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Background: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection., Methods: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual., Findings: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p<0·0001), BA.1 (107·3 [86·40-133·2] vs 648·9 [523·5-804·5]; p<0·0001), and BA.4/5 (40·63 [31·99-51·60] vs 223·0 [183·1-271·4]; p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (119 [13·7%; 95% CI 11·5-16·2] of 871) than in those treated with vedolizumab (29 [7·0% [4·8-10·0] of 417; p=0·00040). Cox proportional hazards models of time to breakthrough infection after the third dose of vaccine showed infliximab treatment to be associated with a higher hazard risk than treatment with vedolizumab (hazard ratio [HR] 1·71 [95% CI 1·08-2·71]; p=0·022). Among participants who had a breakthrough infection, we found that higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and, hence, a longer time to breakthrough infection (HR 0·87 [0·79-0·95]; p=0·0028)., Interpretation: Our findings underline the importance of continued SARS-CoV-2 vaccination programmes, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy might be reduced, such as those on anti-TNF therapies., Funding: Royal Devon University Healthcare NHS Foundation Trust; Hull University Teaching Hospital NHS Trust; NIHR Imperial Biomedical Research Centre; Crohn's and Colitis UK; Guts UK; National Core Studies Immunity Programme, UK Research and Innovation; and unrestricted educational grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos., Competing Interests: Declaration of interests SL reports non-financial support from Pfizer and Ferring. SS reports grants from Takeda, Tillots Pharma, Janssen, and Amgen; speaker honoraria from Janssen, Tillotts Pharma, Amgen, AbbVie, and Ferring; personal fees from Takeda, Janssen, and Tillots Pharma; and serving as an advisory board member for Takeda. CAL declares research support or fees for development and delivery of non-promotional education from Janssen, Takeda, AbbVie, AstraZeneca, Eli Lilly, Orion, Pfizer, Roche, Sanofi Aventis, Ferring, Dr Falk, UCB, Biogen, and Genentech. ALH has served as consultant, advisory board member, or speaker for AbbVie, Arena, Atlantic, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Ferring, Galapagos, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire, and Takeda and serves on the global steering committee for Genentech. 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. CWL reports personal consulting fees from Galapagos, AbbVie, Takeda, Pfizer, Janssen, and Iterative Scopes; institutional consulting fees from Trellus Health; and personal fees and support for attending meetings from Galapagos, AbbVie, Takeda, Pfizer, Janssen, GSK, Gilead, Fresenius Kabi, Ferring, and Dr Falk. JRG reports grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos during the study. KMP is chief, principal, or co-investigator for vaccine clinical trials and experimental medicine studies (NCT05007275, NCT04753892, EudraCT 2020-001646-20, NCT04400838, NCT04324606, EudraCT 2017-004610-26, NCT03970993, and NCT03816137), is a member of the data safety monitoring board for two vaccine trials (NCT05249829 and NCT05575492), has received a fee for speaking from Seqirus and Sanofi Pasteur, and has research funding from the Chan Zuckerberg Initiative, the UK Medical research Council/UK Research and Innovation, the Vaccine Task Force, and National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC), outside the submitted work. NAK reports grants from F Hoffmann-La Roche AG, Biogen, Celltrion Healthcare, Takeda, and Galapagos during the conduct of the study; grants and non-financial support from AbbVie, MSD, Napp, Pfizer, Celgene, and Pharmacosmos; grants and personal fees from Celltrion; personal fees and non-financial support from Janssen, Tillots Pharma and Dr Falk; and personal fees from Allergan, Ferring, Pharmacosmos, Takeda, Amgen, Bristol-Myers Squibb, and Mylan, outside the submitted work. TA reports grants from F Hoffmann-La Roche AG, Biogen, Celltrion Healthcare, Takeda, Galapagos, and Crohn's and Colitis UK during the conduct of the study; payment for educational events for Takeda; and serving as medical advisor to Crohn's and Colitis UK, outside of the submitted work. NP reports grants from F Hoffmann-La Roche AG, Biogen, Celltrion Healthcare, Takeda, Galapagos, and Crohn's and Colitis UK during the conduct of the study; research grants from Bristol Myers Squibb and Pfizer; and personal fees from Takeda, Janssen, Pfizer, Galapagos, Bristol-Myers Squibb, AbbVie, Roche, Lilly, Allergan, Celgene, and Astra Zeneca outside the submitted work; and has served as a speaker or advisory board member for AbbVie, Allergan, Bristol-Myers Squibb, Celgene, Dr Falk, Galapagos, AstraZeneca, and Vifor Pharma. SL is supported by a Wellcome GW4-CAT fellowship. NC acknowledges support from Crohn's and Colitis UK. CAL acknowledges support from the NIHR Newcastle BRC and the support of the Programmed Investigation Unit at Royal Victoria Infirmary, Newcastle upon Tyne. CWL is funded by a UKRI Future Leaders Fellowship. NP is supported by the NIHR Imperial BRC. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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.)

