularly in younger patients, have been noted with anti-TNF therapy particularly in combination with purine analog immunomodulators [129].
Summary Colorectal cancer remains a major threat to patients with longstanding ulcerative colitis and Crohn colitis. Due to patients’ and physicians’ desires to avoid unnecessary surgery, prophylactic colectomies are rarely performed in these patients. Instead, caregivers and IBD patients tend to elect a program of dysplasia surveillance in an effort to simultaneously minimize cancer mortality and unnecessary colectomies. Although only circumstantial evidence supports the use of such a strategy as a means of reducing CRC-related mortality, dysplasia surveillance will remain the standard of care until better tests are available. Extra caution should be given to pediatric patients whose relative risk and lifetime risk of cancer is increased. Small intestinal cancer occurs at an increased rate in patients with Crohn enteritis, but the absolute risk remains small. Extraintestinal malignancies are uncommon in IBD but lymphomas, biliary tract cancers and squamous cell cancers of the skin may occur at an increased rate in IBD patients. The mechanisms for all of these processes remain elusive, but it is hoped that advances in molecular medicine will help to unravel these issues in the future. References 1. Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: The role of inflammation. Am J Physiol Gastrointest Liver Physiol 2004;287:G7–17. 2. Itzkowitz SH. Inflammatory bowel disease and cancer. Gastroenterol Clin North Am 1997;26:129–39. 3. Itzkowitz SH, Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroenterology 2004;126:1634–48. 4. Brentnall TA, Crispin DA, Rabinovitch PS, Haggitt RC, Rubin CE, Stevens AC, Burmer GC. Mutations in the p53 gene: An early marker of neoplastic progression in ulcerative colitis. Gastroenterology 1994;107:369–78. 5. Brentnall TA, Crispin DA, Bronner MP, Cherian SP, Hueffed M, Rabinovitch PS, Rubin CE, Haggitt RC, Boland CR. Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. Cancer Res 1996;56:1237–40. 6. Suzuki H, Harpaz N, Tarmin L, Yin J, Jiang HY, Bell JD, Hontanosas M, Groisman GM, Abraham JM, Meltzer SJ. Microsatellite instability in ulcerative colitis-associated colorectal dysplasias and cancers. Cancer Res 1994;54:4841–4. 7. Crohn BB, Rosenberg H. The sigmoidoscopic picture of chronic ulcerative colitis. Am J Med Sci 1925;170:220–228. 8. Bargen TA. Chronic ulcerative colitis associated with malignant disease. Arch Surg 1928;17:862–868. 9. Devroede GJ, Taylor WF, Sauer WG, Jackman RJ, Stickler GB. Cancer risk and life expectancy of children with ulcerative colitis. N Engl J Med 1971;285:17–21. 10. Bargen JA, Gage RP. Carcinoma and ulcerative colitis: Prognosis. Gastro 1960;39:385–392. 11. Slaney G, Brooke BN. Cancer in ulcerative colitis. Lancet 1959;2:694–698. 12. Rozen P, et al. Low incidence of significant dysplasia in a successful endoscopic surveillance program of patients with ulcerative colitis. Gastroenterology. 1995;108:1361–70.
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57. Becker JM. Surgical therapy for ulcerative colitis and Crohn disease. Gastroenterol Clin North Am 1999;28:371–90, viii–ix. 58. Stern H, Walfisch S, Mullen B, McLeod R, Cohen Z. Cancer in an ileoanal reservoir: A new late complication? Gut 1990;31:473–5. 59. Thompson-Fawcett MW, Marcus V, Redston M, Cohen Z, McLeod RS. Risk of dysplasia in long-term ileal pouches and pouches with chronic pouchitis. Gastroenterology 2001;121:275–81. 60. Morson BC, Pang LS. Rectal biopsy as an aid to cancer control in ulcerative colitis. Gut 1967;8:423–34. 61. Cook MG, Goligher JC. Carcinoma and epithelial dysplasia complicating ulcerative colitis. Gastroenterology 1975;68:1127–36. 62. Ransohoff DF, Riddell RH, Levin B. Ulcerative colitis and colonic cancer. Problems in assessing the diagnostic usefulness of mucosal dysplasia. Dis Colon Rectum 1985;28:383–8. 63. Taylor BA, Pemberton JH, Carpenter HA, Levin KE, Schroeder KW, Welling DR, Spencer MP, Zinsmeister AR. Dysplasia in chronic ulcerative colitis: Implications for colonoscopic surveillance. Dis Colon Rectum 1992;35:950–6. 64. Dickinson RJ, Dixon MF, Axon AT. Colonoscopy and the detection of dysplasia in patients with longstanding ulcerative colitis. Lancet 1980;2:620–2. 65. Levin B, Lennard-Jones J, Riddell RH, Sachar D, Winawer SJ. Surveillance of patients with chronic ulcerative colitis. WHO Collaborating Centre for the Prevention of Colorectal Cancer. Bull World Health Organ 1991;69:121–6. 66. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 1997;92:204–11. 67. Brostrom O, Lofberg R, Ost A, Reichard H. Cancer surveillance of patients with longstanding ulcerative colitis: A clinical, endoscopical, and histological study. Gut 1986;27:1408–13. 68. Blackstone MO, Riddell RH, Rogers BH, Levin B. Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: An indication for colectomy. Gastroenterology 1981;80:366–74. 69. Lashner BA, Silverstein MD, Hanauer SB. Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program. Dig Dis Sci 1989;34:1536–41. 70. Lashner BA, Kane SV, Hanauer SB. Colon cancer surveillance in chronic ulcerative colitis: Historical cohort study. Am J Gastroenterol 1990;85:1083–7. 71. Lennard-Jones JE, Morson BC, Ritchie JK, Shove DC, Williams CB. Cancer in colitis: Assessment of the individual risk by clinical and histological criteria. Gastroenterology 1977;73:1280–9. 72. Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB. Precancer and cancer in extensive ulcerative colitis: Findings among 401 patients over 22 years. Gut 1990;31:800–6. 73. Lofberg R, Brostrom O, Karlen P, Tribukait B, Ost A. Colonoscopic surveillance in long-standing total ulcerative colitis–a 15-year follow-up study. Gastroenterology 1990;99:1021–31. 74. Lynch DA, Lobo AJ, Sobala GM, Dixon MF, Axon AT. Failure of colonoscopic surveillance in ulcerative colitis [see comments]. Gut 1993;34:1075–80. 75. Nugent FW, Haggitt RC, Gilpin PA. Cancer surveillance in ulcerative colitis [see comments]. Gastroenterology 1991;100:1241–8. 76. Rutegard J, Ahsgren L, Stenling R, Janunger KG. Ulcerative colitis. Cancer surveillance in an unselected population. Scand J Gastroenterol 1988;23:139–45. 77. Woolrich AJ, DaSilva MD, Korelitz BI. Surveillance in the routine management of ulcerative colitis: The predictive value of low-grade dysplasia [see comments]. Gastroenterology 1992;103: 431–8. 78. Ullman T, Croog V, Harpaz N, Sachar D, Itzkowitz S. Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003;125:1311–9. 79. Karlen P, Kornfeld D, Brostrom O, Lofberg R, Persson PG, Ekbom A. Is colonoscopic surveillance reducing colorectal cancer mortality in ulcerative colitis? A population based case control study. Gut 1998;42:711–4. 80. Velayos FS, Loftus EV, Jr., Jess T, Harmsen WS, Bida J, Zinsmeister AR, Tremaine WJ, Sandborn WJ. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: A case-control study. Gastroenterology 2006;130:1941–9. 81. Gage TP. Managing the cancer risk in chronic ulcerative colitis. A decision- analytic approach. J Clin Gastroenterol 1986;8:50–7.
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82. Delco F, Sonnenberg A. A decision analysis of surveillance for colorectal cancer in ulcerative colitis. Gut 2000;46:500–6. 83. Inadomi JM. Cost-effectiveness of colorectal cancer surveillance in ulcerative colitis. Scand J Gastroenterol Suppl 2003:17–21. 84. Delco F, Sonnenberg A. A decision analysis of surveillance for colorectal cancer in ulcerative colitis. Gut 2000;46:500–6. 85. Provenzale D, Kowdley KV, Arora S, Wong JB. Prophylactic colectomy or surveillance for chronic ulcerative colitis? A decision analysis [see comments]. Gastroenterology 1995;109:1188–96. 86. Riddell RH, Goldman H, Ransohoff DF, Appelman HD, Fenoglio CM, Haggitt RC, Ahren C, Correa P, Hamilton SR, Morson BC, et al. Dysplasia in inflammatory bowel disease: Standardized classification with provisional clinical applications. Hum Pathol 1983;14:931–68. 87. Eaden J, Abrams K, McKay H, Denley H, Mayberry J. Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis. J Pathol 2001;194:152–7. 88. Dixon MF, Brown LJ, Gilmour HM, Price AB, Smeeton NC, Talbot IC, Williams GT. Observer variation in the assessment of dysplasia in ulcerative colitis. Histopathology 1988;13:385–97. 89. Melville DM, Jass JR, Morson BC, Pollock DJ, Richman PI, Shepherd NA, Ritchie JK, Love SB, Lennard-Jones JE. Observer study of the grading of dysplasia in ulcerative colitis: Comparison with clinical outcome. Hum Pathol 1989;20:1008–14. 90. Connell WR, Talbot IC, Harpaz N, Britto N, Wilkinson KH, Kamm MA, Lennard-Jones JE. Clinicopathological characteristics of colorectal carcinoma complicating ulcerative colitis. Gut 1994;35: 1419–23. 91. Ullman TA, Loftus EV, Jr., Kakar S, Burgart LJ, Sandborn WJ, Tremaine WJ. The fate of low grade dysplasia in ulcerative colitis. Am J Gastroenterol 2002;97:922–7. 92. Brentnall T, Bronner M, Rubin C, Rabinovitch P, Kimmey M, Kowdley K, Edmond M, Haggitt R. Natural history and management of low-grade dysplasia in ulcerative colitis. Gastroenterology 1999;116:A382. 93. Befrits R, Ljung T, Jaramillo E, Rubio C. Low grade dysplasia in flat colonic mucosa in patients with extensive longstanding inflammatory bowel disease – a follow-up study. Gastroenterology 1999;116:A376. 94. Befrits R, Ljung T, Jaramillo E, Rubio C. Low-grade dysplasia in extensive, long-standing inflammatory bowel disease: A follow-up study. Dis Colon Rectum 2002;45:615–20. 95. Lim CH, Dixon MF, Vail A, Forman D, Lynch DA, Axon AT. Ten year follow up of ulcerative colitis patients with and without low grade dysplasia. Gut 2003;52:1127–32. 96. Rubin CE, Haggitt RC, Burmer GC, Brentnall TA, Stevens AC, Levine DS, Dean PJ, Kimmey M, Perera DR, Rabinovitch PS. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology 1992;103:1611–20. 97. Eaden JA, Ward BA, Mayberry JF. How gastroenterologists screen for colonic cancer in ulcerative colitis: An analysis of performance. Gastrointest Endosc 2000;51:123–8. 98. Ullman T, White J, Harpaz N, Itzkowitz S. Assessment of Biopsy Practices in Colonoscopic Surveillance in Ulcerative Colitis. Gastroenterology 2001;120:A–446. 99. Rubin PH, et al. Colonoscopic polypectomy in chronic colitis: Conservative management after endoscopic resection of dysplastic polyps. Gastroenterology. 1999;117:1295–300. 100. Engelsgjerd M, Farraye FA, Odze RD. Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis [see comments]. Gastroenterology 1999;117:1288–94; discussion 1488–91. 101. Odze RD, Farraye FA, Hecht JL, Hornick JL. Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis. Clin Gastroenterol Hepatol 2004;2:534–41. 102. Vieth M, Behrens H, Stolte M. Sporadic adenoma in ulcerative colitis: Endoscopic resection is an adequate treatment. Gut 2006;55:1151–5. 103. Selaru FM, Xu Y, Yin J, Zou T, Liu TC, Mori Y, Abraham JM, Sato F, Wang S, Twigg C, Olaru A, Shustova V, Leytin A, Hytiroglou P, Shibata D, Harpaz N, Meltzer SJ. Artificial neural networks distinguish among subtypes of neoplastic colorectal lesions. Gastro 2002;122:606–613. 104. Bernstein CN, Weinstein WM, Levine DS, Shanahan F. Physicians’ perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis [see comments]. Am J Gastroenterol 1995;90:2106–14.
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47 Quality Improvement in Inflammatory Bowel Disease Richard B. Colletti and Peter A. Margolis
Introduction In recent decades research has generated an enormous growth of medical science, technology and therapeutics. Knowledge from basic research, translational research, randomized clinical trials and outcomes research has enabled experts in many fields to develop and disseminate evidencebased clinical practice guidelines with recommendations for medical practitioners. Yet health services research suggests that health care could perform a great deal better than it does today. For example, an audit of medical records of 4,000 adults in 12 cities in the USA showed that only 55% of recommended preventive, acute and chronic care was being received [1]. A study of 3,000 hospitals found that for only 5 of 10 measures was recommended care provided to a large majority of patients [2]. A report of the Institute of Medicine, Crossing the Quality Chasm, calls for improvements in six dimensions of health care performance: Safety, Timeliness, Efficiency, Effectiveness, Equity and Patient-centeredness (STEEEP) [3]. The National Scorecard on U.S. Health System Performance, an assessment of health care outcomes, quality, access, equity and efficiency, found that the U.S. achieves an average score of only 66%. If the U.S. improved performance in key areas, it could save an estimated 100,000 to 150,000 lives and 50 to 100 billion dollars annually [4]. To improve the care of patients requires more than knowledge; achievement of improvements requires the application of the principles of continuous quality improvement [5, 6]. Quality improvement is a structured organizational process for involving personnel in planning and executing a continuous flow of improvements to provide quality health care that meets or exceeds expectations [7]. Quality improvement in health care is the application of knowledge to make changes that result in better care and outcomes. One of the barriers to quality improvement is unnecessary variation in care. Unnecessary variation, which erodes quality and reliability and adds to costs, is derived in part from habitual differences in practice style that are not grounded in knowledge or reason [8]. Quality improvement efforts can reduce unnecessary variation. To attain continuous quality improvement in health care it is necessary to repeatedly measure the processes and outcomes of care, design and implement interventions to improve the processes of care, and re-measure to determine the effect of the interventions [9]. In this chapter we will present an introduction to quality improvement and how
Richard B. Colletti, MD, Vice-Chair, Department of Pediatrics, Associate Chief, Vermont Children’s Hospital, E-203 Given Medical Bldg, University of Vermont, Burlington VT 05405-0068, Phone: 802-6560027, Fax: 802-656-2077, E-mail:
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it can apply to pediatric inflammatory bowel disease, with brief discussions of variation in care, the Chronic Illness Care Model, the need for quality improvement, the Improvement Model, the Improvement Collaborative, and the role of a collaborative network.
Variation in Care Inflammatory bowel disease (IBD) is the most common serious chronic gastrointestinal disease afflicting children and adolescents in North America. Yet there is currently considerable variation in the way gastroenterologists diagnose and treat IBD. Variation in care can be due to underuse, overuse or misuse of diagnostic and therapeutic interventions. An example of underuse is failure to obtain a small bowel series x-ray, or neglecting to identify and treat growth failure; an example of overuse is unnecessary prolonged prednisone treatment; and an example of misuse is prescribing infliximab to a patient with tuberculosis. While some variations are due to patient needs or preferences, many variations are due to a lack of adherence by practitioners to best practices. Standardization of care occurs when a network of physicians agrees to provide care in a uniform manner using an evidence-based protocol of care appropriate for each patient. Standardization of care reduces unnecessary variation and, when combined with systematic studies of planned variations (including randomized studies), can lead to increased knowledge and improved outcomes. Figure 47.1A is a theoretical example of a wide variation in the number of diagnostic tests performed prior to initiating treatment (labeled Before). When a larger number of tests than average are performed it could indicate overuse of some tests, while a smaller number than average could indicate underuse. In this example, after a successful quality improvement project leading to less unnecessary variation in care, there is less overuse and less underuse than before, although the average number of tests is the same. Figure 47.1B is a theoretical example of a wide variation and a low percentage of patients at most sites having a skin test for tuberculosis before initiating infliximab therapy (labeled Before). After a successful improvement project there is less variation and a higher rate of skin testing. Variation in care has been demonstrated in pediatric IBD [10, 11, 12, 13]. Preliminary data are available on variation in care from prospective cohort studies of PIBDNet—the Pediatric IBD Network for Research and Improvement. Pediatric gastroenterologists enrolled patients with Crohn disease who were starting treatment with a thiopurine (6-mercaptopurine or azathioprine) or infliximab. Data from 250 patients at 80 sites were examined for variation in diagnostic and therapeutic interventions. Diagnostic studies in which care was uniform included the complete blood count, sedimentation rate, liver function tests and colonoscopy, performed in 95% to 100% of patients; as well as fecal calprotectin and genetic testing (NOD2), performed in only 2% to 3%. Less uniformly performed evaluations included small bowel series radiography, performed
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Figure 47.1. Variation in care. A. Improving quality by decreasing variation. B. Improving quality by shifting distribution.
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in 72% of patients, stool pathogens in 71%, C-reactive protein in 65%, thiopurine methyltransferase (TPMT) in 60%, and diagnostic serology (perinuclear type anti-neutrophil cytoplasmic antibody (pANCA) or anti-Saccharomyces cerevisiae antibody (ASCA)) in 38%. There was also variation in therapeutic interventions, including concurrent treatment with mesalamine in 60% of patients and a vitamin supplement in 37%. The dose of mesalamine varied between 13 and 145 mg/kg/d. In addition, of 220 patients treated with a thiopurine medication, there was variation in the measurement of TPMT, the drug selected (azathioprine versus 6-mercaptopurine) and the dosage prescribed. Patients in whom TPMT had been measured were more likely to receive the recommended dose of thiopurine. Thus, there is clear documentation of considerable variation in diagnostic and therapeutic care in pediatric IBD, suggesting the presence of underuse, overuse and potentially misuse of interventions, as well as the opportunity for considerable improvement. Documentation of variation in care has been important in efforts to standardize and improve care in other fields of medicine [14]. For example, the Epidemiologic Study of Cystic Fibrosis has demonstrated large variations in practice patterns regarding the prescription of various therapies as well as the fact that a significant proportion of CF patients are not monitored as recommended by the Cystic Fibrosis Foundation (CFF) [15, 16]. In this study, only 58% of patients had quarterly visits to their CF Care Center, 76% had biannual spirometry, 79% had annual airway cultures and 68% had annual chest radiographs [17]. CF Registry reports are now presented in such a way as to reveal practice variation among practice sites, partly in order to motivate an evaluation of this variation and to promote standardization where indicated.
The Chronic Illness Care Model The Chronic Illness Care Model provides a useful framework for developing changes to the system of IBD care [18, 19]. Wagner and colleagues conducted an exhaustive literature review and program assessment to identify the key components of systems of health care delivery that result in improved outcomes for patients with chronic illness. Wagner’s model includes the following components: family and patient self-management support, decision support, delivery system design, clinical information systems, community resources and the health care organization (Figure 47.2). Family and patient self-management support includes the methods used by the clinic to increase families’ participation in care. Decision support includes the use of care protocols that are integrated into practice systems. The delivery system design component includes the use of planned encounters, clarity in the roles and responsibilities of team members with appropriate training, and the use of regular meetings of the care team to review performance. The clinical information system refers to the ability of caregivers to access data and use registries for care and to provide regular feedback to the team, and also information technology to facilitate scheduling and patient tracking. A prepared proactive practice team interacts with an informed activated patient to improve functional and clinical outcomes. The application of improvement science has lead to major advances in quality in the automobile, microchip and other industries [20–22]. Does quality improvement work in health care? Quality improvement interventions utilizing the Chronic Care Illness Model in asthma, congestive heart failure, depression and diabetes have improved clinical outcomes, processes of care and quality of life. Studies of controlled trials of interventions that contain at least one element of the Chronic Care Model have demonstrated significant improvements in care [23]. In a cohort study to determine the effect of a specialist nurse on the outcome of 340 patients with IBD, intervention resulted in a 38% reduction in hospital visits, a 19% reduction in hospital length of stay, a 10% increase in patients in remission and improvement in patient satisfaction [24]. A multicenter randomized controlled trial of a quality improvement project in IBD showed similar results [25].
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Figure 47.2. The chronic illness care model. Adapted from EH Wagner, Joint Commission Journal on Quality Improvement 2001;27:65, by permission of the Joint Commission Journal on Quality Improvement.
The Need for Quality Improvement in IBD Has disease outcome in Crohn disease improved during the last four decades? In a report published in 2004, a structured systematic literature review was performed to evaluate measurable outcomes in Crohn disease. Evaluation of mortality, cancer, disease recurrence, extra-intestinal manifestations and medication use failed to show hard evidence for improvement in disease outcome in Crohn disease during the last four decades [26]. Despite advances in research and therapy, the application of knowledge to the improvement of health outcomes and quality of life has lagged. Are patients with IBD receiving optimal care? A study found that adults with IBD referred for a second opinion often were not receiving optimal medical therapy [27]. There was suboptimal dosing of mesalamine and immunomodulatory medications, prolonged use of corticosteroids, failure to use steroid-sparing agents, inadequate measures to prevent metabolic bone disease and inadequate screening for colorectal cancer. The PIBDNet study of variation in care found that many patients diagnosed with Crohn disease had not been tested for intestinal pathogens, had not had imaging of the small intestine, were not receiving a multi-vitamin supplement, had not been tested for TPMT prior to treatment with a thiopurine, had not been tested for tuberculosis prior to treatment with infliximab and were receiving suboptimal dosage of medications. Quality improvement in adult gastroenterology has previously focused on endoscopic procedures [28–35]. However, the American Gastroenterological Association Task Force on Quality in Practice issued a report recommending the formation of an AGA Quality Center to assure uniform documentable excellence in quality of clinical care and GI practice, to support the aims for quality health care set forth by the Institute of Medicine, to identify key quality of care indicators in the treatment of digestive diseases and how they will be measured, to develop programs and tools to assist in implementing evidence-based guidelines and measuring and reporting adherence to quality indicators, and to develop patient education materials to ensure that patients have appropriate expectations regarding high-quality, patient-centered, evidence-based care [36]. The Task Force agreed that the evolving national mandate for assessment of quality of clinical care makes it essential and urgent that a national outcomes database be developed. The initial focus for such a database should be those conditions highest on the list of the Gastroenterology Burden of Disease
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Report, and quality measures should be established in areas where valid evidence-based guidelines exist, including the management of Crohn disease. In addition, the Task Force recommended identifying physicians and groups that evaluate and document high quality patient care and patient safety initiatives and disseminate their best practices. The AGA Task Force report highlights the need to apply the principles of improvement science to IBD.
