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Background: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P) 1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). It is known that non-serious treatment-emergent adverse events (TEAEs) may not lead to UC drug discontinuation but can affect treatment tolerability., Objectives: This post hoc analysis evaluated the incidence of specific, common, non-serious TEAEs reported in the etrasimod UC clinical programme and the characteristics of affected patients., Design: Data included patients from the Placebo-controlled UC cohort (phase II OASIS, and phase III ELEVATE UC 52 and ELEVATE UC 12 trials) receiving QD etrasimod (2 or 1 mg) or placebo., Methods: Proportions and incidence rates (IRs; the number of patients with a TEAE divided by the total exposure in patient-years (PYs), per 100 PY) of Headache, Pyrexia, Nausea and Dizziness TEAEs were reported. Changes in heart rate among patients with Dizziness TEAEs were also evaluated., Results: Among 943 patients (etrasimod 2 mg, N  = 577 (276.7 PY); etrasimod 1 mg, N  = 52 (11.4 PY); placebo, N  = 314 (115.1 PY)), 48, 34, 27 and 21 patients experienced events of Headache, Pyrexia, Nausea and Dizziness, respectively. All events were non-serious; one patient treated with etrasimod was discontinued due to a Pyrexia TEAE. Numerically, IRs of Headache and Dizziness TEAEs were higher, and Nausea slightly higher, with etrasimod versus placebo (13.45 vs 8.63 per 100 PY, 6.52 vs 1.69 and 7.18 vs 5.13 per 100 PY, respectively); IRs were similar for Pyrexia. The duration of most TEAEs was 1-10 days., Conclusion: In the etrasimod UC clinical programme, all Headache, Pyrexia, Nausea and Dizziness events were non-serious. Headache and Dizziness were more frequent, and Nausea slightly more frequent, among patients receiving etrasimod versus placebo. The post hoc nature of this analysis is a limitation. These results reiterate the favourable safety profile and tolerability of etrasimod., Trial Registration: ClinicalTrials.gov: NCT02447302; NCT03945188; NCT03996369., Competing Interests: C.W.L. has received speaker fees from AbbVie, Dr Falk, Ferring, Hospira, Janssen, MSD, Pfizer Inc., Shire, Takeda and Warner-Chilcott; has receiving consultant fees from AbbVie, Dr Falk, Gilead, GSK, Hospira, Iterative Scopes, Janssen, MSD, Oshi Health, Pfizer Inc., Pharmacosmos, Takeda, Topivert, Trellus Health and Vifor Pharma and has received research funding from AbbVie and Gilead. J.T. has received advisory board fees from AbbVie, Bristol-Myers Squibb, Janssen and Pfizer Inc.; has received research grants from AbbVie and Janssen and has received speaker fees from AbbVie, Galapagos, Janssen and Pfizer Inc. Y.L. has served on advisory committee/as a board member for AbbVie, Celltrion, Eli Lilly, Janssen, Pfizer Inc., Sandoz, Takeda and has acted as a consultant for AbbVie, Eli Lilly, Janssen, Pfizer Inc. and Takeda. S.V. has received research grants from AbbVie, Galapagos, J&J, Pfizer and Takeda and has received speakers’ and/or consultancy fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer Inc., Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance, Tillotts Pharma AG, VectivBio, Ventyx and Zealand Pharma. M.F., I.M., A.M., K.L., M.K. and J.W. are employees and shareholders of Pfizer Inc. M.G. is an employee and shareholder of Pfizer AG. E.V.L. has received consulting fees from AbbVie, Alvotech, Amgen, Arena, Astellas, Avalo Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion Healthcare, Eli Lilly Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota Biosciences, Iterative Health, Janssen, KSL Diagnostics, Morphic Therapeutic, Ono Pharma, Protagonist, Scipher Medicine, Sun Pharma, Surrozen, Takeda, TR1X and UCB Pharma; has received research support from AbbVie, AstraZeneca, Bristol-Myers Squibb, Celgene/Receptos, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer Inc., Takeda, Theravance and UCB Pharma and is a shareholder of Exact Sciences., (© The Author(s), 2024.)

Background: Long-term vedolizumab (VDZ) outcomes in real-world cohorts have been largely limited to 1-year follow-up, with few bio-naïve patients or objective markers of inflammation assessed., Objectives: We aimed to assess factors affecting VDZ persistence including clinical, biochemical and faecal biomarker remission at 1, 3 and 5 years., Design: We performed a retrospective, observational, cohort study., Methods: All adult inflammatory bowel disease (IBD) patients who had received VDZ induction for ulcerative colitis (UC)/IBD-unclassified (IBDU) were included. Baseline phenotype and follow-up data were collected via a review of electronic medical records., Results: We included 290 patients [UC n  = 271 (93.4%), IBDU n  = 19 (6.6%)] with a median time on VDZ of 27.6 months (interquartile range: 14.4-43.2). At the end of follow-up, a total of 157/290 (54.1%) patients remained on VDZ. The median time to discontinuation was 14.1 months (7.0-23.3). Previous exposure to ⩾1 advanced therapy, steroid use at baseline and disease extension (E3 and E2 versus E1) were independent predictors for worse VDZ persistence. Clinical remission (partial Mayo < 2) was 75.7% (171/226), 72.4% (157/217) and 70.2% (127/181) at years 1, 3 and 5, respectively. Steroid use during maintenance VDZ therapy occurred in 31.7% (92/290), hospitalization in 15.5% (45/290) and surgery in 3.4% (10/291). The rate of serious adverse events was 1.2 per 100 patient-years of follow-up., Conclusion: VDZ effectiveness appears enduring with favourable long-term safety profile. VDZ persistence was influenced by previous exposure to biologics/small molecules, disease distribution and steroid use at baseline in our study., Competing Interests: BG has served as acted as consultant to Galapagos and Abbvie and as speaker for Abbvie, Jansen, Takeda, Pfizer and Galapagos. NP has served as a speaker for Janssen, Takeda and Pfizer. Professor CWL has acted as a consultant to Abbvie, Janssen, Takeda, Pfizer, Galapagos, Bristol Myers Squibb, B.I., Sandoz, Novartis, GSK, Gilead, ViforPharma, Dr Falk, Trellus Health and Iterative Scopes; he has received speaking fees and travel support from Pfizer, Janssen, Abbvie, Galapagos, MSD, Takeda, Shire, Ferring, Hospira and Dr Falk. G-RJ has served as a speaker for Takeda, Janssen, Abbvie, Fresnius and Ferring. LAAPD has served on advisory board for Sandoz and Abbvie, and as a speaker for Janssen. CN has acted as a consultant to Galapagos. None of the other authors reported any conflicts of interest., (© The Author(s), 2024.)

