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Aim: To evaluate the usefulness of small intestine contrast-enhanced ultrasonography (SICUS) using an oral contrast agent in routine clinical practice by assessing the level of agreement with the established techniques, small bowel follow-through (SBFT) and computed tomography (CT), and diagnostic accuracy compared with the final diagnosis in the detection of small bowel Crohn's disease (CD) and luminal complications in a regional centre.Materials and Methods: All symptomatic known or suspected cases of CD who underwent SICUS were retrospectively reviewed. The level of agreement between SICUS and SBFT, CT, histological findings, and C-reactive protein (CRP) level was assessed using kappa (κ) coefficient. Sensitivity was demonstrated using the final diagnosis as the reference standard defined by the outcome of clinical assessment, follow-up, and results of investigations other than SICUS.Results: One hundred and forty-three patients underwent SICUS of these 79 (55%) were female. Eighty-six (60%) were known to have CD and 57 (40%) had symptoms suggestive of intestinal disease with no previous diagnosis. Forty-six (55%) of the known CD patients had had at least one previous surgical resection. The sensitivity of SICUS in detecting active small bowel CD in known CD and undiagnosed cases was 93%. The kappa coefficient was 0.88 and 0.91 with SBFT and CT, respectively. SICUS detected nine patients who had one or more small bowel strictures and six patients with a fistula all detected by SBFT or CT.Conclusion: SICUS is not only comparable to SBFT and CT but avoids radiation exposure and should be more widely adopted in the UK as a primary diagnostic procedure and to monitor disease complications in patients with CD. [ABSTRACT FROM AUTHOR]

Background: Maintenance treatment with 5-aminosalicylic acid (5-ASA) is recommended in ulcerative colitis (UC), but accurate estimates of discontinuation and adherence in adolescents transitioning to young adulthood are lacking., Aim: To determine rates and risk factors for discontinuation and adherence to oral 5-ASA in adolescents and young adults 1 year following diagnosis of UC., Design and Setting: Observational cohort study using the UK Clinical Practice Research Datalink among adolescents and young adults (aged 10-24 years) diagnosed with UC between 1 January 1998 and 1 May 2016., Method: Time to oral 5-ASA discontinuation (days) and adherence rates (proportion of days covered) were calculated during the first year of treatment using Kaplan-Meier survival analysis. Cox regression models were built to estimate the impact of sociodemographic and health-related risk factors., Results: Among 607 adolescents and young adults starting oral 5-ASA maintenance treatment, one-quarter ( n = 152) discontinued within 1 month and two- thirds ( n = 419) within 1 year. Discontinuation was higher among those aged 18-24 years (74%) than younger age groups (61% and 56% in those aged 10-14 and 15-17 years, respectively). Adherence was lower among young adults than adolescents (69% in those aged 18-24 years versus 80% in those aged 10-14 years). Residents in deprived versus affluent postcodes were more likely to discontinue treatment (adjusted hazard ratio [aHR] 1.46, 95% confidence interval [CI] = 1.10 to 1.92). Early corticosteroid use for an acute flare lowered the likelihood of oral 5-ASA discontinuation (aHR 0.68, 95% CI = 0.51 to 0.90)., Conclusion: The first year of starting long-term therapies in adolescents and young adults diagnosed with UC is a critical window for active follow-up of maintenance treatment, particularly in those aged 18-24 years and those living in deprived postcodes., (© The Authors.)

Background: The impact of diagnostic delay on the clinical course of inflammatory bowel disease (IBD) remains uncertain., Aim: To perform a systematic review of time to diagnosis and the impact of delayed diagnosis on clinical outcomes in Crohn's disease (CD) and ulcerative colitis (UC)., Methods: We searched EMBASE and Medline from inception to 30th November 2022 for studies reporting diagnostic interval, from symptom onset to IBD diagnosis. We calculated the median, interquartile range (IQR) and pooled weighted median, of median diagnostic intervals of eligible studies. We defined delayed diagnosis as individuals above the 75th centile of longest time to diagnosis in each study. Using random effects meta-analysis, we pooled odds ratios (ORs) with 95% confidence intervals (CI) for studies reporting clinical outcomes, according to delayed diagnosis., Results: One hundred and one studies representing 112,194 patients with IBD (CD = 59,359; UC = 52,835) met inclusion criteria. The median of median times to diagnosis was 8.0 (IQR: 5.0-15.2) and 3.7 months (IQR: 2.0-6.7) in CD and UC, respectively. In high-income countries, this was 6.2 (IQR: 5.0-12.3) and 3.2 months (IQR: 2.2-5.3), compared with 11.7 (IQR: 8.3-18.0) and 7.8 months (IQR: 5.2-21.8) in low-middle-income, countries, for CD and UC respectively. The pooled weighted median was 7.0 (95% CI: 3.0-26.4) and 4.6 (95% CI: 1.0-96.0) months, for CD and UC respectively. Eleven studies, representing 6164 patients (CD = 4858; UC = 1306), were included in the meta-analysis that examined the impact of diagnostic delay on clinical outcomes. In CD, delayed diagnosis was associated with higher odds of stricturing (OR = 1.88; CI: 1.35-2.62), penetrating disease (OR = 1.64; CI: 1.21-2.20) and intestinal surgery (OR = 2.24; CI: 1.57-3.19). In UC, delayed diagnosis was associated with higher odds of colectomy (OR = 4.13; CI: 1.04-16.40)., Conclusion: Delayed diagnosis is associated with disease progression in CD, and intestinal surgery in both CD and UC. Strategies are needed to achieve earlier diagnosis of IBD., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

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: 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.)