The Improvement Model The Improvement Model is the foundation of a system for innovation and a framework for developing, testing and implementing incremental change [37]. The model is based on three questions (Figure 47.3): What are we trying to accomplish? How will we know that a change is an improvement? What change can we make that will result in improvement? Any approach to improvement must be based on building and applying knowledge. Within the overall framework, the Plan-Do-Study-Act (PDSA) Cycle is a structured application of the scientific method that provides a means to learn rapidly in complex organizational settings. The Plan phase consists of stating the objective of the test, making predictions, and developing a plan to carry out the test. The Do phase consists of carrying out the test, documenting problems and unexpected observations, and beginning an analysis of the data. The Study phase consists of completing the analysis of the data, comparing the test data to predictions and summarizing what was learned. The Act phase consists of deciding upon and carrying out the changes to be made, and considering what will be the objective of the next cycle. The Improvement Model means applying the principles of using data; developing, testing and implementing changes; and working collaboratively to bring about improvement in the outcomes of health care (Figure 47.4).
Model for Improvement What are we trying to accomplish? (AIM) How will we know that a change is an improvement? (MEASURE) What changes can we make that will result in improvement? (IDEAS)
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Figure 47.3. The improvement model. Adapted from Langley, Nolan, Nolan, Norman and Provost [37], page 10, by permission of Jossey Bass.
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Figure 47.4. Repeated use of the Plan-Do-Study-Act cycle. Adapted from Langley, Nolan, Nolan, Norman and Provost [37], page 9, by permission of Jossey Bass.
The Improvement Collaborative An Improvement Collaborative in IBD is a sequential process in which a group of multidisciplinary teams from 10 or more different practice sites work intensively together using the principals of improvement science to improve the delivery of care and the quality of life of patients with IBD. Improvements consist of redesigning delivery systems to ensure that patients receive recommended care, and are not subject to underuse, overuse or misuse. An Improvement Collaborative includes three main phases: 1) a design and development phase, in which the aim and measures for the project are developed (see Table 47.1), and changes to be tested are identified and summarized using formal methods for the design of new processes and systems, 2) an implementation phase in which practice sites work together to test and adapt changes in care delivery, and 3) a dissemination phase, where, as changes in the process of care delivery are tested and reliably achieve desired goals, they are disseminated to other and eventually all pediatric gastroenterology practice sites. Participating sites gather data about their patients’ care, share data about the outcomes of care with all of the other sites, identify sites that are performing better, examine reasons for the better performance, set benchmarks for outcomes, and share ideas to enable the other sites to improve their outcomes. Participating sites gather together for learning sessions to share data and ideas, and then return to their sites to perform PDSA improvement projects there, gathering and sharing new data in an incremental process (Figure 47.5).
Table 47.1. Measurable outcomes of treatment of pediatric IBD. Disease activity Remission rate Interval between relapses Complication rates (e.g., fistula) Nutritional status Growth, final adult height Days missed from school Emergency department visits Hospitalization rate Hospital length of stay Surgery Patient and family satisfaction Patient quality of life
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Figure 47.5. A schematic drawing of the sequence of events in an Improvement Collaborative. Adapted from a presentation of the Institute for Healthcare Improvement.
An Improvement Collaborative is intended to encourage practices to adopt a more organized approach to IBD care. It is based on models of behavior change and diffusion of innovations in medical practice including involvement of opinion leaders in the medical community, recognition of a performance gap, involving physicians and staff in developing a strategy to make changes to close the gap, compatibility of the intervention with current practice, and reinforcement of positive change [38]. It is designed to identify and address barriers in the way care is delivered in IBD clinics. This type of systems intervention is especially important in pediatric IBD clinics because many pediatric IBD practice sites operate within large tertiary medical centers with relatively rigid infrastructures requiring significant and determined effort to change; IBD care is characterized by a complex mixture of preventive and chronic therapeutic interventions; distance and other factors make frequent return visits difficult for many patients, so accidental omission of services and other missed opportunities for care are harder to correct; and the responsibility for care is shared by multidisciplinary teams and multiple physicians with diverse responsibilities who may overestimate the consistency with which they deliver specific services. As efforts to improve quality and safety are just beginning, many opportunities exist for improvement in IBD care. These include a need to measure the current disease status, quality of life and other measurable outcomes of a large population of children and adolescents with IBD, and monitor these measures over time; and to measure and monitor variation in diagnostic testing and treatment of Crohn disease and ulcerative colitis. In addition it is important to perform improvement collaboratives to standardize the diagnostic evaluation of Crohn disease and ulcerative colitis; to standardize methods of assessing growth in Crohn disease, identifying patients at risk for or with growth failure, and intervening to improve growth, including final adult height; to standardize the initial treatment of mild to moderate Crohn disease, with subsequent cluster randomization (randomization by site) to compare outcomes using alternate protocols; to standardize treatment that avoids the use of corticosteroids, to optimize treatment with thiopurines, and to improve patient adherence. It is also important to develop a prospective database to determine the incidence of major adverse effects of thiopurines, infliximab, adalimumab and other immunomodulators, including serious infection and malignancy, and to improve the monitoring and reporting of adverse drug reactions. The first Improvement Collaborative in pediatric IBD was begun in early 2007, with an emphasis on improving diagnosis, growth and treatment with thiopurines.
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Collaborative Networks Whereas the purpose of research is to gain knowledge, the goal of quality improvement is to improve care and outcomes. Ultimately knowledge gained through research can be applied to clinical care, and quality improvement depends on research to advance care, so both research and quality improvement are necessary to improve outcomes. The potential benefit of collaboration by pediatric specialists to improve care is exemplified by the successes of the Cystic Fibrosis Foundation and the Children’s Oncology Group [39]. By working collaboratively in research and improvement, pediatric gastroenterologists can reduce unnecessary variation, implement uniform best practices, standardize care and perform randomized studies. By developing protocols that standardize care to reduce unintended variation, a large network of collaborating pediatric gastroenterologists can more readily learn from planned systematic variation, such as in randomized studies. Newly discovered diagnostic and therapeutic interventions can be more readily incorporated into standardized care protocols, resulting in a more rapid dissemination of clinical advances with the opportunity to assess their impact. By working collaboratively in research and improvement, pediatric gastroenterologists can bring about a dramatic improvement in the care, outcomes and quality of life of children and adolescents with Crohn disease and ulcerative colitis. References 1. McGlynn EA, Asch SM, Adams J, Keesey J, Hicks J, DeCristofaro A, Kerr EA. The quality of health care delivered to adults in the United States. N Engl J Med 2003;348:2635–45. 2. Jha AK, Li Z, Orav EJ, Epstein AM. Care in U.S. hospitals—the hospital quality alliance program. N Engl J Med 2005;353:265–74. 3. Institute of Medicine. Crossing the Quality Chasm: A New Health System for the Twenty-first Century. Washington, DC: National Academy Press, 2001. 4. http://www.cmwf.org/publications/publications_show.htm?doc_id=401577doc401577 5. Berwick DM, Nolan TW. Physicians as leaders in improving health care. Ann Intern Med 1998;128: 289–92. 6. Clemmer TP, Spuhler VJ, Berwick DM, Nolan TW. Cooperation: The foundation of improvement. Ann Intern Med 1998;128:1004–1009. 7. McLaughlin CP, Kaluzny AD. Defining quality improvement. In McLaughlin CP, Kaluzny AD (eds): Continuous quality improvement in health care: Theory, implementation, and applications. Sudbury: Jones and Bartlett Publishers, 2005:3–40. 8. Berwick DM. Controlling variation in health care. Med Care 1991:29:1212–25. 9. Ferguson TB, Peterson ED, Coombs LP, Eiken MC, Carey ML, Grover FL, DeLong ER. Use of continuous quality improvement to increase use of process measures in patients undergoing coronary artery bypass graft surgery. JAMA 2003;290:49–56. 10. Colletti R, Baldassano R, Milov D, Margolis P, for PIBDNet—the Pediatric IBD Network for Research and Improvement. Variation in initial evaluation and treatment of pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2005;41:537. 11. Colletti RB, Baldassano RN, Milov DE, Margolis PA, PIBDNet –the Pediatric IBD Network for Research and Improvement. Variation in initial 6-mercaptopurine dosage in pediatric Crohn disease. Gastroenterol 2006;130:A652. 12. Kappelman MD, Bousvaros A, Hyams J, Markowitz J, Pfefferkorn M, Kugathasan S, Rosh J, Otley A, Mack D, Griffiths A, Evans J, Grand R, Langton C, Kleinman K, Finkelstein JA. Intercenter variation in initial management of children with Crohn’s disease. Inflam Bowel Dis 2007;13:890–5, 2007 13. Colletti RB, Baldassano RN, Milov DE, for PIBDNet—the Pediatric IBD Network for Research and Improvement. Predictors of outcome of treatment of pediatric Crohn’s disease with 6-mercaptopurine or azathioprine. J Pediatr Gastroenterol 2006;43(supp2):S40 14. Jha AK, Li Z, Orav EJ, Epstein AM. Care in U.S. hospitals—the Hospital Quality Alliance program. New Engl J Med 2005;353:265–74.
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15. Morgan WJ, Butler SM, Johnson CA, et al. Epidemiologic study of cystic fibrosis: Design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada. Pediatr Pulmonol 1999;28:231–41. 16. Konstan MW, Butler SM, Schidlow DV, Morgan WJ, Julius JR, Johnson CA: Patterns of medical practice in cystic fibrosis: Part II. Use of therapies. investigators and coordinators of the epidemiologic study of cystic fibrosis. Pediatr Pulmonol 1999;28:248–54. 17. Konstan MW, Butler SM, Schidlow DV, Morgan WJ, Julius JR, Johnson CA: Patterns of medical practice in cystic fibrosis: Part I. Evaluation and monitoring of health status of patients. Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Pediatr Pulmonol 1999;28:242–7. 18. Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with chronic illness. JAMA 2002;1775–9. 19. www.improvingchroniccare.org 20. Deming WE. Out of the Crisis. Cambridge, MIT Center for Advanced Engineering Study, 1982 21. Imai M. Kaizen, the Key to Japan’s Competitive Success. New York, McGraw-Hill Publishing Company, 1986. 22. Grove AS. Efficiency in the health care industries. JAMA 2005;294:490–2. 23. Tsai AC, Morton SC, Mangione CM, Keeler EB. A meta-analysis of interventions to improve care for chronic illnesses. Am J Manag Care 2005;11:478–88. 24. Nightingale AJ, Middleton W, Middleton SJ, Hunter JO. Evaluation of the effectiveness of a specialist nurse in the management of inflammatory bowel disease (IBD). Eur J Gastroenterol Hepatol 2000;12:967–73. 25. Kennedy AP, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, Rogers AE, Sculpher M, Thompson DG, the North-West Regional Gastrointestal Research Group. A randomized controlled trial to assess the effectiveness and cost of a patient orientated self management approach to chronic inflammatory bowel disease. Gut 2004;53:1639–45. 26. Wolters FL, Russel MGVM, Stockbrugger RW. Systematic review: Has disease outcome in Crohn disease changed during the last four decades? Aliment Pharmacol Ther 2004;20:483–96. 27. Reddy SI, Friedman S, Telford JJ, Strate L, Ookubo R, Banks PA. Are patients with inflammatory bowel disease receiving optimal care? Amer J Gastroenterol 2005;100:1357–61. 28. Ball JE. Osbourne J. Jowett S. Pellen M. Welfare MR. Quality improvement programme to achieve acceptable colonoscopy completion rates: Prospective before and after study. BMJ 2004;329:665–7. 29. Zebris J. Maurer W. Quality assurance in the endoscopy suite: Sedation and monitoring. Gastroint Endosc Clin N Amer 2004;14:415–29. 30. de Lange T. Moum BA. Tholfsen JK. Larsen S. Aabakken L. Standardization and quality of endoscopy text reports in ulcerative colitis. Endosc.2003;35:835–40. 31. Robertson DJ. Lawrence LB. Shaheen NJ. Baron JA. Paskett E. Petrelli NJ. Sandler RS. Quality of colonoscopy reporting: A process of care study. Amer J Gastroenterol 2002;97:2651–6. 32. Johanson JF. Continuous quality improvement in the ambulatory endoscopy center. Gastrointestinal Endosc Clin N Amer 2002;12:351–65. 33. Seematter-Bagnoud L. Vader JP. Wietlisbach V. Froehlich F. Gonvers JJ. Burnand B. Overuse and underuse of diagnostic upper gastrointestinal endoscopy in various clinical settings. International Journal for quality in health care 1999;11:301–8. 34. O’Connor JB. Sondhi SS. Mullen KD. McCullough AJ. A continuous quality improvement initiative reduces inappropriate prescribing of prophylactic antibiotics for endoscopic procedures. Amer J Gastroenterol 1999; 94:2115–21. 35. Rogers A. Kennedy A. Nelson E. Robinson A. Patients’ experiences of an open access follow up arrangement in managing inflammatory bowel disease. Qual Saf Health Care 2004;13:374–8. 36. Brotman M, Allen JI, Bickston SJ, Campbell DR, Huddleston JM, Peterson LE, Schoenfeld PS, Sennett CS, Willis JR. The AGA task force on quality in practice: A national overview and implications for GI practice. Gastroenterol 2005;129:361–9. 37. Langley GL, Nolan KM, Nolan TW, Norman CL, Provost LP. The Improvement Guide. A Practical Approach to Enhancing Organizational Performance. San Francisco: Jossey-Bass, 1996:xiv–xxix. 38. Rogers E. Diffusion of Innovations. New York: The Free Press, 2004. 39. Simone JV. History of the treatment of childhood ALL: A paradigm for cancer cure. Best Practice Res Clin Haematol 2005;19:353–9.
48A Advocacy for Pediatric Patients with Inflammatory Bowel Disease Janis Arnold, Athos Bousvaros, and Jennifer C. Jaff∗
Introduction Physicians who treat patients with chronic illnesses know that the practice of medicine has come to involve the practice of patient advocacy. Whether it be justifying a prescription for a non-formulary medication or trying to help a child obtain necessary accommodations from a school, physicians who treat children with IBD have to learn to be advocates. Although this is not something we are taught in medical school, it has become an integral facet of practicing collaborative medicine in the United States in the 21st century. The following chapter is written by three individuals: a pediatric gastroenterologist, a pediatric clinical social worker who works with patients with IBD, and an attorney who runs a nonprofit that provides advocacy services to patients with chronic diseases. Although we focus on the role of the physician as a patient advocate, we firmly believe that the use of a medical team approach is most effective in meeting the advocacy needs of patients. The medical team may involve the physician, nurses, social workers, nutritionists, psychologists, and administrative staff. In smaller centers, providers may find themselves taking on multiple roles. We will discuss the following four substantive areas in which advocacy for patients is necessary: 1. Navigating school administrative requirements to enable optimal academic plans for ill children with IBD to attend school; 2. Insurance company denials of a needed therapy, including mental health services; 3. Social Security disability assistance for children and adolescents; and 4. Family and medical leave for caretakers of children with IBD. We have written previously about 1BD patient advocacy issues and how they affect physicians. This current paper expands and elaborates on our prior piece1 .
∗ Executive Director, Advocacy for Patients with Chronic Illness, Inc., 18 Timberline Drive, Farmington, CT 06032, Phone: 860-674-1370, Fax: 860-674-1378, E-mail:
[email protected], www.advocacyforpatients.org 1 An earlier version of this article appeared as: Jaff, JC, Arnold, J, Bousvaros, A, Effective Advocacy for Patients with Inflammatory Bowel Disease: Communication with Insurance Companies, school administrations, employers, and other health care overscors. Inflamm Bowel Dis 2006; 12:814-23.
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Advocacy Directed at Schools We recently identified a child who has not been in school for a year and one-half because his parents did not understand that they could request accommodations for him that would have allowed him to stay in school. They essentially just waited for something to change; they had no idea where to go for help. When the school district sent them forms to fill out to begin the process of evaluating the child for accommodations, they did not understand what they were being asked to permit, so they withheld their consent. The result was that this child hid in his room for nearly 18 months while the parents waited for something – anything – to happen. There are two related statutes that provide protection for students with IBD: the Individuals with Disabilities Education Act (“IDEA”),2 and Section 504 of the Rehabilitation Act of 1973 (“Section 504”).3 The IDEA applies to state and local education agencies, whereas Section 504 applies to educational institutions that are recipients of federal funds. The two statutes are related, but they are not identical. Whereas the IDEA applies only to grade and secondary schools, Section 504 pertains to all levels of education – grade school to college to graduate schools that accept federal funding. The IDEA primarily is geared toward students who need special education services related to a learning disability as apposed to students with a physical condition like IBD, whereas Section 504 is broader, and includes physical disabilities as well as learning disabilities. Patients with IBD usually do not have a lifelong learning disability that requires placement in special education classes. However, they may require some accommodations due to school absence during periods of illness, or because their illness sometimes limits their participation. Thus, patients with IBD are more likely to be eligible for accommodations under section 504 than they are for accommodations under IDEA. The IDEA provides that a child with a disability who needs special education is entitled to a free appropriate public education. The IDEA defines a child with a disability to include children with a number of specific types of disabilities, including visual and hearing impairments, speech and language impairments, autism, traumatic brain injury, emotional disturbances. While inflammatory bowel disease is not explicitly stated in the IDEA, the law does include a proviso providing assistance to children with “other health impairments.” Generally, however, children who qualify for assistance under the IDEA have a physical or mental disability that affects their ability to fully participate in school without some form of assistance. Under the IDEA, the first requirement imposed on the states is to “identify, locate and evaluate” children in need of special education services (called “child find”). Once children are located, the IDEA requires states to meet the needs of those children. The core of the IDEA is the “individualized education program” or “IEP.” Under the IDEA, states are required to conduct an evaluation before special education benefits are granted. The evaluation determines whether the child is, in fact, a “child with a disability” and has special educational needs. The process should be initiated by the school, which should provide notice of the evaluation to the parents. The child may be tested and evaluated using a variety of tools; after this evaluation is completed, the actual IEP is formulated. The IEP should be a separate written statement for each qualifying student that includes a statement of the child’s level of educational performance; a statement of goals; a statement of the special education and related services to be provided; an explanation of the extent, if any, of the child’s participation in mainstream programs; a statement of any individual modifications; the projected date for commencement of these services; and the duration of the services. In fashioning the IEP, the strengths of the child, the parents’ concerns, and the results of the most recent evaluation of the child must be considered. 2 3
20 U.S.C. § 1400, et seq. 29 U.S.C. § 794(a).
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The IEP “team” includes the parents, at least one non-special education teacher, at least one special education teacher, a representative of the local agency who is qualified to assist in formulating IEPs, other experts brought in at the request of the parents or the State, and, if appropriate, the child. The IDEA provides safeguards to ensure parental involvement at all stages of the child’s education, and parents may challenge any aspect of an IEP by requesting a hearing, and if they remain dissatisfied, they may file suit in federal court. Schools that provide services under the IDEA also are eligible for financial support through the state and federal government. In contrast, Section 504 of the Rehabilitation Act was enacted to promote the inclusion and integration of people with disabilities into the mainstream. Section 504 provides that disabled children cannot be denied the benefits of any program that receives federal financial assistance, including public education. In general, a child is disabled if he or she has a “physical or mental impairment” that “substantially limits” one or more “major life activities” as those terms are used in the Americans with Disabilities Act.4 Major life activities include eating and disposal of bodily waste. Once the student’s medical disability is established, the next step is to determine what special accommodation are needed. While section 504 is a more inclusive statute than the IDEA, school districts providing services under 504 plans are not reimbursed for their expenses by the federal government. Because Section 504’s definition of disability is broader than the IDEA’s, many IBD patients will qualify under Section 504 but not under the IDEA. These are called “504-only students.” For some patients, accommodations are minimal (e.g., providing medication during school hours, or being excused from physical education class), whereas for other students, accommodations are more extensive (including limiting home work loads, home tutoring, and special education). Under Section 504, any assistance a student receives from a school must be provided for free. Any child who needs accommodation under IDEA or section 504 must be the subject of an evaluation before taking any action with respect to placement. Once testing is concluded, schools use the results, as well as teacher recommendations, physical condition, social or cultural background, and adaptive behavior in designing the plan for the student. Parents must have notice and opportunity to examine the evaluation records, there must be a hearing opportunity at which the parents and/or other guardian can appear if they are dissatisfied with the plan, and there must be a procedure for review of the decision. There are at least two issues that face IBD patients that are not well addressed by the law. First, children who do well in school are presumed not to need help. The IDEA defines “child with a disability” to mean a child with health problems “who, by reason thereof, needs special education and related services.” A student who does not need special education because she is performing well academically is not a “child with a disability” under the IDEA. Therefore, only children with IBD who have neurologic or developmental conditions that impair learning are covered under the IDEA. Second, neither statute provides explicit guidance for children with a chronic disease that remits and relapses. Because chronic illness is cyclical in nature, there will be times when a student needs home schooling or temporary access to typed handouts, and other times when the student has no need for help. This presents a challenge for both the parents and the school, because the IEP or Section 504 plan is not intended to apply only intermittently. The waxing and waning course of IBD and the unpredictability of the illness necessitates that the 504 plan for an IBD patient be flexible and change depending on whether the patient is ill or in remission. Generally, it is the child’s parents in conjunction with members of the health care team that realize that educational accommodations may be needed for their chronically ill child. In patients with IBD, this need often is recognized during a period of prolonged illness (such as in a hospitalization for intravenous medication or surgery). At this point, parents and members of the
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health care team should list the child’s needs in writing, and work with school officials to develop a written plan. A plan under either the IDEA or Section 504 may include accommodations such as seating chart placement, extended time for testing, adjustment of class schedules, use of aids such as tape recorders, permission to photocopy a classmate’s handwritten notes, class and/or homework assistance, administration of medication, behavioral support, initiation of tutoring prior to the standard 14 consecutive day absence, access to bathroom without required hall passes, permission to have a water bottle in class, or multiple sets of textbooks. For chronically ill patients with IBD, parents and school officials should have this integrated academic plan for IBD students in place.5 The IBD Center at Boston’s Children’s Hospital had the opportunity to work with a high school student who experienced her first severe flare-up of her ulcerative colitis, which had been wellcontrolled for many years. Her symptoms initially were unresponsive to various medications. She ultimately was placed on tacrolimus, which lead her to develop the side effects of hand tingling, joint pain, and hand tremors. Though her medication regimen decreased her GI symptoms enough to allow school re-entry, the side-effects from the necessary medication left her unable to fully participate in the classroom requirements, including note taking. Consequently, this interfered with her ability to have the adequate review materials to study for tests. We collaborated with the patient’s mother and the school to develop a 504 plan for the patient. Among other plan provisions, relevant accommodations included allowing her to identify a classmate in each course whose notes she had permission to photocopy. It also was detailed that the teacher would, when appropriate, provide the student with typed copies of the class notes and outlines. An additional item was written into her 504 plan that stated that, if she had to be absent unpredictably, the plan coordinator would be responsible for getting the student a copy of the classmates’ notes and teacher outlines within 48 hours of missed school days. This protected the student’s academic performance and reduced the anticipatory anxiety regarding not being able to keep up with the class notes – anxiety that could lead to exacerbation and prolonging of her disease’s symptoms. Although a Section 504 plan can be implemented during periods of illness, many families and patients find it helpful to coordinate and delineate these educational adaptations prior to what may be experienced as a medical crisis or complications, given our awareness that these disease process is unpredictable and can change quickly. It is often difficult and burdensome to try to arrange these meetings and plan at times when families are simultaneously focusing on acute medical demands and the family reorganization that must accommodate them. Nonetheless, it is critical that normal school attendance, curriculum participation and activity should be encouraged during periods of remission. (See Appendix 1).