Background: Upadacitinib is a Janus kinase inhibitor, which has recently been approved for treating Crohn's disease. There are limited real-world studies on the outcomes of upadacitinib in Crohn's disease., Objective: Our aim was to evaluate the outcomes of upadacitinib in a real-world Crohn's disease cohort., Methods: We conducted a retrospective, multicentre, cohort study over a 2-year period across National Health Service (NHS) Lothian and Royal Devon University Healthcare NHS Foundation Trust. The primary outcome was treatment persistence at week 24. Secondary endpoints were corticosteroid-free clinical remission (Harvey-Bradshaw Index (HBI)<5) and biomarker remission (C-reactive protein (CRP)≤5 mg/L and faecal calprotectin (FCAL)<250 µg/g) at 12, 24 and 52 weeks. We recorded adverse events., Results: 135 patients commenced upadacitinib as of the 1 January 2024, of which 93 patients with active Crohn's disease were included with a minimum of 12 weeks follow-up. The median follow-up time was 25 weeks (IQR 15-42 weeks). 82% of the cohort had exposure to at least two classes of advanced therapies, and 52% had exposure to at least three classes of advanced therapies. Treatment persistence was 87.1% at week 12, 81.7% at week 24 and 62.8% at week 52. Rates of clinical remission were 64% (42/66), 48% (22/46) and 38% (8/21) at weeks 12, 24 and 52, respectively. Significant reductions in HBI, CRP and FCAL were observed during follow-up. 14% (13/91) had a hospitalisation due to Crohn's disease. Adverse events occurred in 40% (37/93) of the cohort, of which 12% (11/93) were serious., Conclusion: Upadacitinib was effective in a real-world, highly refractory, Crohn's disease cohort with good persistence., Competing Interests: Competing interests: BG has served as consultant to Galapagos and Abbvie and as speaker for Abbvie, Janssen, Takeda, Pfizer and Galapagos. NP has served as a speaker for Janssen, Takeda and Pfizer. JG has received grants from F. Hoffmann-La Roche AG, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos NV, nonfinancial support from Immundiagnostik, outside the submitted work. NAK has acted as a consultant to Amgen, Bristol Myers Squibb, Celltrion, Falk, Janssen, Pfizer, Pharmacosmos, Galapagos, Takeda and Tillotts, received speaking fees from Amgen, Celltrion, Falk, Janssen, Pharmacosmos, Galapagos, Takeda and Tillotts and travel support from AbbVie, Falk, Janssen and Pharmacosmos. His institution has received grants from AbbVie, Biogen, Celgene, Celltrion, Galapagos, MSD, Napp, Pfizer, Pharmacosmos, Roche and Takeda. TA reports grants and non-financial support from F. Hoffmann-La Roche AG, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, personal fees from Biogen, grants and personal fees from Celltrion Healthcare, personal fees and nonfinancial support from Immundiagnostik, personal fees from Takeda, personal fees from ARENA, personal fees from Gilead, personal fees from Adcock Ingram Healthcare, personal fees from Pfizer, personal fees from Genentech, nonfinancial support from Tillotts, outside the submitted work. CWL has acted as a consultant to Abbvie, Janssen, Takeda, Pfizer, Galapagos, Bristol Myers Squibb, B.I., Sandoz, Novartis, GSK, Gilead, ViforPharma, Dr Falk and Iterative Health; he has received speaking fees and travel support from Pfizer, Janssen, Abbvie, Galapagos, MSD, Takeda, Shire, Ferring, Hospira and Dr Falk., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments., Methods and Analysis: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures., Ethics and Dissemination: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk., Trial Registration Number: ISRCTN96296121., Competing Interests: Competing interests: TA reports personal grants from F. Hoffmann-La Roche, Biogen, AbbVie, Janssen, Celltrion, Galapagos, Immunodiagnostik and Takeda, outside the submitted work; personal fees for educational development/delivery from Pfizer, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Takeda and F. Hoffman-La Roche; support for attending meetings from Celltrion, Tillotts and Pfizer. CAA reports grants from the Wellcome Sanger Institute Quinquennial Review 2021–2026, Crohn’s and Colitis Foundation (USA), the Medical Research Council, Open Targets UK and the Helmsley Charitable Trust; consulting fees from BridgeBio, Genomics and Brigham & Women’s Hospital Boston; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GlaxoSmithKline; support for attending meetings and/or travel membership from the Wellcome Sanger Institute Quinquennial Review 2021–2026; (Chair) of the Board of Trustees for the Sanger Prize; other interests as Director of Anderson Genomics Consultancy. MB reports partial personal salary funding from the Medical Research Council. ALH reports personal consulting fees from AbbVie, BMS, Celltrion, Falk, Galapagos, Janssen, Pfizer, Takeda and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, Celltrion, Falk, Galapagos, Janssen, Pfizer, Takeda, Roche and AbbVie; support for attending meetings and/or travel from BMS, Celltrion, Falk, Galapagos, Janssen, Pfizer, Takeda, Roche and AbbVie. PI reports personal grants from Celltrion, Galapagos and Pfizer, outside the submitted work; personal consulting fees from AbbVie, Takeda, BMS, Janssen, Arena, Pfizer, Galapagos, Lilly, Boehringer-Ingelheim and Celgene; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Takeda, Janssen, Lilly, BMS, Pfizer and Galapagos; support for attending meetings and/or travel from AbbVie and Tillotts. LJ-D reports grants from the Wellcome Trust, the Royal Society, the Kennedy Trust for Rheumatology Research, the Helmsley Charitable Trust and the Medical Research Council; grants from Novartis Pharmaceutical, outside the submitted work; consulting fees from Nightingale Health and Genomics. CK reports partial salary funding from the Medical Research Council. NAK reports grants from AbbVie, Biogen, Celltrion, Galapagos and Immunodiagnostik; consulting fees from AbbVie, Bristol-Meyers Squibb and Dr Falk; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Dr Falk, Tillotts, Galapagos and Takeda; support for attending meetings and/or travel from Tillotts; participation (Chair) on the Board of the British Society of Gastroenterology IBD Clinical Research Group. CAL reports grants from and/or consultancy for Janssen, Takeda, AbbVie, AstraZeneca, Eli Lilly, Orion, Pfizer, Roche, Sanofi Aventis, UCB, Biogen, GSK, Bristol-Myers Squibb and Genentech; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Ferring, Takeda, Janssen, Nordic Pharma and Dr Falk; participation (Secretary) on the British Society of Gastroenterology IBD Section; participation on the Steering Committee of IBD UK. CWL reports grants from UKRI Future Leaders Fellowship; personal consulting fees from AbbVie, Pfizer, Janssen, Takeda, Galapagos, Fresnius Kabi, Novartis/Sandoz, BMS and Celltrion; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Pfizer, Janssen, Takeda, Galapagos, Fresnius Kabi, Novartis/Sandoz, BMS, Ferring, Dr Falk and Celltrion. JOL reports grants from AbbVie, and Gilead; personal consulting fees from Allergan, AbbVie, Bristol-Myers Squibb, Celgene, Cornerstones US, Galapagos, Gilead, GSK, Lilly, MSD UK, Shire UK, Shire International, Ferring UK, Ferring International, Celltrion, Takeda, Pfizer and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Bristol-Myers Squibb, Cornerstones US, Galapagos, Ferring UK, Ferring International, Celltrion, Takeda, Pfizer and Janssen; support to attend meetings and/or travel from AbbVie and Janssen. RHM reports that she is an independent membership on the Trial Steering Committee for the National Institute for Health