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.)

Objective: Depression is a potential risk factor for developing IBD. This association may be related to GI symptoms occurring before diagnosis. We aimed to determine whether depression, adjusted for pre-existing GI symptoms, is associated with subsequent IBD., Design: We conducted a nested case-control study using the Clinical Practice Research Datalink identifying incident cases of UC and Crohn's disease (CD) from 1998 to 2016. Controls without IBD were matched for age and sex. We measured exposure to prevalent depression 4.5-5.5 years before IBD diagnosis. We created two sub-groups with prevalent depression based on whether individuals had reported GI symptoms before the onset of depression. We used conditional logistic regression to derive ORs for the risk of IBD depending on depression status., Results: We identified 10 829 UC cases, 4531 CD cases and 15 360 controls. There was an excess of prevalent depression 5 years before IBD diagnosis relative to controls (UC: 3.7% vs 2.7%, CD 3.7% vs 2.9%). Individuals with GI symptoms prior to the diagnosis of depression had increased adjusted risks of developing UC and CD compared with those without depression (UC: OR 1.47, 95% CI 1.21 to 1.79; CD: OR 1.41, 95% CI 1.04 to 1.92). Individuals with depression alone had similar risks of UC and CD to those without depression (UC: OR 1.13, 95% CI 0.99 to 1.29; CD: OR 1.12, 95% CI 0.91 to 1.38)., Conclusions: Depression, in the absence of prior GI symptoms, is not associated with subsequent development of IBD. However, depression with GI symptoms should prompt investigation for IBD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections., Design: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020., Results: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001)., Conclusions: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy., 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. JRG 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. DC reports non-financial support from Ferring, personal fees and non-financial support from Pfizer, outside the submitted work. SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. RC reports personal fees from Takeda, outside the submitted work. NMC reports trial funding, advisory board and speaker fees paid to his institution from AbbVie, Eli Lilly, Takeda, Shire, Pfizer and Janssen. ALH reports personal fees from Abbvie, personal fees from Allergan, personal fees from BMS, personal fees from Celltrion, personal fees from Falk, personal fees from GSK, personal fees from Takeda, personal fees from Pfizer, personal fees from Janssen, personal fees from Galapogos, personal fees from Astra Zeneca, 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. 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. JKL reports personal fees from MSD, personal fees from Janssen, grants and personal fees from Takeda, grants and personal fees from Galapagos, personal fees from Tillotts, 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. DPBM reports grants from the Leona M. and Harry B. Helmsley Charitable Trust, during the conduct of the study; personal fees from Takeda Pharmaceuticals, personal fees from Pfizer, personal fees from Bridge Biotherapeutics, personal fees from Palatin Technologies, personal fees from Boehringer-Ingelheim, personal fees and other from Prometheus Biosciences, personal fees from Gilead, outside the submitted work. KVP reports personal fees and non-financial support from Takeda, personal fees and non-financial support from Janssen, personal fees and non-financial support from Abbvie, personal fees from DrFalk, non-financial support from Ferring, 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. RKR reports grants from NHS Research Scotland Senior Research Fellowship, personal fees from Nestlé, personal fees from AbbVie, personal fees from Dr Falk, personal fees from Takeda, personal fees from Napp, personal fees from Mead Johnson, personal fees from Nutricia, personal fees from 4D Pharma, outside the submitted work. CPS reports grants and personal fees from AbbVie, grants and personal fees from Janssen, grants and personal fees from Takeda, personal fees from Dr Falk, personal fees from Pfizer, personal fees from Galapagos, personal fees from Arena, personal fees from Fresenius Kabi, outside the submitted work. PJS reports speaker fees and advisory board sponsorship from Janssen, Celltrion 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. SS reports grants from Takeda, Abbvie, AMGEN, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Falk Pharma, Tillots pharma, Cellgene, Pfizer, Phamrmacocosmos, 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, 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 Inc, 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.)