Advocacy Directed at Insurance Companies Inflammatory bowel disease is a costly illness; one 1992 study estimated the per capita annual costs of Crohn’s disease (“CD”) to be approximately $6,500 dollars, though a small number of patients account for the bulk of that cost.6 Charges for a hospitalization may approach $30,000, especially when that hospitalization involves surgery.7 For these reasons, coverage by third party payors is essential for most patients. When coverage for a therapy is denied by an insurance company, the patient in all likelihood will not be able to pay for it him or herself. Thus, appealing the decision may be necessary. 5
Ketlak D. Advocating for your chronically ill child within the school setting. Pediatric Crohn’s and Colitis Association Website http://pcca.hypermart.net/advocating.html 2002. 6 Hay JW, Hay AR. Inflammatory bowel disease: costs-of-illness. J Clin Gastroenterol 1992; 14:309–17. 7 Cohen RD, Larson LR, Roth JM, Becker RV, Mummert LL. The cost of hospitalization in Crohn’s disease. Am J Gastroenterol 2000; 95:524–30.
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Nationally, approximately 70% of health insurance appeals are granted.8 That means that, in most cases, appealing is not a waste of the patient’s time. However, without the physician’s help and advocacy, appeals are difficult, if not impossible. Yet, not all physicians know what to say to an insurance company. For example, when one physician was sent a denial of coverage for a 30-day supply of Zofran, and the patient asked her to call her insurance company and appeal the denial, the physician’s response was “what do you want me to say?” In this case, the patient was also a patient advocate, and could coach her doctor through the appeal by telling her to explain that everything else had been tried and failed, and that intractable nausea required this medication. But what happens to a patient whose physician does not know how to be an advocate? There are at least two main categories of appeals: medical necessity appeals and appeals from denials of coverage due to the nature of the medicine, device or other treatment. For medical necessity appeals, the physician and patient must highlight the particulars of the patient’s medical condition, and why a given condition requires a specific medication. As an example of a medical necessity appeal, a patient who develops nausea from generic sulfasalazine but tolerates entericcoated brand name sulfasalazine may initially have the brand name drug denied. However, a brief letter from the physician describing the precise adverse event to the generic medication, and the need for the brand name drug will usually result in approval by the insurance company. Here, both forms of the medication have similar proven efficacy, but one form is medically necessary because it is better tolerated by the patient. The second category, appeals from denials of coverage, typically occurs with a newer, more expensive therapy that is beginning to enter the armamentarium of accepted treatments. Typically, in this circumstance, the physician has access to published literature that supports a claim that a given medication or treatment will help their patient. However, the insurance company or other payor either is unaware of the published literature or does not feel the evidence in support of this new treatment is sufficient to provide reimbursement. For this reason, the payor denies coverage and refuses to reimburse for therapy. This type of appeal (appeal of coverage denial) is the more difficult. The physician and patient must demonstrate that the patient has failed other conventional treatments, highlight the patient’s specific need for the novel therapy requested, and provide published, peer-reviewed literature and supportive information that support the novel treatment’s safety and efficacy. When appealing the denial of coverage of a treatment that the insurer states is experimental, investigational or unproven, attach as much peer-reviewed medical literature as possible. Insurers tend to appreciate longitudinal trials in which patients are followed for a significant period of time, and which involve placebos. This may well be impossible in all cases; for example, if a patient or physician is seeking coverage for a medical device, there may not be a functional equivalent of a placebo that ethically could be used. However, the best literature will be peer-reviewed articles published in medical journals documenting randomized trials in which the treatment is compared to a control group of some kind. Other evidence, including open label trial data or recent proceedings from medical meetings, also may be useful, but will not carry the same weight. If feasible, the physician also should obtain a letter of support from experts in the field stating that the proposed treatment plan is appropriate. In one instance, a physician prescribed adalimumab, and coverage initially was denied as “experimental, investigational or unproven.” In this case, once the payor was provided with sufficient information regarding the patient’s Crohn’s disease, the failure of other treatments, and the medical literature supporting the efficacy of adalimumab for this condition, they agreed to reimburse for the necessary treatment.
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Block S. Don’t take it lying down if your insurer refuses to pay. USA Today Sept 1, 2005; State of Connecticut’s Office of the Health Care Advocate. Connecticut survey of managed care. Available online at http://www.ct.gov/oha/cwp/view.asp?a=2277&q=299978 2002.
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A third type of denial by insurers is an administrative denial. Administrative denials do not involve a medical necessity determination. This type of denial occurs when there is a coverage request for a treatment that is expressly excluded from coverage. For example, if an insurance policy expressly excludes abdominoplasty, a coverage request for abdominoplasty will be denied without regard for medical necessity. Even in this type of case, though, it is possible to force an insurer to conduct a medical necessity review. For example, if a patient requires a medically necessary stoma revision and hernia repair that cannot be performed without the abdominoplasty, the physician may be able to convince the insurance company to consider the medical necessity of the abdominoplasty as long as the insurer agrees that the stoma revision and hernia repair are medically necessary. Regardless of the type of appeal, there are some general considerations. Insurers will not grant benefits solely based on a patient’s subjective report of symptoms. The physician and patient in describing the indication for the appeal, must provide “objective medical evidence” ( i.e., evidence that can be measured scientifically). In addition to describing the patient’s current symptoms (i.e., abdominal pain, diarrhea, fatigue), the physician should provide results of recent blood tests, radiographs, and endoscopic examinations that demonstrate ongoing intestinal inflammation. In addition, if a patient develops an adverse event (AE) to a conventional therapy, the AE should be described in detail (e.g., not simply “infusion reaction to infliximab” but “chest pain and hives with infliximab, which recurred on rechallenge”). While the provider should not ignore the patient’s subjective reports of symptoms, subjective evidence of ongoing disease activity may not be sufficient to prove medical necessity. A physician who writes a letter of medical necessity according to the above guidelines (summarized in Appendix 2) stands a good chance of getting the needed treatment covered. Another area in which letters of medical necessity may be necessary is in obtaining mental health referrals for patients with IBD. Given the stress of IBD and the social stigma associated with its symptoms the risk for exacerbations of IBD during periods of stress, and the mood-altering effects of medications, patients with CD and ulcerative colitis (“UC”) often derive significant benefit from psychological support. We are aware that there often are significant associated psychological and social effects resulting from both short and long-term steroid use, including mood lability, mania, anxiety and symptoms mirroring those of depression. Many children with IBD not only have to cope with the unpredictable impact of these emotional ramifications, but also the body image issues that often are secondary to side effects of the unavoidable and recurrent steroid administration necessary to keep the disease process controlled. Studies have demonstrated that a significant proportion of adolescents and young adults with IBD have symptoms of depression, which in turn contribute to decreased quality of life.967 Most payors are receptive to the concept that treatment of a chronic illness in childhood requires psychological as well as medical support. On occasion, however, payors will deny mental health services on the grounds that coping with IBD does not warrant formal treatment by a psychologist or psychiatrist. Health care providers caring for children with IBD are acutely aware that anxiety and depression may impact both disease activity and compliance with the medical regimen. Thus, properly timed psychological or psychosocial intervention often is a crucial factor in overall the treatment success and likelihood of a prolonged remission. Appealing a denial of psychological support is similar to appealing a denial of any other medically necessary therapy. A letter from the medical team should summarize relevant literature
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Szigethy E, Levy-Warren A, Whitton S, et al. Depressive Symptoms and Inflammatory Bowel Disease in Children and Adolescents: A Cross-Sectional Study. J Pediatr Gastroenterol Nutr 2004; 39:395–403; Engstrom I. Mental health and psychological functioning in children and adolescents with inflammatory bowel disease: a comparison with children having other chronic illnesses and with health children. Journal of Child Psychology and Psychiatry and Allied Disciplines 1992; 33:563–582
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that describes the psychological needs in patients with IBD. The letter also can emphasize the complex relationship between a patient’s GI condition, mental health, compliance, and quality of life. It should be emphasized that a patient who is psychologically sound is less likely to undergo recurrent testing and hospitalization for a symptom related to stress and anxiety, all of which would be more costly for the insurance company. This usually is a sufficient reason for insurers to grant limited benefits. While a limited series of sessions is not ideal, these sessions at least allow the patient to gain entrance into the mental health system. At that point, a mental health provider can then determine further indications for ongoing treatment (See Appendix 3). In one instance, a 14-year old patient with Crohn Disease had a complicated course of her illness, having been hospitalized twice for unpredictable flares of her disease and a blood clot in the venous portion of her brain, both times leading to lengthy admissions followed by intensive outpatient follow-up. Her illness’ sporadic and inconsistent response to her treatment plan led to periods of intense stress and pressure, thereby exacerbating symptoms of her disease. The family lived in a small town in a different state from the one in which her gastroenterologist practices, and the only local mental health providers available practiced from a more psychotherapeutic framework. Her insurance company would not cover services at the urban hospital’s specialized medical coping clinic, which was out-of-network for mental health services, yet which provided the specific cognitive behavioral approach that the medical team and family felt would be the best fit for her targeted goals of learning relaxation strategies and coping with the present medical demands. The social worker and physician composed a letter to the insurance company outlining the patient’s specific circumstances, the physical and psychological complications, and the importance of the patient obtaining mental health services that were based in a framework specific to her needs at that time. The letter detailed that the clinic specialized in treating children and teenagers with treatment specifically geared toward helping management of comorbid medical and emotional issues related to IBD. The appeal highlighted that the patient’s access to particular cognitive-behavioral strategies could reduce the risk factors for a necessary and more costly medical or psychological hospitalization, and the unavailability of access these services through local providers covered under the plan. Her insurance company ultimately authorized coverage for 10 treatment sessions, allowing her to learn biofeedback and other concrete mechanisms to help her best cope with the concurrent medical challenges, and provide a forum for ongoing formal assessment and treatment of depression or an anxiety disorder related to the disease process. Although a good result was achieved in this case, what happens if denials continue to occur? At this point, it may be appropriate to have your patient enlist the assistance of an individual with expertise in conducting health insurance appeals, such as a patient advocate or an attorney. All group health insurance that is obtained through an employer in the United States is governed by the Employee Income Retirement Security Act (ERISA),10 which requires “full and fair review” of coverage requests. ERISA’s “full and fair review” requirements mean that insurers must provide a free copy of a patient’s file, and insurers must give reasons for a denial of coverage. The file that must be produced includes any data the insurer relied upon for the decision, as well as information in the file on which the insurer did not rely (i.e., information supporting coverage that the insurer rejected). The purpose of this requirement is to enable patients and their representatives to file a targeted appeal that responds to the specific information upon which the insurer relied, as well as to know what additional information to provide. This “full and fair review” requirement includes the rule that insurers must produce a copy of their clinical criteria for approval or denial of coverage. This is critical. If a patient and a physician have the clinical criteria for approval or denial, the provider can explain how the patient meets criteria for approval. Otherwise, physicians and nurses are left guessing as to what the insurer’s
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29 U.S.C. § 1001, et seq.
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standard is for approving coverage. When a patient requests a copy of the file and clinical criteria in writing for appeal purposes and these materials are not produced within thirty (30) days, a patient can allege that the insurer has violated ERISA. ERISA “full and fair review” also requires that the insurer provide sufficient reasons for the denial to allow the patient to address the issues raised in an appeal. A statement by an insurance company that a treatment is unproven, without further explanation, is insufficient for a denial of coverage. When it has been shown that an insurance company violates ERISA’s provisions, the majority of courts simply grant the benefits to the patient. Therefore, ERISA’s “full and fair review” provisions can be a tremendously useful tool in an insurance appeal. While physicians and health care providers are not expected to be experts in law and public policy, it is important that health care providers be aware of patient’s rights under ERISA. If a physician and patient are both frustrated by repeated denials of a treatment thought to be medically necessary, consider three steps: 1. Have your patient discuss the difficulty with the human resources department at their employer, especially if they work for a large employer that self-insures. The employee can ask the employer to grant what is called an “extra-contractual benefit,” providing coverage for something that otherwise would not be covered. 2. Request a copy of the insurance company’s file, which is guaranteed by ERISA. This information may be valuable in the future. 3. Consider referral to an attorney or patient advocate. Health insurance appeals can be labor intensive. In addition to the patient’s physician, a team of professionals (including nurses, social workers, therapists, and attorneys) may need to assist in preparing the appeal. However, in the United States in 2006, effective advocacy to explain medical needs to third party payors has become an essential element of care of complex patients.
Social Security Disability Many people do not realize that children may be eligible for Supplemental Security Income (“SSI”), one of two forms of Social Security disability benefits.11 However, medically impaired children up to the age of 18 may receive benefits if the income and resources of the parents and child are within allowed limits, as long as the parent worked long enough to be insured under the Social Security system (typically, 40 quarters, or a total of 10 years, with 20 of those quarters occurring in the last 10 years). The child must not be doing any substantial work, and must have a medical condition that has lasted or is expected to last for at least 12 months. A child eligible for SSI will qualify for Medicaid. Whether a child is considered disabled depends on whether he or she has a physical or mental condition that can be medically proven and which results in marked and severe functional limitations that last or are expected to last at least 12 months. A physical or mental condition that results in marked and severe functional limitations might be one that meets the applicable listing of impairments (see Appendix 4), or it might involve a combination of impairments (for example, Inflammatory Bowel Disease and Attention Deficit Hyperactivity Disorder, or IBD and depression).
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The other form of Social Security disability is called Social Security Disability Income, or SSDI. This benefit is available only to patients who have worked and paid into the Social Security system for 40 credits, or 40 quarters (10 years). As such, this benefit is available only to adults.
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Although both the income and the benefit levels for SSI are low, the value of Medicaid is great for children with IBD. While some physicians do not accept Medicaid assignments, Medicaid coverage for children under the Early and Periodic Screening, Diagnostic and Treatment services (“EPSDT”) is extraordinarily broad – broader than most commercial insurance, especially for children with mental health and even dental needs. In order to assist a family to apply for SSI, the health care provider should consult the listings of impairments set forth in Appendix 4 and write a letter that addresses each element of the listing. The listing itself tells you what sorts of evidence the Social Security Administration (“SSA”) will need. For all intents and purposes, this is the same as the “objective evidence” needed in commercial insurance appeals. In addition, the listings may require specific testing. For example, the listing for malnutrition associated with a gastrointestinal problem requires a measure of stool fat excretion, even though the current medical standard may be other diagnostics, such as blood tests. Therefore, while the physician can include any diagnostic testing relevant to the patient’s case, he/she should expressly include the diagnostic testing required by the SSA. Although the SSA will ask you for your medical records, a letter of support that culls the records and explains the child’s condition in the terms set forth in the listings of impairments may well be the key to obtaining these benefits. A physician who is asked to write a letter in support of an application for SSI should track the listings of impairments as closely as possible and attach the evidence that the listings mention. The physician or provider who facilitates this process, and who helps successfully obtains SSI benefits for a patient who needs such assistance, is playing a critical role in improving the likelihood of the success of the prescribed treatment plan. In addition, an integral part of living with any chronic illness is helping maintain self-identity, so that self-esteem and feeling victimized by the disease demands does not disempower the patient. As health care providers, we want to attempt to help the patient preserve that sense of control and self-esteem, and thus avoid an internalized notion of a “disabled” self-concept. This is another reason to help make the process of securing entitlement from these state programs as efficient and seamless as possible. The burden of having to go to such lengths to prove disability can often take on a life of it’s own in the pursuit, and this would be counterproductive to the message we reinforce – the child as a whole person, who is more than the disease. Health care providers who can facilitate the SSI application to prevent a lengthy proof process, can be doing their part to help preserve this message.
Family and Medical Leave for Caregivers Caregivers of children with IBD risk losing their jobs when they take time off to care for their children. Providers may be able to spare them this crisis by educating them on the availability of, and helping them to obtain leave and maintain employment security under, the Family and Medical Leave Act (“FMLA”).12 Covered employers must grant an eligible employee up to a total of 12 workweeks of unpaid leave during a 12-month period to care for an immediate family member (spouse, child, or parent) with a serious health condition. The FMLA applies only to an employee who has been working for the same employer for at least 12 months, for at least 1,250 hours during the previous 12 months, and at a location where at least 50 individuals are employed by the employer within a 75-mile area. A child has a “serious health condition” if he or she is “incapable of self-care” due to a mental or physical disability that limits one or more of the “major life activities.” Just as is the case under the Americans with Disabilities Act, processing of bodily waste is a “major life activity,” so
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29 U.S.C. § 2601, et seq. Many states have their own, more liberal version of family and medical leave. You should consult your State’s Department of Labor for more information.
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children with active IBD have a “serious health condition” under the FMLA.9 Even if symptoms are inactive, children with an IBD diagnosis have the potential to require this care, due to the cyclical nature of chronic illness. The FMLA does not provide for paid leave. In addition, an employer may permit an employee to use all available accrued but unused vacation, sick or PTO time during such leave. The use of other such leave does not extend the time off beyond 12 weeks. One of the lesser-known aspects of the FMLA is that the 12 weeks of leave need not be consecutive. For example, a parent of a child who is infliximab treatments can take a day or two of leave every few weeks under FMLA. Primary caregivers of children with IBD should ask for FMLA leave at the beginning of every year, whether or not they use it, so that they are protected if the child’s disease becomes active. In order to obtain FMLA leave, the employee must request it in writing, and the physician often must complete paperwork that employers give the employee and provide a medical certification establishing the need or potential need for FMLA leave. An FMLA medical certification can describe IBD as a serious health condition falling into various descriptive categories. Depending on the symptom severity, demonstrating need for FMLA leave may best be accomplished by the physician. The medical certification supporting the need for FMLA leave is in some ways similar to a letter of medical necessity one prepares for a health insurance appeal (See Appendix 5). If a physician anticipates a child will require increased parental care because of the worsening of illness, this should be discussed with the family. Parents who may need to take time off from work should request FMLA leave before the crisis occurs. Parents who do so will protect their jobs as long as they do not take more than the maximum twelve weeks of leave during the year. This job security can go far in helping ease caregiver’s anxiety, allowing them to better focus on coping with the child’s acute needs and the impact on the family.
Summary Inflammatory bowel disease affects more than a patient’s intestines; it affects their life, including otherwise routine functions of school and work. In addition, IBD affects families, not just individual patients. Therefore, physicians should become familiar with the ways they can help patients and their families overcome the varied hurdles facing children with IBD. In particular, providers should train themselves, or be trained, in how to appeal insurance company denials, assist in the development of a plan of accommodation for a school-aged child, support an application for Social Security benefits, and point out the availability of Family and Medical Leave to caregiver parents. Collaboration with other members of the medical team such as nurses and social workers to address these issues is essential, as is the ability to identify advocacy resources in the community, such as Advocacy for Patients with Chronic Illness. By providing such services, the physician may alleviate some of the financial, educational and social complications that can turn a flare of IBD into a more serious family crisis. The provider who is an effective advocate will derive gratification from the knowledge that they have helped their patient have a better quality of life.
Appendix 1. Sample Letter for Patient’s Student File Regarding Educational Accommodations Needed for an IBD Diagnosis To Whom It May Concern: This letter is being written on behalf of our patient, XXXXX (DOB: XX/XX/XX), who was recently diagnosed with Crohn’s Disease, a chronic inflammatory bowel disease of the intestines. As chronic illness is cyclical in nature, XXX can face gastrointestinal symptoms in a recurrent
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pattern, with periods of symptom inactivity in between active flare-ups and complications. Cramps may be severe and may be worse when there is a need to use the toilet; symptoms may worsen in an unpredictable manner and conversely, may go into remission for varying lengths of time. The medical team is currently working to coordinate the long-term treatment plan as the team explores the impact of these symptoms on her body and her body’s response to the medication regimen. Even if a patient no longer requires an inpatient hospitalization, we could expect the patient to still experience ongoing symptoms until the medical team is able to arrange her maintenance treatment regimen. XXX has been seen for her first outpatient follow-up appointment since diagnosis, and the medical team continues to monitor her symptoms, which continue to intermittently interfere with her ability to attend school for a full day. In the long-term, however, with the understanding and support of her teachers and other school personnel, we expect XXX to participate in school activities. When the medical team better determines the best course of maintenance treatment for her, we have no reason to expect that it should routinely interfere with her academic plan or performance. In addition, XXX may be tardy or absent from school from time to time if her condition is flaring. The disease process can affect many aspects of a person’s life; depending on the current symptoms, patients can find it difficult to cope as there is an interference with their physical and social functioning. We feel it would be helpful for XXX’s school re-entry to begin in a partial day format, as her body continues to adjust. In the immediate, short-term, we believe it is in XXX’s best interest that she be eligible for home tutorial services so that her academic studies are not compromised by this acute period of her condition. These services would also be recommended to have in place, should flare-ups occur in the future, causing her to intermittently and unpredictably miss schoolwork. We know that the emotional and physical pieces are interrelated in complex ways, and patients can experience flare-ups during times of emotional tensions and stress. This can relate to changes in the physiologic functioning of the gastrointestinal tract. While periods of intense stress and pressure can exacerbate symptoms, it is important to note that they do not cause the disease and are not responsible for the development of the illness. Please understand the extenuating circumstances facing XXX, should the physical or emotional adjustment to the demands of her chronic illness intermittently impact her ability to carry out her academic responsibilities. Please contact XXX with further questions. Thank you for your time and understanding. We look forward to being able to collaborate with the school in any manner that will optimize her future academic and medical plans.
Appendix 2. Preparing an Effective Insurance Company Letter of Medical Necessity • Patient’s Name (and name of insured if not the patient); • Patient’s Insurance ID number, Social Security number and date of birth; • The treatment requested and denied; • Your specialty and years of experience; • Your experience with the particular device, medication or treatment; • The patient’s diagnosis, including both subjective and objective support for the diagnosis (patient’s subjective complaints plus weight loss, recent barium study, endoscopy reports with pathology, etc.); • What treatments have been tried over what period of time (go back to the date of diagnosis and describe all that has been tried and failed, explain the reason for the failure, i.e. failure to control disease, allergic reaction, adverse event such as pancreatitis);
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• If device, medication or other treatment is considered by the insurance company to be experimental, investigational or unproven, summary of the medical literature, preferably including copies of the literature (both summary and copies of literature are enclosed); • Why you believe this therapy or service is clinically indicated for this patient at this time. • Describe your plan to assess treatment efficacy (whether your therapy will help this patient). For example, in a patient with CD involving the ascending colon, state you will follow the patient monthly, and monitor exam, hematocrit, C-reactive protein, and perform a colonoscopy after 6 months to assess mucosal healing. • Summarize your medically necessary request again, and offer to talk to any health care professional from the insurance company if additional information is needed.
