Ulcerative colitis

Abstract

Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually presents with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. The aim of management is to induce and then maintain remission, defined as resolution of symptoms and endoscopic healing. Treatments for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immunosuppressants. Some patients can require colectomy for medically refractory disease or to treat colonic neoplasia. The therapeutic armamentarium for ulcerative colitis is expanding, and the number of drugs with new targets will rapidly increase in coming years.

Conflict of interest statement

Declaration of interests

RCU has no conflicts of interest. SM has served as a consultant for Pfizer Inc and receives research funding support from Takeda Pharmaceuticals. PBA has received Speaker fees for MSD, AbbVie, Allergen, Ferring, Warner Chilcott, and Napp. LP-B has received consulting fees from Merck, AbbVie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Therakos, Pharmacosmos, Pilège, Bristol-Myers Squibb, Union Chimique Belge (UCB) Pharmaceuticals, Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer, HAC Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, and Samsung Bioepis, and lecture fees from Merck, AbbVie, Takeda, Janssen, Takeda, Ferring, Norgine, Tillots, Vifor, Therakos, Mitsubishi, and HAC Pharma. J-FC has served as consultant or advisory board member for AbbVie, Amgen, AstraZeneca, ABScience, Boehringer, Bristol-Meyers Squibb, Celgene, Celltrion, Danone, Enterome, Evidera, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssen & Janssen, Immune Pharmaceuticals, Intestinal Biotech Development, Kyowa Kirin Pharma, Lilly, Medimmune, Merck Sharp Dohme, Merck & Co, Millennium Pharmaceuticals Inc, Navigant Consulting, Neovacs, Nestle Nutrition Sciences Partner, Nutrition Science Partners Ltd, Pfizer, Prometheus Laboratories, Protagonist Therapies, Receptos, Sanofi, Schering Plough Corporation, Second Genome, Shire, Takeda, Teva Pharmaceuticals, Tigenix, UCB, UEGW AbbVie Advisory Board, UEGW AbbVie Symposium, Vertex, and Dr August Wolff GmbH Co.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Increase in worldwide incidence of ulcerative colitis over time

*Statistically significant increase in incidence over time (p

Figure 2. Overview of the intestinal immune system in the healthy state and for ulcerative colitis with a focus on proven and promising therapeutic targets

During the healthy state, barrier function is maintained by the mucus layer and epithelial cells bound across tight junctions. Additionally, IgA and antimicrobial factors such as RegIIIγ sequester luminal microflora away from the mucosal immune system. Specialised antigen-presenting cells such as dendritic cells process and present antigen to T and B cells within the draining lymph nodes, defaulting to a tolerising phenotype. Intestinal DCs also imprint T and B lymphocytes to express gut-homing molecules α4β7 and CCR9. Lymphocytes thus imprinted within the gastrointestinal tract enter the systemic circulation and upon reaching intestinal high endothelial venules, the gut-imprinted, α4β7-expressing lymphocytes engage locally expressed MAdCAM and egress the circulation to enter into the intestinal lamina propria. Coordinated activity of innate and adaptive immune cells maintains homoeostasis within the intestinal mucosa at steady state. Ulcerative colitis is associated with damage to the mucosal barrier (inset), allowing the luminal microflora to trigger a sustained and uninhibited inflammatory response. Among the inflammatory cells, TH9 cells perpetuate enterocyte apoptosis and inhibit mucosal healing. IL-13, produced by NK T cells, also contributes to epithelial injury. Additionally, innate lymphoid cells (inset), homeostatic at steady state, contribute to the cytokine production, perpetuating inflammation. Mucosal injury and damage is associated with dysbiosis, which perhaps contributes to the inflammatory cascade. An increasing understanding of the mucosal immune system has led to an expanding array of therapeutic targets. Of these, TNF-α antagonists and homing inhibitors are currently in clinical practice (green text), while the others are in early to advanced stages of clinical development (purple text). Illustration by Jill Gregory. Printed with permission of ©Mount Sinai Health System. IgA=immunoglobulin A. DC=dendritic cell. MAdCAM=mucosal addressin cell associated molecule. IL=interleukin. Th=T-helper cell. TREG=regulatory T cell. IFN=interferon, Mϕ=macrophage. TGF=transforming growth factor. ER=endoplasmic reticulum. MHC=major histocompatibility complex. NK T cell=natural killer T cell. MLN=mesenteric lymph node.

Figure 3. Ulcerative colitis phenotypes by Montreal Classification

Symptoms and treatment strategy can differ based on extent of disease. Illustration by Jill Gregory. Printed with permission of ©Mount Sinai Health System.

Figure 4. Suggested treatment approach algorithm for mild to moderate ulcerative colitis

Based on Toronto Consensus and European Crohn’s and Colitis Organisation guidelines., For patients needing and responding to steroids, the choice for maintenance medication can be either 5-ASA, thiopurine, or a biological drug. 5-ASA can be considered if partial initial response and first course of steroids. Thiopurines can be used if no response to 5-ASA, low risk of complications, and first course of steroids. Biological drugs should be used if unable to taper steroids, second course of steroids, or higher risk of complications. 5-ASA=5-aminosalicylic acid.

Figure 5. Suggested treatment approach algorithm for moderate to severe ulcerative colitis

Based on Toronto Consensus and European Crohn’s and Colitis Organisation guidelines., 5-ASA=5-aminosalicylic acid. IV=intravenous. DI=dose intensification.