and Care Research funded ALLEGRO trial. JRM reports personal consulting fees from EnteroBiotix and Cultech; patent held (without financial gain) on Clostridium difficile therapy (WO2019197836A1), participation (Chair) on the IDMC Board. NMcG reports partial (10%) salary funding from the Medical Research Council. REM reports personal salary funding from the Wellcome Sanger Institute. JO reports stock held in Novartis. MP reports grants from Pfizer and Gilead; personal consulting fees from Galapagos; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen. NP reports grants from Bristol-Myers Squibb, Takeda and Pfizer; consulting fees from AbbVie, Allergan, AstraZeneca, Bristol-Myers Squibb, Celgene, Celltrion, Galapagos, GSK, Takeda and Vifor; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Bristol-Myers Squibb, Ferring, Galapagos, Janssen, Roche, Pfizer, Takeda and Tillotts; support for attending meetings and/or travel from AbbVie, Allergan, Celltrion, Janssen and Takeda; participation on a data safety monitoring board or advisory board for AbbVie, Allergan, AstraZeneca, Bristol-Myers Squibb, Celgene, Celltrion, Galapagos, GSK, Takeda and Vifor. TR reports personal grants from AbbVie; personal consulting fees from AbbVie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, Mylan, MSD, Novartis, Pfizer, Roche, Sandoz, Takeda, UCB and XAP therapeutics; participation on the board of UCB, membership (Chair) of the ECCO Guidelines Committee, membership of the UEG Scientific Committee. JS reports grants from Crohn’s and Colitis UK, the Helmsley Charitable Trust, ECCO, the European Commission, CCFA and Action Medical Research; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche; participation on a Data Safety Monitoring Board or Advisory Board for the MODULATE trial and the TRIBUTE trial; leadership or fiduciary role as the Director of the Royal College of Physicians IBD Registry, and Governing Body Fellow at Green Templeton College. AS reports personal consulting fees from GSK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Falk, and AbbVie; payment of conference fees to attend the British Society of Gastroenterology Annual Conference 2022 from Celltrion; participation on a Data Safety Monitoring Board or Advisory Board for the IBD-RESPONSE study (unpaid), and AbbVie; participation on the British Society of Gastroenterology IBD Section Committee. CJS reports personal consultancy fees from Astarte Medical; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Nestle Nutrition Institute. JW reports grants from Intercept; consulting fees from Worg and UCB; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen; participation on a Data Safety Monitoring Board or Advisory Board for Roche. KW reports grants from the Helsmsley Charitable Trust, Crohn’s and Colitis UK, Almond Board of California, Danone, International Dried Fruit and Nut Council, Medical Research Council, National Institute for Health and care Research; royalty or license payments for Volatile organic compounds in the diagnosis and management of irritable bowel syndrome, and Wiley BDA Advances in Nutrition & Dietetics book series; personal consulting fees from Danone; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen; support for attending meetings and/or travel from Yakult; participation on a Data Safety Monitoring Board or Advisory Board for the MODULATE trial (unpaid)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant., Methods: In this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n = 63), infliximab (n = 45), thiopurine and infliximab combination therapy (n = 48), ustekinumab (n = 45), vedolizumab (n = 46) or tofacitinib (n = 24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664)., Findings: Both heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p < 0.0001). Multivariable models demonstrated that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in patients with IBD on infliximab (Geometric Mean Ratio (GMR) 0.19 [0.10, 0.36], p < 0.0001), infliximab and thiopurine combination (GMR 0.25 [0.13, 0.49], p < 0.0001) or tofacitinib (GMR 0.43 [0.20, 0.91], p = 0.028), but not in patients on thiopurine monotherapy, ustekinumab, or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against wild-type (p = 0.037) and BA.4/5 (p = 0.045)., Interpretation: A third dose of a COVID-19 mRNA vaccine based on the wild-type spike glycoprotein significantly boosts neutralising antibody titres in patients with IBD. However, responses are lower against the Omicron variant BA.4/5, particularly in patients taking anti-TNF and JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed patients with IBD may receive additional benefit from bivalent vaccine boosters which target Omicron variants., Funding: Pfizer., Competing Interests: ALH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Arena, Atlantic, Bristol Myers Squibb, Celltrion, Ferring, Dr Falk, Galapagos, Janssen, MSD, Napp, Pfizer, Pharmacosmos, Shire, and Takeda; participation on the Global Steering Committee for Genentech. AJK reports consulting fees from Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer and Takeda; support for attending meetings or travel from Janssen, Tillotts, and Norgine; and participation in a data safety monitoring board or advisory board for AbbVie. CWL received personal consulting fees from Galapagos, AbbVie, Takeda, Pfizer, Janssen and Iterative Scopes; institutional consulting fees from Trellus Health; and support for attending meetings from Galapagos, AbbVie, Takeda, Pfizer, Janssen, GSK, Gilead, Fresenius Kabi, Ferring, and Dr Falk. GRJ received speaker fees from Takeda, Ferring, Janssen, AbbVie and Fresenius Kabi. JLA received support for attending meetings from Takeda. JRG reports grants from Roche, Biogen, Celltrion Healthcare, Takeda and Galapagos. KVP received consulting fees from AbbVie, Janssen, Galapagos and Pfizer; reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Dr Falk, Janssen, Galapagos, Pfizer, Takeda, Tillotts and Ferring; support for attending meetings or travel from AbbVie, Dr Falk, Janssen, Galapagos, Pfizer, Takeda, Tillotts and Ferring; and participation on a data safety monitoring board or advisory board for AbbVie, Galapagos, Pfizer and Janssen. SB received research grant from Bowel Research UK and support for attending conferences from Ferring and Dr Falk, outside the submitted work. KMP is a member of the data safety monitoring board for NCT05249829 and NCT05575492; has received a fee for speaking from Seqirus and Sanofi Pasteur, and has research funding from the Chan Zuckerberg Initiative, the MRC/UKRI, the Vaccine Task Force, and NIHR Imperial BRC outside the submitted work. KK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and Ferring; support for attending meetings or travel from Janssen and Takeda; and participation on a data safety monitoring board or advisory board for Janssen and PredictImmune. MP received research grant from Pfizer and speaker fees from Janssen. NAK reports grants from AbbVie, Biogen, Celgene, Celltrion, Galapagos, MSD, Napp, Pfizer, Pharmacosmos, Roche, and Takeda; consulting fees from Amgen, Bristol Myers Squibb, Dr Falk, Janssen, Mylan, Pharmacosmos, Galapagos, Takeda, and Tillotts; personal fees from Allergan, Celltrion, Dr Falk, Ferring, Janssen, Pharmacosmos, Takeda, Tillotts, and Galapagos; and support for attending meetings from AbbVie, Dr Falk, Tillotts and Janssen, outside the submitted work. PMI reports grants from Celltrion, Takeda, MSD, Pfizer, and Galapagos; personal fees from Gilead, Pfizer, Galapagos, Takeda, AbbVie, Celltrion, Janssen, Bristol Myers Squibb, Lilly, and Arena; speaker fees from