Objective: Management of acute severe UC (ASUC) during the novel COVID-19 pandemic presents significant dilemmas. We aimed to provide COVID-19-specific guidance using current British Society of Gastroenterology (BSG) guidelines as a reference point., Design: We convened a RAND appropriateness panel comprising 14 gastroenterologists and an IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellists rated the appropriateness of interventions for ASUC in the context of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores and disagreement index (DI) were calculated. Results were discussed at a moderated meeting prior to a second survey., Results: Panellists recommended that patients with ASUC should be isolated throughout their hospital stay and should have a SARS-CoV-2 swab performed on admission. Patients with a positive swab should be discussed with COVID-19 specialists. As per BSG guidance, intravenous hydrocortisone was considered appropriate as initial management; only in patients with COVID-19 pneumonia was its use deemed uncertain. In patients requiring rescue therapy, infliximab with continuing steroids was recommended. Delaying colectomy because of COVID-19 was deemed inappropriate. Steroid tapering as per BSG guidance was deemed appropriate for all patients apart from those with COVID-19 pneumonia in whom a 4-6 week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general, biologics were more likely to be deemed appropriate than azathioprine or tofacitinib. Panellists deemed prophylactic anticoagulation postdischarge to be appropriate in patients with a positive SARS-CoV-2 swab., Conclusion: We have suggested COVID-19-specific adaptations to the BSG ASUC guideline using a RAND panel., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

The use of corticosteroids to treat patients with inflammatory bowel disease [IBD] has been the bedrock of IBD therapeutics since the pioneering work of Truelove and Witts in the UK in the 1950s and subsequent large cohort studies in the USA and Europe. Nevertheless, although effective for induction of remission, these agents do not maintain remission and are associated with a long list of recognised side effects, including a risk of increased mortality. With the arrival of an increasing number of therapies for patients with IBD, the question arises as to whether we are using these agents appropriately in contemporary practice. This review discusses the historical background to steroid usage in IBD, and also provides a brief review of the literature on side effects of corticosteroid treatment as relevant to IBD patients. Data on licensed medications are presented with specific reference to the achievement of corticosteroid-free remission. We review available international data on the incidence of corticosteroid exposure and excess, and discuss some of the observations we and others have made concerning health care and patient-level factors associated with the risk of corticosteroid exposure, including identification of 'at-risk' populations., (© The Author(s) 2020. 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 and Aims: Lack of timely referral and significant waits for specialist review amongst individuals with unresolved gastrointestinal (GI) symptoms can result in delayed diagnosis of Inflammatory Bowel Disease (IBD)., Aims: To determine the frequency and duration of GI symptoms and predictors of timely specialist review before the diagnosis of both Crohn's Disease (CD) and ulcerative colitis (UC)., Methods: Case-control study of IBD matched 1:4 for age and sex to controls without IBD using the Clinical Practice Research Datalink from 1998-2016., Results: We identified 19,555 cases of IBD, and 78,114 controls. 1 in 4 cases of IBD reported gastrointestinal symptoms to their primary care physician more than 6 months before receiving a diagnosis. There is a significant excess prevalence of GI symptoms in each of the 10 years before IBD diagnosis. GI symptoms were reported by 9.6% and 10.4% at 5 years before CD and UC diagnosis respectively compared to 5.8% of controls. Amongst patients later diagnosed with IBD, <50% received specialist review within 18 months from presenting with chronic GI symptoms. Patients with a previous diagnosis of irritable bowel syndrome or depression were less likely to receive timely specialist review (IBS: HR=0.77, 95%CI 0.60-0.99, depression: HR=0.77, 95%CI 0.60-0.98)., Conclusions: There is an excess of GI symptoms 5 years before diagnosis of IBD compared to the background population which are likely attributable to undiagnosed disease. Previous diagnoses of IBS and depression are associated with delays in specialist review. Enhanced pathways are needed to accelerate specialist referral and timely IBD diagnosis., (© Crown copyright 2020.)

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials., Competing Interests: Competing interests: For details of conflicts of interest see online supplementary table 1., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Smokers are less likely to develop ulcerative colitis (UC) but the impact of smoking and subsequent cessation on clinical outcomes in UC is unclear., Aim: To evaluate the effect of smoking status and smoking cessation on disease outcomes., Methods: Using a nationally representative clinical research database, we identified incident cases of UC during 2005-2016. Patients were grouped as never-smokers, ex-smokers and smokers based on smoking status recorded in the 2 years preceding UC diagnosis. We defined subgroups of persistent smokers and smokers who quit within 2 years after diagnosis. We compared the rates of overall corticosteroid use, corticosteroid-requiring flares, corticosteroid dependency, thiopurine use, hospitalisation and colectomy between these groups., Results: We identified 6754 patients with a new diagnosis of UC over the study period with data on smoking status, of whom 878 were smokers at diagnosis. Smokers had a similar risk of corticosteroid-requiring flares (OR 1.16, 95% CI 0.92-1.25), thiopurine use (HR 0.84, 95% CI 0.62-1.14), corticosteroid dependency (HR 0.85, 95% CI 0.60-1.11), hospitalisation (HR 0.92, 95% CI 0.72-1.18) and colectomy (HR 0.78, 95% CI 0.50-1.21) in comparison with never-smokers. Rates of flares, thiopurine use, corticosteroid dependency, hospitalisation and colectomy were not significantly different between persistent smokers and those who quit smoking after a diagnosis of UC., Conclusions: Smokers and never-smokers with UC have similar outcomes with respect to flares, thiopurine use, corticosteroid dependency, hospitalisation and colectomy. Smoking cessation was not associated with worse disease course. The risks associated with smoking outweigh any benefits. UC patients should be counselled against smoking., (© 2019 John Wiley & Sons Ltd.)

