Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications

Interventional Inflammatory Bowel Disease

Endoscopic Management and Treatment of Complications

Editor

Bo Shen

The Cleveland Clinic Foundation, Cleveland, OH, United States

Table of Contents

Cover image

Title page

Copyright

Dedication

List of Contributors

Preface

Chapter 1. Overview of Diagnosis and Medical Treatment of Inflammatory Bowel Diseases

Introduction

Epidemiology

Etiology and Pathogenesis

Diagnosis

Differential Diagnosis

Classification of UC

Classification of CD

Medical Treatment of UC

Medical Treatment of CD

Summary and Recommendations

Chapter 2. Classification and Reclassification of Inflammatory Bowel Diseases: From Clinical Perspective

Introduction

Conventional Theories of Pathogenesis of IBD

Features of Classic IBD

Conventional Classification of IBD

Genetic Contributions in Development of IBD

IBD With EIMs

Overlap of IBD and AimDs

Overlap of IBD and AinDs

Spectrum of Immune-Mediated Disorders of the Gut

Triggering Factors for De Novo IBD: Concept of Secondary IBD

The Two-Hit Theory

Reclassification of IBD and IBD-Like Conditions

Summary and Conclusion

Chapter 3. Pathogenesis of Crohn's Disease- and Ulcerative Colitis-Related Strictures

List of Abbreviations

Introduction

Risk Factors

Pathogenesis

Medical Therapy

Summary and Conclusion

Chapter 4. Pathogenesis of Crohn's Disease–Associated Fistula and Abscess

Introduction

Definition

Morphological Characterization of Crohn's Fistulas

Current Understanding of Mechanisms of Crohn's Fistula

Abscess in CD

Summary and Conclusions

Chapter 5. Overview of Histopathology of Ulcerative Colitis and Crohn's Disease

Normal Histology of the Bowel

Overview of Histopathology of IBD

Neoplasia in IBD

Summary and Conclusions

Chapter 6. Clinical and Endoscopic Diagnosis of IBD-Related Stricture, Fistula, and Abscess

Introduction

Stricture

Fistula

Abscess

Summary and Conclusions

Chapter 7. Role of Abdominal Imaging in the Diagnosis of IBD Strictures, Fistulas, and Postoperative Complications

Introduction

Stricturing Disease

Intra-abdominal Penetrating Disease

Perianal Disease

Postoperative Complications

Ileal Pouch-Anal Anastomosis

summary and Conclusion

Chapter 8. Classification of Strictures From Crohn's Disease, Ulcerative Colitis, and Inflammatory Bowel Disease–Related Surgery

Introduction

Definition and Source of Stricture

Underlying Diseases

Features of Stricture

Summary and Conclusions

Chapter 9. Classification of Crohn's Disease and Inflammatory Bowel Disease Surgery-Related Fistulae

Introduction

Classification of Perianal Fistula From CD (Expansion of the Park's Classification)

Classification of Enterocutaneous Fistula

Classification of Enteroenteric Fistula

Classification of Fistula From Bowel to Adjacent Non-GI Organs

Classification of Fistula or Leak From Anastomosis

Summary and Recommendations

Chapter 10. Principles of Endoscopic Therapy in Inflammatory Bowel Diseases

Introduction

The Patient

The Disease

The Target Lesion

Goals of Endoscopic Therapy

Timing of Endoscopic Intervention

The Endoscopy Team

Prevention of Procedure-Associated Complications

Summary and Conclusions

Chapter 11. Preparation of Endoscopic Therapy for Inflammatory Bowel Diseases

Introduction

Screening for Candidate Patients

Pre- and Post- Procedure Imaging

Room Settings

Bowel Preparation

Antibiotic Prophylaxis

Management of Anticoagulation Agents

Sedation and Monitoring

Informed Consent

Postprocedure Monitoring

Equipment and Supplies

Summary and Recommendations

Chapter 12. Endoscopic Evaluation of Surgically Altered Bowel in Patients With Inflammatory Bowel Diseases

Introduction

Preparation

Endoscopy via Anastomosis

Endoscopy via Stoma

Endoscopy for Ileal Pouch

Endosocpy for Diverted Bowel

Endoscopy in Strictureplasty

Endoscopy After Bypass Surgery for Crohn's Disease

Unique Challenges in Endoscopic Therapy

Summary and Recommendations

Chapter 13. Endoscopic Balloon Dilation of Inflammatory Bowel Disease Strictures

Introduction

Indications

Techniques

Factors Associated With Efficacy of EBD

Summary and Recommendations

Chapter 14. Endoscopic Stricturotomy

Introduction

The Rationale for Endoscopic Stricturotomy

Techniques

Procedure-Associated Complications and Precautions

Summary and Conclusions

Chapter 15. Endoscopic Stent Treatment for Crohn's Disease

Introduction

Types of Stents

Stent Treatment of Strictures

Stent Treatment of Anastomotic Leaks and Fistula in CD

Summary and Conclusions

Chapter 16. Endoscopic Therapy for the Treatment of Inflammatory Bowel Disease-Related Fistula, Sinus, and Abscess

Introduction

Principles of Endosocpic Treatment of Fistula, Sinus, and Abscess

Endoscopic Fistulotomy

Endoscopic Sinusotomy

Endoscopic Injection of Filling Agents

Endoscopic Drainage of Abscess

Endoscopic Closure of Fistula and Anastomotic Leak

Endoscopic Ultrasound–Guided Treatment of Perianal Fistula

Common Endoscopy Procedure-Associated Complications and Their Prevention

Summary and Conclusions

Chapter 17. Endoscopic Evaluation and Management of Perianal Crohn's Disease

Introduction

Endoscopic Evaluation

Interventional Uses of Endoscopy for Perianal Fistulas

Summary and Conclusions

Chapter 18. Stem-Cell Therapy in Fistulizing Perianal Crohn's Disease

Introduction

General Aspects of Stem-Cell Therapy

Stem-Cell Therapy in Fistulizing Perianal Crohn's Disease

Combination Therapy

Stem-Cell Therapy in Non-Crohn Disease Fistula

Summary and Conclusions

Chapter 19. Endoscopic Detection and Removal of Colitis-Associated Dysplasia

Introduction

Surveillance Techniques

The SCENIC International Consensus

Image-Enhanced Endoscopy

Principles of Endoscopic Removal of Colitis-Associated Neoplasia

Endoscopic Mucosal Resection

Endoscopic Submucosal Dissection

Complications of Endoscopic Resection

Summary and Conclusions

Chapter 20. Endoscopic Management of Hepatobiliary Complications of Inflammatory Bowel Disease

