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      Landscape of new drugs and targets in inflammatory bowel disease


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          Although the therapeutic armamentarium of Inflammatory bowel diseases (IBD) physicians has expanded rapidly in recent years, a proportion of patients remain with a suboptimal response to medical treatment due to primary no response, loss of response or intolerance to currently available drugs. Our growing knowledges of IBD pathophysiology has led to the development of a multitude of new therapies over time, which may, 1 day, be able to address this unmet medical need. This review aims to provide physicians an update of emerging therapies in IBD by focusing on drugs currently in phase 3 clinical trials. Among the most promising molecules are anti‐IL‐23, JAK‐inhibitors, anti‐integrins and S1P modulators. While the results in terms of efficacy and safety are fairly clear for some classes, the question of safety remains more uncertain for other classes. Molecules at a more preliminary stage of development (phase 1 and 2), one of which may 1 day offer an optimal benefit‐risk ratio, will also be presented as well as their respective mechanisms of action.

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          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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            Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis

            Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.
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              Vedolizumab as induction and maintenance therapy for ulcerative colitis.

              Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P 1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

                Author and article information

                United European Gastroenterol J
                United European Gastroenterol J
                United European Gastroenterology Journal
                John Wiley and Sons Inc. (Hoboken )
                16 September 2022
                December 2022
                : 10
                : 10 , Changing Paradigms in Management of Inflammatory Bowel Disease ( doiID: 10.1002/ueg2.v10.10 )
                : 1129-1166
                [ 1 ] Hepato‐Gastroenterology and Digestive Oncology University Hospital CHU of Liège Liège Belgium
                [ 2 ] Department of Gastroenterology and Endoscopy IRCCS San Raffaele Hospital and Vita‐Salute San Raffaele University Milan Italy
                [ 3 ] Department of Biomedical Sciences Humanitas University Pieve Emanuele Milan Italy
                [ 4 ] Université de Lorraine CNRS Laboratoire IMoPA Nancy France
                [ 5 ] Department of Gastroenterology University of Lorraine CHRU‐Nancy Nancy France
                [ 6 ] University of Lorraine Inserm, NGERE Nancy France
                Author notes
                [*] [* ] Correspondence

                Laurent Peyrin‐Biroulet, Department of Gastroenterology and NGERE (INSERM U1256), Nancy University Hospital, University of Lorraine1 Allée du Morvan, Vandœuvre‐lès‐Nancy, France.

                Email: peyrinbiroulet@ 123456gmail.com

                © 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                : 13 July 2022
                : 22 August 2022
                Page count
                Figures: 1, Tables: 3, Pages: 38, Words: 18346
                Funded by: Fonds De La Recherche Scientifique ‐ FNRS , doi 10.13039/501100002661;
                Award ID: 40001034
                Review Article
                Inflammatory Bowel Disease
                Custom metadata
                December 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.2 mode:remove_FC converted:15.12.2022

                clinical trials,inflammatory bowel disease,new drugs,phase 1,phase 2,phase 3


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