Background: Magnetic resonance enterography and enteric ultrasonography are used to image Crohn's disease patients. Their diagnostic accuracy for presence, extent and activity of enteric Crohn's disease was compared., Objective: To compare diagnostic accuracy, observer variability, acceptability, diagnostic impact and cost-effectiveness of magnetic resonance enterography and ultrasonography in newly diagnosed or relapsing Crohn's disease., Design: Prospective multicentre cohort study., Setting: Eight NHS hospitals., Participants: Consecutive participants aged ≥ 16 years, newly diagnosed with Crohn's disease or with established Crohn's disease and suspected relapse., Interventions: Magnetic resonance enterography and ultrasonography., Main Outcome Measures: The primary outcome was per-participant sensitivity difference between magnetic resonance enterography and ultrasonography for small bowel Crohn's disease extent. Secondary outcomes included sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease extent, and sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease presence; identification of active disease; interobserver variation; participant acceptability; diagnostic impact; and cost-effectiveness., Results: Out of the 518 participants assessed, 335 entered the trial, with 51 excluded, giving a final cohort of 284 (133 and 151 in new diagnosis and suspected relapse cohorts, respectively). Across the whole cohort, for small bowel Crohn's disease extent, magnetic resonance enterography sensitivity [80%, 95% confidence interval (CI) 72% to 86%] was significantly greater than ultrasonography sensitivity (70%, 95% CI 62% to 78%), with a 10% difference (95% CI 1% to 18%; p  = 0.027). For small bowel Crohn's disease extent, magnetic resonance enterography specificity (95%, 95% CI 85% to 98%) was significantly greater than ultrasonography specificity (81%, 95% CI 64% to 91%), with a 14% difference (95% CI 1% to 27%). For small bowel Crohn's disease presence, magnetic resonance enterography sensitivity (97%, 95% CI 91% to 99%) was significantly greater than ultrasonography sensitivity (92%, 95% CI 84% to 96%), with a 5% difference (95% CI 1% to 9%). For small bowel Crohn's disease presence, magnetic resonance enterography specificity was 96% (95% CI 86% to 99%) and ultrasonography specificity was 84% (95% CI 65% to 94%), with a 12% difference (95% CI 0% to 25%). Test sensitivities for small bowel Crohn's disease presence and extent were similar in the two cohorts. For colonic Crohn's disease presence in newly diagnosed participants, ultrasonography sensitivity (67%, 95% CI 49% to 81%) was significantly greater than magnetic resonance enterography sensitivity (47%, 95% CI 31% to 64%), with a 20% difference (95% CI 1% to 39%). For active small bowel Crohn's disease, magnetic resonance enterography sensitivity (96%, 95% CI 92% to 99%) was significantly greater than ultrasonography sensitivity (90%, 95% CI 82% to 95%), with a 6% difference (95% CI 2% to 11%). There was some disagreement between readers for both tests. A total of 88% of participants rated magnetic resonance enterography as very or fairly acceptable, which is significantly lower than the percentage (99%) of participants who did so for ultrasonography. Therapeutic decisions based on magnetic resonance enterography alone and ultrasonography alone agreed with the final decision in 122 out of 158 (77%) cases and 124 out of 158 (78%) cases, respectively. There were no differences in costs or quality-adjusted life-years between tests., Limitations: Magnetic resonance enterography and ultrasonography scans were interpreted by practitioners blinded to clinical data (but not participant cohort), which does not reflect use in clinical practice., Conclusions: Magnetic resonance enterography has higher accuracy for detecting the presence, extent and activity of small bowel Crohn's disease than ultrasonography does. Both tests have variable interobserver agreement and are broadly acceptable to participants, although ultrasonography produces less participant burden. Diagnostic impact and cost-effectiveness are similar. Recommendations for future work include investigation of the comparative utility of magnetic resonance enterography and ultrasonography for treatment response assessment and investigation of non-specific abdominal symptoms to confirm or refute Crohn's disease., Trial Registration: Current Controlled Trials ISRCTN03982913., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 42. See the NIHR Journals Library website for further project information., Competing Interests: Stuart A Taylor reports personal fees from Robarts Clinical Trials Inc. (London, ON, Canada) outside the submitted work. Simon Travis reports receiving fees for consultancy work and/or speaking engagements from the following: AbbVie Inc. (Chicago, IL, USA), Centocor Inc. (Horsham, PA, USA), Schering-Plough (Kenilworth, NJ, USA), Bristol-Myers Squibb (New York, NY, USA), Chemocentryx Inc. (Mountain View, CA, USA), Cosmo Pharmaceuticals (Dublin, Ireland), Elan Pharma Inc. (Dublin, Ireland), Genentech Inc. (San Francisco, CA, USA), Giuliani SpA (Milan, Italy), Merck & Co. Inc. (Kenilworth, NJ, USA), Takeda UK Ltd (Woodburn Green, Buckinghamshire, UK), Otsuka Pharmaceuticals (Tokyo, Japan), PDL BioPharma (Nevada, NV, USA), Pfizer Inc. (San Francisco, CA, USA), Shire Pharmaceuticals UK (St Helier, Jersey), Glenmark Pharmaceuticals (Maharashtra, India), Synthon Biopharmaceuticals (Nijmegen, the Netherlands), NPS Pharmaceuticals (Bedminster, NJ, USA), Eli Lilly and Company (Indiana, IN, USA), Warner Chilcott Ltd, Proximagen Group Ltd (London, UK), VHsquared Ltd (Cambridge, UK), Topivert Pharma Ltd (London, UK), Ferring Pharmaceuticals (Saint-Prex, Switzerland), Celgene Corporation (Summit, NJ, USA), GlaxoSmithKline plc (Brentford, UK), Amgen Inc. (Thousand Oaks, CA, USA), Biogen Inc. (Cambridge, MA, USA), Enterome SA (Paris, France), Immunocore Ltd (Oxford, UK), Immunometabolism/Third Rock Ventures (Boston, MA, USA), Bioclinica Inc. (Newtown, PA, USA), Boehringer Ingelheim GmBH (Ingelheim am Rhein, Germany), Gilead Sciences Inc. (Foster City, CA, USA), Grunenthal Ltd (Aachen, Germany), Janssen Pharmaceutica (Beerse, Belgium), Novartis AG (Basel, Switzerland), Receptos Inc. (San Diego, CA, USA), Pharm-Olam International UK Ltd (Bracknell, UK), Sigmoid Pharma (Dublin, Ireland), Theravance Biopharma Inc. (Dublin, Ireland), Given Imaging Ltd (Yokneam Illit, Israel), UCB Pharma SA (Brussels, Belgium), Tillotts Pharma AG (Rheinfelden, Switzerland), Sanofi Aventis SA (Paris, France), Vifor Pharma (St Gallen, Switzerland), Abbott Laboratories Ltd (Chicago, IL, USA) and Procter and Gamble Ltd (Cincinnati, OH, USA). Simon Travis reports directorships of charities IBD2020 (Barnet, UK; UK 09762150), Cure Crohn’s Colitis (Sydney, Australia; ABN 85 154 588 717) and the Truelove Foundation (London, UK; UK 11056711). Simon Travis also reports receiving fees from the following for expert testimony work and/or royalties: Santarus Inc. (San Diego, CA, USA), Cosmo Technologies Ltd (Dublin, Ireland), Tillotts Pharma AG, Wiley-Blackwell Inc. (Hoboken, NJ, USA), Elsevier Ltd (Amsterdam, the Netherlands) and Oxford University Press (Oxford, UK). Simon Travis has received research grants from the following: AbbVie Inc., the International Organization for the Study of Inflammatory Bowel Disease, Eli Lilly and Company, UCB Inc. (Brussels, Belgium), Vifor Pharma, Norman Collisson Foundation (Bicester, UK), Ferring Pharmaceuticals, Schering-Plough, Merck Sharpe & Dohme Corp. (Kenilworth, NJ, USA), Procter and Gamble Ltd, Warner Chilcott Ltd, Abbott Laboratories Ltd, PDL BioPharma Inc. (Incline Village, NV, USA), Takeda UK Ltd and the International Consortium for Health Care Outcomes Measurement. Ailsa Hart reports personal fees from AbbVie Inc., Atlantic Healthcare Ltd (Saffron Walden, UK), Bristol-Myers Squibb, Celltrion Inc. (Incheon, South Korea), Dr Falk Pharma UK Ltd (Bourne End, UK), Ferring Pharmaceuticals, Janssen Pharmaceuticals, Merck Sharpe & Dohme Corp., Napp Pharmaceuticals Ltd (Cambridge, UK), Pfizer Inc., Pharmacosmos A/S (Holbæk, Denmark), Shire Pharmaceuticals UK and Takeda UK Ltd, and non-financial support from Genentech Inc. Alastair Windsor reports personal fees from Takeda, grants from Allergan Inc. (Dublin, Ireland), personal fees from Allergan, personal fees from Cook Medical Inc. (Bloomington, IN, USA) and grants and personal fees from Bard Ltd (Crawley, UK) outside the submitted work. Andrew Plumb reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme outside the submitted work, grants from the NIHR Fellowships programme during the conduct of the study and honoraria for educational lectures delivered at events arranged by Acelity Inc. (Crawley, UK), Actavis Pharma Inc. (Parsippany-Troy Hills, NJ, USA), Dr Falk Pharma UK Ltd, Janssen-Cilag Ltd (High Wycombe, UK) and Takeda UK Ltd on the subject of inflammatory bowel disease. Ilan Jacobs reports share ownership in General Electric Company (Boston, MA, USA), which manufacturers and sells magnetic resonance imaging equipment. Charles D Murray reports personal fees from AbbVie Inc., Merck Sharpe & Dohme Corp. and Janssen Pharmaceutica outside the submitted work. Antony Higginson reports personal fees from Toshiba Corporation (Tokyo, Japan) outside the submitted work. Steve Halligan reports non-financial support from iCAD Inc. (Nashua, NH, USA) outside the submitted work, and sat on the HTA commissioning board (2008–14). Stephen Morris reports Health Services and Delivery Research (HSDR) Board membership (2014–18), HSDR Evidence Synthesis Sub Board membership (2016), HTA Commissioning Board membership (2009–13) and Public Health Research Board membership (2011–17).