Objective: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD., Design: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study., Results: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups., Conclusions: Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant., Trial Registration Number: ISRCTN45176516., Competing Interests: Competing interests: NAK reports grants from F. Hoffmann-La Roche, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos, non-financial support from Immundiagnostik, during the conduct of the study; grants and non-financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, personal fees and non-financial support from Dr Falk Pharma, outside the submitted work. SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. LWH declares an interest in SENISCA as founder and Chief Scientific Officer. KBK reports personal fees from Janssen, personal fees from Takeda, personal fees from PredictImmune, personal fees from Amgen, outside the submitted work. CAL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. PJS reports speaker fees and advisory board sponsorship from Janssen, Celltrion, AbbVie, Tillotts Pharma, Galapagos, Amgen, Dr Falk Pharma and Takeda outside the submitted work. AH reports personal fees from AbbVie, personal fees from Allergan, personal fees from BMS, personal fees from Celltrion, personal fees from Dr Falk Pharma, personal fees from GSK, personal fees from Takeda, personal fees from Pfizer, personal fees from Janssen, personal fees from Galapogos, personal fees from AstraZeneca, outside the submitted work. RCP reports acting as consultant, advisory board member, speaker or recipient of educational grant from Dr Falk Pharma, Ferring, Janssen, Pharmacosmos and Takeda, outside the submitted work. CWL reports personal fees from AbbVie, personal fees from Janssen, personal fees from Pfizer, personal fees from Takeda, grants from Gilead, personal fees from Gilead, personal fees from Galapagos, personal fees from Iterative Scopes, personal fees from Trellus Health, personal fees from Celltion, personal fees from Ferring, personal fees from BMS, during the conduct of the study. RB and DA are members of the Global T cell Expert Consortium and have consulted for Oxford Immunotec outside the submitted work. SS reports grants from Takeda, AbbVie, Amgen, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Dr Falk Pharma, Tillots Pharma, Cellgene, Pfizer, Pharmacocosmos, outside the submitted work. NP reports personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from AbbVie, personal fees from Roche, personal fees from Lilly, personal fees from Allergan, personal fees from Celgene, outside the submitted work; and NP has served as a speaker/advisory board member for AbbVie, Allergan, Bristol-Myers Squibb, Celgene, Dr Falk Pharma, Ferring, Janssen, Pfizer, Tillotts Pharma, Takeda and Vifor Pharma. JRG reports grants from F. Hoffmann-La Roche, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos, non-financial support from Immundiagnostik, during the conduct of the study. TA reports grants and non-financial support from F. Hoffmann-La Roche, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos, non-financial support from Immundiagnostik, during the conduct of the study; personal fees from Biogen, grants and personal fees from Celltrion Healthcare, personal fees and non-financial 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, non-financial support from Tillotts Pharma, outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID-19 pandemic offered a unique opportunity to understand inflammatory bowel disease (IBD) management during unexpected disruption. This could help to guide practice overall., Aims: To compare prescribing behaviour for IBD flares and outcomes during the early pandemic with pre-pandemic findings METHODS: We performed an observational cohort study comprising patients who contacted IBD teams for symptomatic flares between March and June 2020 in 60 National Health Service trusts in the United Kingdom. Data were compared with a pre-pandemic cohort after propensity-matching for age and physician global assessment of disease activity., Results: We included 1864 patients in each of the pandemic and pre-pandemic cohorts. The principal findings were reduced systemic corticosteroid prescription during the pandemic in Crohn's disease (prednisolone: pandemic 26.5% vs. 37.1%; p < 0.001) and ulcerative colitis (UC) (prednisolone: pandemic 33.5% vs. 40.7%, p < 0.001), with increases in poorly bioavailable oral corticosteroids in Crohn's (pandemic 15.6% vs. 6.8%; p < 0.001) and UC (pandemic 11.8% vs. 5.2%; p < 0.001). Ustekinumab (Crohn's and UC) and vedolizumab (UC) treatment also significantly increased. Three-month steroid-free remission in each period was similar in Crohn's (pandemic 28.4% vs. 32.1%; p = 0.17) and UC (pandemic 36.4% vs. 40.2%; p = 0.095). Patients experiencing a flare and suspected COVID-19 were more likely to have moderately-to-severely active disease at 3 months than those with a flare alone., Conclusions: Despite treatment adaptations during the pandemic, steroid-free outcomes were comparable with pre-pandemic levels, although concurrent flare and suspected COVID-19 caused worse outcomes. These findings have implications for IBD management during future pandemics and for standard practice., (© 2022 John Wiley & Sons Ltd.)