Introduction

Diagnosis of Primary Sclerosing Cholangitis

Endoscopic Treatment of Primary Sclerosing Cholangitis

Diagnosis of Cholangiocarcinoma and Indeterminate Strictures

Summary and Conclusions

Chapter 21. Overview of Surgical Therapy for Crohn's Disease

Introduction

Medical Treatment of Crohn's Disease

Indications for Surgery

Preoperative Considerations

The Initial Operation

Surgical Treatment of Perianal Disease

Stoma Indication and Construction

Summary and Conclusions

Chapter 22. Multidisciplinary Approach to Stricturing Crohn's Disease: Medical Versus Endoscopic Versus Surgical Therapy

Introduction

Medical Therapy

Endoscopic Therapy

Surgical Therapy

Summary and Recommendation

Chapter 23. Overview of Surgical Treatment for Ulcerative Colitis

Introduction

Total Proctocolectomy With Permanent Ileostomy

Restorative Proctocolectomy With Ileal Pouch-Anal Anastomosis

Subtotal Colectomy With End Ileostomy and Hartmann Pouch

Colectomy With Ileorectal Anastomosis

Continent Ileostomy (Kock Pouch)

Summary and Conclusions

Chapter 24. Common Complications of Surgery for Crohn's Disease and Ulcerative Colitis

Introduction

Surgical Site Infection (Wound Infection)

Abscess and Sepsis

Anastomotic Hemorrhage

Anastomotic Leak, Fistula, and Sinus

Anastomotic Strictures

Summary and Conclusions

Chapter 25. Postoperative Crohn's Disease Recurrence and Role of Endoscopy

Introduction

Endoscopy in Guiding Management of Postoperative Crohn's Disease

Medical Management of Postoperative Crohn's Disease

Endoscopic Management of Anastomotic Stricture

Summary and Conclusions

Chapter 26. Diagnosis and Treatment of Inflammatory Bowel Disease–Associated Bleeding

Introduction

Frequency

Etiology and Risk Factors

Diagnosis

Medical Treatment

Endoscopic Treatment

Interventional Radiology Treatment

Surgical Treatment

Summary and Conclusions

Chapter 27. Endoscopic Treatment of Bezoars and Foreign Bodies in Patients With Inflammatory Bowel Disease

Introduction

Risk Factors for Bezoars

Clinical Presentations

Diagnosis

Treatment

Summary and Recommendations

Chapter 28. Fecal Microbiota Transplantation as Therapy for Inflammatory Bowel Disease

Introduction

Human Microbiota and Inflammatory Bowel Disease

Background on Fecal Microbiota Therapy

Fecal Microbiota Transplantation as Therapy for Inflammatory Bowel Disease

Summary and Recommendations

Chapter 29. Damage Control: Management of Procedure-Associated Complications

Introduction

Iatrogenic Perforation

Iatrogenic Bleeding

Postprocedure Abdominal Distention and Ileus

Stricture Resulting From Endoscopy Therapy

Summary and Conclusions

Index

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1800, San Diego, CA 92101-4495, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2018 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

ISBN: 978-0-12-811388-2

For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Mica Haley

Senior Acquisition Editor: Stacy Masucci

Editorial Project Manager: Samuel Young

Production Project Manager: Poulouse Joseph

Designer: Matthew Limbert

Typeset by TNQ Books and Journals

Dedication

To my patients for their trust and privilege of caring for them; to my colleagues for their support and backing; to my mentors for their guidance; and to my family, Lan-Ping, Ling, Jing-Jing, Wan-Gao, and Xiu-Zhi, for their patience, understanding, encouragement, and love.

List of Contributors

Jay P. Abraham,     University of California Los Angeles, Los Angeles, CA, United States

Jean-Paul Achkar,     The Cleveland Clinic Foundation, Cleveland, OH, United States

Saeed Ali,     University of Central Florida College of Medicine, Florida Hospital, Orlando, FL, United States

Jean H. Ashburn,     The Cleveland Clinic Foundation, Cleveland, OH, United States

David H. Bruining,     Mayo Clinic College of Medicine, Rochester, MN, United States

Michael D. Chang,     University of Florida, Gainesville, FL, United States

Shannon Chang,     New York University Langone Medical Center, New York, NY, United States

Min Chen,     Zhongnan Hospital of Wuhan University, Wuhan, China

Parakkal Deepak,     Mayo Clinic College of Medicine, Rochester, MN, United States

Ann Honor,     Vanderbilt University Medical Center, Nashville, TN, United States

Tonya Kaltenbach,     University California San Francisco, San Francisco, CA, United States

Ammar O. Kheir,     University California San Francisco, San Francisco, CA, United States

Jeffrey Z. Ko,     University of California Los Angeles, Los Angeles, CA, United States

Udo Kronberg,     Clinica Las Condes, Santiago, Chile

Yi Li,     Medical School of Nanjing University, Nanjing, China

Amy L. Lightner,     Mayo Clinic College of Medicine, Rochester, MN, United States

Xiuli Liu,     University of Florida, Gainesville, FL, United States

Leyla Maric,     Cleveland Clinic Florida, Weston, FL, United States

Udayakumar Navaneethan,     University of Central Florida College of Medicine, Florida Hospital, Orlando, FL, United States

Abigail Oberc,     The Cleveland Clinic Foundation, Cleveland, OH, United States

Malav P. Parikh,     The Cleveland Clinic Foundation, Cleveland, OH, United States

Madhusudhan R. Sanaka,     The Cleveland Clinic Foundation, Cleveland, OH, United States

Alison Schneider,     Cleveland Clinic Florida, Weston, FL, United States

David A. Schwartz,     Vanderbilt University Medical Center, Nashville, TN, United States

Shannon P. Sheedy,     Mayo Clinic College of Medicine, Rochester, MN, United States

Bo Shen,     The Cleveland Clinic Foundation, Cleveland, OH, United States

David Q. Shih,     University of California Los Angeles, Los Angeles, CA, United States

Roy Soetikno,     Advanced Gastrointestinal Endoscopy, Mountain View, CA, United States

Claudio Wainstein,     Clinica Las Condes, Santiago, Chile

Xian-rui Wu,     The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

Weiming Zhu,     Medical School of Nanjing University, Nanjing, China

Preface

The field of inflammatory bowel disease (IBD) has been evolving in many aspects for the past 2  decades, ranging from better understanding of etiopathogenesis and the spectrum of diseases, and emerging of diagnostic modalities, to advances in medical and surgical treatment. The dysregulated immune system in IBD dictates its chronic, relapsing, and recurrent nature, even after initially effective medical and later on surgical therapy. This is the case for both Crohn's disease and ulcerative colitis. The long duration of disease process nearly uniformly results in microscopic and macroscopic tissue structural damage, leading to various complications, such as stricture, fistula, abscess, and colitis-associated neoplasia.