Background: Magnetic resonance enterography (MRE) and ultrasound are used to image Crohn's disease, but their comparative accuracy for assessing disease extent and activity is not known with certainty. Therefore, we did a multicentre trial to address this issue., Methods: We recruited patients from eight UK hospitals. Eligible patients were 16 years or older, with newly diagnosed Crohn's disease or with established disease and suspected relapse. Consecutive patients had MRE and ultrasound in addition to standard investigations. Discrepancy between MRE and ultrasound for the presence of small bowel disease triggered an additional investigation, if not already available. The primary outcome was difference in per-patient sensitivity for small bowel disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). This trial is registered with the International Standard Randomised Controlled Trial, number ISRCTN03982913, and has been completed., Findings: 284 patients completed the trial (133 in the newly diagnosed group, 151 in the relapse group). Based on the reference standard, 233 (82%) patients had small bowel Crohn's disease. The sensitivity of MRE for small bowel disease extent (80% [95% CI 72-86]) and presence (97% [91-99]) were significantly greater than that of ultrasound (70% [62-78] for disease extent, 92% [84-96] for disease presence); a 10% (95% CI 1-18; p=0·027) difference for extent, and 5% (1-9; p=0·025) difference for presence. The specificity of MRE for small bowel disease extent (95% [85-98]) was significantly greater than that of ultrasound (81% [64-91]); a difference of 14% (1-27; p=0·039). The specificity for small bowel disease presence was 96% (95% CI 86-99) with MRE and 84% (65-94) with ultrasound (difference 12% [0-25]; p=0·054). There were no serious adverse events., Interpretation: Both MRE and ultrasound have high sensitivity for detecting small bowel disease presence and both are valid first-line investigations, and viable alternatives to ileocolonoscopy. However, in a national health service setting, MRE is generally the preferred radiological investigation when available because its sensitivity and specificity exceed ultrasound significantly., Funding: National Institute of Health and Research Health Technology Assessment., (Copyright © 2018 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: It is unclear whether adherence to prescribing standards has been achieved in inflammatory bowel disease (IBD)., Aim: To determine how prescribing of 5-aminosalicylates (5-ASAs), steroids and thiopurines has changed in response to emerging evidence., Methods: We examined trends in oral and topical therapies in 23 509 incident IBD cases (6997 with Crohn's disease and 16 512 with ulcerative colitis) using a nationally representative sample between 1990 and 2010. We created five eras according to the year of diagnosis: era 1 (1990-1993), era 2 (1994-1997), era 3 (1998-2001), era 4 (2002-2005) and era 5 (2006-2010). We calculated the proportion of patients treated with prolonged 5-ASAs (>12 months) and steroid dependency, defined as prolonged steroids (>3 months) or recurrent (restarting within 3 months) steroid exposure. We calculated the cumulative probability of receiving each medication using survival analysis., Results: Half of the Crohn's disease patients were prescribed prolonged oral 5-ASAs during the study, although this decreased between era 3 and 5 from 61.8% to 56.4% (P = 0.002). Thiopurine use increased from 14.0% to 47.1% (P < 0.001) between era 1 and 5. This coincided with a decrease in steroid dependency from 36.5% to 26.8% (P < 0.001) between era 1 and 2 and era 4 and 5 respectively. In ulcerative colitis, 49% of patients were maintained on prolonged oral 5-ASAs. Despite increasing thiopurine use, repeated steroid exposure increased from 15.3% to 17.8% (P = 0.02) between era 1 and 2 and era 4 and 5 respectively., Conclusions: Prescribing in clinical practice insufficiently mirrors the evidence base. Physicians should direct management towards reducing steroid dependency and optimising 5-ASA use in patients with IBD., (© 2016 John Wiley & Sons Ltd.)