Appendix 3. Sample Letter for Appeal of Denial of Mental Health Benefits To Whom It May Concern: This letter is being written on behalf of our patient, XXX (DOB:), whom we follow for her diagnosis of Crohn’s Disease, a chronic inflammatory bowel disease of the colon and small intestine. We submit this letter in support of her being permitted to receive out-of-network mental health benefits at/through (agency name/private provider) as a clinical case exception. XXX has had a complicated course of her illness, having been hospitalized several times for unpredictable flares of her disease, both times leading to lengthy admissions followed by intensive outpatient follow-up. Her illness’ response to our treatment plan has been sporadic and inconsistent, causing great stress on both her mind and body. We know that the emotional and physical pieces are interrelated in complex ways, and patients can experience flare-ups during times of emotional tensions and stress. This can relate to changes in the physiologic functioning of the gastrointestinal tract; we have seen this occur with XXX. Her medical complications have led to periods of intense stress and pressure, thereby exacerbating symptoms. XXX’s specific circumstances are physically and psychologically complicated, and it is crucial to be able to integrate the medical and psychiatric services; this will be critical to providing the most comprehensive and cost-effective care. (agency name/private provider) specializes in diagnosing and treating children and teenagers with comorbid physical and psychiatric/psychological issues. (Agency) provides and coordinates integrated plans of treatment, including psychopharmacology, cognitive behavioral therapies, and family work specifically geared toward helping manage these comorbid populations. Studies have shown that this type of integration of medical and psychiatric services can decrease both medical and psychiatric morbidity, and thus medical costs. XXX’s ability to access these services could be essential in reducing the risk factors for a necessary medical or psychological hospitalization. A hospitalization would be much more costly, both financially and in terms of the missed developmental learning opportunities in the social and academic realms. It is in XXX’s best interest to receive ongoing psychological care in a formal clinical model. However, we would request authorization for at least a two–session evaluation so that the formulation and treatment recommendations can be passed on to community psychiatric providers in their network. We feel strongly that the optimal coordinated care plan would include your insurance plan’s willingness to authorize 12–14 treatment sessions so that XXX and her family can have access to the specialized skills of (agency/provider), thereby reducing the chances of an emergent, and perhaps more costly, hospitalization. Please understand the extenuating circumstances impacting XXX. Thank you very much for your time and consideration in this urgent matter. Feel free to contact XXX with further questions. We look forward to hearing your response.
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Appendix 4. Social Security Listing of Impairments for Children with IBD Section 105.00, Digestive Impairments in Children A. Disorders of the digestive system which result in disability usually do so because of interference with nutrition and growth, multiple recurrent inflammatory lesions, or other complications of the disease. Such lesions or complications usually respond to treatment. To constitute a listed impairment, these must be shown to have persisted or be expected to persist despite prescribed therapy for a continuous period of at least 12 months. B. Documentation of gastrointestinal impairments should include pertinent operative findings, appropriate medically acceptable imaging studies, endoscopy, and biopsy reports. Where a liver biopsy has been performed in chronic liver disease, documentation should include the report of the biopsy. Medically acceptable imaging includes, but is not limited to, x-ray imaging, computerized axial tomography (CAT scan) or magnetic resonance imaging (MRI), with or without contrast material, myelography, and radionuclear bone scans. “Appropriate” means that the technique used is the proper one to support the evaluation and diagnosis of the impairment. C. Growth retardation and malnutrition. When the primary disorder of the digestive tract has been documented, evaluate resultant malnutrition under the criteria described in 105.08. Evaluate resultant growth impairment under the criteria described in 100.03. Intestinal disorders, including surgical diversions and potentially correctable congenital lesions, do not represent a severe impairment if the individual is able to maintain adequate nutrition, growth and development. D. Multiple congenital anomalies. See related criteria, and consider as a combination of impairments. 105.07 Chronic inflammatory bowel disease (such as ulcerative colitis, regional enteritis), as documented in 105.00. With one of the following: A. Intestinal manifestations or complications, such as obstruction, abscess, or fistula formation which has lasted or is expected to last 12 months; or B. Malnutrition as described under the criteria in 105.08; or C. Growth impairment as described under the criteria in 100.03. 105.08 Malnutrition, due to demonstrable gastrointestinal disease causing either a fall of 15 percentiles of weight which persists or the persistence of weight which is less than the third percentile (on standard growth charts). And one of the following: A. Stool fat excretion per 24 hours: 1. More than 15 percent in infants less than 6 months. 2. More than 10 percent in infants 6–18 months. 3. More than 6 percent in children more than 18 months; or B. Persistent hematocrit of 30% or less despite prescribed therapy; or C. Serum carotene of 40 mcg/100 ml. or less; or D. Serum albumin of 3.0 g/100 ml. or less.
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Appendix 5. Preparing an Effective Letter for Family Medical Leave Act Provisions • Caregiver/parent’s name (employee). • Patient’s name. • Patient’s diagnosis, date of diagnosis, length of treatment – chronic illness requires lifelong medical attention of some level. • If relevant, recent or upcoming overnight stay in a hospital including estimation of incapacity after discharge home. • Explain incapacity as inability to attend school or perform other regular daily activities during the times of hospitalization, recovery or scheduled outpatient medical procedures. • All occasions and specifics of ongoing and continued treatment by a health care provider as an outpatient, specifically outlining caregiver’s responsibility for medication administration, monitoring and reporting of bowel habits at home, coordination with other sub-specialty providers, as applicable. • Phrases indicating episodic, intermittent, unpredictable, cyclical nature of the IBD disease process, with the need for ongoing, periodic outpatient visits. • Emphasis of importance of the caregiver being present at these visits for active and ongoing discussion with the medical team to be able to participate in progressive treatment plan decisions that impact the child. • Explanation that child’s intermittent incapacity, may cause the caregiver to work intermittently or on less than a full schedule. • Identification of any potential future treatment or collateral providers in the child’s care, including medication infusion at a day hospital center, routine exploratory procedures, imaging studies. • Anticipate the potential involvement of radiologists, laboratory technicians, infusion center staff, physical therapists, dieticians, mental health professionals, so that if a caregiver has to accompany a child to an appointment with one of these providers, without your presence, it can still be validated by the employer as qualifying for FMLA hours. • Specification that child requires basic medical assistance for medical decision making, transportation to appointments, and psychological comfort to assist in the management of the impact of the treatment regimen, given the interruption to daily functioning, and the invasive nature of portions of the treatment plan.
48B Legislative Advocacy Suzanne Rosenthal∗
Introduction From the earliest days of its founding in 1967, the goal of the Crohn’s & Colitis Foundation of America (CCFA) was to raise awareness of the public and among Members of Congress concerning the significant impact of inflammatory bowel diseases (IBD) in the United States. Its purpose was to dramatically increase IBD research supported by CCFA and by the National Institutes of Health (NIH). CCFA became and remains the only national voluntary health agency dedicated to seeking the cause and cure of IBD and to improve the quality of life of people with these diseases. The combined efforts of CCFA and the leading national gastrointestinal professional societies, including the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN), added to the effectiveness and success of several important IBD legislative initiatives. The IBD research appropriations at the NIH started in the early 1960‘s with $25,000. Today’s IBD research budget at the NIH exceeds $70 million – primarily targeted to the IBD programs at the National Institute of Diabetes, Digestive & Kidney Diseases (NIDDK) and the National Institute of Allergy and Infectious Diseases (NIAID). Current legislative initiatives are seeking to add new dollars and new programs, particularly regarding the estimated 140,000 children and adolescents with IBD, or 10% of the estimated total IBD population of 1,400,000. The CCFA recognized in the mid-1970s, that it was important to have a professional presence in Washington, D. C. to recommend and represent advocacy efforts affecting patients with IBD. For over 28 years, (1978) the Health & Medicine Counsel of Washington (HMCW) has assisted CCFA on IBD advocacy programs by coordinating both the Foundation’s own IBD-specific efforts as well as more encompassing efforts through the Digestive Disease National Coalition (DDNC). The DDNC was founded by CCFA leadership in 1978. The DDNC currently is comprised of 26 lay and medical member organizations and works to collectively seek Congressional authorization of certain new initiatives and to increase appropriations for all digestive disease research. The DDNC also addresses certain patient care issues within the NIH, Food and Drug Administration (FDA) and Medicare (CMS).
∗ CCFA Co-Founder, Chairman of the Board Emerita, Crohn’s & Colitis Foundation of America, Inc., 386 Park Avenue South, 17th flr., New York, NY 10016-212-685-3440, E-mail:
[email protected]
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Legislative Initiatives Since 1996, CCFA has worked with HMCW to meet specific IBD research and quality of life goals through federal legislation. CCFA’s most important initiatives included the creation of IBD specific legislation. IBD Bill Signed by President George W. Bush and enacted into law on November 30, 2004 The “Inflammatory Bowel Disease Research Act”, was introduced in the House in January 2003 by original co-sponsors – Rep. Sue Kelly (R-NY) and Rep. Jesse Jackson, Jr. (D-IL). In February 2003, original co-sponsors Senators Harry Reid (D-NV) and Thad Cochran (R-MS) introduced the same Bill in the Senate, and CCFA launched a national effort to seek co-sponsors of the Bill in both Houses of Congress. Web e-mail and daily Internet announcements, letter campaigns and telephone calls from the national and chapter offices and from hundreds of volunteers helped to secure the co-sponsorship of 183 Representatives and 37 Senators. With the large number of bi-partisan co-sponsors supporting the Bill, President Bush was quickly able to sign it into law. It was enacted as the “Research Review Act” on November 30, 2004 - just short of two years after the introduction of the Bills in early 2003. Professional and lay organizations that added support to CCFA’s effort to seek passage of the Bill were: Digestive Disease National Coalition (DDNC); NASPGHAN; American Gastroenterological Association (AGA); American College of Gastroenterology (ACG); United Ostomy Association (UOA); American Society for Gastrointestinal Endoscopy (ASGE); International Foundation for Functional Gastrointestinal Disorders (IFFGD) and the Hepatitis Foundation International (HFI). The “Research Review Act: provided two major benefits for patients with IBD: A. Studies by the General Accountability Office (GAO): Social Security Disability Report and Medicare and Medicaid Coverage Report. In 2005, as mandated by the “Research Review Act”, the GAO undertook the first federal studies specific to patients with IBD. The first study investigated the challenges patients with IBD patients are facing when applying for Social Security Disability. The second study focused on Medicare and Medicaid coverage of IBD therapies including FDA approved therapies for Crohn disease and ulcerative colitis, ostomy supplies, medical necessary foods, enteral nutrition formula, and parenteral nutrition. CCFA and the United Ostomy Association (UOA) leaders met with GAO researchers in Washington in January of 2005 to discuss both issues. The GAO released the Social Security Disability study (GAO-05-495) in May of 2005. The report made several recommendations for improving the disability process for patients with IBD and has proven to be a beneficial resource when pursuing disability claims with the Social Security Administration. The Medicare/Medicaid study (GAO-06-63) was issued in December of 2005 and provides a comprehensive analysis of national Medicare coverage of IBD therapies, and state-based Medicaid policies (including analysis of Medicaid coverage in all 50 states and the District of Columbia). The report serves as a guide for advocacy efforts to address gaps in coverage for Medicare and Medicaid beneficiaries. B. The Establishment of Centers for Disease Control Inflammatory Bowel Disease Epidemiology Program In 2002, CCFA prioritized the need to financially support a National IBD Epidemiology Study to determine the true prevalence of the disease and the unique demographic characteristics of the IBD patient population. It sought a proposal from the CDC to be underwritten by CCFA in the amount of $750.000 to create and monitor the Study. In 2005, with the passage of the “Research
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Review Act” CCFA secured the same amount from Congress to continue the IBD Epidemiology Program. Subsequently in 2006 and 2007, President Bush requested and Congress provided approximately $1.4 million to CDC to continue the program. CCFA serves as the administrator of the epidemiology study and directs all research activities in partnership with CDC utilizing the funds provided by the Congress. In September 2005, the proposed Bills, H.R. 3616 AND S. 1931: “Inflammatory Bowel Disease Research Act” were introduced in the House by the same co-sponsors as for the first IBD Bill: Rep. Jesse Jackson, Jr. (D-IL) and Rep. Sue Kelly (R-D) and Senators Harry Reid (D-NV) and Thad Cochran (R-MS). After the passage of the “Research Review Act”, it was necessary to continue to raise the profile of IBD in Congress, and to encourage the NIH and the CDC to expand support for IBD research, particularly in pediatrics. These Bills were supported again by many of the same digestive disease organizations that supported the first Bill. With concentrated activity, as of mid-September 2006, 100 House Members and 20 Senators had become co-signors. However, CCFA had not secured sufficient numbers of co-sponsors before Congress went into Election Recess which required a new Bill to be designed and introduced in the new 2007 Congress. H.R.1113 Introduced in 2007 On February 16th, 2007, H.R. 1113 -the “Inflammatory Bowel Disease Research Enhancement Act” was introduced in the House by Rep. Jessie Jackson, Jr. (D-IL) and Rep. Michael Castle (R-DE). At the time of this writing CCFA is seeking the original co-sponsorship of Senators Reid and Cochran to introduce their IBD Bill in the Senate. H.R. 1113 cites 1,400,000 people in the U.S. suffer from IBD, 30% of them were diagnosed during their childhood years. It indicates that an estimate of $2,000,000,000 is spent annually on IBD patient care. It has much of the same language as in the prior 2005 Bill and a new important program initiative. The bill would do the following: 1. Expand inflammatory Bowel Disease at the NIH-NIDDK with a specific focus on: A) B) C) D)
Pediatric related research. Genetic and environmental research into the cause and progression of IBD. Clinical research, including translational studies and treatment trials. Support for the training of new investigators specializing in IBD with an emphasis on pediatric care.
2. Establish a “Pediatric IBD Patient Registry” through the Centers for Disease Control and Prevention. This Registry would collect and analyze data on: the incidence and prevalence of the diseases in children, genetic and environmental factors associated with pediatric disease, and treatment approached and outcomes for pediatric IBD patients. The Centers for Disease Control and Prevention (CDC) would work in consultation with …“a national voluntary patient organization with experience serving the population of individuals with pediatric inflammatory bowel diseases and the organizations representing physicians and other health professionals specializing in the treatment of this population”. To carry out this section of the Bill, there would be authorized to be appropriated $5,000,000 for fiscal year 2008 and such sums as may be necessary for years 2009 and 2010. 3. Require the CDC to develop a “National Inflammatory Bowel Disease Action Plan.” This plan would detail a comprehensive strategy for addressing the burden of IBD in both pediatric and adult populations. Specifically, the plan would create mechanisms for increasing awareness of IBD and preventing its progression and related complications, such as colorectal cancer.
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Looking Back One Could Ask How did passage of the first Bill happen so quickly? What was done to raise awareness of Digestive Diseases in Congress and to educate the public? What actions by lay and medical organizations made the NIH-NIDDK and its DD-N Sub-council, a reality? What was done to increase Digestive Disease research appropriations at the NIH? How did the NIDDK budget for IBD research of $25,000 in the late 1960‘s grow to today’s budget of over $ 70 million? The First National Digestive Disease Commission CCFA advocated with national GI professional associations to rename the National Institute of Arthritis and Metabolic Diseases (NIAMD) to the National Institute of Arthritis, Metabolism, and Digestive Diseases (NIAMDD) (May, 1972; PL 92–305) thus securing a separate digestive disease division at the NIH. CCFA worked in the 1970‘s with GI professional and lay associations to create the first National Digestive Disease Commission (NDDC) and worked to have key elements of its findings and conclusions implemented. The Arthritis, Diabetes, and Digestive Disease Amendments of 1976 (Oct, 1976, PL 94-562) created the first National Commission on Digestive Diseases with the goal of establishing a long-term plan for digestive disease research in the United States. CCFA represented the digestive disease lay community as Chair of the NDDC’s Patient and Public Education Work Group. Silvio O. Conte Digestive Disease Research Centers In December of 1980, the Commission’s efforts led to Congress enacting Public Law 96–541, which changed the NIAMDD to the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases (NIADDK). This Public Law also created the statutory authority for the Digestive Disease Research Centers Program (DDRC), the National Digestive Diseases Information Clearinghouse, and an intramural NIDDK digestive disease epidemiology data program. CCFA worked with the late Congressman Silvio O. Conte (R-MA) and Congressman William Natcher (D-KY) to support the creation and funding for the Conte Digestive Disease Research Centers Program within the NIDDK. The first grants, six of them, were awarded in November of 1984. Currently there are 21 Digestive Disease Research Centers, several of which have a primary focus on Inflammatory Bowel Disease. The DDRCC Program provides a mechanism for funding shared resources (core facilities) that serve to integrate, coordinate, and foster interdisciplinary cooperation between groups of established investigators who conduct programs of high quality research that are related to a common theme in digestive diseases research. An existing base of high quality digestive disease-related research is a prerequisite for the establishment of a Center. National Digestive Disease Information Clearinghouse CCFA and other lay organizations, sought for years the creation and funding of an important digestive diseases education resource. Finally, the National Digestive Diseases Information Clearinghouse (NDDIC) was formed in 1980 through PL 96-541 which established an Executive Committee and an Advisory Board that meets annually. All the lay GI and many professional organizations are members of the NDDIC Advisory Board. Digestive Disease National Coalition CCFA was the founding organization of the Digestive Disease National Coalition (DDNC) created in 1978 to provide a forum for all professional and voluntary organizations interested in digestive diseases to work together to address national issues related to research, patient care and
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public/professional awareness of digestive diseases. The collective number of patients and lay and medical members represented by 26 DDNC member organizations was formidable. Founding organizations included CCFA, NASPGHAN, the AGA, the ACG, the ASGE, the American Liver Foundation, the International Foundation for Functional Gastrointestinal Disorders, as well as a number of Celiac Disease groups. The DDNC has been successful in advocating for additional funding for digestive disease research, improving patient access to preventive and diagnostic GI care, and serving as the collective voice of the digestive disease community on all matters related to national health policy and digestive diseases. Consistently, the DDNC has had high quality representation from the IBD patient, scientific and medical community. National Colorectal Cancer Roundtable CCFA, as a Founding Member of the National Colorectal Cancer Roundtable (NCCRT), sought the originating legislation to create and fund the NCCRT. It was authorized in 1997 and funded in the 1998 Labor, Health and Human Services appropriations. The NCCRT is supported through a cooperative agreement by the Centers for Disease Control and Prevention and the American Cancer Society. The National Cancer Institute (NCI) is also a lead organization. The NCCRT meets annually with work done in several committees throughout the year. It has grown to 50 member organizations, and has the major goal of increasing the safe and effective use of proven colorectal cancer screening tests among appropriate populations. A major accomplishment of the NCCRT was to develop consensus CRC screening guidelines among all professional and voluntary organizations concerned with Colorectal Cancer. Important medical publications arising out of NCCRT have advanced the knowledge of prevention of colorectal cancer. NCCRT has created many attractive public awareness programs for radio and television and produced educational materials for many different ethnic and age populations targeted to the high risk populations. The CDC’s entire colorectal cancer prevention and screening program is funded in 2006 at approximately $12 million annually, including upwards of $1 million for the NCCRT. Crohn’s & Colitis Foundation of America – Government Affairs Committee In the 1970‘s, CCFA created a Government Affairs Committee (GAC) of the Board of Trustees to monitor, recommend actions and implement activities to advance IBD research at the NIH and other federal entities including: 1. Activity targeted to seek the co-sponsorship of those Members of the House and Senate Health Sub-Committees that consider and recommend to their full committees, authorization legislation and its associated appropriations. Co-sponsorship is simultaneously sought from the rest of the Members of Congress. Letter-writing, faxes and emails are encouraged to promote CCFA’s agenda before all federal legislators. 2. Organizing “IBD Days on the Hill” starting in 2003. Cumulatively through June 2006, over 500 hundred men, women and children have made pilgrimages to Washington, D.C. to participate in CCFA’s advocacy effort. They meet and educate legislators about IBD and its impact on patients and their families, and to urge support of important NIH and CDC initiatives through their co-sponsorship of IBD legislation, efforts to increase IBD appropriations and other IBD related matters. This is an annual effort maintained to keep new legislators and new legislative aides aware of CCFA’s mission and to seek increased funding for the NIH and CDC Inflammatory Bowel Disease programs. 3. In 2004, the GAC created its National IBD Advocacy Network which has a current enrollment of several thousands of people with IBD and their families who are provided with the opportunity to engage in advocacy efforts from their homes and offices and go to Washington, D.C. on CCFA’s annual IBD Days on the Hill.
49 Transition from Pediatric to Adult Care George D. Ferry∗ and M. Susan Moyer
Introduction Transition of care is an integral part of any chronic care model and is applicable across subspecialties, including inflammatory bowel disease. The term “transition” can have several meanings and it is important to define what this term means for pediatric patients with inflammatory bowel disease. One definition that is somewhat limited is passage from one place to another, for example, movement from the pediatric care setting to an adult care setting. Another, perhaps broader and more encompassing definition might be evolution from one stage to another, such as from adolescence to adulthood and from a dependent to an independent life. The latter definition more closely fits the intent of this chapter. One role of the pediatric gastroenterologist is to help adolescents attain their full potential for growth, development and the ability to be self-sufficient adults. This is especially critical for children and adolescents with special needs, which includes chronic illnesses such as Crohn disease and ulcerative colitis. One excellent model of chronic care that addresses transition and preparation for independence is a national program, “Improving Chronic Illness Care” (ICIC). This model, funded by the Robert Wood Johnson Foundation, was developed through Group Health Cooperative’s MacColl Institute for Healthcare Innovation. The basic tenets of this model (an overview can be found at www.improvingchroniccare.org) involve the community, the health system, and a self-management program, along with an appropriate delivery system design, decision support, and a clinical information system that can provide timely reminders for providers and patients and monitor performance. Community involvement means patient involvement with community support organizations and professional partnering to support and develop interventions that fill gaps in needed services. The health system must create a culture, organization and mechanisms that promote high quality care, including transition, or self-management support. The aim of this latter effort is to empower and prepare patients to manage their health and health care. Next, the delivery system must define roles and distribute tasks among team members to prepare and use planned interactions to facilitate the patient’s final transition to independence. The ultimate goal is a prepared, proactive healthcare team and an informed, active patient – a concept particularly applicable to inflammatory bowel disease. In addition to independence and self-management, evidence supports the eventual need for appropriate termination of pediatric relationships as part of the transition process. Evidence *Texas Children’s Hospital, 6621 Fannin (CC 1010), Houston, Texas 77030, 832-822-3131, E-mail:
[email protected]
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further supports the idea that pediatric and adult-oriented medicine represent two different medical subcultures. If young adults and family members are not well prepared for participation in the adult health care system, they will have trouble with this transition and may not receive the care they need [1]
Background Transition is part of normal healthy development and the need for more consistent and defined methods of transition and evolution of care from pediatrics to adult medicine has been recognized for some time, but the focus in the past has been more on children with disabilities and special needs as adults [2, 3]. In 2002 the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) published a medical position statement on transition of the patient with inflammatory bowel disease from pediatric to adult care [4]. This statement addressed a number of issues that adolescents must face, including their own feelings about growing up, moving from parental oversight to independence and self-reliance, and leaving the nurturing type of medical care common to pediatric practices. In addition, there was some focus on how families must adapt and give up control and how pediatric care givers (including physicians, nurses, and many other health care providers) must relinquish the medical care of their patients and facilitate transition to an adult sub-specialist. None of these issues necessarily come easily to the patients, families or the health care team.