For years, clinicians have been searching for modalities to treat those structural complications, which ideally are more effective than medical therapy, yet less invasive than surgery. Comes naturally the endoscopy to the stage. While its evaluation along with tissue biopsy provides the most important tool for the diagnosis and differential diagnosis of IBD, endoscopy with therapeutic intervention, namely interventional IBD, has emerged to become an integrated component of multidisciplinary management approach to complex IBD. For example, endoscopic balloon dilation has become a valid option for the primary and secondary strictures in IBD. Endoscopic stricturotomy, fistulotomy, sinusotomy, and endoscopic submucosal dissection of colitis-associated neoplasia are being performed in tertiary care centers. The goals of endoscopic therapy are set to relieve patients' symptoms, to improve their quality of life, to reduce the risk for hospital admission and surgery, and to manage surgical complication and postsurgical disease recurrence, in a safe and cost-effective way.

This book consists of 29 chapters, covering various aspects of IBD, from bench to bedside, from diagnosis to management, and from principles and techniques to damage prevention and control of therapeutic endoscopy. While interventional IBD can be technically demanding, it is important to master the principles first, following the sequence of principles, techniques, equipment, and devices. The best outcome of therapeutic endoscopy can only be achieved by a properly trained IBD interventionist with its application to the right patient, right disease, right lesion, at the right time and right setting. Challenges and opportunities often come hand in hand. I hope that this book will provide useful information and guidance for better management of complex IBD to clinicians and stir interest in choosing interventional IBD as a career by our students, trainees, and young faculty.

The Editor is grateful to the panel of national and international experts for their contribution to the Book. The Editor is deeply thankful to Mr. and Mrs. Story, Mr. Klise, Mr. Horing, and Mr. Spero and other generous philanthropists for their continuous support for the Center for Ileal Pouch Disorder and the Interventional IBD Unit at the Cleveland Clinic Foundation and to Ms. Beth Halasz and Mr. Joe Pangrace for their great art work. The Editor would like to pay special gratitude to Xian-Yong Meng, MD and Victor Fazio, MD for mentoring and guidance. The Editor is also thankful for grant support from National Institutes of Health, the American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, American College of Gastroenterology, American Society of Colorectal Surgery, Crohn's and Colitis Foundation, Broad Foundation, and Cleveland Clinic Foundation. Finally, the Editor deeply appreciates the help and support from acquisition and managing editors of Elsevier, Mrs. Stacy Masucci, Mr. Sam Young, and Mr. Joseph Poulouse.

I hope that our readers enjoy reading of the Book and provide constructive feedback for our future edition.

Bo Shen, MD,     Cleveland, Ohio

Chapter 1

Overview of Diagnosis and Medical Treatment of Inflammatory Bowel Diseases

Min Chen¹, and Bo Shen²     ¹Zhongnan Hospital of Wuhan University, Wuhan, China     ²The Cleveland Clinic Foundation, Cleveland, OH, United States

Abstract

Inflammatory bowel diseases (IBDs), mainly consisting of ulcerative colitis and Crohn's disease (CD), are chronic inflammatory disorders. The incidence rate of IBD is increasing worldwide. The IBD is believed to result from a complex interplay among genetic susceptibility and environmental and microbial factors, leading to abnormal innate and adaptive immune responses. The diagnosis of IBD is usually established by a combined assessment of history, clinical presentation, and endoscopic, histologic, radiologic, and laboratory features. Medical therapy includes mesalamines, glucocorticosteroids, immunomodulators, and various biological agents; CD can also be treated with antibiotics. In this chapter, we provide an overview of epidemiology, pathogenesis, diagnosis, and clinical management of IBD.

Keywords

Crohn's disease; Diagnosis; Inflammatory bowel disease; Pathogenesis; Treatment; Ulcerative colitis

List of Abbreviations

6MP   6-mercaptopurine

ADA   Adalimumab

ASCA   Anti-Saccharomyces cerevisiae antibody

AZA   Azathioprine

CD   Crohn's disease

CDAI   The Crohn's Disease Activity Index

CDEIS   Crohn's Disease Endoscopic Index of Severity

CMV   Cytomegalovirus

CRP   C-reactive protein

CT   Computed tomography

DAI   Disease Activity Index

EIM   Extra-intestinal manifestations

ESR   Erythrocyte sedimentation rate

GI   Gastrointestinal

GWAS   Genome-wide association studies

IBD   Inflammatory bowel disease

IBS   Irritable bowel syndrome

IFX   Infliximab

ITB   Intestinal tuberculosis

MMX   Multimatrix

MRI   Magnetic resonance imaging

MTX   Methotrexate

NOD2   Nucleotide-binding oligomerization domain 2

NSAID   Nonsteroidal antiinflammatory drugs

OmpC   Outer membrane porin

pANCA   Perinuclear antineutrophil cytoplasmic antibody

PML   Progressive multifocal leukoencephalopathy

PSC   Primary sclerosing cholangitis

RCT   Randomized controlled trial

SES-CD   Simple Endoscopic Score for Crohn's Disease

TNF   Tumor necrosis factor

TPMT   Thiopurine S-methyltransferase

UC   Ulcerative colitis

VCE   Video capsule endoscopy

Introduction

Inflammatory bowel disease (IBD) is an idiopathic chronic gut inflammatory condition. It comprises two major entities: ulcerative colitis (UC) and Crohn's disease (CD). UC is characterized by chronic inflammation limited to mucosal and superficial submucosal layers of the large bowel, whereas CD is segmental and transmural bowel inflammation that may involve any parts of the entire gastrointestinal (GI) tract. One of the hallmarks of CD is the presence of non-caseating granulomas on histology.