Background: Little is known about the rates of perianal surgery (PAS) in Crohn's disease (CD). Our aim was to determine trends in PAS, the timing of surgery relative to the diagnosis of CD and to identify subgroups at risk of PAS., Materials and Methods: We identified 9391 incident cases of CD between 1989 and 2009. We defined three eras: era 1 (1989-1995), era 2 (1996-2002) and era 3 (2003-2009), and determined trends in procedure type and the time to first PAS relative to the date of diagnosis. We used Kaplan-Meier analysis to calculate the rate of first PAS and performed Cox regression to determine subgroups at risk of PAS., Results: Among the 9391 incident cases of CD, 405 (4.3%) underwent PAS. The overall rate of PAS was 5.5% [95% confidence interval (CI): 4.9-6.2%] 10 years after diagnosis. 34% (n=137) of all patients undergoing PAS had surgery in the 5 years before CD diagnosis. Abscess drainage increased from 34 to 58%, whereas proctectomy decreased from 16 to 6% between eras 1 and 3, respectively. Men [hazard rate (HR) 1.51, 95% CI: 1.24-1.84], those aged 17-40 years (HR 1.69, 95% CI: 1.09-2.02 vs. those aged >40 years) and those with a history of previous intestinal resection (HR 28.5, 95% CI: 22.2-36.5) were more likely to have PAS., Conclusion: Around one-third of patients have a PAS in the 5 years preceding their diagnosis of CD. Surgical practice has changed over 20 years, with a decrease in proctectomy and a concurrent increase in abscess drainage that is likely to reflect improvements in therapeutic practice.