Pfizer, Galapagos, Takeda, AbbVie, Celltrion, Janssen, Bristol Myers Squibb, Lilly, and Arena, outside the submitted work. SS reports grants from Tillotts, Takeda, Janssen, Pfizer and AbbVie; received personal fees from AbbVie, Tillotts, Janssen, Takeda, Dr Falk, Lilly and Bristol Myers Squibb; received support for attending meetings from Janssen, AbbVie and Celltrion; and serves as a member of the data safety monitoring board for AbbVie, Janssen, Takeda, Celltrion, Lilly and Bristol Myers Squibb. TA reports grant funding from Pfizer to deliver this study; grants from Celltrion, Roche, Takeda, Biogen, and Galapagos; and honoraria for lectures from Takeda and Roche, outside the submitted work. NP is the principal investigator on the research grant from Pfizer that funded the VIP study; has received research grants from Bristol Myers Squibb, Roche, Biogen, Celltrion Healthcare, Takeda, Galapagos, CCUK, AstraZeneca, Helmsley Charitable Trust, outside the submitted work; reports personal fees from Takeda, Janssen, Pfizer, Galapagos, Bristol Myers Squibb, AbbVie, Roche, Lilly, Allergan, Celgene and AstraZeneca outside the submitted work; and has served as a speaker or advisory board member for AbbVie, Allergan, Bristol Myers Squibb, Celgene, Dr Falk, AstraZeneca, Galapagos and Vifor; and serves as a member of the data safety monitoring board for Bristol Myers Squibb and AstraZeneca. All other authors declare no competing interests., (© 2023 The Author(s).)

Background and Aims: The progressive nature of Crohn's disease is highly variable and hard to predict. In addition, symptoms correlate poorly with mucosal inflammation. There is therefore an urgent need to better characterize the heterogeneity of disease trajectories in Crohn's disease by utilizing objective markers of inflammation. We aimed to better understand this heterogeneity by clustering Crohn's disease patients with similar longitudinal fecal calprotectin profiles., Methods: We performed a retrospective cohort study at the Edinburgh IBD Unit, a tertiary referral center, and used latent class mixed models to cluster Crohn's disease subjects using fecal calprotectin observed within 5 years of diagnosis. Information criteria, alluvial plots, and cluster trajectories were used to decide the optimal number of clusters. Chi-square test, Fisher's exact test, and analysis of variance were used to test for associations with variables commonly assessed at diagnosis., Results: Our study cohort comprised 356 patients with newly diagnosed Crohn's disease and 2856 fecal calprotectin measurements taken within 5 years of diagnosis (median 7 per subject). Four distinct clusters were identified by characteristic calprotectin profiles: a cluster with consistently high fecal calprotectin and 3 clusters characterized by different downward longitudinal trends. Cluster membership was significantly associated with smoking (P = .015), upper gastrointestinal involvement (P < .001), and early biologic therapy (P < .001)., Conclusions: Our analysis demonstrates a novel approach to characterizing the heterogeneity of Crohn's disease by using fecal calprotectin. The group profiles do not simply reflect different treatment regimens and do not mirror classical disease progression endpoints., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Switching from originator infliximab (IFX) to biosimilar IFX is effective and safe. However, data on multiple switching are scarce. The Edinburgh inflammatory bowel disease (IBD) unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021)., Objective: The primary endpoint of this study was to assess CT-P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety., Methods: We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT-P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, C-reactive protein (CRP), faecal calprotectin (FC), IFX trough/antibody levels, and drug survival., Results: 297 patients (CD n = 196 [66%], ulcerative colitis/inflammatory bowel disease unclassified n = 101, [34%]) were switched (followed-up: 7.5 months [6.8-8.1]). This was the third, second and first IFX switch for 67/297 (22.5%), 138/297 (46.5%) and 92/297 (31%) of the cohort respectively. 90.6% of patients remained on IFX during follow-up. The number of switches was not independently associated with IFX persistence after adjusting for confounders. Clinical (p = 0.77), biochemical (CRP ≤5 mg/ml; p = 0.75) and faecal biomarker (FC<250 µg/g; p = 0.63) remission were comparable at baseline, week 12 and week 24., Conclusion: Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients., Methods: Faecal and serum samples were prospectively collected from infliximab-treated patients with IBD in the CLARITY-IBD study undergoing vaccination against SARS-CoV-2. Antibody responses were measured following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Patients were classified as having responses above or below the geometric mean of the wider CLARITY-IBD cohort. 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) were performed on faecal samples. Univariate, multivariable and correlation analyses were performed to determine gut microbial and metabolomic predictors of response to vaccination., Findings: Forty-three infliximab-treated patients with IBD were recruited (30 Crohn's disease, 12 ulcerative colitis, 1 IBD-unclassified; 26 with concomitant thiopurine therapy). Eight patients had evidence of prior SARS-CoV-2 infection. Seventeen patients (39.5%) had a serological response below the geometric mean. Gut microbiota diversity was lower in below average responders (p = 0.037). Bilophila abundance was associated with better serological response, while Streptococcus was associated with poorer response. The faecal metabolome was distinct between above and below average responders (OPLS-DA R 2 X 0.25, R 2 Y 0.26, Q 2 0.15; CV-ANOVA p = 0.038). Trimethylamine, isobutyrate and omega-muricholic acid were associated with better response, while succinate, phenylalanine, taurolithocholate and taurodeoxycholate were associated with poorer response., Interpretation: Our data suggest that there is an association between the gut microbiota and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine may be important in mitigating anti-TNF-induced attenuation of the immune response., Funding: JLA is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-502), funded by Imperial College London and The Joyce and Norman Freed Charitable Trust. BHM is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-002). The Division of Digestive Diseases at Imperial College London receives financial and infrastructure support from the NIHR Imperial Biomedical Research Centre (BRC) based at Imperial College Healthcare NHS Trust and Imperial College London. Metabolomics studies were performed at the MRC-NIHR National Phenome Centre at Imperial College London; this work was supported by the Medical Research Council (MRC), the National Institute of Health Research (NIHR) (grant number MC&#95;PC&#95;12025) and infrastructure support was provided by the NIHR Imperial Biomedical Research Centre (BRC). The NIHR Exeter Clinical Research Facility is a partnership between the University of Exeter Medical School College of Medicine and Health, and Royal Devon and Exeter NHS Foundation Trust. This project is supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care., Competing Interests: Declaration of interests Dr Saifuddin has received travel expense support from Janssen. Dr Lin reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. Dr. Kennedy reports grants from AbbVie, Biogen, Celgene, Celtrion, Galapagos, MSD, Napp, Pfizer, Pharmacosmos, Roche