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      Recent advances and emerging therapies in the non-surgical management of ulcerative colitis

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      F1000Research
      F1000 Research Limited
      ulcerative colitis, therapy, small molecules, biologicals

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          Abstract

          The so-called “biologicals” (monoclonal antibodies to various inflammatory targets like tumor necrosis factor or integrins) have revolutionized the treatment of inflammatory bowel diseases. In ulcerative colitis, they have an established role in inducing remission in steroid-refractory disease and, thereafter, maintaining remission with or without azathioprine. Nevertheless, their limitations are also obvious: lack of primary response or loss of response during maintenance as well as various, in part severe, side effects. The latter are less frequent in anti-integrin treatment, but efficacy, especially during induction, is delayed. New antibodies as well as small molecules have also demonstrated clinical efficacy and are soon to be licensed for ulcerative colitis. None of these novel drugs seems to be much more effective overall than the competition, but they provide new options in otherwise refractory patients. This increasing complexity requires new algorithms, but it is still premature to outline each drug’s role in future treatment paradigms.

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          Ulcerative colitis

          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.

            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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              Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial.

              Ulcerative colitis (UC) is difficult to treat, and standard therapy does not always induce remission. Fecal microbiota transplantation (FMT) is an alternative approach that induced remission in small series of patients with active UC. We investigated its safety and efficacy in a placebo-controlled randomized trial.
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                Author and article information

                Contributors
                Role: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Journal
                F1000Res
                F1000Res
                F1000Research
                F1000Research
                F1000 Research Limited (London, UK )
                2046-1402
                7 August 2018
                2018
                : 7
                : F1000 Faculty Rev-1207
                Affiliations
                [1 ]Department of Internal Medicine 1, University of Tübingen, Tübingen, Germany
                Author notes

                Competing interests: Jan Wehkamp has received lecture fees from Falk, AbbVie, Takeda, MSD, Roche, Ferring, and Shire and consulting fees from MSD, Takeda, Novartis, Shire, AbbVie, and Ardeypharm; he is a board member of Defensin Therapeutics and has received honoraria for clinical trials from Amgen, Novartis, Falk, and AbbVie. Eduard F. Stange has received lecture fees from AbbVie, Dr. Falk Pharma, Ferring, and Takeda and advisory board fees from Merck, Takeda, and Jansen. He has received honoraria for clinical studies from AbbVie, Falk, Takeda, Celgene, Gilead, Amgen, Boehringer, Salix, and Pfizer.

                Author information
                https://orcid.org/0000-0002-6474-7387
                Article
                10.12688/f1000research.15159.1
                6081982
                aa70d8ce-14d2-4bcb-80b5-b507482904e3
                Copyright: © 2018 Wehkamp J and Stange EF

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 August 2018
                Funding
                The author(s) declared that no grants were involved in supporting this work.
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                ulcerative colitis,therapy,small molecules,biologicals
                ulcerative colitis, therapy, small molecules, biologicals

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