(DOCX) pone
(DOCX) pone.0233781.s020.docx SB756050 (92K) GUID:?A195504D-C13F-427F-8318-9FCE0B288826 S2 Table: Risk of bias assessment. short-term, wort-case, C) entire, best-case, D) entire, worst-case.(TIFF) pone.0233781.s011.tiff (792K) GUID:?4D0AFA0C-3A21-4944-AA78-82105021DB09 S11 Fig: Forest plot, entire, worst-case scenario, per drug with correction for zero-event studies. (JPG) pone.0233781.s012.jpg (761K) GUID:?A254734E-18AE-4DF6-9B44-6E0B6B9BB9D4 S12 Fig: Forest plot, entire, best-case scenario with correction for zero-event studies. (JPG) pone.0233781.s013.jpg (735K) GUID:?17779DBD-92B8-4977-B135-0229FFE0B6DF S13 Fig: Forest plot, entire, best-case scenario, per drug with correction for zero-event studies. (JPG) pone.0233781.s014.jpg (751K) GUID:?56A7AF8B-3BEC-4ABA-9F8F-972BAAFF28B9 S14 Fig: Forest plot, entire, worst-case scenario, per indication with correction for zero-event studies. (JPG) pone.0233781.s015.jpg (789K) GUID:?6AAC4C50-23A6-4DD3-825B-4CCBBE27E788 S15 Fig: Forest plot, entire, best-case scenario, per indication, per indication with correction for zero-event studies. (JPG) pone.0233781.s016.jpg (784K) GUID:?8A9322DE-B49D-4406-8748-F47C689033A8 S16 Fig: Forest plot, short-term, worst-case scenario with correction for zero-event studies. (JPG) pone.0233781.s017.jpg (665K) GUID:?34619C3F-CEC0-4A3A-BE22-BA2F43904473 S17 Fig: Forest plot, short-term, worst-case scenario, per drug with correction for zero-event studies. (JPG) pone.0233781.s018.jpg (712K) GUID:?FE007D79-0A6D-4706-A894-C93BB21782EB S18 Fig: Forest plot, short-term, worst-case scenario, per indication with correction for zero-event studies. (JPG) pone.0233781.s019.jpg (735K) GUID:?3D222E37-3353-4CBB-98D3-A374D33DA0F8 S1 Table: Studies included in the systematic review. (DOCX) pone.0233781.s020.docx (92K) GUID:?A195504D-C13F-427F-8318-9FCE0B288826 SB756050 S2 Table: Risk of bias assessment. (DOCX) pone.0233781.s021.docx (32K) GUID:?4A8CEE43-F146-46A9-B4F3-3B53A23014EC Data Availability StatementAll relevant data are within the paper and its Supporting Information files. Abstract Objective Cases of SB756050 inflammatory bowel disease (IBD) during treatment with interleukin (IL)-17 antagonists have been reported from trials in psoriasis, psoriatic arthritis, and ankylosing spondylitis. The aim of this study was to assess the overall risk for development of IBD due to IL-17 inhibition. Design Systematic review and meta-analysis of studies conducted 2010C2018 of treatment with IL-17 antagonists in patients with psoriasis, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. We compared risk of IBD development in anti-IL-17 treated patients compared to placebo treatments. We also computed incident rates of IBD overall. A worst case scenario defining subjects ambiguous for prevalent versus incident cases for the latter was also applied. Results Sixty-six studies of 14,390 patients exposed to induction and 19,380 patients exposed to induction and/or maintenance treatment were included. During induction, 11 incident cases of IBD were reported, whereas 33 cases were diagnosed during the entire treatment period. There was no difference in the pooled risk of new-onset IBD during induction studies for both the best-case [risk difference (RD) 0.0001 (95% CI: -0.0011, 0.0013)] and worst-case scenario [RD 0.0008 (95% CI: -0.0005, 0.0022)]. The risk of IBD was not different from placebo when including data from maintenance and long-term extension studies [RD 0.0007 (95% CI: -0.0023, 0.0036) and RD 0.0022 (95% CI: -0.0010, 0.0055), respectively]. Conclusions The risk for development of IBD in patients treated with IL-17 antagonists is not elevated. Prospective surveillance of patients treated with IL-17 antagonists with symptom and biomarker assessments is warranted to assess for onset of IBD in these patients. Introduction The inflammatory bowel diseases (IBD), Crohns disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions which can affect various segments of the gastrointestinal tract and the colon only, respectively. Typical symptoms include diarrhea, abdominal pain and rectal bleeding, as well as development of stenoses, abscesses and fistulas in case of CD. IBD manifests in genetically susceptible patients, potentially triggered by environmental factors and/or perturbations of the gut microbiota leading to a dysregulated mucosal immune system and development of chronic intestinal inflammation [1, 2]. In genome-wide association studies, several genetic loci were identified in patients with IBD overlapping with other immune mediated inflammatory diseases (IMIDs) such as chronic plaque psoriasis and ankylosing spondylitis [3]. Patients with psoriasis and psoriatic arthritis are more likely to develop IBD [4, 5] and there is an increased risk of developing CD in patients with ankylosing spondylitis [6]. The interleukin-17 family cytokines (IL-17A to IL-17F) that signal via several IL-17 receptors (IL-17R A to E) [7, 8] are strong inducers of inflammation contributing to tissue destruction in IMIDs. Secukinumab (SEC) and Ixekizumab (IXE), both monoclonal IgG4 antibodies directed against the IL-17A, as well as brodalumab (BRO), a monoclonal antibody directed its receptor, IL1R1 antibody have been successfully used for treating various autoimmune mediated disorders such as chronic plaque psoriasis (SEC, IXE, BRO), psoriatic arthritis (SEC), and ankylosing spondylitis (SEC) [8C12]. Notably, inhibition of IL-17A has been shown to worsen colitis in mouse models [13, 14] and blocking of IL-17A and IL-17RA with the monoclonal antibodies SEC and BRO, respectively, in patients with CD not only failed efficacy, but appeared to worsen disease activity [15, 16]. The risk of IBD in patients with IMIDs.