Diagnostic imaging plays a key role in the diagnosis and management of inflammatory bowel disease (IBD). However due to the relapsing nature of IBD, there is growing concern that IBD patients may be exposed to potentially harmful cumulative levels of ionising radiation in their lifetime, increasing malignant potential in a population already at risk. In this review we explore the proportion of IBD patients exposed to high cumulative radiation doses, the risk factors associated with higher radiation exposures, and we compare conventional diagnostic imaging with newer radiation-free imaging techniques used in the evaluation of patients with IBD. While computed tomography (CT) performs well as an imaging modality for IBD, the effective radiation dose is considerably higher than other abdominal imaging modalities. It is increasingly recognised that CT imaging remains responsible for the majority of diagnostic medical radiation to which IBD patients are exposed. Magnetic resonance imaging (MRI) and small intestine contrast enhanced ultrasonography (SICUS) have now emerged as suitable radiation-free alternatives to CT imaging, with comparable diagnostic accuracy. The routine use of MRI and SICUS for the clinical evaluation of patients with known or suspected small bowel Crohn's disease is to be encouraged wherever possible. More provision is needed for out-of-hours radiation-free imaging modalities to reduce the need for CT.

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the large bowel and is associated with a significant risk of both requirement for surgery and the need for hospitalisation. Thiopurines, and more recently, anti-tumour necrosis factor (aTNF) therapy have been used successfully to induce clinical remission. However, there is less data available on whether these agents prevent long-term colectomy rates or the need for hospitalisation. The focus of this article is to review the recent and pertinent literature on the long-term impact of thiopurines and aTNF on long-term surgical and hospitalisation rates in UC. Data from population based longitudinal research indicates that thiopurine therapy probably has a protective role against colectomy, if used in appropriate patients for a sufficient duration. aTNF agents appear to have a short term protective effect against colectomy, but data is limited for longer periods. Whereas there is insufficient evidence that thiopurines affect hospitalisation, evidence favours that aTNF therapy probably reduces the risk of hospitalisation within the first year of use, but it is less clear on whether this effect continues beyond this period. More structured research needs to be conducted to answer these clinically important questions.

Background: The role of early thiopurine treatment in inflammatory bowel disease (IBD) is unproven., Aim: To quantify the impact of timing and duration of thiopurines on the risk of first surgery in children and young people with IBD using a population-based cohort., Methods: We constructed an incident cohort of children and young people aged <25 years, diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) from 1990 to 2009. We used Cox proportional hazards modelling to determine the impact of early thiopurine use, commenced within a year of diagnosis on risk of first surgery., Results: We identified 1595 and 1175 incident cases of CD and UC respectively with a mean length of follow-up of 4.3 years/person. There were 216 (13.5%) and 73 (6.2%) surgeries for CD and UC patients between 1990 and 2009 respectively. In CD among thiopurine users, the absolute risk of surgery at 5 years for early thiopurine use vs. late was 15.3% (95% CI: 10.5-22.1) vs. 22.1% (95% CI: 18.1-26.9) respectively. After adjustment, the early use of thiopurines was associated with a reduction in risk of first surgery of 39% (HR 0.61, 95% CI: 0.41-0.91) over the 20-year study period. In UC, early thiopurine use offered no additional benefit., Conclusions: In Crohn's disease, early treatment with thiopurines in children and young people is associated with an appreciable reduction in the risk of surgery, but early treatment does not reduce surgical risk in UC., (© 2015 John Wiley & Sons Ltd.)

Background: The impact of thiopurine (TP) use on perianal surgery is uncertain. Our aim was to determine trends in perianal surgery and the impact of timing and duration of TPs on the risk of first perianal surgery., Methods: We identified a population-based cohort of incident cases of Crohn's disease between 1995 and 2009. We used Kaplan-Meier analysis to determine trends in TP usage and first perianal surgery by era of diagnosis: era 1 (1995-2002) and era 2 (2003-2009). We quantified the impact of duration and timing of TPs on the risk of perianal surgery using a Cox regression model., Results: We identified a cohort of 5235 incident cases of Crohn's disease. The 5-year cumulative probability of first perianal surgery decreased from 2.7% to 1.7% between era 1 and era 2, respectively (P = 0.03). TP use for greater than 18 months was associated with a 40% risk reduction for first perianal surgery (hazard ratio: 0.60, 95% confidence interval: 0.39-0.95) and 49% if TPs were used for 2 years or more (hazard ratio: 0.51, 95% confidence interval: 0.32-0.99). There was no demonstrable additional benefit from early TP use within the first year after diagnosis (hazard ratio: 0.85, 95% confidence interval: 0.52-1.40, P = 0.53)., Conclusions: Over the past 15 years, TP use has increased by 50%, whereas perianal surgery rates have decreased by 37% among UK population with Crohn's disease. Sustained use for 18 months was associated with a reduced risk of perianal surgery by almost a half in the first 5 years after diagnosis.