Background: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose., Methods: VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data., Findings: Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p<0·0001), infliximab plus thiopurine (1818·3 U/mL [6·7]; p<0·0001), and tofacitinib (8071·5 U/mL [3·1]; p=0·0018) compared with the healthy control group (16 774·2 U/mL [2·6]). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL [2·2]; p=0·099), ustekinumab (11 089·3 U/mL [2·8]; p=0·060), or vedolizumab (13 564·9 U/mL [2·4]; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 [95% CI 0·11-0·21]; p<0·0001), tofacitinib (0·52 [CI 0·31-0·87]; p=0·012), and thiopurine (0·69 [0·51-0·95]; p=0·021), but not with ustekinumab (0·64 [0·39-1·06]; p=0·083), or vedolizumab (0·84 [0·54-1·30]; p=0·43). Previous SARS-CoV-2 infection (1·58 [1·22-2·05]; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 [0·80-0·97]; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021)., Interpretation: A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors., Funding: Pfizer., Competing Interests: Declaration of interests JLA reports sponsorship from Vifor Pharma for accommodation and travel to BSG 2019, outside the submitted work. NAK 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, and Galapagos; and support for attending meetings from AbbVie, Falk, and Janssen, outside the submitted work. AS has received travel expense support from Janssen. SS reports grants from Takeda, AbbVie, Tillots Pharma, Janssen, Pfizer, and Biogen; and personal fees from Takeda, AbbVie, Janssen, Pharmacocosmos, Biogen, Pfizer, Tillots Pharma, and Falk Pharma, outside the submitted work. ALH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, Atlantic, Bristol Myers Squibb, Celltrion, Falk, Galapogos, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire, and Takeda; 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, AstraZeneca, Atlantic, Bristol Myers Squibb, Galapogos, Janssen, Pfizer, and Takeda. PMI reports grants and personal fees from Celltrion, Takeda, Pfizer, Galapagos; grants from MSD; and personal fees from Gilead, AbbVie, Janssen, Bristol Myers Squibb, Lilly, and Arena, outside the submitted work. MP receives unrestricted educational grants from Pfizer for genetic analyses to support the IBD BioResource, and speaker fees from Janssen. GRJ has received grants from Wellcome Trust and ECCO; speaker fees from Takeda, Ferring, and Janssen; and support for attending meetings or travel from Ferring. 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 Predict Immune. SB reports funding from Ferring and Dr Falk for accommodation, travel, and meeting fees. KVP reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Dr Falk, Janssen, PreddictImmune, and Takeda; support for attending meetings or travel from AbbVie, Ferring, Janssen, and Tillots; and participation on a data safety monitoring board or advisory board for AbbVie, Galapagos, and Janssen. 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, Tillots, and Norgine; and participation on a data safety monitoring board or advisory board for AbbVie. LCH reports support for attending meetings or travel from AbbVie. CWL reports a Future Leaders Fellow award from UKRI; personal consulting fees from Galapagos, AbbVie, Takeda, Pfizer, Janssen, and Iterative Scopes; 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. RJB and DMA are members of the Global T cell Expert Consortium and have consulted for Oxford Immunotec outside the submitted work. JRG reports grants from F Hoffmann-La Roche AG; grants from Biogen, Celltrion Healthcare, and Galapagos NV; and non-financial support from Immundiagnostik, during the conduct of the study. TA 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. Financial support for the VIP study was provided as a research grant by Pfizer and NP is the principal investigator on this grant. NP has received research grants from Bristol Myers Squibb outside the submitted work; reports personal fees from Takeda, Janssen, Pfizer, Bristol Myers Squibb, AbbVie, Roche, Lilly, Allergan, and Celgene, outside the submitted work; and has served as a speaker or advisory board member for AbbVie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda, and Vifor Pharma. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The COVID-19 pandemic has raised considerable concerns that patients with inflammatory bowel disease (IBD), particularly those treated with immunosuppressive therapies, may have an increased risk of SARS-CoV-2 acquisition, develop worse outcomes following COVID-19, and have suboptimal vaccine response compared with the general population. In this review, we summarise data on the risk of COVID-19 and associated outcomes, and latest guidance on SARS-CoV-2 vaccines in patients with IBD. Emerging evidence suggests that commonly used medications for IBD, such as corticosteroids but not biologicals, were associated with adverse outcomes to COVID-19. There has been no increased risk of de novo, or delayed, IBD diagnoses, however, an overall decrease in endoscopy procedures has led to a rise in the number of missed endoscopic-detected cancers during the