Who is the Target Not only the patient, but virtually everyone involved in the patient’s life is potentially a target for a program developed for transition and evolution. In addition to the patient and physician relationship, multiple family members are involved at many levels, including parents, grandparents, siblings and stepparents. All may be intimately involved in the care of a child with IBD and must be part of the transition process. Critical issues in the patient, family and doctor interaction that must be addressed include: 1) involvement of multiple care givers (in the case of IBD this might include surgeons, rheumatologists, dieticians); 2) normal patterns of adolescent denial; 3) confidentiality (the direct doctor/patient relationship); 4) normal independence and control issues; and 5) appropriate ways to educate both the patient and the family [5]. From a practical perspective, pediatric and adult gastroenterologists/nurses are probably the main focus.
Goals/objectives Transition for an adolescent with a chronic condition requires developmentally appropriate healthcare services and teaching materials that continue uninterrupted from adolescence to adulthood. These should be patient-centered (developmental readiness is crucial) and advocated by pediatric gastroenterologists and nurses (provide the tools). This means that the providers must understand the rationale for transition from child-oriented to adult-oriented healthcare, have the knowledge to facilitate the process, and know when transition is appropriate – patient readiness rather than disease or physician/nurse specific. The goals for both the family and members of the healthcare team are to support the process of transitioning toward independence by establishing appropriate self-management goals and to avoid fostering ongoing dependence. The fundamental principals of transition outlined in a position paper from the Society for Adolescent Medicine [6] include five points: 1) services need to be appropriate for chronological age and developmental attainment; 2) Adolescents and young adults with chronic conditions share
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many of the same health issues and concerns as their peers – including growth and development, sexuality, mood and other mental health disorders, and substance abuse; 3) Many adolescents with chronic conditions are at higher risk for dependency, developmental difficulties, and psychological delay; 4) transition programs should be flexible enough to meet the needs of a wide range of young people, health conditions, and circumstances; 5) health care transition is most successful when there is a designated professional who, together with the patient and family, takes responsibility for the process. The following first steps from A Consensus Statement On Healthcare Transitions For Young Adults With Special Healthcare Needs [7] were directed toward primary care providers, however, they are applicable to sub-specialists: 1. Ensure that all young people with special healthcare needs have an identified healthcare professional (pediatric gastroenterologist, nurse, other?) who facilitates self-management and transition. This may be a physician, nurse or another member of the healthcare team. 2. Identify the core knowledge and skills required to provide developmentally appropriate healthcare services to ensure success in self-management. 3. Help the patient and family prepare and maintain an up-to-date medical summary that is portable and accessible. 4. Create a written health care transition plan (this should be a general plan for all patients) that could start any time after age 12–14. An individual plan for a specific patient and family might also be useful. Since the pediatric gastroenterologist is often the only physician that sees these patients, the general guidelines for primary and preventive care applicable to all adolescents and young adults may need to be incorporated. These could include, for example, appropriate immunizations for children and adolescents with inflammatory bowel disease for which guidelines have been published [8]. 5. Be an advocate for affordable, continuous health insurance coverage for all young people with special healthcare needs throughout adolescents and young adulthood
Transition Steps The skill sets needed for successful transition include both general skills and skills related specifically to IBD. There are a number of specific guidelines and checklists for transition of care (one sample can be found on the Children’s Digestive Health and Nutrition Foundation website at www.cdhnf.org) and these often are based on chronological age [9]. The following steps are a suggestion as a starting point. Each institution or practice may have different needs from those outlined in this chapter, but the basic approach to a transition plan is the same. Patients whose disease starts later in adolescence, or a patient who enters a practice at an older age, may need these goals condensed into a shorter time frame. Also, if patients are followed closely by their primary care physician, they may already have learned some of the more general health skills. Teaching of transition skills (those chosen as most important by each practice or institution) might be undertaken by a nurse, other personnel, or even the gastroenterologist, depending on staffing and availability. It is most important for the physician to convey the importance of the process to both the patient and family so that they buy into the process and recognize the benefits of knowledge and growing independence. The patient and family should play an integral role in defining specific self-management goals for the next visit. The list of skills for each step should be discussed and given to the patient and family. The appropriate age to begin teaching these skill sets will vary with each patient’s level of maturity and interest, but starting by age 12–14 years gives adequate time for the process and allows each patient the opportunity to gradually assume more responsibility for taking care of their
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own unique problems. The skill sets involve accruing knowledge, developing self-management skills based on that knowledge, and understanding the mutual impact of inflammatory bowel disease and lifestyle decisions on future health and well being. Skill set 1 – knowledge related to their illness. This first step is designed to help patients learn about their specific disease, either Crohn disease or ulcerative colitis. This should include both gastrointestinal and extra-intestinal symptoms, recognizing when they are having a flare, when they should be visiting their physician, and what might be precipitating the flare (diet, stress, other medications, etc.) In addition to handouts with these key points, providing specific age appropriate web sites can help patients develop resources for ongoing education and new information (e.g., www.ccfa.org/kidsteens). Skill set 2 – knowledge related to medications. This step provides information about specific medications they are taking – name, dose, why they are taking the medication, timing of each dose, possible side effects, and finally, establishing a plan to take medications on their own without being reminded. Any complementary or alternative therapies should also be included in this learning process. Skill set 3 – knowledge related to procedures and tests. This would include laboratory tests, diagnostic imaging and endoscopic procedures used in managing the patient with IBD. The goal is for patients to not only be comfortable with the different tests and procedures, but also to recognize their importance in managing their disease long term. Skill set 4 – basic medical knowledge. This step emphasizes basic medical knowledge that all patients should know, regardless of the presence or absence of a chronic illness. This includes knowing how to measure their weight, take their temperature and read a thermometer. It also includes learning or knowing where to find the doctors telephone number, the hospital number and location, and emergency numbers for family or friends. This may take a little time in the office demonstrating some of these skills and it will require some work from the family to help set up their own system for reinforcing this information. In addition, patients might be asked to prepare questions ahead of time for the doctor and nurse or dietician. Skill set 5 – general self-management skills. Skills attained in this set put the knowledge acquired in the other skill sets to practical use and help patients move toward independence. They should learn to call in their own prescriptions, make their own clinic appointments, begin to collect copies of their health records, understand the concept of medical insurance and perhaps even carry an insurance card. Eventually they should know and understand more specific details related to medical insurance coverage including eligibility requirements, co-pays and other potential resources for coverage such as SSI. Skill set 6 – health and lifestyle decisions. In this set, the patient gains a general understanding of the importance of health maintenance and the potential interplay of their disease and lifestyle decisions. General knowledge includes the beneficial effects of exercise and an appropriate diet as well as the adverse effects of drugs, alcohol and smoking. The specific impact of disease activity on fertility and sexuality should be discussed as well as the consequences of non-adherence.
Monitoring the Process Some system should be established to monitor both the teaching of the above skills as well as what has been learned and retained. This might be done through popup messages on an electronic medical record, where objectives and follow-up learning must be recorded by date, or a special form could be kept in the patients chart to check off each set once taught and then mastered. The patient could also be given a copy of this so they know what the entire skill set contains. A member of the healthcare team should be dedicated to documenting this process to be sure patients
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are making progress in becoming independent. Having set questions at follow-up to document what has been learned is also important. Typical questions that patients might be expected to answer at a follow-up visit are: 1) can you describe your disease; 2) what are your symptoms of IBD; 3) what situations should you avoid; 4) when should you call or see the doctor; 4) what is your doctor’s or nurse’s phone number; 5) did you make this appointment; 6) have you called in one of your prescriptions for refill; 7) what health records have you collected (endoscopy reports, etc.); and 8) who is your insurance carrier. Before final transition, time should be set up to do a final review of their competence in all areas and then, when the patient is ready, preparations can be made to transition care to an adult provider. At this point the patient should already be taking care of his or her health issues and a successful outcome for transition is likely. References 1. Reiss J, Gibson R, Walker L. Health care transition: youth, family, and provider perspectives. Pediatr 2005;115:112–20. 2. American Academy of Pediatrics Committee on Children with Disabilities and Committee on Adolescence (AAP). Transition of care for adolescents with special health care needs. Pediatr 1996;98:1203–6. 3. Freed G, Hudson E. Transitioning children with chronic diseases to adult care: current knowledge, practices, and directions. J Pediatr 2006;148:824–7. 4. Medical Position Statement. Transition of the patient with inflammatory bowel disease from pediatric to adult care: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2002;34:245–8. 5. Ferry G. Pediatric patient, family, doctor interactions. In: Bayless T and Hanauer S, editors. Advanced therapy of inflammatory bowel disease. Hamilton: B.C. Decker, Inc., 2001:5–7. 6. Rosen D, Blum R, Britto M, et al. Transition to adult health care for adolescents and young adults with chronic conditions. Position paper of the Society for Adolescent Medicine. J Adolescent Health 2003;33:309–11. 7. A consensus statement on health care transition for young adults with special health care needs. American Academy of Pediatrics, America Academy of Family Physicians, American College of PhysiciansAmerican Society of Internal Medicine. Pediatr 2002;110:1304–6. 8. Sands BE, Cuffari C, Katz J, Kugathasan S, Onken J, Vitek C, Orenstein W. Guidelines for immunizations in patients with inflammatory bowel disease. Inflamm Bowel Dis 2004;10:677–92. 9. Hait E, Arnold J, Fishman, L. Educate, communicate, anticipate – practical recommendations for transitioning adolescents with IBD to adult health care. Inflamm Bowel Dis 2006;12:70–3.
Index
Abatacept (CTLA-4 fusion protein), 404, 417 Abdominal distension, 162 Abdominal mass, 169, 172 Abdominal pain, 91, 159–160, 167, 169, 172, 182, 278, 434, 438, 448 Abdominal radiographs, 194, 198 ABT-874 (J695) interleukin-12/23 p40 subunit antibody, 404, 413 ACCENT studies, 372, 388–391, 393, 436 Acetaminophen, 450 Acetyl-5-aminosalicyclic acid, 598 Acquired immunodeficiency syndrome, 171, 172 Acrodermatitis enteropathica, 95 Active colitis, in chronic IBD, 241–242 Active Crohn disease, antibiotic therapy in, 330 Acute appendicitis, 167 Acute hemorrhagic colitis, 243 Acute lymphoblastoid leukemia (ALL), 313 Acute self-limited colitis (ASLC) and IBD, 144–145, 252 Adalimumab, 403–407, 438, 440, 637 Adaptive immune responses, differences in pediatric and adult populations, 24–25 Adaptive intestinal immunity and IBD, 19–22 adaptive immune cells development, 22 B cells, 22 T cells, 19–21, 26 TREG cells, 21–22 Adenocarcinoma, 71, 492, 617 of rectum, 408 of small intestine and CD, 624 Adenovirus, 170 Adipocytes, 279 Adrenarche, 134 Adrenocorticotropic hormone (ACTH), 33 Adult Crohn disease, infliximab therapy for, 388–389 Agile Patency CapsuleTM , 268 Alanine aminotransferase (ALT), 179–180, 183–184 Albumin test, 179 Alicaforsen (ISIS 2302), 404, 412 Alinia® , 333 Alkaline phosphatase (ALP), 179–180 American Cancer Society, 659 American College of Gastroenterology (ACG), 656, 659 American Gastroenterological Association (AGA), 429, 656, 659
American Gastroenterological Association Task Force on Quality in Practice, 634 American Society for Gastrointestinal Endoscopy (ASGE), 496, 656, 659 Americans with Disabilities Act, 643, 649 4-Aminobenzoyl- alanine, 319 5-Aminosalicylate olsalazine, 78 5-Aminosalicylates, 387 Aminosalicylates, in pregnancy, 597–599 5-Aminosalicylate therapy, 317–325 action mechanism, 320 adherence and compliance to, 324 future directions, 324–325 indications and efficacy, 320–323 chemoprevention of colorectal carcinoma, 322–323 in Crohn disease, 321–322 post-operative recurrence in Crohn disease, 322 in ulcerative colitis, 320–321 pharmacokinetics, 317–320 side effects and safety, 323–324 5-Aminosalicylic acid (5-ASA), 184, 317, 593–594, 598, 617, See also 5-Aminosalicylate therapy derivatives for perianal Crohn disease fistulae, 431 therapy, 112 Amitriptyline, 588 Amoxicillin, 332, 491 Amoxicillin-clavulanic acid, 332 Ampicillin, 212, 332 Amyloidosis, 98–99 Anal abscess, 160, 173 Anal fissures, 173 Anal fistula, 160, 162 Androgen, 134 Anemia, 98, 161, 181–182, 278 Anencephaly, 600 Ankylosing spondylitis, 91–93, 403, 409 Anorexia, 97, 159–160, 167 Anti-adhesion, in biologic therapies, 410–412 alicaforsen (ISIS 2302), 412 MLN02, 411–412 natalizumab, 410–11 Antibiotics, use in pregnancy, 598–599 Antibiotic therapy in active CD, 330 in Crohn disease, 330–332 emerging therapies, 333–334
667
668
Index
in IBD, 329–334 in perianal Crohn disease, 331 for perianal Crohn disease fistulae, 431–432 in postoperative recurrence of Crohn disease, 330 in ulcerative colitis, 332–3 Antibody-dependent cellular cytotoxicity (ADCC), 388 Anticholinergics, 450 Antigen-presenting cells (APC), 17 Anti-interleukin 12/23, in biologic therapies, 413–414 ABT-874 (J695) interleukin-12/23 p40 subunit antibody, 413 apilimod mesylate (STA-5326), 414 CNTO 1275 interleukin-12/23 p40 subunit antibody, 413 Anti-interleukin-2 receptor (ANTI-CD25), in biologic therapies, 414 Anti-Saccharomyces cerevisiae antibody (ASCA), 70, 185–186, 267, 633 Anti-tumor necrosis factor, in biologic therapies, 403–410 adalimumab, 403–407 CDP571, 409 certolizumab pegol (CDP870), 408 etanercept, 409 infliximab, 387–397 onercept, 410 Anti-tumour-necrosis-factor-alpha (Anti-TNF, 19, 113, 388 for treatment of perianal Crohn disease fistulae, 438 Anxiolysis, 214 Aphthous lesions, 94, 160, 215, 228 Aphthous ulcers, 92, 160, 169 Apilimod mesylate (STA-5326), 404, 414 Appendectomy, and IBD, 53 Appendicitis, 167 Arg381Gln, 7 Arteritis, 98 Arthralgias, 93 Arthritic pain, 438 Arthritis, 160–161, 168, 487 Asacol® , 318–320, 324–325, 334, 602 ASCEND II trial, 320, 324 Aspartate aminotransferase (AST), 177–178, 183–184 Aspergillosis, 437 Asthma, 633 ATG16L1 autophagy gene, association to Crohn disease, 8 Atropine, 597 Atypical lymphocytes, 18–19 Autoimmune encephalitis, 7 Autoimmune enterocolitis, 242 Autoimmune enteropathy, 171–172 Autoimmune hepatitis, 91 Azathioprine (AZA), 78, 87, 94, 97, 309–311, 313, 331, 379, 387, 391–392, 394, 396, 406, 411, 414, 432–434, 437, 439, 449, 464, 597–598, 602–603, 625, 632–633 and growth management, 112 for treatment of perianal Crohn disease fistulae, 432–434, 437 Azulfidine® , 318–319
Back ache, 438 Backwash ileitis, 479 in CD and UC, 255 and Crohn of ileum, 145, 148 Bacteremia, 227 Bacteroides, 496 Balloon Low Profile Tubes, 497 Balloon Replacement Gastrostomy Tubes, 497 Balsalazide, 318–319, 323 Bard® tube, 496 Barium enema, 450 Baron Scale, 535 Baron’s classification, 516 Basiliximab, 404, 414 B Cell lymphoma, 407 B Cells, 22, 24, 122 B Cells Monocytes, 415 Beclomethasone diproprionate, 364 Behcet’s disease, 172 Belmont Report, 543 Benzodiazepine, 215 Best Pharmaceuticals for Children Act (BPAC), 545 Betamethasone, 599 Bifidobacterium, 351, 491 Bifidobacterium animalis lactis, 354 Bifidobacterium longum, 352 Bile duct cancers, 624 Biologic therapies abatacept (CTLA-4 fusion protein), 417 anti-adhesion, 410–412 alicaforsen (ISIS 2302), 412 MLN02, 411–412 natalizumab, 410–411 anti-interleukin 12/223, 413–414 ABT-874 (J695) interleukin-12/23 p40 subunit antibody, 413 apilimod mesylate (STA-5326), 414 CNTO 1275 interleukin-12/23 p40 subunit antibody, 413 anti-interleukin-2 receptor (ANTI-CD25), 414 basiliximab, 414 daclizumab, 414 anti-tumor necrosis factor, 403–410 adalimumab, 403–407 CDP571, 409 certolizumab pegol (CDP870), 408 etanercept, 409 infliximab, 403–410 onercept, 410 CCX282-B (antagonist to chemokine receptor 9), 417 filgastrim (G-CSF), 415 fontolizumab (anti-interferon , 416 interleukin-10, 415–416 RDP58, 417 sargramostim (GM-CSF), 414–415 visilizumab (anti-CD3), 416–417 Biopsy, 145 distinguishing features of UC and CD in, 243–245 Bisacodyl enemas, 243 Bisphosphonate therapy, 286–287
Index Bladder fistulae, 204 Blood tests, 179–181 acute phase reactants, 182–183 anemia, 181–182 anti-saccharomyces cerevisisae, 185–186 ESR and CRP, 182–183 liver function tests, 180, 183 platelets, 182 Bloody stools, 91 BMD z-scores, 285 Body mass index (BMI), 10, 296, 299–300, 339 Bone, See also Bone health assessment disease, 93–94 intestinal inflammation effects, 123–128 animal models, 123–124 human studies, 124–128 mass, 119–120 modeling and remodeling, 119–121 T cells and, 123 Bone and joint disease, radiologic evaluation of, 205–206 Bone cells and inflammation, 121–123 osteoblasts, 123 osteoclasts and RANKL/OPG system, 121–123 T cells and bone loss, 123 Bone health assessment biochemical markers of bone metabolism, 278 bone status in children and adolescents, 280–283 classification of bone health, 280–281 limitations of DXA, 281–283 peripheral quantitative CT, 283 relation to fracture risk, 280–281 clinical studies for, 283–285 cortical and trabecular bone changes with growth, 277 and pediatric IBD, 275–287 skeletal modeling and bone accrual during childhood, 276–277 therapies for bone health, 285–287 bisphosphonates, 286–287 physical activity, 285 vitamins and minerals, 285–286 threats to bone health, 278–280 biomechanical loading of skeleton, 279 decreased muscle mass, 279 glucocorticoid induced osteopenia, 279–280 inflammation and bone loss, 280 malnutrition, 278 Bone marrow suppression, 384, 434, 597 Bone mineral density (BMD), 206, 277, 280–281, 338 Bone-specific alkaline phosphatase (BSAP), 278 Bowel obstruction and perforation, radiologic evaluation of, 204 Bowel rest, concept of, 346 Breastfeeding, 602–603 and IBD, 53 safety of IBD medications during, 603 Bronchiectasis, 99 Bronchiolitis obliterans, 99 Bronchitis, 99, 438 Brooke ileostomy, 476, 618 Budenofalk® , 364–365