Epidemiology

The annual incidence of IBD varies significantly all over the world. The highest incidence rates of UC and CD have been reported in Europe (24.3 per 100,000 person-years)¹ and Australia (29.3 per 100,000 per person-years).² The lowest incidence rates of UC and CD were both found in Asia, with 0.36 per 100,000 person-years for UC in Thailand and 0.24 per 100,000 person-years for CD in Malaysia.³ The highest reported prevalence for IBD was in Europe (UC, 505 per 100,000 persons-years; CD, 322 per 100,000 persons-years) and North America (UC, 249 per 100,000 persons-years; CD, 319 per 100,000 persons-years).¹

The incidence and prevalence of IBD have shown evident geographic variations. There is a North–South disease gradient within European countries, such as Scandinavian countries, France, Italy, Spain, and Portugal.⁴ The incidence of IBD was found to be higher in the northern than southern latitude.⁴ The same trend was also observed in the United States.⁵ In contrast, another study demonstrated an East–West disease gradient in Canada.⁶

There is a bimodal age distribution of IBD with the initial peak being in the second to third decade and the second peak being in the sixth decade. The median age of onset of CD was slightly younger than that of UC.⁷ There was an equal gender distribution for UC.³,⁶,⁷ In contrast, there is gender-specific distribution in CD. Studies from the West showed a slight female predominance in CD, although a male predominance is present in low-incidence areas.³,⁶,⁷

Etiology and Pathogenesis

The pathogenesis of IBD is not entirely clear. It is a reason why some investigators have used the term idiopathic inflammatory bowel disease. The IBD is believed to result from a dysregulated immune response to the intestinal microbiota on the background of genetic susceptibility.

Genetic Susceptibility

Numerous studies have confirmed that genetic factors contribute to the pathogenesis of IBD. Studies found that the first-degree relatives of patients with IBD are approximately 3–20 times more likely to develop the disease than general population.⁸,⁹ The Ashkenazi Jews have 3–4 times higher risk of disease than non-Jewish population.¹⁰ The concordance rate for CD in monozygotic twins was as high as 50%, further suggesting the heritable risk of IBD.¹¹

The genome-wide association studies (GWAS) have identified more than 160 susceptibility loci for IBD, the majority associated with both UC and CD.¹² The nucleotide-binding oligomerization domain 2 (NOD2) was the first susceptibility gene identified to be associated with CD.¹³ The wild-type NOD2 gene actives nuclear factor κB in response to the muramyl dipeptide, a fragment of bacterial peptidoglycan; this process is deficient in CD patients with mutant forms of NOD2. The discovery of other IBD susceptibility genes associated with autophagy-modulating innate immune (ATG16L1, IRGM, and LRRK), genes related to Th17/IL-23 pathway (IL23R, IL12B, STAT3, JAK2, TNFSF15, and TYK2), and genes regulating epithelial function (OCTN2, ECM1, CDH1, HNF4A, and GNA12) suggest the key role of epithelial barrier dysfunction in the inflammation of IBD. The genetic assessment of IBD for the diagnostic purpose, however, is not recommended in routine clinical practice, as only 13.1% of the disease heritability can be explained by genetic variations.¹⁴ This may be due to the fact that IBD is a spectrum of polygenic disorders. On the other hand, it should be pointed out that IBD or IBD-like conditions can be monogenic disorders (such as IL-10 and IL-10R mutations), especially in infant and pediatric onset IBD.

Microbiota

Multiple layers of evidences suggest that gut microbiota or microbiome plays a crucial role in the pathogenesis of IBD. Rodent models of IBD found that the animals of developed colitis in the presence of normal microflora, but not in germ-free conditions.¹⁵ Studies in patients with CD showed that CD would not recur at the neoterminal ileum after ileocolonic resection in the presence of ileostomy or fecal diversion.

The intestinal microbiota is acquired at birth and then remains fairly stable over time. However, fluctuations in quality, quantity, and composition of microbiota may occur in response to environmental and developmental factors, as well as disease conditions.¹⁶ The alterations in both diversity and density of microbes, that is, dysbiosis, have been observed in patients with IBD.¹⁷ Although no specific bacteria has been found to have consistent association with IBD, some dominant bacterial species have been implicated in the intestinal inflammation of the disease. In CD, an increase in Escherichia coli and a decrease in Firmicutes were reported.¹⁸,¹⁹ Decreased biodiversity, with a lower proportion of Firmicutes and an increased proportion of Proteobacteria and Enterobacteriaceae, was reported in patients with UC.¹⁹

Immune Dysregulation

Most previous studies have focused on the role of abnormal adaptive immune responses of IBD. Earlier evidence suggests that UC is a modified T-helper-2 (Th2) disease, whereas CD is Th1 driven.²⁰,²¹ Present studies showed that there are many other subtypes of CD4-positive T-helper cells, including regulatory T cells, Th17, Tfh, and Th9 cells, in addition to Th1 and Th2.²² All these subtypes of CD4-positive T-helper cells play a central role in the immune-mediated inflammation of IBD. Humoral immunity also plays an important part in the pathogenesis of IBD, as evidenced by alterations in production of immunoglobulin subclasses.

The innate immune also contributes to inflammatory process in IBD. At healthy state, intestinal epithelium, mucus layer, and IgA work in concert and separate luminal microflora from the mucosal immune system.²³ IBD is initiated by the breach of mucosal barrier, which allows for luminal microflora to trigger a sustained and uninhibited inflammatory response.²⁴ The innate immune response is mediated by various cells including epithelial cells, neutrophils, dendritic cells, monocytes, macrophages, Paneth cells, and natural killer cells.²³ The innate immune dysregulation found in IBD includes an increased intestinal permeability, abnormal mucin production, deficiency in antimicrobial peptides, dysfunctioned epithelial cells, Paneth cells, dendritic cells, neutrophils, monocytes/macrophages, along with excessive immune cell recruitment and activation, and an increased production of inflammatory cytokines and other proinflammatory mediators.²⁰,²¹

Environmental Factors

Although the pathogenesis of IBD remains not entirely clear, epidemiological studies has identified a number of risk factors that may be associated with the development of IBD, including smoking, appendectomy, diet, and the use antibiotics, oral contraceptives or nonsteroidal antiinflammatory drugs (NSAIDs).¹⁰ Smoking and appendectomy have different effects on UC and CD. Smoking increases the risk for CD,²⁵ in contrast, it may be a protective factor for UC.²⁶ The risk of CD increases significantly after appendectomy, which may be due to the misdiagnosis in patients with incipient CD.²⁷ In contrast, appendectomy has been shown to be protective for the development of UC.²⁸ Other risk factors include the Western diet (processed, fried, sugary, and fatty foods).¹⁰

Diagnosis

There are no standard diagnostic criteria for IBD. The diagnosis of IBD is usually established by a combined assessment of clinical presentation and endoscopic, histopathological, radiographic, and laboratory findings. A definitive diagnosis of IBD can not be made without detailed endoscopic and histologic evaluation.