and Takeda, consulting fees from Amgen, Bristol-Myers Squibb, Falk, Janssen, Mylan, Pharmacosmos, Galapagos, Takeda and Tillotts, personal fees from Allergan, Celltrion, Falk, Ferring, Janssen, Pharmacosmos, Takeda, Tilllotts, Galapagos, and support for attending meetings from AbbVie, Falk and Janssen outside the submitted work. Prof. Sebastian reports grants from Takeda, Abbvie, Tillots Pharma, Janssen, Pfizer, Biogen and personal fees from Takeda, Abbvie, Janssen, Pharmacocosmos, Biogen, Pfizer, Tillots Pharma and Falk Pharma, outside the submitted work. Dr Hart reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, AZ, Atlantic, Bristol-Myers Squibb, Celltrion, Falk, Galapogos, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda and Global Steering Committee for Genentech, support for attending meetings from Abbvie, Takeda and Janssen, and Participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AZ, Atlantic, Bristol-Myers Squibb, Galapogos, Janssen, Pfizer and Takeda. Prof. Lees reports a Future Leaders Fellow award from UKRI, personal consulting fees from Galapagos, Abbvie, Takeda, Pfizer, Janssen, Iterative Scopes and institutional consulting fees from Trellus Health, personal fees from Galapagos, Abbvie, Takeda, Pfizer, Janssen, GSK, Gilead, Fresnius Kabi, Ferring and Dr Falk, and support for attending meetings from Galapagos, Abbvie, Takeda, Pfizer, Janssen, GSK, Gilead, Fresnius Kabi, Ferring and Dr Falk. Dr. Goodhand reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study. Prof. Ahmad reports grant funding from Pfizer to his institution to deliver this study, grants from Celltrion, Roche, Takeda, Biogen and Galapagos and honoraria for lectures from Takeda and Roche, outside the submitted work. Dr Powell has received research grant(s) from Bristol Myers Squibb outside the submitted work. Dr. Powell reports personal fees from Takeda, Janssen, Pfizer, Bristol-Myers Squibb, Abbvie, Roche, Lilly, Allergan, and Celgene, outside the submitted work; Dr. Powell has served as a speaker/advisory board member for Abbvie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda and Vifor Pharma. The following authors have nothing to declare: Dr Alexander, Dr Ibraheim, Claire Bewshea, Rachel Nice, Dr Liu, Dr Mullish, Dr Danckert, Melissa Torkizadeh, Jesús Miguéns Blanco, Lauren A Roberts, Hemanth Prabhudev, Caroline Sands, Verena Horneffer-van der Sluis, Matthew Lewis, Professor Teare, Martin Olbei, Tamas Korcsmaros and Professor Marchesi., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD)., Aim: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab., Results: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure., Conclusion: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Tools for stratification of relapse risk of Crohn's disease (CD) after anti-tumor necrosis factor (TNF) therapy cessation are needed. We aimed to validate a previously developed prediction model from the diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressants (STORI) trial, and to develop an updated model., Methods: Cohort studies were selected that reported on anti-TNF cessation in 30 or more CD patients in remission. Individual participant data were requested for luminal CD patients and anti-TNF treatment duration of 6 months or longer. The discriminative ability (concordance-statistic [C-statistic]) and calibration (agreement between observed and predicted risks) were explored for the STORI model. Next, an updated prognostic model was constructed, with performance assessment by cross-validation., Results: This individual participant data meta-analysis included 1317 patients from 14 studies in 11 countries. Relapses after anti-TNF cessation occurred in 632 of 1317 patients after a median of 13 months. The pooled 1-year relapse rate was 38%. The STORI prediction model showed poor discriminative ability (C-statistic, 0.51). The updated model reached a moderate discriminative ability (C-statistic, 0.59), and included clinical symptoms at cessation (hazard ratio [HR], 2.2; 95% CI, 1.2-4), younger age at diagnosis (HR, 1.5 for A1 (age at diagnosis ≤16 years) vs A2 (age at diagnosis 17 - 40 years); 95% CI, 1.11-1.89), no concomitant immunosuppressants (HR, 1.4; 95% CI, 1.18-172), smoking (HR, 1.4; 95% CI, 1.15-1.67), second line anti-TNF (HR, 1.3; 95% CI, 1.01-1.69), upper gastrointestinal tract involvement (HR, 1.3 for L4 vs non-L4; 95% CI, 0.96-1.79), adalimumab (HR, 1.22 vs infliximab; 95% CI, 0.99-1.50), age at cessation (HR, 1.2 per 10 years younger; 95% CI, 1-1.33), C-reactive protein (HR, 1.04 per doubling; 95% CI, 1.00-1.08), and longer disease duration (HR, 1.07 per 5 years; 95% CI, 0.98-1.17). In subanalysis, the discriminative ability of the model improved by adding fecal calprotectin (C-statistic, 0.63)., Conclusions: This updated prediction model showed a reasonable discriminative ability, exceeding the performance of a previously published model. It might be useful to guide clinical decisions on anti-TNF therapy cessation in CD patients after further validation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: It is unclear how the compounding prevalence of inflammatory bowel disease (IBD) has translated into the causes and rates of hospitalisation, particularly in an era of increased biologic prescribing. We aimed to analyse these trends in a population-based IBD cohort over the last 10 years., Design: The Lothian IBD registry is a complete, validated, prevalent database of IBD patients in NHS Lothian, Scotland. ICD-10 coding of hospital discharge letters from all IBD patient admissions to secondary care between 1 January 2010 and 31 December 2019 was interrogated for admission cause, with linkage to local/national data sets on death and prescribed drugs., Results: Fifty-seven per cent (4673/8211) of all IBD patients were admitted to secondary care for >24 h between 1 January 2010 and 31 December 2019. In patients <40 years, IBD was the commonest reason for admission (38% of admissions), whereas infection was the most common cause in those >60 years (19% of admissions). Three per cent (243/8211) of IBD patients accounted for 50% of the total IBD bed-days over the study period. Age-standardised IBD admission rates fell from 39.4 to 25.5 admissions per 100,000 population between 2010 and 2019, an average annual percentage reduction of 3% (95% CI -4.5% to -2.1%, p < 0.0001). Non-IBD admission rates were unchanged overall (145-137 per 100,000 population) and specifically for serious (hospitalisation) and severe (ITU admission or death) infection over the same period., Conclusion: Despite compounding prevalence and increased biologic use, IBD admission rates are falling. The cause of admission varies with age, with infection the predominant cause in older patients., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Inflammatory bowel disease is a progressive and debilitating condition. Early and effective treatment using a treat-to-target approach is key to improving patient outcomes. Therefore, proactive monitoring is essential to ensure that treatment strategies are working and targets are being met. In this review we discuss the current monitoring tools available to us and how they can be used. We also discuss the importance of monitoring during key phases of the disease and propose an optimum treat-to-target monitoring strategy for Crohn's disease and ulcerative colitis. Regarding the advent of new technology, we discuss how this may improve our monitoring capabilities and how we envisage future monitoring strategies of inflammatory bowel diseases., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients., (© 2022. The Author(s).)