pandemic. The impact of IBD medication on vaccine response has been a research priority recently. Data suggest that patients with IBD treated with antitumour necrosis factor (TNF) medications had attenuated humoral responses to SARS-CoV-2 vaccines, and more rapid antibody decay, compared with non-anti-TNF-treated patients. Reassuringly, rates of breakthrough infections and hospitalisations in all patients who received vaccines, irrespective of IBD treatment, remained low. International guidelines recommend that all patients with IBD treated with immunosuppressive therapies should receive, at any point during their treatment cycle, three primary doses of SARS-CoV-2 vaccines with a further booster dose as soon as possible. Future research should focus on our understanding of the rate of antibody decay in biological-treated patients, which patients require additional doses of SARS-CoV-2 vaccine, the long-term risks of COVID-19 on IBD disease course and activity, and the potential risk of long COVID-19 in patients with IBD., Competing Interests: Competing interests: SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. LL has no conflict of interest to declare. NC has no conflict of interest to declare. NAK reports grants from F. Hoffmann-La Roche AG, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, grants and non-financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, personal fees and non-financial support from Dr Falk, outside the submitted work. SCN has served as speakers for Janssen, Abbvie, Takeda, Ferring, Tilotts, Menarini, Pfizer and have received research grants from Olympus, Ferring, Janssen and Abbvie, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Age is a major prognostic factor for COVID-19 outcomes. The effect of inflammatory bowel disease [IBD] activity on COVID-19 is unclear. We examined the relationship between IBD activity and COVID-19 severity according to age., Methods: We included IBD patients diagnosed with COVID-19, reported to SECURE-IBD between March 13, 2020 and August 3, 2021. Clinical IBD activity was measured by physician global assessment [PGA]. COVID-19-related outcomes were [1] intensive care unit [ICU] admission, ventilation or death, and [2] hospitalization. Using generalized estimating equations, we determined adjusted odds ratios [aOR, 95% confidence interval] for moderate and severe PGA vs clinical remission/mild PGA, controlling for demographics, medications and COVID-19 diagnosis period. We performed stratified analyses by age [≤50 vs >50 years]., Results: Among 6078 patients, adverse COVID-19 outcomes were more common with active IBD: ICU/ventilation/death in 3.6% [175/4898] of remission/mild, 4.9% [45/920] of moderate and 8.8% [23/260] of severe [p < 0.001]; and hospitalization in 13% [649/4898] of remission/mild, 19% [178/920] of moderate and 38% [100/260] of severe [p < 0.001]. Stratified by decade, effect sizes were larger for younger patients. In patients ≤50 years, severe PGA was independently associated with ICU/ventilation/death (aOR 3.27 [1.15-9.30]) and hospitalization (aOR 4.62 [2.83-7.55]). In contrast, severe PGA was not independently associated with COVID-19 outcomes in those older than 50 years., Conclusions: Clinically active IBD may be a risk factor for severe COVID-19, particularly in younger patients. IBD disease control, including through medication compliance, and strategies to mitigate the risk of COVID-19 infection amongst patients with active IBD [e.g. distancing, immunization] are key to limit adverse COVID-19 outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs., Methods: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing., Findings: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·7]; p<0·0001), or tofacitinib (429·5 U/mL [3·1]; p=0·0012) compared with controls (1578·3 U/mL [3·7]). There were no significant differences in antibody concentrations between patients treated with thiopurine monotherapy (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) and healthy controls. In multivariable modelling, lower anti-SARS-CoV-2 spike protein antibody concentrations were independently associated with infliximab (geometric mean ratio 0·12, 95% CI 0·08-0·17; p<0·0001) and tofacitinib (0·43, 0·23-0·81; p=0·0095), but not with ustekinumab (0·69, 0·41-1·19; p=0·18), thiopurines (0·89, 0·64-1·24; p=0·50), or vedolizumab (1·16, 0·74-1·83; p=0·51). mRNA vaccines (3·68, 2·80-4·84; p<0·0001; vs adenovirus vector vaccines) were independently associated with higher antibody concentrations and older age per decade (0·79, 0·72-0·87; p<0·0001) with lower antibody concentrations., Interpretation: For patients with IBD, the immunogenicity of COVID-19 vaccines varies according to immunosuppressive drug exposure, and is attenuated in recipients of infliximab, infliximab plus thiopurines, and tofacitinib. Scheduling of third primary, or booster, doses could be personalised on the basis of an individual's treatment, and patients taking anti-tumour necrosis factor and tofacitinib should be prioritised., Funding: Pfizer., Competing Interests: Declaration of interests JLA reports sponsorship from Vifor Pharma for accommodation and travel to the British Society of Gastroenterology annual meeting 2019, outside the submitted work. NAK 