Endoscopic Evaluation

The endoscopy plays an important role in the diagnosis of UC and CD. A proper colonoscopy for the diagnosis and differential diagnosis in IBD should include intubation of the terminal ileum, photo documentation and tissue biopsy of each segment of the terminal ileum and large bowel. We should emphasize the importance of photo documentation and biopsy in the index colonoscopy for the diagnosis and differential diagnosis of UC and CD.

On colonoscopy, UC typically involves the rectum and extends proximally in a continuous pattern. In mild UC, endoscopy may show granular, erythematous mucosa with a loss of vascular pattern. In moderate UC, erosions or microulceration may emerge. In severe UC, shallow or deep ulceration with spontaneous bleeding may be evident. Pseudopolyps, mucosal bridge, and mucosal scars may be present in patients with UC due to recurrent episodes of relapse and remission. The right colon including the ileocecum area is generally normal in patients with proctitis or left-sided UC. However, occasionally a small area of inflammation surrounding the appendiceal orifice (i.e., the cecal patch) can be found in some patients with proctitis or left-sided UC, particularly in pediatric patients. The terminal ileum of patients with UC is typically normal, but a limited segment of distal ileum may be involved in some with pancolitis, a condition known as backwash ileitis. Diffuse colitis with backwash ileitis is often seen in patients with concurrent primary sclerosing cholangitis (PSC). We believe that nontreated UC always involves the rectum and always have diffuse pattern of inflammation in the involved portion of the large bowel on the index colonoscopy. Medical treatment, topical or systemic, can result in rectal sparing or segmental disease distribution in UC, which may be confused with CD.

Colonoscopy with biopsy is an the important modality for the diagnosis of CD. Any parts of GI tract, from the oral cavity to anus, can be affected by CD, the most common being the terminal ileum and colon. The disease process of CD is typically segmental and asymmetrical. The patients with CD may present with small or aphthous ulcers in early stage. The typical endoscopic findings of CD include longitudinal ulcerations (predominantly along the mesentery side) and cobblestoning lesions. An upper endoscopy is recommended in children suspected of CD or in adults with CD having upper GI symptoms. Push enteroscopy or balloon-assisted enteroscopy can be used to evaluate and biopsy the lesions of small bowel of patients with suspected CD. Video capsule endoscopy (VCE) has been used in the diagnosis and differential diagnosis of CD. Although VCE is a sensitive modality for the assessment of inflammation and ulcers in the small bowel, there have been concerns in its lower specificity, inability of obtaining tissue sample, and the risk for capsule retention.

Histologic Evaluation

Histologic evaluation is essential in patients with IBD to establish the chronicity of inflammation and to rule out other causes of colitis. Pathology is not everything, but without pathology, there is no IBD diagnosis. Both UC and CD share a number of histologic features of chronic, structural alterations, including crypt architecture distortion, crypt abscess, mucus depletion, lamina propria mononuclear cell infiltration, basal lymphoplasmacytosis, and pyloric gland metaplasia or Paneth cell metaplasia. Although none of these features are specific, the presence of two or more these features is highly suggestive of IBD.²⁹

Histologic findings are helpful to differentiate CD from UC. Microscopically, inflammation of UC is typically superficial, diffuse and continuous, involving mucosa, lamina propria, muscularis mucosae, and even to the level of superficial submucosa, which is different from multifocal, discontinuous, and transmural lesions of CD. The histologic hallmarks of CD is the presence of are non-caseating granulomas and transmural inflammation. However, granulomas are seen in only 30%–40% of cases with CD on mucosal biopsy.³⁰

Abdominal Imaging

Abdominal imaging is not recommended as the primary modality in the initial diagnosis of UC because of its low diagnostic sensitivity for early disease. Changes at early stage of UC, including edema, hyperemia, and abnormal mucin production, are beyond the spatial resolution of computed tomography (CT). With disease progression, mural stratification and bowel wall thickening can be visualized on CT in patients with UC.³¹ These CT findings are not specific since they can be seen in CD and other forms of colitis. The imaging features on magnetic resonance imaging (MRI) in UC is similar to those of CT.

Cross-sectional abdominal imaging, such as CT or MRI, has been useful in the evaluation of CD, to diagnose and monitor bowel inflammation, perianal disease and complications (for example, stricture, fistula, and abscess). The imaging features of CD include ulcerations, enhancement, mural stratification (enhancement of only the inner layer of bowel wall), bowel wall thickening (generally  >  3  mm), increased mesenteric fat density (fibrofatty proliferation), mural edema, and engorged vasa recta (the comb sign).³¹ The MRI is less commonly performed than CT for evaluating CD in clinical practice, due to its high cost, technical difficulties, limited availability, and a greater interobserver variability in interpreting images. However, MRI with a special protocol is more accurate in assessing fistula and abscess than CT.³²

Laboratory Evaluation

A complete blood count, liver enzymes, urea, creatinine, electrolytes and iron panel, and C-reactive protein (CRP) should be periodically obtained in patients with IBD. Patients with severe disease may have anemia, low albumin, and electrolyte abnormalities due to diarrhea, dehydration, or malnutrition.

Fecal or serological markers are helpful in assessing and monitoring disease activity. The most commonly used serological markers for the measurement of disease activity are erythrocyte sedimentation rate (ESR) and CRP. Fecal markers such as calprotectin, lactoferrin, and S100A12 are able to identify active disease or bowel inflammation, distinguishing it from functional disorders, such as irritable bowel syndrome (IBS).³³–³⁵ A number of antibodies have been detected in patients with IBD. Anti-Saccharomyces cerevisiae antibody (ASCA) and perinuclear antineutrophil cytoplasmic antibody (pANCA) may be useful in differentiating UC from CD. A high ASCA level was reported to be associated with CD, with a high specificity level of 96%–100%, whereas an increased level of pANCA was shown to be more common among patients with UC.²⁹,³⁶ Other reported serological markers for the diagnosis, differential diagnosis, and prognosis include E. coli outer membrane porin C antibody (anti-OmpC), CBir1 flagellin antibody, anti-Pseudomonas fluorescens (anti-I2), and anti-glycan antibodies (e.g., anti-laminaribioside carbohydrate antibody, anti-chitobioside carbohydrate antibody, anti-mannobioside carbohydrate antibody).

In case of severe or refractory disease or disease flare-up, stool testing for enteric pathogens are recommended for example, cytomegalovirus (CMV), Clostridium difficile, Campylobacter species, and E. coli 0157:H7.

