The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

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Abstract

<p class="first" id="P1">The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field. </p>

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Ulcerative colitis

Ryan Ungaro, Saurabh Mehandru, Patrick Allen … (2017)

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.

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Infliximab for induction and maintenance therapy for ulcerative colitis.

Paul Rutgeerts, William J Sandborn, Brian Feagan … (2005)

Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.) Copyright 2005 Massachusetts Medical Society.

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Crohn's disease.

Joana Torres, Saurabh Mehandru, Jean-Frédéric Colombel … (2017)

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract, with increasing incidence worldwide. Crohn's disease might result from a complex interplay between genetic susceptibility, environmental factors, and altered gut microbiota, leading to dysregulated innate and adaptive immune responses. The typical clinical scenario is a young patient presenting with abdominal pain, chronic diarrhoea, weight loss, and fatigue. Assessment of disease extent and of prognostic factors for complications is paramount to guide therapeutic decisions. Current strategies aim for deep and long-lasting remission, with the goal of preventing complications, such as surgery, and blocking disease progression. Central to these strategies is the introduction of early immunosuppression or combination therapy with biologicals in high-risk patients, combined with a tight and frequent control of inflammation, and adjustment of therapy on the basis of that assessment (treat to target strategy). The therapeutic armamentarium for Crohn's disease is expanding, and therefore the need to develop biomarkers that can predict response to therapies will become increasingly important for personalised medicine decisions in the near future. In this Seminar, we provide a physician-oriented overview of Crohn's disease in adults, ranging from epidemiology and cause to clinical diagnosis, natural history, patient stratification and clinical management, and ending with an overview of emerging therapies and future directions for research.