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Budesonide, 363–364, 491 enemas in ulcerative colitis, 368 maintenance treatment in Crohn disease, 368 pharmacokinetics, 364–365 side effects in children, 366–367 treatment in Crohn disease, 365–366 Buried bumper syndrome, 496 Butterfly rash, 395 C4136A, 6 Caffeine, 588 Calcium polycarbophil, 588 Campylobacter, 180, 186, 251 Canasa® , 318–319 Cancer in IBD, pathogenesis and molecular basis, 611–613 Candida, 496 Capsule endoscopy (CE), See Video capsule endoscopy (CE) Carcinoid, 71 CARD15/NOD2 gene, 3, 19, 23 Cataracts, 97, 161 Catheter probe-assisted endoscopic ultrasonography, 234 C57BL/6-Rag1−/− mice, 124 CCX282-B (antagonist to chemokine receptor 9), in biologic therapies, 404, 417 CD28, 20 CD34, 20 CD40, 24 CD4+CD25+ cell, 21 CD4+ CD45RBhigh T cells, 346 CD4+CD25+ Tcell, 22 CD3+ cells, 124 CD8+ cells, 19 CD8+ cytotoxic T cells, 23 CD4+ human lymphocytes, 8 CD8+ human lymphocytes, 8 CD19+ human lymphocytes, 8 CD62L selectin (L-selectin), 20–21 CDP571, 404, 409, 439 CD40-positive endothelial cells, 180 CD4+ T cells, 19–24, 36–37, 39, 414 CD8+ T cells, 19, 22, 32, 39 CD4+ TCR T cells, 20 CD4+ Th1 cells, 35, 37 CD4+ Th1 T cells, 38 CD4+ Th2 T cells, 38 CD4+ T–lymphocytes, 32–34 CD8+ T–lymphocytes, 33 Celiac disease, 91, 170, 586 Centers for Disease Control and Prevention, 657 Centers for Disease Control Inflammatory Bowel Disease Epidemiology Program, 656–657 Central nervous system lymphoma, 407 Certolizumab pegol (CDP870), 392, 404, 408 Chediak-Higashi syndrome, 414 Chemokine receptor 7 (CCR7), 20–21, 417 Chemokine receptor 9 (CCR9), 21, 417 Chemoprevention of colorectal carcinoma, 5-aminosalicylate therapy in, 322–323 Child Health Questionnaire, 572
670
Index
Children’s Digestive Health and Nutrition Foundation (CDHNF), 561, 663 Children’s Oncology Group, 638 Children with Crohn disease, See Pediatric patients with Crohn disease Chlamydia trachomatis, 52 Cholangiocarcinoma, 98 Cholangiogram, 97 Cholelithiasis, 98, 594 Chondrocytes, 279 Chromosome 5p13, association of gene desert on, 8 Chronic active colitis, in chronic IBD, 243–244 Chronic active hepatitis, 98 Chronic caloric insufficiency, and growth impairment in pediatric IBD, 107–108 Chronic colitis, in chronic IBD, 243 Chronic diarrhea, 91 Chronic granulomatous disease (CGD), 251 Chronic IBD pathology, 241–257 active colitis, 241–242 chronic active colitis, 243–244 chronic colitis, 243 eosinophilic colitis, 243 focal active colitis, 242–243 non-disease related alterations, 243 Chronic Illness Care Model, 633–634 Chronic inflammatory bowel disease, See Chronic IBD Chronic intestinal symptoms, 167–168 Chronic phlegmon, 458 Chronic pseudo-obstruction, 242 Chronic recurrent multifocal osteomyelitis (CRMO), 94 Ciprofloxacin, 330–332, 335, 355, 432–433, 477, 490–492, 597–599, 602–603 Cirrhosis, 97 Claversal® , 319 Clinical research in pediatric IBD gastrointestinal endoscopy indices, 515–517 CDEIS, 515, 517, 530 PCDEIS, 517 ulcerative colitis, 516–517, 527 indices for, 509–517, 521–526 CDAI, 509–510, 512–513, 515, 521–522 PCDAI, 509–513, 516–517, 522–524 PDAI, 513, 524–525 UCDAI, 513–515, 526 QOL instruments, 516–517 Clinical research instruments, assessment of, 507–509 Clinical trials clinical perspective, 531–538 design features, 545 dosing and consent/assent for, 549 drug development and, 541–547 industry perspective, 541–549 markers and indexes of disease activity, 531–536 practicing physicians and conduct of, 547–548 quality of life assessment in, 536–537 using IMPACT to assess HRQOL in pediatric IBD, 574 Clostridia difficile, 355 Clostridium difficile, 166–167, 186, 332, 447, 490
infection, 143 toxin, 180 Clostridium perfringens, 487 CNTO 1275 interleukin-12/23 p40 subunit antibody, 404, 413 Cobblestone mucosa, 215, 256 Coccidiomycosis, 437 Codeine, 597 Code of Federal Regulations (CFR), United States, 543 Cognitive behavioral therapy, 588 Colazal® , 318–319, 321 Colectomy, 76, 79, 88, 387, 463, 604 Colicky abdominal pain, 172 Colitis-associated cancers, 612 Colitis-associated colorectal cancer, 612 Colitis-associated neoplasia, 612 Colitis Symptom Score, 514 Collaborative networks, in quality improvement in IBD, 638 Collagenous colitis, 242 Colonic IBD type unclassified, 150 Colonic malignancy, in ulcerative colitis, 246–248 Colonoscope sigmoid loops, 220 Colonoscopy, 145, 450, 596, 632 bowel preparation for, 213–214 Colorectal cancer (CRC), 611 in Crohn disease, 622–624 surveillance, 622 in ulcerative colitis, 613–621, 623 age of UC onset, 615–616 anatomic extent of UC, 615 chemoprevention, 617 clinical practice and, 613–625 duration of UC, 614–615 dysplasia surveillance, 619–623, 625 epidemiology, 613–614 family history, 616 folic acid, 617 inflammation, 617 methods to reduce risk/mortality, 618 pharmacotherapy, 617 primary sclerosing cholangitis, 616 risk factors, 614, 618 risk modifiers, 614 sulfasalazine, 617 surgery, 618–619 surveillance, 622 Colorectal carcinoma, chemoprevention of, 322–323 Committee for Human Medicinal Products (CHMP), 541, 546, 547 Common variable immunodeficiency, 170 Complete blood count, 179–180 Computed tomography (CT), 195, 198, 207 Computed tomography enterography (CTE), 263, 266 Confocal laser endomicroscopy (CLE), 235 Congestive heart failure, 633 Consensus Statement On Healthcare Transitions For Young Adults With Special Healthcare Needs, 663 Constipation, 160, 438 Constipation predominant IBS, 582
Index Conte Digestive Disease Research Centers Program, 658 Continent ileostomy, 474 Contract Research Organizations (CRO), 541, 543 Contrast enema, 198 Cortical osteopenia, 285 Corticosteroids, 54, 76–79, 93–97, 99, 119, 330, 338–339, 342, 385, 388–390, 392, 394, 411, 446–448, 473, See also Budesonide and growth impairment in pediatric IBD, 109 and growth management, 112, 114 in pregnancy, 595, 597, 601 systemic corticosteroids, 364 therapy, 363–368, 450, 470, 475 topical corticosteroids, 364–365 for treatment of perianal Crohn disease fistulae, 431 withdrawal with infliximab therapy, 390–391 working mechanism of, 363–364 Cortisol, 103, 139 Cortisone, 76 Coxsackie infection, 447 Crohn and Colitis Foundation of America, 432 Crohn Disease Activity Index (CDAI), 330, 365–366, 388, 405, 509–510, 512–513, 515, 523–424, 533, 534, 586 with pediatric modifications, 534 Crohn disease (CD), 16, 19, 25–26, 31, 45–46 adenocarcinoma of small intestine, 624 5-aminosalicylate therapy, 321–322 antibiotic therapy in, 330–332 appendectomy protective effects, 53 ATG16L1 autophagy gene association, 8 backwash ileitis, 254 bone density in children with, 125–126 breast feeding, 53 budesonide maintenance treatment in, 368 budesonide treatment in, 365–366 CE diagnostic utility in suspected, 265–266 clinical trials in, 531–538 cobblestone appearance in, 231 colonic stricture in, 228, 232 CRC in, 620–623 deep aphthous ulcer in, 227–228 descriptive epidemiology, 46–49 dietary factors and, 53 distinguishing from ulcerative colitis algorithm for, 151 backwash ileitis and Crohn of ileum, 145, 148 endoscopy and biopsy, 145–146 gastritis in patients with IBD, 147–148 non-classical findings, 147 periappendiceal inflammation, 148 radiographic imaging studies, 149 rectal sparing and patchiness, 148–149 serologies and genetic testing, 149–150 video capsule endoscopy, 150 distinguishing pathologic features, 245, 248–251 elective surgery, 458–459 esophageal disease in, 215 gastritis in, 217 gender and, 49 gene desert on chromosome 5p13 association, 8
671
genetic epidemiology ethnic and racial variations, 4 family studies, 4 twin studies, 4–5 gene variants, 5–7 DLG5 gene, 6 epidemiology of NOD2 mutations, 5–6 functional effects of NOD2 mutations, 5 HLA type, 6–7 NOD2/CARD15 gene, 5 SLC22A4/A5 variants at IBD5 locus, 6 genome-wide association studies, 7–8 geographic trends, 46–49 granulomas, 249–251 and growth impairment, 105–107 growth of children with, 105 IL23R polymorphisms association, 7–8 indeterminate colitis and, 83–89 indications for surgery, 456–457 infectious agents and, 52–53 intestinal commensal flora, 52–53 laparoscopy, 462 medical therapy for, 457 medical therapy impact on surgery in, 464 methotrexate therapy in, 379–384 Montreal classification, 152 of oesophagus, 216 oral lesions in, 94 peripheral joint inflammation, 93 post-operative recurrence, 322, 464 puberty and, 135–136 racial and ethnicity trends, 49 radiologic evaluation, 193–198 computed tomography, 195–194 contrast studies, 194–195 imaging techniques, 195–198 magnetic resonance imaging, 195–196 plain abdominal radiographs, 194 ultrasound, 196 rectal sparing and patchiness, 253–254 skip lesions in, 228, 230 small intestine cancer, 624 stricturoplasty, 461–462 subclassification of, 152–153 surgical emergencies, 457–458 surgical frequency in, 69–70 surgical treatment of, 64, 455–465 symptoms, 160–162 terminal ileal, 233 terminal ileum, 249–250 time trends in, 46 transmural disease in, 249–250 upper GI tract involvement in, 255 whole body BMC Z-scores in, 284 Crohn disease endoscopic index of severity (CDEIS), 392, 515, 517, 530 Crohn of ileum and backwash ileitis, 145, 148 Crohn’s and Colitis Foundation of America (CCFA), 561, 655–659 CRP (C-reactive protein), 179–180, 182–183
672
Index
Cryptitis, 145, 166 Cryptosporidium parvum, 333 CTLA-4 (cytotoxic T lymphocyte antigen-4), 20 CTLA-4 fusion protein, 417 Curative resection, 71 Cyclooxygenase-2-inhibitors, 93 Cyclosporine, 78, 97, 387, 450, 595, 599–601 in pregnancy, 595, 599 Cyclosporine A, for treatment of perianal Crohn disease fistulae, 434, 440 Cystic Fibrosis Foundation (CFF), 633, 638 Cytochrome p450 3A (CYP3A) enzymes, 364 Cytokine-inducible signaling (SOCS-3), 139 Cytokines anti-inflammatory, 31–32, 37–39 IL-4, 31–32, 38 IL-10, 31–32, 39 TGF–, 32, 38 and growth impairment in pediatric IBD, 108–9 IL-5, 31–32 IL-15, 39 IL-22, 39 IL-32, 39 IL-33, 39 IL-1ra, 32 pro-inflammatory, 32–37 IL-1, 31, 33–34 IL-2, 31, 34 IL-6, 31–32, 34–35 IL-12, 31, 35 IL-13, 31, 37 IL-17, 36 IL-18, 31, 36–37 IL-23, 36 interferon gamma, 31, 33 tumor necrosis factor alpha, 31–33 TIL-1A, 39 Cytomegalovirus (CMV), 52, 169, 396, 490 Daclizumab, 404, 414 Data and Safety Monitoring Boards (DSMB), 543 Data Monitoring Committee (DMC), 543 Dehydration, 161 Dehydroepiandrosterone sulfate (DHAS), 134–135 Delayed puberty, 160–161 Dendritic cells (DCs), 17–19, 21, 23, 122, 415 Depression, 633 Dermatitis, 502 Dexamethasone, 597 Diabetes, 633 Diarrhea, 159–160, 167, 168, 182, 278 Diarrhea predominant IBS, 582 Diazepam, 214 Dietary factors and IBD, 53–54 Dietary Reference Intakes, 296 Differential diagnosis, pediatrics IBD, 165–171 abdominal mass, 172 acute appendicitis, 167 acute onset diarrhea, 165–166 autoimmune enteropathy, 170
celiac disease, 170 chronic or recurrent intestinal symptoms, 167–171 eosinophilic gastroenteropathy, 170 esophagogastroduodenal involvement, 173 food allergy, 167 intestinal infection, 167–170 intestinal neoplasm, 170 isolated perianal disease, 171 primary or acquired immunodeficiency diseases, 169 vasculitis disorders, 170 Diffuse rash, 438 Diffuse superficial ulcers, 215 Digestive Disease National Coalition (DDNC), 655, 656–657 Digestive Disease Research Centers (DDRCs), 658 Digestive Disease Research Centers Program, 658 Digital rectal examination, 162 Dihydrofolate reductase (DHFR) enzymes, 380 Dipentum® , 318–319, 321 Diphenhydramine, 450 Diphenoxylate, 597, 603 Disease activity, markers and indexes of, 529–534 Disease activity index (DAI), evaluation of, 508 Diversion colitis, 242 DLG5 (Drosophila Discs Large Homolog 5) gene, 6, 16 DLG5 gene variants and IBD, 6 Double balloon endoscopy (DBE), 231–233 Double balloon enteroscopy, 212, 231–233, 235, 263 D-penicillamine, 97 Drug development clinical trial design features, 545 economics of, 548 good clinical practice, 546–547 informed consent requirements, 546 Institutional Review Board and Ethics Committee in, 542–543 International Committee for Harmonization Guidelines, 542 investigator responsibilities, 542 key participants in, 541–543 National Institutes of Health in, 542 pharmaceutical and biotech industries in, 542 principle investigator role in, 542 process, 543–544 regulatory agencies and regulatory process, 545 regulatory agencies in, 541–542 Drugs and IBD, 54 Dual-energy x-ray absorptiometry (DEXA), 94, 137, 206 Dual x-ray absorptiometry (DXA), 120, 280–283 BMD, 280–285 limitations of DXA in children and adolescents, 281–283 Dysplasia-associated lesions or masses (DALMs), 246, 621–622 Dysplasias, 492–493, 612–613 Dysplasia surveillance, in CRC, 619–621, 625
Index Early and Periodic Screening, Diagnostic and Treatment services (EPSDT), 649 Eosinophils, 170 Employee Income Retirement Security Act (ERISA), 647 Endocrines, and growth impairment in pediatric IBD, 109 Endometrial cancer, 624 Endoscopic Clinical Correlation Index (ECCI), 514 Endoscopic retrograde cholangiopancreatography (ERCP), 97, 205 Endoscopic techniques in IBD, 214–235 confocal laser endomicroscopy, 235 double balloon endoscopy, 231–233 endosonography, 233–234 enteroscopy, 229–231 findings, 227–233 follow-up and surveillance ileocolonoscopy, 228–229 high magnification chromoscopic colonoscopy, 234–235 ileocolonoscopy, 217–229 cecum, 222–223 complications of, 226–227 dilation of strictures, 226 endoscope withdrawal, 225–226 equipment, 217–218 getting started and patient positioning, 218 hepatic flexure and ascending colon, 220–222 ileal intubation, 222–224 ileum, 224–226 practical tips, 218–219 rectal intubation, 219 sigmoid and descending colon, 219–220 splenic flexure and transverse colon, 220–221 techniques, 218–226 upper gastrointestinal endoscopy, 214–217 Endoscopic ultrasound (EUS), 200, 263 Endoscopy, 145–146, See also Endoscopic techniques in IBD bowel preparation for, 212–214 history, 211–212 monitoring and sedation, 214–215 patient preparation for, 212 sedation and reversal medications employed, 214 Endosonography, 233–234 Endothelial leukocyte adhesion molecule (ELAM), 34 Entameoba histolytica, 168, 186 Enteral feeding devices complications, 495–501 fistula formation, 500 granulation tissue, 500–501 infections, 496, 499 leakage, 499–500 tube migration, 496, 499 tube obstruction, 501 Enteral nutrition (EN), and growth management, 111–112, 114, 343 Enteral nutrition (EN) therapy, 387 adverse effects, 345–346 in combination with medical therapy, 345 effectiveness in CD, 338–340 efficacy, 343–344
673
growth improvement, 111–112, 114, 343 mucosal healing, 343 quality of life improvement, 344 factors affecting response, 340–343 disease duration, 342–343 disease location, 343 duration of therapy, 343 fat composition, 342 formula composition, 340–342 polymeric versus elemental/semi-elemental diets, 340–342 formula composition, 346 immunologic effects, 346–347 long term outcomes, 344–345 as maintenance therapy, 344–345 mechanisms, 346–347 post-operative effects, 345 Enteric fistula, radiologic evaluation, 202–204 Enteric nervous system, in IBS, 585–586 Enterobacter cloacae, 496 Enterococcus, 350 Enterocolitis, 170 Enterocutaneous fistulae, 435, 438, 458 Enteroscopy, 229–231 Entocort® , 364–365 Eosinophilic colitis, 242–243 Eosinophilic gastroenteropathy, 168–169 Epilepsy, 99 Epiphyseal chondrocytes, mitosis of, 103 Episcleritis, 92, 96–97, 161 Epithelial cells, 23–24 barrier, 16–17, 19 Epithelial dysplasia, 246 EP4 (PTGER4), 8 Epstein-Barr virus (EBV) infection, 170, 396 Erythema nodosum, 92, 94–95, 160–162, 167–168, 487 Erythromycin, 491 Escherichia, 350 Escherichia coli, 24, 52, 167, 180, 186, 333, 352–363, 356, 447, 487, 496 Esophageal disease, in CD, 215 Esophagogastroduodenal involvement, 171 Esophagogastroduodenoscopy (EGD), 215, 263, 265, 267 ESR (Erythrocyte sedimentation rate), 167, 177–178, 180–181 Estradiol (E2), 133–134 17-Estriol, 138 Estrogen, 133, 137–139 Estrone (E1), 133–134 Etanercept, 404, 409, 601–602 Ethics Committee, US, 542–543, 546 Ethynylestradiol, 140 Etiology and pathogenesis of pouchitis, 485–488 bacterial overgrowth, 487 Crohn disease, 487 extra-intestinal manifestations, 487–48 fecal stasis, 487 immunosuppression, 486–487
674
Index
mucosal ischemia, 487 smoking, 488 EudragitTM , 318–319 Eudragit-LTM , 318–319, 324, 365 Eudragit-STM , 318–319 European Agency for Evaluation of Medicinal Products (EMEA), 537, 541, 546 European Cooperative Crohn’s Disease Study (ECCDS), 67, 321 European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), 142, 159, 365 Extraintestinal disease, radiologic evaluation, 205 Eye lesions, 96–97 Familial adenomatous polyposis (FAP) syndrome, 485–486, 491–493, 611 Family and Medical Leave Act (FMLA), 649–650, 654 Fatigue, 97, 438 Fatty liver, 98 FDA Modernization Act, 545, 549 Fecal calprotectin, 184, 186–187 Fecal lactoferrin, 183, 187–188 Federal Drug Administration (FDA), 541, 545, 547 Fentanyl, 214 Fertility and pregnancy, 594–595 Fever, 169 Fever of unknown origin (FUO), 161 Fibrosing colonopathy, 242 Filgastrim (G-CSF), in biologic therapies, 404, 415 Fistula Drainage Assessment, 513, 517, 525 Fistulotomy, 463 Flumazenil, 214 Fluorescence in situ hybridization (FISH), 25 Fluoroquinolones, 599 Fluticasone, 364 Focal active colitis (FAC), in chronic IBD, 242–243 Focal gastritis, 255 Folic acid, 594, 600, 617 Follicle-associated epithelium (FAE), 16–17, 19 Follicle stimulating hormone (FSH), 133–135 Fontolizumab (anti-interferon , in biologic therapies, 404, 416 Food, Drug and Cosmetic Act 1938, US, 545, 549 Food allergy, 166 Food and Drug Administration (FDA), 655–656 Foxp3+ T regulatory cells, 38 Frankfort plane, 297–298 Fulminant colitis treatment of, 447–450 in ulcerative colitis, 256–257 F usobacterium varium, 332 G113A, 6 Gallstones, 98 radiologic evaluation of, 205 Gastritis in CD, 217 Gastrocolonic fistulas, 500 Gastroenterology Burden of Disease, 634
Gastrointestinal endoscopy indices, 515–517 CDEIS, 515, 517, 530 PCDEIS, 515 ulcerative colitis, 516–517, 528 Gastrojejenunostomy tube complications, 495–500, See also Gastrostomy Gastro-jejunal tubes, 498 Gastrostomy, 495–496 tube complications, 495–501 fistula formation, 500 granulation tissue, 500–501 infections, 496, 499 leakage, 499–500 migration, 496, 499 tube obstruction, 501 Gene desert on chromosome 5p13, association to Crohn disease, 8 Genetic influence, on growth impairment in pediatric IBD, 110 Genetics, and irritable bowel syndrome, 583–584 Genetic testing and serologies, 149–150 Gentamicin, 212, 332 Giardia intestinalis, 169 Giardia lamblia, 333 Gingival hyperplasia, 434, 450 Glaucoma, 97, 161 Glomerulonephritis, 99 Glucocorticosteroids (GCS), 361, 377, 385, See also Corticosteroids associated side effects, 366–368 -Glutamyl transpeptidase (GGT), 178, 182 Gonadotropin releasing hormone (GnRH), 133, 136–137 Good clinical practice (GCP), 546–548 Graft versus host disease, 242 Granulation tissue, 501 Granulocyte-colony stimulating factor (G-CSF), 415 Granulocyte macrophage-colony stimulating factor (GM-CSF), 414 Granulomas, 166 in Crohn disease, 249–251 differential diagnosis in colon, 251 Granulomatous hepatitis, 98 Granulomatous lung disease, 99 Granulomatous skin lesion, 92 Granulosa cells, 133 Greulich and Pyle Atlas, 302 Growth and nutritional status anthropometry body mass index, 299–300 growth velocity, 297–298 height, 297 indicators of nutritional status, 298–299 measurement of growth, 296 reference data for, 301 upper arm anthropometry, 300 upper arm fat and muscle area, 301 weight, 297 assessment in pediatric IBD, 295–304 medical history and laboratory evaluation, 295–296