Background and Aims: Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients., Methods: We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8-14 weeks) and maintenance (16-26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models., Results: Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41-60%) and 37% (26-45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31-50%) and 29% (23-36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%)., Conclusion: Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: L.A.L., none declared. N.C.-C., none declared. N.P. has received consultancy fees from Takeda, and speaker fees and/or travel support from Abbvie, Takeda and Norgine. S.S., none declared. L.A.A.P.D., none declared. G.-R.J., none declared. C.W.L. has received research support from Abbvie and Gilead; consultancy fees from Abbvie, Pfizer, Janssen, Gilead, Celltrion, Pharmacosmos, Takeda, Vifor, Iterative Scopes and Trellus Health; and speaker fees and/or travel support from Janssen, Abbvie, Pfizer, Dr Falk, Ferring, Hospira and Takeda., (© The Author(s), 2021.)

Introduction: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Outcome prediction based on early treatment response, along with clinical and laboratory variables, would be very useful for clinical practice. The aim of this study was to determine early variables predictive of responder status in patients with UC treated with tofacitinib., Methods: Data were collected from patients treated with tofacitinib 10 mg twice daily in the OCTAVE Induction 1 and 2 studies (NCT01465763 and NCT01458951). Logistic regression and random forest analyses were performed to determine the power of clinical and/or laboratory variables to predict 2- and 3-point partial Mayo score responder status of patients at Weeks 4 or 8 after baseline., Results: From a complete list of variables measured in OCTAVE Induction 1 and 2, analyses identified partial Mayo score, partial Mayo subscore (stool frequency, rectal bleeding, and Physician Global Assessment), cholesterol level, and C-reactive protein level as sufficient variables to predict responder status. Using these variables at baseline and Week 2 predicted responder status at Week 4 with 84-87% accuracy and Week 8 with 74-79% accuracy. Variables at baseline, Weeks 2 and 4 could predict responder status at Week 8 with 85-87% accuracy., Conclusion: Using a limited set of time-dependent variables, statistical and machine learning models enabled early and clinically meaningful predictions of tofacitinib treatment outcomes in patients with moderately to severely active UC., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CWL has served as a speaker for AbbVie, Dr Falk, Ferring, Hospira, Janssen, MSD, Pfizer Inc, Shire, Takeda, and Warner-Chilcott; has served as a consultant for AbbVie, Dr Falk, Gilead, GSK, Hospira, Iterative Scopes, Janssen, MSD, Oshi Health, Pfizer Inc, Pharmacosmos, Takeda, Topivert, Trellus Health, and Vifor Pharma; and has received research funding from AbbVie and Gilead. MC has served as a speaker for AbbVie, Janssen, Medtronic, Pfizer Inc, and Takeda; and has served as a consultant for AbbVie, Arena, BMS, Medtronic, Pfizer Inc, Prometheus, and Takeda. MD has received personal fees from AbbVie, Chiesi, Ferring, Janssen, MSD, Pfizer Inc, and Quintiles; has received grants and personal fees from Takeda; has received non-financial support from SOFAR; and has been involved in clinical trials for Eli Lilly, Galapagos, Gilead, Janssen, MSD, Roche, and Takeda. GB owns stocks and shares in Fair Dynamics Consulting, which is a paid consultant contracted by Health Services Consulting Corporation in connection with this study. JJD, RG, PBB, and IM are employees of, and owns stocks and shares in, Pfizer Inc. RAE is a Principal in Health Services Consulting Corporation, and was a paid consultant to Pfizer Inc in connection with this study., (© The Author(s), 2021.)

Background & Aims: The level of fecal calprotectin (FC) correlates with endoscopic evidence of inflammation in Crohn's disease (CD). A treat-to-target algorithm for patients with CD, that incorporates FC, outperforms a treatment strategy based on symptoms alone in the induction of mucosal healing at 12 months. We investigated whether normalization of FC within 12 months of diagnosis of CD is associated with a reduction in disease progression., Methods: We performed a retrospective cohort study at a tertiary IBD centre in the United Kingdom. We identified all incident cases of CD diagnosed from 2005 through 2017. Patients with a FC measurement ≥250 μg/g at diagnosis who also had at least 1 follow-up FC measurement within the first 12 months of diagnosis and >12 months of follow up were included. The last FC measurement within 12 months of diagnosis was used to determine normalization (cut-off <250 μg/g). The primary endpoint was time to first disease progression (composite of progression in Montreal disease behavior B1 to B2/3, B2 to B3, or new perianal disease; CD-related surgery; or CD-related hospitalization). Cox proportional hazards regression analysis was used to determine independent factors associated with time to first disease progression., Results: A total of 375 patients out of 1389 incident cases were included, with a median follow up of 5.3 years (interquartile range, 3.1-7.4 years). Normalization of FC within 12 months of diagnosis was confirmed in 43.5% of patients. Patients with normalized levels of FC had a significantly lower risk of composite disease progression (hazard ratio [HR], 0.36; 95% CI, 0.24-0.53; P < .001). They also had a lower risk of reaching any of the separate progression endpoints (progression in Montreal behavior or new perianal disease HR, 0.22; 95% CI, 0.11-0.45; P < .001; hospitalization HR, 0.33; 95% CI, 0.21-0.53; P <.001; surgery HR, 0.39; 95% CI, 0.19-0.78; P = .008) CONCLUSIONS: Normalization of FC within 12 months of diagnosis is associated with a reduced risk of progression of CD., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Since publication of the top 10 research priorities in inflammatory bowel disease (IBD) based on the James Lind Alliance Priority Setting Partnership, the question remains whether this has influenced the IBD-research landscape. This study aimed to create an overview of the current distribution of research interests of trials in the UK., Methods: The ClinicalTrials.gov database and European Union Clinical Trials Register were screened for clinical trials set up from 9 August 2016 to 16 November 2019 in the UK involving adult patients with IBD., Results: Of 20 non-industry-sponsored studies, a quarter investigated treatment strategies considering efficacy, safety and cost-effectiveness (priority 1). Four evaluated the role of diet (priorities 3 and 7). Development/assessment of biomarkers for patient stratification (priority 2) and fatigue (priority 8) were subject of three studies. IBD-related pain and control of diarrhoea/incontinence were each subject of 2 studies (priorities 4 and 6). The effect of gut microbiota (priority 10) and optimal strategy for perianal Crohn's disease (priority 5) was the focus of 2 studies each. One study evaluated surgery for terminal ileal Crohn's disease (priority 9). Of 63 industry-sponsored studies, 59 focused on priority 1., Conclusions: This study presents an impression of the breadth of the IBD-research landscape in the UK, in light of the top 10 research priorities published in 2016. Optimal treatment strategy has been the most studied research priority by academic and industry-sponsored trials. Fewer studies focused on patient-reported outcomes. It remains debatable to what extent the current research landscape adequately represents all stakeholders' viewpoints on needs for expanded knowledge in IBD, particularly the patients' perspective., Competing Interests: Competing interests: JG, J-FL, LL: no competing interests. JS: was actively involved in the trial 'STOP-Colitis pilot trial protocol: a prospective, open-label, randomised pilot study to assess two possible routes of faecal microbiota transplant delivery in patients with ulcerative colitis. 