Differential Diagnosis

The IBD is a lifelong disease and the establishment of a firm diagnosis is meant a lifelong commitment from both patient's and clinician's perspective. There is a long list of diseases that can mimic IBD, including IBS, microscopic colitis, celiac disease, infectious colitis, radiation colitis, ischemic colitis, and medication-associated colitis.

Irritable Bowel Syndrome

IBS is considered as a part of functional bowel disease spectrum. Symptomatology of IBS and IBD may overlap, including chronic abdominal pain, diarrhea, and bloating. In fact, some patients with IBD may report IBS-like symptoms long before being diagnosed as having IBD. However, patients with IBS typically do not have the red flags, such as weight loss, anemia, incontinence, nocturnal seepage, and tenesmus. Colonoscopy with biopsy typically suffices the distinction between IBS and IBD or microscopic colitis.

Microscopic Colitis

Microscopic colitis consists of two forms, lymphocytic colitis and collagenous colitis. The main histologic feature of both forms of microscopic colitis is the presence of intraepithelial lymphocytosis. Thickened submucosal collagen band is an additional feature for collagenous colitis. The main symptoms of patients with microscopic colitis are diarrhea and abdominal cramps. Some patients may also have endoscopic inflammation with erythema and even aphthous ulcers. Interestingly, a few patients with microscopic colitis may progress into IBD, whereas IBD patients may have concurrent intraepithelial lymphocytosis and even thickened submucosal collagen band. Therefore, microscopic colitis may be considered as a part of IBD or IBD-like disease spectrum (see Chapter 2).

Celiac Disease

Diarrhea, abdominal pain, weight loss, and anemia are common presentation of celiac disease and CD. Serology tests for celiac disease, small bowel biopsy, and proper response to gluten free diet are critical for the differential diagnosis.

Acute Infectious Colitis

At the time of presentation, acute infectious colitis should be excluded before making a diagnosis of IBD. The information in recent traveling, antibiotic use, and GI infection should be sought. In patients having diarrhea for more than 4 weeks, a suspicion of IBD or IBS should be raised. A positive stool testing for specific enteric pathogens can help to identify the infectious etiology. However, a negative stool examination does not necessarily imply a diagnosis of IBD. Under this circumstance, histopathological evaluation is needed. The presence of histologic features of chronicity, such as mononuclear cell infiltration in the lamina propria, crypt architecture distortion, basal lymphoplasmacytosis, and pyloric gland or Paneth cell metaplasia, favors the diagnosis of IBD. Pseudomembranous colitis and erupting volcano lesion on histology are characteristic features of Clostridium difficile infection.

Differentiating IBD from acute infectious colitis is usually not difficult. Proper follow-up and close observation of clinical course over time may be the best approach. Of note, infectious colitis may occur on top of IBD. Therefore, the presence of one of these pathogens can't exclude a diagnosis of IBD. In addition, IBD can be triggered by an enteric infection. Therefore, stool testing for these specific pathogens should be performed at the time of the initial presentation and at the time of disease flare-up.

Chronic Infectious Colitis

The distinction between IBD and chronic infectious colitis from intracellular bacteria, such as intestinal tuberculosis (ITB), Samonella, and Yersinia could be challenging.

For patients from developing countries, such as India and China, ITB is the most important one for the differential diagnosis, as the treatment of IBD and ITB is completely different. ITB at the terminal ileum and cecum can mimic CD. The presence of caseating granulomas, typically large in number and size, and positive finding for acid-fast bacilli are diagnostic features of tuberculosis. Grouped or circumferential ulcers (vs. longitudinal ulcers in CD), nodules, and deformed ileocecal valve are the features favoring ITB. Patients with Yersinia or Salmonella infection may present aphthoid ulcers at the terminal ileum, which may resemble CD. Special microbiological work up for Yersinia includes cold culture of stool specimens.

Radiation Colitis

Radiation can cause mucosal inflammation that mimic UC. Radiation colitis may develop weeks to years after abdominal or pelvic irradiation. Although being nonspecific, histologic findings suggestive of radiation colitis include eosinophilia infiltrates, epithelial atypia, fibrosis, capillary telangiectasia, and vasculopathy. Radiation therapy is occasionally used in patients with underlying IBD for IBD-associated or non-IBD-associated neoplasia. Radiation injury to gut mucosa in patients with underlying IBD has been a challenge for the diagnosis and management.

Ischemic Colitis

Ischemia can cause intestinal inflammation which mimics both UC and CD. Differential diagnosis between ischemic colitis and late-onset CD can be difficult. Their endoscopic features may overlap to a great degree. Patients with atherosclerotic disease, congestive heart failure, or recent hypotensive events have an increased risk of developing ischemic colitis. Patients with ischemic colitis present with abdominal pain and bleeding. The common locations of ischemic colitis are splenic flexure, rectal sigmoid junction, and proximal ascending colon. Acute ischemic colitis has intramucosal hemorrhage, and chronic ischemic colitis can have intramucosal fibrosis and crypt drop out, which are not common in patients with IBD. Basal lymphoplasmocytosis, a common histologic feature of UC and CD, is rare in ischemic colitis.

Diversion Colitis

Patients with diversion colitis have a clear history of surgically excluded bowel and prominent lymphoid hyperplasia on histology. Although clinical history can make differential diagnosis between diversion colitis and IBD, it has been difficult to identify the dominant histopathological component in IBD patients with diverting ostomies. The treatment of diversion colitis and that of IBD do not entirely overlap.

Diverticulitis

Patients with diverticulitis may have a known history of diverticulosis and present with acute or recurrent left-lower-quadrant pain or painless bleeding. Detection of diverticula and localized inflammation at and around diverticula on colonoscopy or cross-sectional imaging favors the diagnosis of diverticulitis.

Diverticular colitis is considered as a disease phenotype related to mucosal prolapse and/or ischemia, which is easily confused with diverticulitis and Crohn's colitis with or without diverticulosis, as both have a segmental distribution. Mucosa around mouth of diverticulum, not diverticulum itself, is normally inflamed in diverticular colitis, which is different from diverticulitis. Mucosal biopsy of inflamed mucosa near the diverticulum typically shows prolapse or ischemic changes.

Medication-Associated Colitis

Nonsteroidal antiinflammatory drugs can also cause chronic diarrhea and ulcers and inflammation along the GI track. However, patients with NSAID-associated colitis usually have a clear history of medication use and may not show basal lymphoplasmacytosis on histology. Some medications, such as check-point immune therapy drugs, may cause IBD or IBD-like conditions (Chapter 2).