Index sexual maturation, 303–304 skeletal maturation, 302 Growth failure, 160–161 Growth hormone (GH), 134, 138–139 Growth impairment, in pediatric IBD chronic caloric insufficiency, 107–108 corticosteroids effects, 109 Crohn disease and, 105–107 cytokine effects, 108–109 endocrine mediators of, 109 factors contributing to, 107 genetic influence, 109 management, 110–113 anti-inflammatory treatments and effects on growth, 111 anti-tumour necrosis factor alpha, 113 azathioprine, 112 corticosteroids, 112, 114 enteral nutrition, 111–112, 114 hormonal interventions, 113 6-mercaptopurine effects, 112 surgery, 112–113 monitoring and assessment of growth, 104 pathophysiology of, 107–109 prevalence of, 104 psychosocial impact, 110 ulcerative colitis and, 105, 107 Guillain-Barré syndrome, 407 Gut-associated lymphoid tissue (GALT), 16, 21–23 Gut microbes, 23–24 Haemophilus influenzae, 24 Harvey Bradshaw Index (HBI), 509–510, 511, 521 Headache, 434, 438, 450 Health and Medicine Counsel of Washington (HMCW), 655–656 Health-related quality of life (HRQOL), 536, 566–575, See also Quality of life (QOL) assessment for IBD, 569–571 in pediatric IBD, 571–572 in pediatrics, 568–569 deficiencies in evaluation, 576–577 future research in, 576–577 IMPACT questionnaire for, 572–576 measurement approaches, 567–568 characteristics, 568 for IBD, 570 needs, 567 score, 72 Heat shock protein (HSP)- 70, 7 Heidelberg pouchitis activity score, 489 Height in pediatric CD, infliximab therapy for restoration, 390 Height velocity, 532 Heineke-Mikulicz stricturoplasty, 461–462 Helicobacter pylori, 217, 255, 354 Helminthes, 333 Hematochezia, 159–160
675
Hematologic abnormalities, 98 Hemicolectomy, 604 Hemolytic uremic syndrome, 242 Hemolytic anemia, 597 Henoch–Schöenlein purpura (HSP), 170, 242 Hepatic fibrosis, 434 Hepatic necrosis, 437 Hepatitis Foundation International (HFI), 656 Hepatobiliary disease, radiologic evaluation of, 205–206 Hepatomegaly, 97 Hepatosplenic T-cell lymphomas, 72, 396, 450, 625 Hepatotoxicity, 434 Hereditary non-polyposis colorectal cancer (HNPCC), 611 Hermansky-Pudlack syndrome, 171 High magnification chromoscopic colonoscopy (HMCC), 234–235 Hirschsprung’s disease, 242 Hirsutism, 434 Histoplasmosis, 437 HLA-A2, 91 HLA-B, 6 HLA-B27, 91 HLA-B58, 91 HLA-B27 antigen, 93 HLA-B8/DR3, 91 HLA-DP, 6 HLA-DQB1, 6 HLA-DQw5, 91 HLA-DR1, 91 HLA-DRB1, 6, 91 HLA type and IBD susceptibility, 6–7 HMLH1 gene, 79, 612 HMLH2 gene, 612 Hodgkin’s disease, 407 Hormonal interventions, in growth management, 113 Human Herpes virus 6 (HHV6) infection, 396 Human leukocytes antigens (HLA) system, 91 Human TPMT polymorphisms, 310 Hydrocephaly, 600 Hydrocorticone thiopivalate, 364 Hydrocortisone, 332, 394 Hydronephrosis, 447 6-Hydroxybudesonide, 364 16-Hydroxyprednisolone, 364 Hyoscyamine, 213 Hyperamylasemia, 413 Hyperkalemia, 450 Hyperplastic gingivitis, 94 Hypersensitivity pneumonitis, 99 Hypertension, 434, 438, 450 Hypertonic saline, 243 Hypertrichosis, 450 Hypertrophic osteoarthropathy, 94 Hyperuricemia, 413 Hypoalbuminemia, 178, 181, 284 Hypogammaglobulinemia, 167 Hypoproteinemia, 161 Hypoxanthine phosphoribosyl transferase (HPRT) enzyme, 311
676
Index
IBD5 locus, SLC22A4/A5 variants at, 6 IBD therapy current expectations for, 531–532 height velocity, 532 IgA deficiency, 170 IGF-binding protein 3 (IGFBP-3), 108–109 IGFBP-3, 138–139 IKBL (inhibitor of B-like) gene, 79 IL-10-deficient mice, 25 Ileal Pouch-Anal Anastomosis (IPAA), 88–89, 257, 471, 476–480, 485–493, 604 Ileitis, 333 Ileo-anal anastomosis (IAA), 472–474, 485 Ileoanal pouch anastomosis, 387 Ileocecal trans-cutaneous Doppler ultrasonography, 229 Ileocecal valve, 223 Ileocolic anastomosis, 455 Ileocolitis, 333 Ileocolonic Crohn disease, 407 Ileocolonoscopy, 217–229, 265 complications of, 226–227 equipment, 217–218 techniques, 218–226 cecum, 222–223 dilation of strictures, 226 endoscope withdrawal, 225–226 getting started and patient positioning, 218 hepatic flexure and ascending colon, 220–222 ileal intubation, 222–224 ileum, 224–226 practical tips, 218–219 rectal intubation, 219 sigmoid and descending colon, 219–220 splenic flexure and transverse colon, 220–221 Ileocolostomy, 455, 472 Ileorectostomy, 471–472 Ileostomy, 457–458, 463, 469, 471–472, 474, 602, 617 Ileotransversecolostomy, 455 IL-23 heterodimeric receptor, 7 IL-2−/− mice, 124 IL-10−/− mice, 124 IL-1ra cytokine, 32–34 IL23R gene, 7 IL23R (Interleukin 23 receptor) polymorphisms, 7 IL23R protein, 7 Imaging techniques, 192–197 Immunogenicity and autoimmunity, in infliximab therapy, 393–395 Immunomodulators, 77–78, 80, 89, 95 in pregnancy, 599–601 therapy, 379, 502 Immunosuppressive therapy, 170, 491 IMPACT III questionnaire, 534, 572–576 IMPACT II questionnaire, 573, 575 IMPACT I questionnaire, 573 IMPACT questionnaire, 536, 572–577 administration and instructions to respondents, 575 development of, 572–574 instrument, 574–575
practical issues for use, 575–576 scoring, 576 Improvement Collaborative, 636–637 Improvement Model, 632, 635–636 Improving Chronic Illness Care (ICIC) model, 661 Indeterminate colitis (IC), 83, 150, 152, 531, See also Pediatric indeterminate colitis CE diagnostic utility in, 267 radiologic evaluation of, 198 in ulcerative colitis, 256–257 Indices, for pediatric IBD research, 507–517 Individualized education program (IEP), for patients with IBD, 642 Individuals with Disabilities Education Act (IDEA), 642 Infancy-childhood-puberty (ICP) growth, 135 Infections, 434, 437, 450 in infliximab therapy, 395–396 Inflammatory bowel disease (IBD), See also Pediatric IBD acute self-limited colitis and, 144–145 adaptive intestinal immunity and, 19–22 adaptive immune cells development, 22 B cells, 22 T cells, 19–21, 26 TREG cells, 21–22 among new populations, 56 antibiotic therapy, 329–334 appendectomy and, 53 ASLC from, 252 breast feeding and, 53 cancer in, 611–623 challenges, 55–56 classification, 62, 143–153 clinical indices for research in, 507–517 clinical trials in, 529–536 diagnostic evaluation of, 143–144 dietary factors and, 53–54 drugs and, 54 elevated BMI in, 339 endoscopy and histology, 145–146, 227–228 environmental risk factors, 51–53 intestinal commensal flora, 52–53 microbial factors, 52–53 smoking, 51–52 epithelial barrier development, 19 gastritis in patients with, 147–148 genes and environmental interactions impact, 55–56 genetic epidemiology, 4–5, 55 ethnic and racial variations, 4 family studies, 4 genetic epidemiology, 4–5 twin studies, 4–5 genetics of, 3–11 gene variants in, 5–7 DLG5 gene, 6 HLA type, 6–7 genotype-phenotype correlations, 9–10 gut immunity and, 15–26 history, 159–161 HRQOL assessment for, 569–571
Index hygiene hypothesis and epidemiological observation, 49–51 innate and adaptive immune responses, 24–25 innate immune cells development, 19 innate intestinal immunity and, 16–19 atypical lymphocytes, 18–19 dendritic cells, 18 epithelial cell barrier, 16–17, 19 innate immune cells, 17 macrophages, 17–18 laboratory tests, 178 legislative advocacy, 655–659 malignant tumors, 611–625 new approaches, 56 new epidemiology, 55 nutritional therapy, 337–347 nutrition management in, 339–347 pathogenesis adaptive immune cellular dysfunction in, 22 barrier dysfunction in, 16 genetic epidemiology impact on, 55 gut microbes, epithelial cells and lymphocytes in, 23–24 innate immune cellular dysfunction in, 19 pediatrician’s perspective, 15–16 pharmacogenetics, 309–314 physical examination, 161–162 in pregnancy, 593–605 puberty and pediatrics, 133–140 quality improvement in, 631–638 safety of oral contraceptives in, 594 serologies, 180, 185–186 socio-economical, educational and occupational status effect, 54–55 symptoms, 160–162 tests for diagnosis, 144, 180 therapeutic approach to puberty issues in, 139–40 therapeutic targets in, 405 World-wide distribution, 50 Inflammatory Bowel Disease Research Act, 656, 657 Infliximab, 69, 72, 78–80, 89, 93, 94–95, 111, 113, 123, 184, 330, 345, 406–407, 413–415, 448, 450, 463–464, 477, 597, 600–603, 632, 634, 637, 646 Infliximab therapy, 387–397, 403, 491 for adult Crohn disease, 388–389 corticosteroid withdrawal with, 390–391 evidence in favour of, 391–392 and malignancies, 396 and mortality, 397 for pediatric CD, 389–392 in pediatric IBD, 387–388 for pediatric UC, 392–393 restoration of height in paediatric CD, 390 side effects and safety, 393–397 immunogenicity and autoimmunity, 393–395 infections, 395–396 malignancies, 396 mortality, 397 surgeries in pediatric CD and, 393
677
for treatment of perianal Crohn disease fistulae, 429, 433, 435–439 Innate and adaptive immune responses, in pediatrics IBD, 24–25 Innate immune cells, 17, 19 Innate intestinal immunity and IBD, 16–19 atypical lymphocytes, 18–19 dendritic cells, 18 epithelial cell barrier, 16–17, 19 innate immune cells, 17 macrophages, 17–18 Institutional Review board (IRB), US, 542, 546 Insulin, 134 Insulin-like growth factor-1 (IGF-1), 108–110, 113, 123, 134, 138–139, 275, 279, 339, 343, 390 47 Integrin, 411 Inter-cellular adhesion molecule 1 (ICAM-1), 20–21, 34, 412 Inter-cellular adhesion molecule 2 (ICAM–2), 20 Interferon- (IFN-p cytokine, 21, 33 Interferon- (IFN- cytokine, 31–33, 35–37, 39, 122, 392, 416–417, 436, 491 Interferon- inducing factor (IGIF), 36 Interferon- mRNA, 343 Interleukin-1 (IL-1p cytokine, 33, 415, 487 Interleukin-1 (IL-1p cytokine, 33, 121, 138–139, 346, 415–416, 491 Interleukin-1 (IL-1 mRNA, 342–343 Interleukin-1 (IL-1) cytokine, 31–34, 109, 280, 487 Interleukin-2 (IL-2) cytokine, 31–34, 415, 601 Interleukin-4 (IL-4) cytokine, 20, 25, 31–32, 35, 38 Interleukin-5 (IL-5) cytokine, 20, 25, 31–32, 35, 38 Interleukin-6 (IL-6) cytokine, 31–37, 108–109, 113, 138–139, 280, 415 Interleukin-7 (IL-7) cytokine, 32 Interleukin-8 (IL-8) cytokine, 19, 33, 36–37, 415, 491 Interleukin-10 (IL-10) cytokine, 31–32, 35, 37, 39, 122, 363, 436 in biologic therapies, 404, 415–416 Interleukin-12 (IL-12) cytokine, 7, 19–20, 31–32, 35–37, 122, 280, 392, 413–415, 417 Interleukin-13 (IL-13) cytokine, 20, 25, 31–32, 37–38 Interleukin-15 (IL-15) cytokine, 39 Interleukin-17 (IL-17) cytokine, 36 Interleukin-18 (IL-18) cytokine, 31, 36–37 Interleukin-22 (IL-22) cytokine, 39 Interleukin-23 (IL-23) cytokine, 7, 20, 35–36, 413–414 Interleukin-32 (IL-32) cytokine, 39 Interleukin-33 (IL-33) cytokine, 39 Interleukin-1ra (IL-1ra), 487 Interleukin-12R22, 415 Interleukin-1 receptor antagonist (IL1RA), 8–9 Interleukin-1RN∗ 22, 487 International Committee for Harmonization (ICH), 542 International Foundation for Functional Gastrointestinal Disorders (IFFGD), 656 Interstitial pneumonitis, 99 Intestinal commensal flora and IBD, 52–53 Intestinal epithelial cells, 8 Intestinal infection, 165–168
678
Index
Intestinal lymphoma, 170 Intestinal neoplasm, 170 Intraabdominal abscess, radiologic evaluation, 202–204 IPEX (Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked) syndrome, 37, 171 Iris atrophy, 97 Irritable bowel syndrome (IBS), 187 clinical features, 582–583 diagnosis, 583, 586–587 epidemiology, 581–582 pathophysiology, 583–586 altered motility, 584 biochemical changes, 584 enteric nervous system, 585–586 functional and motility abnormalities in IBD, 585–586 genetics, 584–585 low grade inflammation, 584 psychological factors, 585 sensory sensitization and hyperalgesia, 583 in pediatric IBD, 581–589 pouch syndrome, 589 Rome III criteria for diagnoses of, 583 treatment, 587–588 Irritable pouch syndrome, 490 Irvine Perianal Disease Activity Index, 433 Isphagula, 588 Jacob Creutzfeldt polyoma virus, 411 Jaundice, 97 Jejunal feeding tubes, 498 Joint inflammation, 92–93 Junctional adhesion molecule (JAM) protein, 16 Juvenile arthritis, 287 Juvenile rheumatoid arthritis, 182, 382–384, 409 Kefauver Harris Amendments to 1938 Act, 545 Keratinocytes, 415 Ketamine, 214 Kock ileostomy, 476 Kock pouch operation, 474–475 Kudos’ criteria, 234 Laboratory evaluation blood tests, 179–181 acute phase reactants, 182 anemia, 180–182 anti-saccharomyces cerevisisae, 185–186 ESR and CRP, 182–183 liver function tests, 180, 183 platelets, 182 of pediatric IBD, 179–188 stool evaluation, 180, 186–187 fecal calprotectin, 187 fecal lactoferrin, 187 Lactobacillus, 350, 358, 491, 496 Lactobacillus acidophilus, 354 Lactobacillus lactis, 39 Lactobacillus rhamnosus, 353, 355-358
Lactococcus lactis, 415–416 Lamina propria macrophages, 145 Laparoscopy, in Crohn disease, 462 Legislative advocacy for IBD, 655–659 Leiomyoma, 172 Leiomyosarcoma, 71 Lethargy, 159–160 Leucocyte Adhesion Molecule Deficiency, 170–171 Leukemias, 624 Leukocytosis, 95, 98, 180 Leukopenia, 384, 434 Leydig cells, 133 Lichtiger colitis activity index (LCAI), 393 Lichtiger Score, 513–514, 526 Linear ulcers, 215 Listeria monocytogenes, 5, 52 Listeriosis, 437 Liver abscesses, 98 Liver biochemistries, 179–180, 183–184 Liver disease, 97–98, 160 Liver function tests, 180, 183 Lactobacillus johnsonii, 356 Lloyd-Still Index, 514 Loperamide, 588, 597, 603 Lupus arteriosus, 172 Luteinizing hormone (LH), 133–134 Luteinizing hormone releasing hormone (LHRH), 133, 138 Lymphangiectasia, 249 Lymphocytes, 23–24 Lymphocytic colitis, 242 Lymphomas, 170, 450, 624–625 Lymphonodular hyperplasia, 224, 226 Lynch syndrome, 611 MacColl Institute for Healthcare Innovation, 661 Macrophages, 17–18, 23, 415 Macrophage stimulating factor (M-CSF), 121 MAdCAM-1, 21 Magnetic resonance cholangiopancreatography (MRCP), 97, 205–206 Magnetic resonance enterography (MRE), 263, 266 Magnetic resonance imaging (MRI), 195–196, 199, 200, 206–207 MAGUK (membrane-associated guanylate kinase) family, 6 Major histocompatability complex (MHC) genes, 79, 346 Malecot® tube, 496 Matt’s criteria, 234 Mayo-Clinic Score, 514, 516, 527 Mean height percentiles, 10 Medical therapy, and enteral nutrition therapy, 345 Mediterranean lymphoma, 172 Megaloblastic anemia, 597 Meningomyelocele, 600 Menthol, 588 Meperidine, 214 6-Mercaptopurine (6-MP), 87, 92, 98, 309–311, 379, 382, 387, 406, 448–450, 464, 595, 599–600, 601, 625, 632–633 effects on growth management, 112
Index for treatment of perianal Crohn disease fistulae, 432–434, 437, 439 Mesalamine, 68, 77, 317–318, 322–325, 330, 332–334, 353, 448, 464, 491, 597–598, 602–603, 633 Mesalazine, 182, 317, 356 Mesasal® , 319 Mesavance™ , 318, 325 Mesenchymal stems cells, 279 Metabolite monitoring role, of TPMT pharmacogenetics, 313 Metastatic Crohn disease, 94 Metastatic lung cancer, 408 Methotrexate (MTX), 94, 99, 387, 394, 396, 406–407, 597, 600, 602–603 Methotrexate (MTX) therapy Crohn disease, 379–384 dose and administration, 381–382 efficacy, 382–383 mechanism of action, 380 toxicity and monitoring, 383–384 for treatment of perianal Crohn disease fistulae, 434, 440 ulcerative colitis, 380 Methylated-mercaptopurine metabolite (6-MeMP), 311 Methylprednisolone, 448–449 Metronidazole, 330–332, 335, 355, 431–433, 437, 477, 490, 597–599, 602–603 Microbial factors and IBD, 52–53 Midazolam, 214 Milk of magnesia, 588 Ministry of Health, Labour and Welfare (MHLW), 541–542 Mismatch repair (MMR) gene, 611–612 Mitogen-activated protein kinase (MAPK), 5, 363 Mitogens activated protein kinase, 32 MLN02, 79, 404, 411–412 M (microfold) cells, 16–17, 19 Moskowitz criteria, 489–490 Mouth ulcerations, 182 Mucosa associated lymphoid tissue (MALT) lymphoma, 407 Mucosal healing, and enteral nutrition therapy, 343 Mucosal ischemia, 487 Mucosal plasma cells, 22 Multi-drug resistance (MDR-1) gene, 8–9, 77, 364 Multiple sclerosis, 99 Muramyl dipeptide (MDP), 5 Murine colitis, IL-23 in, 7 Muscle spasm, 438 Mushroom low profile tube, 498 Myasthenia gravis, 91 Mycobacterium avium subsp. paratuberculosis, 52, 186 Mycobacterium tuberculosis, 168, 172, 395 Mycophenolate, use in pregnancy, 601 Myoblasts, 279 Myopathy, 99 Myopericarditis, 99
679
Naïve T cells, 16, 20 Naloxone, 214 Nasopharyngitis, 408 Natalizumab, 404, 410–411 National Cancer Institute (NCI), 659 National Colorectal Cancer Roundtable (NCCRT), 659 National Cooperative Crohn Disease Study (NCCDS), 67, 321 National Digestive Disease Commission (NDDC), 658 National Digestive Diseases Information Clearinghouse (NDDIC), 658 National IBD Advocacy Network, 659 National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases (NIADDK), 658 National Institute of Arthritis, Metabolism, and Digestive Diseases (NIAMDD), 658 National Institute of Arthritis and Metabolic Diseases (NIAMD), 658 National Institute of Diabetes, Digestive & Kidney Diseases (NIDDK), 655, 657–658 National Institutes of Health (NIH), 542, 545, 655, 657–659 National Scorecard on U.S. Health System Performance, 629 Nausea, 160, 383, 434, 438 Necrotizing enterocolitis, 242 Neoplasms, 450 Nephroblastoma, 172 Neural hyperplasia, 249 Neuroblastoma, 172 Neurologic manifestations, 99 Neutropenic colitis, 242 Niacin, 95 Nitazoxanide, 333–335 Nitroblue tetrazolium (NBT) test, 251 Nitromidazole, 331 NK cells, 32–33 NKT (Natural killer T) cells, 17–18, 37 NOD2/CARD15 gene, 23, 68, 70, 457 and Crohn disease, 5, 8, 23 NOD2/CARD15 polymorphisms, 5–6, 9–10, 109 NOD2 gene, 53 NOD2 mutations epidemiology, 5–6 functional effects, 5 NOD1 protein, 5, 23 NOD2 protein, 5, 23 Nodularity, 215 Non-balloon replacement gastrostomy tubes, 498 Non-disease related alterations, in chronic IBD, 243 Non-Hodgkin’s lymphoma, 71, 434, 437 Non-steroidal anti-inflammatory drugs (NSAIDs), 54, 268 Normal growth, and pubertal development, 103–104 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN), 339, 561, 655–656, 659, 662 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) IBD working group, 142, 150
680
Index
Nuclear factor-kappa B (NFB) gene, 9, 23, 320, 417 Nucleotide-binding oligomerization domains (NODs), 17 Numbness, 438 Nutritional therapy, 335–345, See also Enteral nutrition (EN) therapy management of nutrition in IBD, 339–343 in pediatric IBD, 337–339 in pregnancy, 602 NuVa® ring, 594 Occludin protein, 16 OCTN (Organic cation transporter proteins), 6, 16 Oesophagus, 216 Office of Human Research Protections (OHRP), 543 Olsalazine, 318–319, 323, 335, 597–598, 603 Omega-6 polyunsaturated fatty acids (n-6 PUFAs), 346 Onercept, 404, 410 OPG-/− mice, 122 Opiates, 450 Optic neuritis, 99 Oral contraceptives (OCP), 54 safety in IBD, 593–594 Oral granulomatous ulcers, 94 Oral lesions, 94 Oral pharynx, 161 Ornidazole, 331–332 Orofacial granulomatosis, 94, 162 Osteoblasts, 119–120, 123, 279 Osteoclastogenesis, 121–122 Osteoclasts, 119–123 Osteonecrosis, 94 Osteopenia, 92–93, 278 radiologic evaluation of, 205–206 Osteoporosis, 92–93, 457 Osteoprotegerin (OPG), 121–122, 279 Ostomy, education and management, 501–502 Oxandrolone (Anavar®), 139 Pancolitis, 246 Pancreatitis, 98, 434, 596, 597 Paneth cells, 19, 246, 414 Papulosquamous, 395 Paresthesias, 434, 450 Patchiness, 148–149 Pediatric colonoscopes, 218 Pediatric colonoscopy, 227 Pediatric Crohn disease cancer risk, 71–72 corticosteroid dependence, 69 disease activity, 67–68 disease phenotype, 68–69 growth, 69 infliximab therapy for, 389–392 methotrexate therapy in, 379–384 natural history of, 67–72 postoperative recurrence in, 70–71 quality of life, 72 surgery in, 69–70 yearly activity, 68
Pediatric Crohn Disease Activity Index (PCDAI), 342–343, 365, 367, 382, 389, 491, 509–513, 517, 522–524, 533 score for, 531 Pediatric IBD, See also Inflammatory bowel disease (IBD) acute onset disease, 165–166 bone health assessment, 275–287 cancer risk, 64 clinical features, 63–64 diagnosis, 63 clinical indices for research in, 509–517 clinical studies of bone health in, 283–285 descriptive epidemiology, 46–49 gender and, 49 geographic trends, 46–49 racial and ethnicity trends, 49 time trends, 46 differential diagnosis, 165–171 endoscopic techniques in, 211, 214–235 epidemiology, 46–49, 61–62 age of diagnosis, 61–62 disease distribution and classification, 61–62 incidence of disease and family history, 61–62 extraintestinal manifestations, 91–99 ankylosing spondylitis, 92 aphthous ulcers, 92 bone disease, 93–94 episcleritis, 92, 96–97 erythema nodosum, 92 eye lesions, 96–97 granulomatous skin lesion, 92 growth failure, 92 hematologic abnormalities, 98 joint inflammation, 92–93 liver disease, 97–98 neurologic manifestations, 99 oral lesions, 94 osteoporosis and osteopenia, 92–93 pancreatitis, 98 peripheral joint inflammation, 92 primary sclerosing cholangitis, 92 pulmonary manifestations, 99 pyoderma gangrenosum, 92 renal manifestations, 99 sacroiliitis, 92 skin lesions, 94–96 uveitis, 92 vascular complication, 98 facilitation of normal growth, 110 by monitoring growth, 110 by prompt recognition of disease, 110 functional gastrointestinal disorders in, 581–589 genotype-phenotype correlations, 9–10 age of disease onset, 10 disease type and location, 9 risk of surgery, 10 growth and nutritional status, 295–304 anthropometry, 296–301 medical history and laboratory evaluation, 295–296