'CWL: is actively involved in the following trial: 'The PRognostic Effect of Environmental Factors in Crohn’s and Colitis (PREdiCCt)'AL Hart: is actively involved in the following trials:· 'STOP-Colitis pilot trial protocol: a prospective, open-label, randomised pilot study to assess two possible routes of faecal microbiota transplant delivery in patients with ulcerative colitis'· 'A supported online self-management tool for symptoms of fatigue, pain and urgency/incontinence in people with inflammatory bowel disease: the IBD-BOOST trial'., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Immune modulating therapies are associated with an increased risk of infections and malignancies. This is of particular concern in elderly inflammatory bowel disease patients. This study aims to compare the safety and efficacy of vedolizumab between young and elderly inflammatory bowel disease patients., Methods: A binational, multicentre, retrospective, cohort study was performed from 2015 to 2019. Patients who underwent treatment with vedolizumab and were followed for at least 14 weeks were studied. They were divided according to age into groups: 40 years or less or 60 years or older. Clinical and endoscopic responses at weeks 14 and 52 and infection development were compared between young and elderly inflammatory bowel disease patient groups., Results: There were 144 patients (82 Crohn's disease and 62 ulcerative colitis) in the elderly cohort and 140 patients (83 Crohn's disease and 57 ulcerative colitis) in the young cohort. The average age was 70.2 ± 7.3 years and 29.6 ± 5.7 years, respectively. Clinical and endoscopic responses were comparable between the groups (week 52 remission of Crohn's disease: 40% vs. 35%, P  = 0.7; week 52 remission of ulcerative colitis: 48% vs. 51%, P  = 0.84). Previous anti-tumour necrosis factor biological therapy was independently associated with poor clinical remission rates at week 52 (Crohn's disease: odds ratio 0.23, 95% confidence interval 0.06-0.79; P  = 0.02 and ulcerative colitis: odds ratio 0.10 95% confidence interval 0.01-0.74; P  = 0.024). There were significantly more infections in the elderly cohort (2% vs. 12%, P  = 0.002), none of which were fatal., Conclusions: Vedolizumab is equally effective in elderly and young inflammatory bowel disease patients. The findings of this study demonstrate an increased risk of infections among the elderly treated with vedolizumab, which may be related to their age and underlying diseases.

Objective: To determine the challenges in diagnosis, monitoring, support provision in the management of inflammatory bowel disease (IBD) patients and explore the adaptations of IBD services., Methods: Internet-based survey by invitation of IBD services across the UK from 8 to 14 April 2020., Results: Respondents from 125 IBD services completed the survey. The number of whole-time equivalent gastroenterologists and IBD nurses providing elective outpatient care decreased significantly between baseline (median 4, IQR 4-7.5 and median 3, IQR 2-4) to the point of survey (median 2, IQR 1-4.8 and median 2, IQR 1-3) in the 6-week period following the onset of the COVID-19 pandemic (p<0.001 for both comparisons). Almost all (94%; 112/119) services reported an increase in IBD helpline activity. Face-to-face clinics were substituted for telephone consultation by 86% and video consultation by 11% of services. A variation in the provision of laboratory faecal calprotectin testing was noted with 27% of services reporting no access to faecal calprotectin, and a further 32% reduced access. There was also significant curtailment of IBD-specific endoscopy and elective surgery., Conclusions: IBD services in the UK have implemented several adaptive strategies in order to continue to provide safe and high-quality care for patients. National Health Service organisations will need to consider the impact of these changes in current service delivery models and staffing levels when planning exit strategies for post-pandemic IBD care. Careful planning to manage the increased workload and to maintain IBD services is essential to ensure patient safety., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies., Methods: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease., Results: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10 -13 ). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10 -4 ). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58)., Conclusions: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Mucosal healing is associated with improved outcomes in patients with Crohn's disease (CD), but assessment typically requires ileocolonoscopy. Calprotectin can be measured in fecal samples to determine luminal disease activity in place of endoscopy-this measurement is an important component of the treat-to-target strategy. We investigated whether levels of fecal calprotectin are associated with subsequent CD progression., Methods: We performed a retrospective study of 918 patients with CD (4218 patient-years of follow-up evaluation; median, 50.6 mo; interquartile range [IQR], 32.8-76.0 mo) managed at a tertiary medical center in Edinburgh, United Kingdom, from 2003 through 2015. Patients were included if they had 1 or more fecal calprotectin measurements made 3 months or more after their diagnosis. We collected clinical data and fecal calprotectin measurements and analyzed these data to identify factors associated with a composite outcome of progression in Montreal behavior, hospitalization, and resection., Results: An increased level of fecal calprotectin at the index visit was associated with subsequent progression of CD, independent of symptoms or disease location. The median level of fecal calprotectin at the index visit was 432 μg/g (IQR, 1365-998 μg/g) in patients who reached the composite end point vs 180 μg/g (IQR, 50-665 μg/g) in patients who did not. In multivariable analysis, a cut-off value of 115 μg/g calprotectin identified patients who met the end point with a hazard ratio of 2.4 (95% CI, 1.8-3.1; P < .0001)., Conclusions: In a retrospective analysis of patients with CD, we found that measurements of fecal calprotectin made during routine monitoring can identify patients at risk for disease progression, independent of symptoms or disease location. It is therefore important to screen asymptomatic patients for mucosal inflammation and pursue complete resolution of inflammation., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: To establish the relationship between trough vedolizumab levels and outcomes during maintenance therapy., Design: Cross-sectional service evaluation was performed on patients with inflammatory bowel disease (IBD) receiving maintenance vedolizumab therapy (minimum of 12 weeks following induction). Prior to infusion, data on clinical activity (Harvey-Bradshaw Index or partial Mayo score), trough C-reactive protein (CRP)/vedolizumab levels and faecal calprotectin were collected. Endoscopic data (±8 weeks from vedolizumab level testing) were obtained by review of medical records. Vedolizumab levels were processed using the