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, and Galapagos; and support for attending meetings from AbbVie, Falk, and Janssen, outside the submitted work. AS has received travel expense support from Janssen. SS reports grants from Takeda, AbbVie, Tillots Pharma, Janssen, Pfizer, and Biogen, and personal fees from Takeda, AbbVie, Janssen, Pharmacocosmos, Biogen, Pfizer, Tillots Pharma, and Falk Pharma, outside the submitted work. ALH 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; participation on the 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. PMI reports grants from Celltrion, Takeda, MSD, Pfizer, and Galapagos, and personal fees from Celltrion, Takeda, Pfizer, Galapagos, Gilead, AbbVie, Janssen, Bristol Myers Squibb, Lilly, and Arena, outside the submitted work. MP receives unrestricted educational grants from Pfizer for genetic analyses to support the IBD BioResource and speaker fees from Janssen. GRJ has received grants from the Wellcome Trust and ECCO; speaker fees from Takeda, Ferring, and Janssen; and support for attending meetings or travel from Ferring. 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. KVP reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, DrFalk, Janssen, PreddictImmune, and Takeda; support for attending meetings or travel from AbbVie, Ferring, Janssen, and Tillots; and participation on a data safety monitoring board or advisory board for AbbVie, Galapagos, and Janssen. 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, Tillots, and Norgine; and participation on a data safety monitoring board or advisory board for AbbVie. LCH reports support for attending meetings or travel from AbbVie. CWL reports a Future Leaders Fellow award from UK Research and Innovation; personal consulting fees from Galapagos, AbbVie, Takeda, Pfizer, Janssen, and Iterative Scopes; 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. RJB and DMA are members of the Global T cell Expert Consortium and have consulted for Oxford Immunotec outside the submitted work. JRG reports grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, and Galapagos, and non-financial support from Immundiagnostik, during the conduct of the study. TA 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. NP is the principal investigator on the research grant from Pfizer that helped to fund the VIP study; has received research grants from Bristol Myers Squibb outside the submitted work; reports personal fees from Takeda, Janssen, Pfizer, Bristol Myers Squibb, AbbVie, Roche, Lilly, Allergan, and Celgene, outside the submitted work; and has served as a speaker or advisory board member for AbbVie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda, and Vifor Pharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. 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: Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-tumour necrosis factor [anti-TNF] level influences serological responses, remains unknown., Methods: Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11 422 (53.3% [6084] male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between January 29 and September 30, 2020. Data were linked to nationally held SARS-CoV-2 PCR results to July 11, 2021., Results: Rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% [178/5893], adalimumab: 3.0% [152/5074], vedolizumab: 6.7% [25/375], p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index [COI] [1.94-9.96] vs 5.02 [2.18-18.70], p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI [4.39-68.10, p < 0.004). Compared to patients with detectable infliximab and adalimumab drug levels, patients with undetectable drug levels [<0.8 mg/L] were more likely to be seropositive for SARS-CoV-2 antibodies. One-third of patients who had PCR testing prior to antibody testing failed to seroconvert, all were treated with anti-TNF. Subsequent positive PCR-confirmed SARS-CoV-2 was seen in 7.9% [12/152] of patients after a median time of 183.5 days [129.8-235.3], without differences between drugs., Conclusion: Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels support a causal relationship, although confounding factors, such as combination therapy with a immunomodulator, may have influenced the results., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Introduction: Acute severe ulcerative colitis (ASUC) traditionally requires inpatient hospital management for intravenous therapies and/or colectomy. Ambulatory ASUC care has not yet been evaluated in large cohorts., Aims: We used data from PROTECT, a UK multicentre observational COVID-19 inflammatory bowel disease study, to report the extent, safety and effectiveness of ASUC ambulatory pathways., Methods: Adults (≥18 years old) meeting Truelove and Witts criteria between 1 January 2019-1 June 2019 and 1 March 2020-30 June 2020 were recruited to PROTECT. We used demographic, disease phenotype, treatment outcomes and 3-month follow-up data. Primary outcome was rate of colectomy during the index ASUC episode. Secondary outcomes included corticosteroid response, time to and rate of rescue or primary induction therapy, response to rescue or primary induction therapy, time to colectomy, mortality, duration of inpatient treatment and hospital readmission and colectomy within 3 months of index