Solitary Rectal Ulcer Syndrome

Patients with solitary rectal ulcer syndrome and UC or Crohn's colitis may have overlapping clinical presentation and endoscopic features. Histologic findings of architectural distortion, fibrosis, and muscle-cell hyperplasia can be helpful in differentiating solitary rectal ulcer syndrome from UC or Crohn's colitis. The endoscopic and histologic abnormalities of solitary rectal ulcer syndrome are prominently at the anterior wall of the rectum, in contrast to the diffuse involvement of UC. In addition, barium defecography and anorectal manometry may reveal rectal prolapse, rectocele, and dyssynergic defecation pattern.

Behcet Syndrome

Behcet disease has many overlapping features with CD, although the former is predominantly vasculitis in nature, with ulcer lesions in oral and perianal, and genital area (Chapter 2).

Classification of UC

An accurate diagnosis of UC should involve defining the extent and severity of inflammation. Various instruments for evaluating disease extent or severity were developed. The most commonly used modalities among them are the Montreal Classification, the Truelove and Witts' severity index, and the Mayo Score.

The Montreal Classification

The Montreal consensus panel proposed a classification system of disease extent and severity for UC based on the anatomic extent, frequency and severity of diarrhea, the presence of systemic symptoms, and laboratory abnormalities (Table 1.1). An accurate classification of disease extent for UC is important as it provides the information for selecting the appropriate pharmaceutical agents and baseline for monitoring disease extension. For example, patient with distal disease responds well to suppositories (in E1 disease) or enemas (in E2 disease). In contrast, those with extensive colitis or previously called pancolitis, oral agents may be the first choice. The Montreal Classification stratifies UC severity into mild, moderate, and severe. A periodic assessment of the disease severity of UC can help clinicians to make the therapeutic decision, therefore improving the short- and long-term outcomes.

Truelove and Witts' Severity Index

In 1955, Truelove and Witts described an instrument to measure disease activity in a clinical trial of oral cortisone for active UC.³⁷ The Truelove and Witts' severity index composed of eight variables: bowel frequency, blood in stool, temperature, pulse, hemoglobin, physical signs, ESR, and X-ray. Subsequently an instrument with simplified version of Truelove and Witts' severity index was developed, which excluded variables of X-ray and physical signs³⁸ (Table 1.2). Although the Truelove and Witts' severity index is helpful to broadly classify patients and used extensively in clinical trials, it is too complicated to be used in daily clinical practice.

Table 1.1

Table 1.2

The Mayo Score

The Mayo Score, also known as the Mayo Clinic Score or Disease Activity Index (DAI), consists of four items: stool frequency, rectal bleeding, endoscopic findings, and physician's global assessment. The Mayo Score quantities disease activity and generated scores ranged from 0 to 12 points.³⁸ (Table 1.3) The Mayo Score have been used routinely in clinical trials and clinical practice.

Classification of CD

After the diagnosis of CD is established, disease activity, severity, extent, and behavior should be assessed and patients should be phenotyped.

The Montreal Classification

The Montreal Classification is widely used to stratify CD according to age at diagnosis, disease location, and disease behavior (Table 1.4). The stratification of age at diagnosis allows for differentiating pediatric CD (below 16  years), classic adult onset CD (between 17 and 40  years), and CD of the elderly (above 40  years). CD can be divided into ileal disease (L1), colonic disease (L2), and ileocolonic disease (L3), based on disease location, whereas L4 (upper GI disease) is a modifier that can be added to the L1–L3 classification when concomitant upper GI disease is present. The classification based on disease location is associated with different types of complications. For example, colonic (particularly rectal) disease was associated with an increased risk of perianal fistula or abscess. The patients with CD can also be classified as non-stricturing and non-penetrating disease (B1), stricturing disease (B2), and penetrating (B3) disease. The perianal disease (P) is also a disease modifier that can be added to B1–B3 classification when concomitantly present. Although the disease location may remain stable after diagnosis, the disease behavior evolves over time, in which an increasing number of patients progressing from inflammatory to stricturing or penetrating disease.³⁹ These different disease behavior are associated with a different risk for the development of complications and disabling disease.

The Crohn's Disease Activity Index

The commonly used instrument for evaluating the disease severity of CD is the Crohn's Disease Activity index (CDAI) (Table 1.5). This composite instrument is scored on a scale from 0 to 1100 and includes abdominal pain, general wellbeing, complications, abdominal mass, anemia, and weight change. The patients with CD can be divided into asymptomatic remission (CDAI  <  150), mild-to-moderate CD (150–220), moderate-to-severe CD (220–450), and severe-fulminant disease (>450).

Crohn's Disease Endoscopic Index of Severity

The Crohn's Disease Endoscopic Index of Severity (CDEIS) scores have been developed for the assessment of the severity of lesions in CD with endoscopy (Table 1.6). The CDEIS is a validated scoring system in which six endoscopic variables (the presence of deep ulcers, superficial ulcers, non-ulcerated stenosis, ulcerated stenosis, proportion of ulcerated surface, and proportion of surface affected by disease) are assessed in the rectum, sigmoid and left colon, transverse colon, right colon, and ileum, respectively. For the five segments, the percentage of ulcerated colonic surface and the percentage of surface affected by any CD lesion are indicated on a 10  cm visual analog scale.⁴⁰ The CDEIS scores range from 0 to 44 with higher scores indicating more severe disease.

Table 1.3

Table 1.4

The Simple Endoscopic Score for CD

The Simple Endoscopic Score for CD (SES-CD) was developed in 2004 as an attempt to simplify CDEIS.⁴¹ The SES-CD is also based on four endoscopic variables (presence and size of ulcers, proportion of surface covered by ulcers, proportion of surface affected by disease, and presence and severity of stenosis) and assessed in five ileocolonic segments (Table 1.7).⁴¹ However, only those characteristics that contribute to clinical symptoms and have good reproducibility are incorporated in the SES-CD. Each of the four SES-CD variables is scored, from 0 to 3, with the sum of the scores for each variable ranging from 0 to 15. The presence and extent of stenosis are scored from 0 to 11, which yield a total SES-CD score of 0–56.

Medical Treatment of UC

The medications commonly used for the treatment of UC include mesalamines, glucocorticosteroids, immunomodulators, and various biological agents. The treatment consists of two phases, induction phase and maintenance phase. The choice of medication depends on disease severity and disease extent, and the goal of therapy (Table 1.8). In addition to medical therapy, endoscopic and surgical treatment plays an important role in the management of UC, which are discussed in separate chapters.