Index sexual maturation, 303–304 skeletal maturation, 302 growth impairment chronic caloric insufficiency, 107–108 corticosteroids effects, 109 Crohn disease and, 105–107 cytokine effects, 108–109 endocrine mediators of, 109 factors contributing to, 107 genetic influence, 109 monitoring and assessment of growth, 104 pathophysiology of, 107–109 prevalence of, 104 preventive management, 110–113 psychosocial impact, 110 ulcerative colitis and, 105, 107 growth of, 63 HRQOL assessment in, 571–572 infliximab therapy in, 387–388 innate and adaptive immune responses, 24–25 irritable bowel syndrome in, 581–589 laboratory evaluation of, 179–188 measurement of quality of life, 565–577 medical management, 63–64 methotrexate therapy in, 379–384 normal growth facilitation in, 110 nutritional impairment in, 337–339 psychological aspects, 555–561 anxiety disorder, 557 behavioral functioning, 555–558 body image and self-esteem, 559 depressive disorders, 556–558 dysthymic disorder, 557 eating disorders, 560 education, 560 emotional functioning, 555–558 family functioning, 559 panic attack, 557–558 social functioning, 558–559 social phobia, 557 stress and coping, 560 psychotherapy and other resources, 561 puberty and, 133–140 radiologic evaluation, 193–207 skeletal health in, 119–128 surgery in, 64 threats to bone health in, 278–280 use of IMPACT to assess HRQOL in, 575 video capsule endoscopy, 263–271 age and size limitations, 271 capsule retention, 268–269 endoscopic placement of capsule, 270–271 precautions and considerations, 271 preparations and prokinetics, 269–270 Pediatric IBD Network for Research and Improvement (PIBDNet), 632, 634 Pediatric indeterminate colitis, See also Indeterminate colitis (IC) definitions, 85 diagnosis, 84, 89
681
epidemiology, 85–86 natural history, 86–89 diagnostic reclassification, 86–87 response to medical management, 87–88 surgical outcomes, 88 Pediatric patients with Crohn disease, See also Pediatric Crohn disease caloric requirements in, 338–339 resting energy expenditure in, 338 Pediatric patients with IBD, See also Pediatric IBD advocacy directed at insurance companies, 644–648 at schools, 641–644 appeal of denial of mental health benefits, 652 educational accommodations needs, 650–651 family and medical leave for caregivers, 649–650, 652–654 medical necessity for, 651–652 social security disability, 648–649, 650–653 Pediatric Research Equity Act (PREA), 545, 549 Pediatric research studies epidemiological data, 46–49, 85–86 impact of pediatric rules, 549 unique issues in, 549 Pediatric Rome Committee, 582 Pediatric to adult care, transition from, 661–665 Pediatric UC Activity Index (PUCAI), 514–515, 517, 528 Pediatric ulcerative colitis, See also Ulcerative colitis (UC) clinical characteristics influencing course, 77 drug modification of natural history, 77–79 aminosalicylates, 77 biologic therapy, 78–79 corticosteroids, 77 immunomodulators, 78 predict course of disease, 79 extent of disease, 77 historical perspective, 75–77 infliximab therapy for, 392–393 natural history, 75–80 severity of disease, 77 Pellagra, 95 Penicillin, 212 Pentasa® , 318–319, 321, 602 Percutaneous endoscopic gastrostomy (PEG), 495–497 Percutaneous radiologic gastrostomy (PRG), 495 Perianal abscess, 438 Perianal Crohn disease, antibiotic therapy in, 331 Perianal Crohn disease activity index, 515 Perianal Crohn disease fistulae classification, 429 diagnosis, 430–431 immunomodulators and biological therapy treatment trials, 439–440 medical treatment 5-aminosalicylic acid derivatives, 431 antibiotics, 431–432 anti-TNF-alpha agents, 438 azathioprine, 432–434, 437 corticosteroids, 431 cyclosporine A, 434, 440
682
Index
infliximab, 429, 433, 435–439 6-mercaptopurine, 432–434, 439 methotrexate, 434, 440 tacrolimus, 435, 439 natural history, 430 novel therapies, 438–439 pathogenesis, 430 treatment of, 431–440 Perianal disease, 171, 202 Perianal Disease Activity Index (PDAI), 513, 524–525 Perianal fistulae, 171, See also Perianal Crohn disease fistulae Perianal ulcers, 94 Periappendiceal inflammation, in ulcerative colitis, 148, 256 Periarteritis nodosa, 172 Perineal disease, surgical treatment of, 463 Perinephritic abscesses, 99 Perinuclear anti-nuclear cytoplasmic antibody (pANCA), 180, 185–186, 633 Peripheral edema, 438 Peripheral joint inflammation, 92 Peripheral neuropathy, 438 Peristomal ulcers, 94 Permanent visual deficits, 97 Pethidine, 214 Peyer’s patches, 22 P-glycoprotein, 364 Pharmaceutical and biotech industries, role in drug development, 542 Pharmacogenetics, in IMB, 309–314 Pharmacokinetics, of TPMT pharmacogenetics, 313 Physician global assessment (PGA), 534 Picornavirus, 170 Pigment deposits, 97 Placebo, 78–79, 112, 325, 330–333, 355, 382, 393, 403, 406, 408, 410, 413, 432, 435, 491, 586 Plan-Do-Study-Act (PDSA) Cycle, 635–637 Plasma testosterone, 138 Platelets, 182 Pleuropericarditis, 99 Pneumocystis carinii pneumonia, 437 Pneumonia, 437 Pneumonitis, 434 Polyethylene glycol, 269, 408, 588 Polymerase chain reaction combined with denaturing gradient gel electrophoresis (PCR/DGGE), 25 Polymerase chain reaction combined with temperature gradient gel electrophoresis (PCR/TGGE), 25 Polymerase chain reaction-denaturing gradient gel electorphoresis (PCR-DGGE), 347 Positron emission tomography (PET), 199, 263 Postoperative Crohn Disease Endoscopic Assessment, 515 Post-operative recurrence CD 5-aminosalicylate therapy in, 322 antibiotic therapy in, 331–332 CE diagnostic utility in, 267 probiotic therapy in, 356–357 Pouchitis, 242, 257, 477–479
after IPAA, 485–493 classification, 489–490, 492 definition and incidence, 486 diagnosis, 488–489 etiology and pathogenesis, 486–489 bacterial overgrowth, 487 Crohn disease, 487 extra-intestinal manifestations, 487 fecal stasis, 487 immunosuppression, 486–487 mucosal ischemia, 487 smoking, 488 probiotic therapy in, 353–355 treatment, 490–492 medical treatment, 490–491 surgical treatment, 491 in ulcerative colitis, 257–258 Pouchitis disease activity index (PDAI), 354–355, 477–478, 489 Pouch syndrome, in IBS, 589 Powell-Tuck Index„ 516, 527, 535 Prednisolone, 363, 364–367, 599, 603 Prednisone, 67–68, 365, 448–449, 491, 599, 603, 632 Pregnancy breastfeeding, 602–603 contraception use, 593–594 effect of IBD on, 595 effect on IBD, 595–596 fertility, 594–595 IBD in, 593–605 management of IBD during, 596–605 clinical assessment, 596 medical therapies, 596–605 medical therapies, 596–605 aminosalicylates, 597–598 antibiotics, 598–599 anti-diarrheals and anti-spasmodics, 597 biologic agents, 600–601 corticosteroids, 599 cyclosporine, 601 etanercept, 601–602 immunomodulators, 599–601 mycophenolate, 601 tacrolimus, 601 thalidomide, 601 mode of delivery, 603 nutritional therapies, 602 onset and diagnosis of CD during, 593 safety of IBD medications during, 597, 603 surgery and, 604 transition care in, 604–605 Primary immunodeficiency diseases, 171 Primary intestinal lymphoma, 71 Primary sclerosing cholangitis (PSC), 97, 184, 614, 616 radiologic evaluation of, 205–206 Principle investigator (PI), in drug development, 542, 546 Probiotic therapy in active ulcerative colitis, 352 arthralgia, 357 Crohn disease, 355–357
Index as maintenance therapy for UC, 352–354 pouchitis, 354 ulcerative colitis, 352–354 Proctitis, 472 Proctocolectomy, 387, 463, 469–471, 485, 589, 604, 618–619 Progressive multifocal leukoencephalopathy (PML), 411 Pruritus, 97 Pseudoinflammatory tumor, 172 Pseudolipomatosis, 243 Pseudomonasaeruginosa, 496 Pseudopolyps, in ulcerative colitis, 246–248 Psoriasis, 409 Psoriatic arthritis, 403, 409 Psyllium, 588 PTGER4-deficient mice, 8 PTGER4 mRNA expression, 8 Puberty delay in patients with IBD, 136–139 nutritional causes, 137–138 pro-inflammatory cytokines-endocrine interactions, 138–139 development and normal growth, 103–104 hormone levels, 134–135 influence of IBD, 135–136 process in healthy children and adolescents, 133–135 psyschosocial issues and, 139 pubertal arrest, 136 therapeutic approach to, 139–140 Pulmonary fibrosis, 434 Pulmonary manifestations, 99 Push enteroscopy, 263, 265 Push-pull enteroscopy, 263 Pyloric gland metaplasia, 254 Pyoderma gangrenosum, 92, 94–96, 161–162, 502 Pyostomatitis vegetans, 94 Quality improvement in IBD, 631–638 Chronic Illness Care Model, 633 collaborative networks, 638 Improvement Collaborative, 636–637 Improvement Model, 635–636 need for, 634–635 variation in care, 632–633 Quality of life (QOL), See also Health-related quality of life (HRQOL) concepts and definitions, 565–566 instruments, 516–517 measurement in pediatric IBD, 565–575 Quantitative computed tomography (QCT), 277, 283 Quiescent colitis, 253–254 Rachmilewitz Index, 513, 516, 527, 535 Radiofrequency identification (RFID), 268 Radiographic imaging studies, in Crohn disease and ulcerative colitis, 149 Radiologic evaluation bone and joint disease, 205–206 bowel obstruction and perforation, 204 complications, 202–205
683
Crohn disease, 193–198 computed tomography, 195 contrast studies, 194–195 imaging techniques, 198–201 magnetic resonance imaging, 195–196 plain abdominal radiographs, 194 ultrasound, 196–198 enteric fistula, 202–204 extraintestinal disease, 205 gallstones, 205 hepatobiliary disease, 205–206 indeterminate colitis, 200 intraabdominal abscess, 202–204 osteopenia, 205–206 pediatric IBD, 193–207 perianal disease, 202 positron emission tomography, 201 primary sclerosing cholangitis, 205 toxic megacolon, 205 ulcerative colitis, 198 computed tomography, 198–199 contrast enema, 198 imaging techniques, 198–199 magnetic resonance imaging, 199 plain abdominal radiographs, 198 ultrasound, 197 white blood cell scan, 200–201 Randomized controlled trials (RCTs), 536–538 RANKL/OPG system, 121–123 Rash, 160–162, 438 RDP58, in biologic therapies, 404, 417 REACH study pediatric CD, 389–391, 393–396 Receptor activator of nuclear factor--B ligand (RANKL), 121–123, 279–280 Recommended daily allowance (RDA), 338 Rectal and anal strictures, surgical treatment of, 463–464 Rectal bleeding, 159–160, 182 Rectal sparing and patchiness, 148–149, 253–254 Rectovaginal fistulae, 435 Recurrent intestinal symptoms, 167 Rehabilitation Act of 1973, 642–643 Relaxin hormone, 596 Renal artery stenosis, 99 Renal insufficiency, 434, 450 Renal manifestations, 99 Research Review Act, 656–657 Resting energy expenditure (REE), in children with Crohn disease, 338 Rheumatoid arthritis, 317, 403, 409 RHuIL-10, 415–416 Rifaximin, 333–334, 355–356, 491 Robert Wood Johnson Foundation, 661 Rotavirus, 170 Rowasa® , 318–319, 602 Rutgeerts endoscopic scoring system, 515 Saccharomyces boulardii, 351, 352, 356, 358 Saccharomyces cerevisiae, 52 Sacroiliitis, 92, 93
684
Index
Safety, Timeliness, Efficiency, Effectiveness, Equity and Patient-centeredness (STEEEP), 631 Salazopyrine, 602 Salmonella, 180, 186, 242, 251 Salofalk® , 319 SAMP1/YitFc mice, 25 Sarcoma, 172 Sargramostim (GM-CSF), in biologic therapies, 404, 414–415 Sclerosing cholangitis, 92, 246–247 Scurvy, 95 Seborrheic dermatitis, 438 Sedation and reversal medications, employed in pediatric endoscopy, 214–215 Seizures, 450 Seizures Hepatotoxicity, 434 Sensory sensitization and hyperalgesia, 583 Seo Index, 514 Sepsis, 437 Serologies and genetic testing, 149–150 Serotonin (5-hydroxytryptamine: 5-HT), 584 Serotonin reuptake transporter gene (SERT) polymorphism, 584 Serpigenous ulcers, 215 Severe combined immunodeficiency (SCID) mouse model, 346 Sex steroids, 103 Sexual maturation, 303–304 Shigella, 180, 186 Sigmoidoscopic index, 516 Sigmoidoscopy, 596 Signal transducer and activator of transcription (STAT) proteins, 108 Simple Clinical Colitis Activity Index, 514 Simplified Endoscopic Activity Score for Crohn disease (SES-CD), 515, 517, 530 Skeletal health bone cells and inflammation, 121–123 osteoblasts, 123 osteoclasts and RANKL/OPG system, 121–123 T cells and bone loss, 123 bone modeling and remodeling, 119–121 growth and maturation, 119–121 intestinal inflammation effects on bone, 123–128 animal models, 123–124 human studies, 124–128 in pediatric IBD, 119–128 Skeletal maturation, 302 Skin lesions, 94–97 Skip lesions, in CD, 228, 230 SLC22A4 gene, 6 SLC22A5 gene, 6 Small bowel radiography (SBR), 265, 267–268 Small intestine cancer, in CD, 624 S-Methyl-4-nitro-5-thioimidazole, 311, 600 Smoking and IBD, 51–52 SNP C3435T, 9 Social Security Disability, 656 Society for Adolescent Medicine, 662 Soiling, 160
Somnolence, 438 Sperm abnormalities, 597 Spondyloarthropathies, 93 Sporadic colorectal cancer, 612 Sporadic colorectal neoplasia, 611 Squamous cell cancer, 624 16S rRNA gene, 25 Staphylococcus aureus, 496 Stoma site selection, 502 Stool evaluation, 179, 186–188 Streptococci, 496 Streptococcus, 351 Streptococcus salivarius, 491 Stricturoplasty, in Crohn disease, 461–462 Sulfapyridine, 317–318, 324, 597 Sulfasalazine, 93, 112, 182, 317–324, 330, 332, 335, 384, 594, 597–598, 602–603, 614, 617, 645 Sulphasalazine, 387 Supplemental Security Income (SSI), 648–649 Suppressors of cytokine signaling (SOCS) proteins, 108 Surgery, and growth management, 112–113 Surgical therapy, history of, 455–456 Surgical treatment of colonic disease, 462–463 of Crohn disease, 455–465 adjuvant procedures, 464–465 elective surgery, 458 indications for surgery, 456–457 laparoscopy, 462 medical therapy impact, 464 post-operative recurrence, 464 stricturoplasty, 461–462 surgical emergencies, 457–458 surgical therapy, 459–461 in pediatric CD and infliximab therapy, 393 of perineal disease, 463–464 of rectal and anal strictures, 463–464 of ulcerative colitis, 469–480 carcinoma, 479 complications, 477–479 indications for surgery, 469–470 outcomes of surgery, 476–477 pouchitis, 477–479 preparation for surgery, 475–476 surgical procedures, 471–475 trends and future considerations, 479–480 Surveillance ileocolonoscopy, 228–229 Sweet’s syndrome, 94–95 Symptoms of IBD, 159–162 Synechiae, 97 Systemic corticosteroids, 364 Tachycardia, 161 Tacrolimus, 449 in pregnancy, 601 for treatment of perianal Crohn disease fistulae, 434, 439 Tanner stages of sexual maturation for boys, 304 for girls, 303
Index Tanner-Whitehouse III system, 302 Tapeworms, 333 T cell apoptosis, 403, 409 T-cell lymphoma, 407 T cells, 16–17, 24, 123–4 T cells, 17–19 Tc-HMPAO WBC scan, of abdomen, 200–201 TCR, 19 TCR, 19 Tegaserod, 588 Teratogenicity, 383–384, 434, 438 Terminal ileum, 225–226 Terminal restriction length polymorphism (T-RFLP), 25 Testosterone (Te), 133–134, 139–140 Tetracyline, 332, 491 TGF- cytokine, 20, 32–33, 35–36, 38–39, 122 Thalidomide, 438, 440, 597, 601, 603 in pregnancy, 599 Th1 cell, 21 Th2 cell, 21 Th3 cell, 21 Th17 cell, 21, 35–36 Th cells, 21 Th1 cytokines, 25 Th2 cytokines, 25 Th1- disease, 392 Th2- disease, 392 T helper cells, 415 6-Thioguanine nucleotides, 434 Thioguanine nucleotides (6-TGN), 311–313 6-Thioguanine triphosphate (6-thio-GTP) nucleotide, 311 Thioinosine monophosphate (TiMP), 311–312 Thiopurine, 632 Thiopurine methyl transferase, 632–633 Thiopurine S−methyltransferase (TPMT) drug-metabolizing enzyme, 307, See also TPMT pharmacogenetics Thiopurines pharmacology, 311–312 Thrombocytopenia, 384 Thrombocytosis, 98, 180, 182 Thrombosis, 98 Th1 T cell, 31 Th2 T cell, 31 Th1 T-helper cells, 39 Th2 T-helper cells, 39 Thyroxine, 103 T lymphocytes, 145 TNF- cytokines, 7, 19, 26, 31–33, 121, 123–124, 138–139, 280, 346, 388–389, 392, 408, 415–417, 435–436 TNF-/− mice, 121 Tobramycin, 332 Toll-like receptors (TLRs), 17, 23 Topical corticosteroids, 364, See also Budesonide pharmacokinetics, 364–365 topical steroid formulations, 365 Toxemia, 596 Toxic megacolon, 160, 205, 450, 470 TPMT pharmacogenetics
685
clinical application of, 312–313 historical perspective of, 309–311 metabolite monitoring role, 313 mutant alleles, 310–311 pharmacokinetics, 313 pharmacology of thiopurines, 311–312 Tracheal obstruction, 99 Transforming growth factor- (TGF– mRNA, 343 Transition care, in pregnancy, 604–605 Transmural disease, in CD, 248–249 Transverse colon, normal triangular appearance, 221 T Regulatory (TREG) cells, 21–22, 34–35 Tremor, 434 T richomonas vaginalis, 598 Tricyclic antidepressants (TCAs), 588 Trimethoprim-sulfamethoxazole, 384 Trinitrobenzene sulfonate (TNBS) model, 138 Trinitrobenzesulfonic acid, 31 Truelove and Witts classification, 513–514, 516, 526 Truelove Score, 535 Tuberculosis, 143, 168–169, 437, 632 Tumor necrosis factor alpha (TNF- cytokine, See TNF- cytokines Tumor necrosis factor (TNF), 6–7, 346 Ulcer, 160 Ulcerative Colitis Disease Activity Indices, 513–515, 527 Ulcerative colitis (UC), 25, 31, 45–46, 240, See also Pediatric ulcerative colitis 5-aminosalicylate therapy, 320–321 anatomic extent of, 614 antibiotic therapy in, 332–333 appendectomy protective effects, 53 backwash ileitis, 254 bone density in children with, 125–126 breast feeding, 53 budesonide enemas in, 368 carcinoma after surgical treatment of, 479 clinical trials in, 531–536 colonic malignancy, 246–248 CRC in, 611–621, 623 descriptive epidemiology, 46–49 dietary factors and, 53 distinguishing from Crohn disease algorithm for, 151 backwash ileitis and Crohn of ileum, 145, 147 endoscopy and biopsy, 145–146 gastritis in patients with IBD, 147–148 non-classical findings, 147 periappendiceal inflammation in ulcerative colitis, 148 radiographic imaging studies, 149 rectal sparing and patchiness, 148–149 serologies and genetic testing, 149–150 video capsule endoscopy, 150 distinguishing pathologic features, 243–246 duration of, 614–615 dysplasia in, 248 frequently used indices in, 535 fulminant and indeterminate colitis, 256–257
686
Index
gender and, 49 genetic epidemiology, 4–5 ethnic and racial variations, 4 family studies, 4 twin studies, 4–5 genetic studies, 8–9 geographic trends, 46–49 and growth impairment, 105, 107 historical perspective, 75–77 among adults, 76–77 among children, 75–76 IL23R polymorphisms association, 7–8 indeterminate colitis and, 83–89 infectious agents and, 52 intestinal commensal flora, 52–53 natural history, 75–80 periappendiceal inflammation in, 148, 256 pouchitis, 257–258 probiotic therapy, 351–354 pseudopolyps, 228, 246–247 puberty and, 135–136 racial and ethnicity trends, 49 radiologic evaluation, 198–199 computed tomography, 198–199 contrast enema, 198 imaging techniques, 198–199 magnetic resonance imaging, 199 plain abdominal radiographs, 198 ultrasound, 199 rectal sparing and patchiness, 253–254 risk of colon cancer in, 64 severity categories of, 536 smoking and, 51–52 stress and, 55 subclassification of, 152–153 surgery in, 64 surgical treatment, 469–480 carcinoma, 479 complications, 477–479 indications for surgery, 469–470 outcomes of surgery, 476–477 pouchitis, 477–479 preparation for surgery, 475 surgical procedures, 471–475 trends and future considerations, 479–480 symptoms, 159–161 time trends in, 46 upper GI tract involvement in, 255 Ulcerative pouchitis, 333 Ultrasound (US), 196–198 United Ostomy Association (UOA), 656 Upper arm anthropometry, 299
Upper arm fat and muscle area, 301 Upper gastrointestinal endoscopy, 215–217 Upper GI tract, involvement in UC and DC, 255 Upper respiratory infection, 438 Ureteral compression, 99 Ursodeoxycholic acid, 97, 618 Uterine cancers, 624 Uveitis, 92, 96–97, 161, 407 Vaginal fistulae, 204 Vancomycin, 212, 332 Vasculitis disorders, 172 VCAM-1, 21 Video capsule endoscopy (CE), 150 diagnostic utility in indeterminate colitis, 267 post-operative recurrence, 267 suspected CD, 265–266 experience in pediatric IBD, 263, 267 practical issues in pediatric patients, 268–271 age and size limitations, 271 capsule retention, 268–269 endoscopic placement of capsule, 270–271 precautions and considerations, 271 preparations and prokinetics, 269–270 specificity of findings, 267–268 uses of, 265–267 Virtual endoscopy, 207 Visilizumab, 79 in biologic therapies, 416–417 Visual perianal examamination, 162 Vitamin D, 286, 296 Vomiting, 160, 434 Wagner’s model, 633 Walmsley’s simple colitis index, 514 Wegener granulomatosis, 172 Weight loss, 159–161, 167, 169, 182, 278 Wireless capsule endoscopy (WCE), 212, 235 Wiskott-Aldrich syndrome, 170 Xanthine oxidase (XO), 311 Xifaxan® , 333 X-linked agammaglobulinemia, 170 Yersinia, 180, 186, 252 Y ersinia enterocolitica, 168, 186 Y ersinia pseudotuberculosis, 168 Zofran, 645