flare. We compared outcomes in three cohorts: (1) patients treated entirely in inpatient setting; ambulatory patients subdivided into; (2) patients managed as ambulatory from diagnosis and (3) patients hospitalised and subsequently discharged to ambulatory care for continued intravenous steroids., Results: 37% (22/60) participating hospitals used ambulatory pathways. Of 764 eligible patients, 695 (91%) patients received entirely inpatient care, 15 (2%) patients were managed as ambulatory from diagnosis and 54 (7%) patients were discharged to ambulatory pathways. Aside from younger age in patients treated as ambulatory from diagnosis, no significant differences in disease or patient phenotype were observed. The rate of colectomy (15.0% (104/695) vs 13.3% (2/15) vs 13.0% (7/54), respectively, p=0.96) and secondary outcomes were similar among all three cohorts. Stool culture and flexible sigmoidoscopy were less frequently performed in ambulatory cohorts. Forty per cent of patients treated as ambulatory from diagnosis required subsequent hospital admission., Conclusions: In a post hoc analysis of one of the largest ASUC cohorts collected to date, we report an emerging UK ambulatory practice which challenges treatment paradigms. However, our analysis remains underpowered to detect key outcome measures and further studies exploring clinical and cost-effectiveness as well as patient and physician acceptability are needed., Trial Registration Number: NCT04411784., Competing Interests: Competing interests: SS holds research grants from Biogen, Takeda, AbbVie, Tillotts Pharma, Ferring and Biohit; served on the advisory boards of Takeda, AbbVie, Merck, Ferring, Pharmacocosmos, Warner Chilcott, Janssen, Falk Pharma, Biohit, TriGenix, Celgene and Tillots Pharma; and has received speaker fees from AbbVie, Biogen, AbbVie, Janssen, Merck, Warner Chilcott and Falk Pharma. GW has served as a speaker and/or advisory board member for AbbVie, Falk and Janssen. He has had support to attend meetings from AbbVie, Falk, Janssen and Norgine. His department has received research funding from Tillotts. NAK has served as a speaker and/or advisory board member for Allergan, Falk, Janssen, Mylan, Pharmacosmos, Takeda and Tillotts. He has had support to attend meetings from AbbVie, Falk, Janssen and Norgine. His department has received research funding from AbbVie, Celgene, Celtrion, MSD, Napp, Pfizer, Pharmacosmos and Takeda. SSu has received speaker fees from MSD, Actavis, Abbvie, Dr Falk pharmaceuticals, Shire and received educational grants from MSD, Abbvie, Actavis and is an advisory board member for Celltrion, Dr Falk pharmaceuticals and Vifor pharmaceuticals. CAL has received research support and/or has received fees for delivery of non-promotional education from: Genentech, Janssen, Takeda, Abbvie, Dr Falk, AstraZeneca, Eli Lilly, Orion, Pfizer, Roche, Sanofi Aventis, Ferring, UCB and Biogen. MJBB has received research grants from Vifor International, Pharmacosmos and Tillots Pharma; has received speaker fee from Abbvie and Vifor International; has been an advisory board member for Tillots Pharma, Vifor International; and received travel/conference expenses from Vifor International, Abbvie and Tillots Pharma. AK has served on the advisory boards for Abbvie, Janssen and BMS Celgene and has received speaker fees from Takeda, Pfizer and Janssen; and received travel/conference expenses from Tillotts, Janssen, Abbvie and Shield Therapeutics. KVP has received honoraria for educational meetings and speaker fees from Abbvie, Janssen, Takeda, DrFalk and Ferring. KVP has received Advisory Board fees from Abbvie and Janssen., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The treatment for COVID-19 often utilizes immune-modulating drugs. These drugs are also used in immune mediated inflammatory diseases (IMIDs). We performed a systematic review about seroconversion after SARS-CoV-2 vaccination in patients with IMIDs and impact of various drugs on seroconversion rates., Methods: Electronic databases were searched to identify relevant studies reporting seroconversion rates following SARS-CoV-2 vaccination in IMIDs. We calculated the pooled seroconversion rates after a single or two doses of vaccination, pooled seroconversion rates in patients with specific IMIDs, and rates in patients on various drugs/drug classes., Results: Twenty-five studies were included in the systematic review. The pooled seroconversion rates after two doses of mRNA vaccination were higher (83.1, 95%CI: 74.9-89.0, I 2  = 90%) as compared to a single dose (69.3, 52.4-82.3, I 2  = 95%). The odds of seroconversion were lower in IMIDs as compared to healthy controls (0.05, 0.02-0.13, I 2  = 21%). The seroconversion rates in patients with inflammatory bowel disease (95.2, 95%CI: 92.6-96.9, I 2  = 0%), spondyloarthropathy (95.6, 95% CI: 83.4-98.9, I 2  = 35%), and systemic lupus erythematosus (90.7, 95%CI: 85.4-94.2, I 2  = 0%) were higher as compared to rheumatoid arthritis (79.5, 95% CI: 65.1-88.9, I 2  = 85%), and vasculitis (70.5, 95% CI: 52.9-83.5, I 2  = 51%). The seroconversion rates following double dose of mRNA were excellent (>90%) in those on anti-tumour necrosis factor (TNF), anti-integrin (vedolizumab), anti-IL 17 (secukinumab), anti-IL6 (Tocilizumab) and