5-Aminosalicylates and Mesalamines

Oral mesalamine is the first-line therapy for the patients with mild-to-moderate UC. It can be started at a lower dose of 2.0–2.4  g/day and increased to the maximum tolerated dose (4.8  g).⁴² Mesalamines generally exert their effect in 2–4  weeks.⁴² The combination therapy of oral with topical mesalamine may yield a higher remission rate than either therapy alone. The topical mesalamine agents are available as suppositories, foams, and enemas. The choice among those agents is based on the disease extent. Enemas can reach as far as 40 cm from the anus; foam reaches the mid-sigmoid colon, whereas suppositories are only effective in distal 10–15  cm of the rectum.

The maintenance therapy is required in all patients with left-sided and extensive UC. Mesalamines are effective in the maintenance of remission in mild-to-moderate UC. The patients who achieve remission with the mesalamines should continue on the same agent.⁴²

Table 1.5

Corticosteroids

Systemic corticosteroids are recommended in patients with moderate-to-severe UC or in those mild-to-moderate active UC who do not respond to mesalamine. The typical starting dose is 0.75  mg/kg oral prednisone daily (40–60  mg/day). Response should be achieved within 2  weeks, and then the corticosteroid agent can be tapered gradually. For severe UC, intravenous corticosteroids, such as methylprednisolone 60  mg every 24  h or hydrocortisone 300–400  mg daily, are needed in the setting of inpatient. The maintenance therapy with corticosteroids should be avoided due to the lack of long-term efficacy and risk of nonreversible adverse effects.

Table 1.6

Table 1.7

Table 1.8

When patients do not respond to oral or intravenous corticosteroids, the salvage therapy, including cyclosporine, tacrolimus, and infliximab (IFX) as inpatient or antitumor necrosis factor (anti-TNF) or anti-integrin agents as outpatient, should be considered.

A topically active budesonide agent, budesonide-multimatrix (MMX) (9  mg/day), has been approved by the US Food and Drug Administration for the induction therapy of mild-to-moderate left-sided UC. The role of budesonide MMX for the maintenance therapy in UC has not been established.

Topical corticosteroids, such as hydrocortisone enemas and budesonide foam, can be tried to induce remission in proctitis or left-sided UC, alone or along with other oral agents. The topical mesalamine appears to be superior to topical corticosteroids at inducing remission.⁴² The chance of clinical and endoscopic improvement could be higher when combining rectal mesalamine and corticosteroid.⁴³

Immunomodulators

Commonly used immunomodulators for the maintenance therapy in UC include azathioprine (AZA), 6-mercaptopurine (6MP), and methotrexate (MTX). Before the initiation of AZA and 6MP, genetic and serological tests for thiopurine S-methyltransferase (TPMT) polymorphism should be performed. Although AZA may be more effective in reducing remission in UC than mesalamine,⁴⁴ immunomodulators are used only for the maintenance therapy. They can be used alone or in combination with other agents. They are commonly used as an adjunctive therapy (with steroids) in patients with steroid-dependent moderate-to-severe UC or adjunctive therapy to anti-TNF in those with steroid-refractory moderate-to-severe UC.⁴⁵

Cyclosporines

Cyclosporine has been shown to be highly effective in treating steroid-refractory moderate-to-severe UC, with a comparable efficacy to IFX.⁴⁶ With its quick action, the agent is mainly used as a rescuing agent in inpatients with UC refractory to intravenous corticosteroids. Cyclosporine can be used as a short-term bridge to therapy with longer acting immunomodulators such as AZA or 6MP or an anti-TNF agent. Due to its adverse effect, this category of agents is not recommended for maintenance therapy in UC.

Biological Therapy

Anti-TNF agents, including IFX,⁴⁷ adalimumab (ADA),⁴⁸,⁴⁹ and golimumab,⁵⁰ have been used for the induction and maintenance therapy for moderate-to-severe UC. Vedolizumab, an anti-intergrinα4β7 agent has been approved by the US Food and Drug Administration for the induction and maintenance therapy for moderate-to-severe UC.⁵¹ It is a standard loading dose and maintenance dose for both UC and CD. Its therapeutic action may take up to 10  weeks. Therefore, the use of the agent is not recommended in an acute inpatient setting.

Other Agents

A new class of pathway-target therapy has been investigated for the treatment of UC as well as CD; and among them are tofacitinib, an oral, small-molecule Janus kinase inhibitor,⁵² and ozanimod, an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5.⁵³ Fecal microbiota transplant has been studied for the treatment of non-Clostridium difficile UC. Its safety and long-term efficacy remain to be clarified.

Medical Treatment of CD

The medical management of UC and CD largely overlaps. Like UC, there are two general approaches for the treatment of CD: step-up therapy and top-down therapy. The accelerated step-up therapy typically starts with medications which are less potent, but have fewer side effects; then escalates to more potent, but more toxic medicines based on the response to the first-line agents. This step-up strategy may have an impact on changing the course of disease. Naturally, the approach is associated with less medication-related adverse effects. In contrast, the top-down strategy is advocated for effective treatment at the time of diagnosis, with an intention to alter the disease course of aggressive CD and subsequently reduce the risk for surgery, disease-associated hospitalization. The top-down approach can be associated with a higher risk for medication-induced side effects. The risks and benefits of the two approaches should be carefully balanced. Therefore the risk stratification is important for the management of CD. The commonly listed risk factors for aggressive form of CD include (1) pediatric-onset CD; (2) female smokers; (3) disease in the upper GI and/or perianal area; (4) penetrating disease; (5) a short interval between the diagnosis and the first surgery, except incidental appendectomy for the initial CD; (6) history of multiple surgeries; (7) small bowel disease in patients with ileostomy or jejunostomy; and (8) disease in patients with short gut syndrome. The patients with the risk factors are recommended for having the top-down approach, even with combined anti-TNF and immunomodulator therapy.

The medications that have been commonly used in the treatment of CD include mesalamines, corticosteroids, antibiotics, immunomodulators, and various biological agents. The proper choice of these medications for different indications and settings is important (Table 1.9).

Table 1.9

5-Aminosalicylates and Mesalamines

Although mesalamine agents have been widely used in treating inflammatory phenotype of CD, especially in developing countries, multiple studies have demonstrated that mesalamines are not effective for the treatment of CD.⁵⁴–⁵⁶ A meta-analysis showed that sulfasalazine, not mesalamines, may be beneficial in