Immundiagnostik monitor ELISA., Setting: The Edinburgh IBD Unit, Western General Hospital (tertiary IBD referral centre)., Patients: Seventy-three patients (30 ulcerative colitis and 43 Crohn's disease) were identified who fulfilled inclusion criteria and had vedolizumab levels matched with clinical activity scores, CRP and faecal calprotectin. Of these, 40 patients also had matched endoscopic data., Main Outcome Measures: The association of trough vedolizumab levels with clinical remission (Harvey-Bradshaw Index <5 or partial Mayo <2), biologic remission (faecal calprotectin <250 µg/g+CRP <5 mg/L) and endoscopic remission (Mayo score 0/no inflammation and ulceration on colonoscopy)., Results: The median trough vedolizumab levels were similar between patients in and not in clinical remission (10.6 vs 9.9 µg/mL, p=0.54); biologic remission (10.6 vs 9.8 µg/mL, p=0.35) and endoscopic remission (8.1 vs 10.2 µg/mL, p=0.21). Quartile analysis revealed no significant increase in the proportion of patients in clinical remission, biologic remission or endoscopic remission with increasing trough vedolizumab levels (p<0.05)., Conclusions: In this cohort, trough vedolizumab levels were not associated with clinical, biological or endoscopic outcomes during maintenance therapy., Competing Interests: Competing interests: PWJ, CSC, ML, RJP and GRJ have no personal interests to declare. NP has received consultancy fees from Takeda, speaker fees and/or travel support from Abbvie, Takeda, Norgine. LMM has received travel support from Janssen. IDA has received consultancy fees from Vifor and travel support from Shire. CWL has received research support from Abbvie and Shire, consultancy fees from Abbvie, Pfizer, Dr Falk, Hospira, MSD, Pharmacosmos, Takeda and Vifor, speaker fees and/or travel support from Abbvie, Pfizer, Dr Falk, Ferring, Hospira, MSD, Shire, Takeda and Warner-Chilcott., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

Background: Thiopurines (azathioprine and mercaptopurine) remain integral to most medical strategies for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Indefinite use of these drugs is tempered by long-term risks. While clinical relapse is noted frequently following drug withdrawal, there are few published data on predictive factors., Aim: To investigate the success of planned thiopurine withdrawal in patients in sustained clinical remission to identify rates and predictors of relapse., Methods: This was a multicentre retrospective cohort study from 11 centres across the UK. Patients included had a definitive diagnosis of IBD, continuous thiopurine use ≥3 years and withdrawal when in sustained clinical remission. All patients had a minimum of 12 months follow-up post drug withdrawal. Primary and secondary end points were relapse at 12 and 24 months respectively., Results: 237 patients were included in the study (129 CD; 108 UC). Median duration of thiopurine use prior to withdrawal was 6.0 years (interquartile range 4.4-8.4). At follow-up, moderate/severe relapse was observed in 23% CD and 12% UC patients at 12 months, 39% CD and 26% UC at 24 months. Relapse rate at 12 months was significantly higher in CD than UC (P = 0.035). Elevated CRP at withdrawal was associated with higher relapse rates at 12 months for CD (P = 0.005), while an elevated white cell count was predictive at 12 months for UC (P = 0.007)., Conclusion: Thiopurine withdrawal in the context of sustained remission is associated with a 1-year moderate-to-severe relapse rate of 23% in Crohn's disease and 12% in ulcerative colitis., (© 2014 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Post-operative recurrence of Crohn's disease is an important management challenge, with 2-year recurrence rates defined by clinical, endoscopic and radiological parameters of up to 77%, 64% and 49%. Clinical and severe endoscopic recurrence vary widely in controlled trials from 13% to 36% and 22% to 56% with thiopurine treatment or 0% and 9% with infliximab treatment respectively at 1 year., Aims: To provide a review of the evidence for thiopurine or anti-TNF use in post-operative Crohn's disease, and to assess the ability to identify those patients at highest risk of recurrent disease., Methods: A literature search was undertaken using Medline, Embase and Cochrane databases to identify studies using search terms 'thiopurine', 'azathioprine', 'mercaptopurine', 'Infliximab', 'adalimumab', 'Anti-TNF', 'Crohn's disease', 'post-operative' and 'recurrence'., Results: Trials to examine this important area have proved difficult to execute, with recruitment and retention of patients posing major challenges to randomised clinical trials. There have been four RCTs of 433 patients of thiopurine therapy (with three meta-analyses of these data), and one of anti-TNF therapy involving 24 patients. Overall the efficacy data for thiopurine use in this setting are inconclusive, and other than smoking, there are no consistent predictors of post-operative relapse., Conclusions: At present, evidence for routine use of thiopurine treatment in post-operative Crohn's disease is heterogeneous and unconvincing. Stratification by risk of relapse emerges as a key challenge in post-operative management that needs to be addressed, using clinical parameters and emerging biomarkers. The evidence for prophylactic anti-TNF use is limited though promising, with its routine use guided by early assessment of relapse., (© 2014 John Wiley & Sons Ltd.)

Introduction: Determining bacterial community structure in fecal samples through DNA sequencing is an important facet of intestinal health research. The impact of different commercially available DNA extraction kits upon bacterial community structures has received relatively little attention. The aim of this study was to analyze bacterial communities in volunteer and inflammatory bowel disease (IBD) patient fecal samples extracted using widely used DNA extraction kits in established gastrointestinal research laboratories., Methods: Fecal samples from two healthy volunteers (H3 and H4) and two relapsing IBD patients (I1 and I2) were investigated. DNA extraction was undertaken using MoBio Powersoil and MP Biomedicals FastDNA SPIN Kit for Soil DNA extraction kits. PCR amplification for pyrosequencing of bacterial 16S rRNA genes was performed in both laboratories on all samples. Hierarchical clustering of sequencing data was done using the Yue and Clayton similarity coefficient., Results: DNA extracted using the FastDNA kit and the MoBio kit gave median DNA concentrations of 475 (interquartile range 228-561) and 22 (IQR 9-36) ng/µL respectively (p<0.0001). Hierarchical clustering of sequence data by Yue and Clayton coefficient revealed four clusters. Samples from individuals H3 and I2 clustered by patient; however, samples from patient I1 extracted with the MoBio kit clustered with samples from patient H4 rather than the other I1 samples. Linear modelling on relative abundance of common bacterial families revealed significant differences between kits; samples extracted with MoBio Powersoil showed significantly increased Bacteroidaceae, Ruminococcaceae and Porphyromonadaceae, and lower Enterobacteriaceae, Lachnospiraceae, Clostridiaceae, and Erysipelotrichaceae (p<0.05)., Conclusion: This study demonstrates significant differences in DNA yield and bacterial DNA composition when comparing DNA extracted from the same fecal sample with different extraction kits. This highlights the importance of ensuring that samples in a study are prepared with the same method, and the need for caution when cross-comparing studies that use different methods.