anti-IL12/23 (Ustekinumab) therapies but attenuated (<70%) in patients on anti-CD20 (Rituximab) or anti-cytotoxic T lymphocyte associated antigen (CTLA-4) therapies (Abatacept). The seroconversion rates were good (70-90%) with steroids, hydroxychloroquine, JAK inhibitors, mycophenolate mofetil and leflunomide. Combination of anti-TNF with immunomodulators (azathioprine, 6-meracptopurine, methotrexate) resulted in an attenuated vaccine response as compared to anti-TNF monotherapy., Conclusion: Seroconversion rates after SARS-CoV-2 vaccination are lower in patients with IMIDs. Certain therapies (anti-TNF, anti-integrin, anti-IL 17, anti-IL6, anti-12/23) do not impact seroconversion rates while others (anti-CD20, anti-CTLA-4) result in poorer responses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine., Design: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine., Results: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine., Conclusion: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab., Trial Registration Number: ISRCTN45176516., Competing Interests: Competing interests: NAK 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; grants and non-financial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, personal fees and non-financial support from Dr Falk, outside the submitted work. SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. JRG reports grants from F. Hoffmann-La Roche AG, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study. DC reports non-financial support from Ferring, personal fees and non-financial support from Pfizer, outside the submitted work. JRFC reports grants and personal fees from Samsung, Pfizer & Biogen; personal fees and non-financial support from Janssen & Abbvie; grants, personal fees and non-financial support from Takeda; personal fees from MSD, Sandoz, Celltrion & NAPP, outside the submitted work. AF reports personal fees from Takeda UK Ltd, personal fees from Dr Falk Pharma, personal fees from Tillotts, personal fees from Abbvie Ltd, personal fees from Sheild, personal fees from Ferring, from Pharmacosmos, personal fees from Allergan, personal fees from Janssen, outside the submitted work. PMI reports grants and personal fees from Takeda, grants from MSD, grants and personal fees from Pfizer, personal fees from Galapagos, personal fees from Gilead, personal fees from Abbvie, personal fees from Janssen, personal fees from Boehringer Ingelheim, personal fees from Topivert, personal fees from VH2, personal fees from Celgene, personal fees from Arena, personal fees from Samsung Bioepis, personal fees from Sandoz, personal fees from Procise, personal fees from Prometheus, outside the submitted work. NK reports personal fees from Janssen, outside the submitted work. KBK reports personal fees from Janssen, personal fees from Takeda, personal fees from PredictImmune, personal fees from Amgen, outside the submitted work. CAL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. JM reports grants and personal fees from Takeda Pharmaceuticals, grants and personal fees from Biogen, personal fees and non-financial support from AbbVie, personal fees from Grifols, personal fees from Sandoz, personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Vifor Pharmaceuticals, personal fees from Predictimmune, personal fees from Bristol Myers Squibb, non-financial support from Ferring Pharmaceuticals, outside the submitted work. RCGP reports acting as consultant, advisory board member, speaker or recipient of educational grant from Dr Falk, Ferring, Janssen, Pharmacosmos and Takeda. TR reports grants and personal fees from Abbvie, personal fees from BMS, personal fees from Celgene, personal fees from Ferring, personal fees from Gilead, personal fees from GSK, personal fees from LabGenius, personal fees from Janssen, personal fees from Mylan, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Sandoz, personal fees from Takeda, personal fees from Galapagos, personal fees from Arena, outside the submitted work. PJS reports speaker fees and advisory board sponsorship from Janssen, Celltrion and Takeda outside the submitted work. AMV reports personal fees and non-financial support from Takeda, personal fees and non-financial support from Celltrion, personal fees and non-financial support from Merck Sharp & Dohme, outside the submitted work. SJ is an employee of Roche Diagnostics and holds Roche shares. SS reports grants from Takeda, Abbvie, AMGEN, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Falk Pharma, Tillots pharma, Cellgene, Pfizer, Pharmacocosmos, outside the submitted work. CWL reports personal fees from Abbvie, personal fees from Janssen, personal fees from Pfizer, personal fees from Takeda, grants from Gilead, personal fees from Gilead, personal fees from Galapagos, personal fees from Iterative Scopes, personal fees from Trellus Health, personal fees from Celltion, personal fees from Ferring, personal fees from BMS, during the conduct of the study. NP reports personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from Abbvie, personal fees from Roche, personal fees from Lilly, personal fees from Allergan, personal fees from Celgene, outside the submitted work; and NP has served as a speaker/advisory board member for Abbvie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda and Vifor Pharma. TA reports grants and non-financial support 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; personal fees from Biogen, grants and personal fees from Celltrion Healthcare, personal fees and non-financial 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, non-financial support from Tillotts, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a paucity of evidence to support safe and effective management of patients with acute severe ulcerative colitis during the COVID-19 pandemic. We sought to identify alterations to established conventional evidence-based management of acute severe ulcerative colitis during the early COVID-19 pandemic, the effect on outcomes, and any associations with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes., Methods: The PROTECT-ASUC study was a multicentre, observational, case-control study in 60 acute secondary care hospitals throughout the UK. We included adults (≥18 years) with either ulcerative colitis or inflammatory bowel disease unclassified, who presented with acute severe ulcerative colitis and fulfilled the Truelove and Witts criteria. Cases and controls were identified as either admitted or managed in emergency ambulatory care settings between March 1, 2020, and June 30, 2020 (COVID-19 pandemic period cohort), or between Jan 1, 2019, and June 30, 2019 (historical control cohort), respectively. The primary outcome was the proportion of patients with acute severe ulcerative colitis receiving rescue therapy (including primary induction) or colectomy. The study is registered with ClinicalTrials.gov, NCT04411784., Findings: We included 782 patients (398 in the pandemic period cohort and 384 in the historical control cohort) who met the Truelove and Witts criteria for acute severe ulcerative colitis. The proportion of patients receiving rescue therapy (including primary induction) or surgery was higher during the pandemic period than in the historical period (217 [55%] of 393 patients vs 159 [42%] of 380 patients; p=0·00024) and the time to rescue therapy was shorter in the pandemic cohort than in the historical cohort (p=0·0026). This difference was driven by a greater use of rescue and primary induction therapies with biologicals, ciclosporin, or tofacitinib in the COVID-19 pandemic period cohort than in the historical control period cohort (177 [46%] of 387 patients in the COVID-19 cohort vs 134 [36%] of 373 patients in the historical cohort; p=0·0064). During the pandemic, more patients received ambulatory (outpatient) intravenous steroids (51 [13%] of 385 patients vs 19 [5%] of 360 patients; p=0·00023). Fewer patients received thiopurines (29 [7%] of 398 patients vs 46 [12%] of 384; p=0·029) and 5-aminosalicylic acids (67 [17%] of 398 patients vs 98 [26%] of 384; p=0·0037) during the pandemic than in the historical control period. Colectomy rates were similar between the pandemic and historical control groups (64 [16%] of 389 vs 50 [13%] of 375; p=0·26); however, laparoscopic surgery was less frequently performed during the pandemic period (34 [53%] of 64] vs 38 [76%] of 50; p=0·018). Five (2%) of 253 patients tested positive for SARS-CoV-2 during hospital treatment. Two (2%) of 103 patients re-tested for SARS-CoV-2 during the 3-month follow-up were positive 5 days and 12 days, respectively, after discharge from index admission. Both recovered without serious outcomes., Interpretation: The COVID-19 pandemic altered practice patterns of gastroenterologists and colorectal surgeons in the management of acute severe ulcerative colitis but was associated with similar outcomes to a historical cohort. Despite continued use of high-dose corticosteroids and biologicals, the incidence of COVID-19 within 3 months was low and not associated with adverse COVID-19 outcomes., Funding: None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

SARS-CoV-2 has caused a global health crisis and mass vaccination programmes provide the best opportunity for controlling transmission and protecting populations. Despite the impressive clinical trial results of the BNT162b2 (Pfizer/BioNTech), ChAdOx1 nCoV-19 (Oxford/AstraZeneca), and mRNA-1273 (Moderna) vaccines, important unanswered questions remain, especially in patients with pre-existing conditions. In this position statement endorsed by the British Society of Gastroenterology Inflammatory Bowel Disease (IBD) section and IBD Clinical Research Group, we consider SARS-CoV-2 vaccination strategy in patients with IBD. The risks of SARS-CoV-2 vaccination are anticipated to be very low, and we strongly support SARS-CoV-2 vaccination in patients with IBD. Based on data from previous studies with other vaccines, there are conceptual concerns that protective immune responses to SARS-CoV-2 vaccination may be diminished in some patients with IBD, such as those taking anti-TNF drugs. However, the benefits of vaccination, even in patients treated with anti-TNF drugs, are likely to outweigh these theoretical concerns. Key areas for further research are discussed, including vaccine hesitancy and its effect in the IBD community, the effect of immunosuppression on vaccine efficacy, and the search for predictive biomarkers of vaccine success., (Copyright © 2021 Elsevier Ltd. All rights reserved.)