Background: The role of thiopurines in altering the risk of colectomy in ulcerative colitis (UC) remains unclear., Aims: To examine predictors of colectomy in UC and determine the impact of thiopurines on the risk of colectomy., Methods: We constructed a population-based cohort of incident cases of UC in the United Kingdom between 1989 and 2009. We determined trends in thiopurine usage and colectomy for three defined cohorts: era 1 (1989-1995), era 2 (1996-2002), era 3 (2003-2009). We used Cox regression to determine predictors of colectomy and quantified the impact of duration and timing of thiopurine use on the risk of colectomy., Results: We identified 8673 incident cases of UC. 5-year colectomy rates increased from 4.2%, 5.1% to 6.9% (P = 0.001) for era 1, era 2 and era 3, respectively, despite increasing thiopurine use. This was not significant after adjustment for predictors of colectomy (P = 0.06). There was a higher risk of colectomy in men (HR 1.44, 95% CI: 1.19-1.73), those diagnosed at an early age (HR 1.35, 95% CI: 1.04-1.75; 16-24 vs. 25-64) and early steroid users (HR 1.94, 95% CI: 1.59-2.37). 5-ASA users were less likely to require a colectomy (HR 0.35, 95% CI: 0.28-0.44). Amongst thiopurine users, those treated for greater than 12 months had a 71% reduction in risk of colectomy (HR 0.29, 95% CI: 0.21-0.40). Early thiopurines offered no additional benefit., Conclusions: Thiopurine exposure for greater than 12 months reduces the likelihood of colectomy by 71%. Young men and those requiring steroids within 3 months of diagnosis are at greatest risk of colectomy, and most likely to benefit from sustained thiopurine use., (© 2014 John Wiley & Sons Ltd.)

Objectives: The efficacy of thiopurines (TPs) in altering the risk of surgery in Crohn's disease (CD) remains controversial. We evaluated the impact of TP therapy, optimal timing, and duration of TP therapy on first intestinal resection rates using a population-based cohort., Methods: We constructed a population-based cohort of incident cases of CD between 1989 and 2005. We used the Kaplan-Meier analysis to calculate time trends in TP use and first intestinal resection in three groups defined by time period of diagnosis: 1989-1993, 1994-1999, and 2000-2005 groups A, B, and C, respectively. We quantified impact of duration and timing of TP treatment on likelihood of surgery using Cox regression and propensity score matching., Results: We identified 5,640 eligible patients with CD. The 5-year cumulative probability of TP use increased from 12, 18, to 25% ( P<0.0001) while probability of first intestinal resection decreased from 15, 12 to 9% (P<0.001) in groups A, B, and C, respectively. Patients treated with at least 6 months of TP therapy had a 44% reduction in the risk of surgery (hazards ratio (HR): 0.56; 95% confidence interval (CI): 0.37-0.85) and those receiving at least 12 months of TP therapy had a 69% reduction in the risk of surgery (HR: 0.31; 95% CI: 0.22-0.44). Early treatment (<12 months from diagnosis) vs. late treatment with TP showed no additional benefit in reducing risk of surgery (HR: 0.41; 95% CI: 0.27-0.61 vs. 0.21; 95% CI: 0.13-0.34)., Conclusions: Over the past 20 years, TP use has doubled, whereas intestinal surgery has fallen by one-third among the UK population of Crohn's patients. Prolonged exposure is associated with a reduced likelihood of surgery whereby more than 12 months TP therapy reduces the risk of first intestinal surgery two-fold; however, early initiation of TP treatment offered no apparent additional benefit.

Objectives: The thiopurine (TP) analogs azathioprine and mercaptopurine have proven efficacy in inducing and maintaining clinical remission in Crohn's disease (CD). Their impact on the long-term need for surgery is uncertain since studies have reported conflicting results. The aim of this systematic review was to summarize and evaluate evidence of the published literature regarding those studies assessing the impact of TPs on the risk of first surgical resection in CD., Methods: We searched Medline, EMBASE, CINAHL, and hand searched reference lists of identified articles, without language restrictions in August 2013., Results: Seventeen retrospective observational studies (eight population based, three multicenter, and six referral center) representing 21,632 participants met our inclusion criteria. Of these 10 studies involving 12,586 participants provided data on the hazard ratio (HR) and 95% confidence intervals (CIs) evaluating use of TPs and surgical risk. The combined pooled HR of first intestinal resection with TP use was 0.59 (95% CI 0.48-0.73)., Conclusions: TP use is associated with a 40% lowered risk of surgical resection in patients with CD. Despite significant reductions in rates of surgical resection in patients with CD over the last 5 decades and increasing use of TPs, a large proportion of patients with CD still require resectional surgery.

Objectives: Increasing use of diagnostic imaging in inflammatory bowel disease (IBD) has led to concerns about the malignant potential of ionising radiation in a cohort that have an increased lifetime risk of gastrointestinal malignancy. The aim was to quantify radiation exposure in IBD patients referred from primary care, determine predictors of high exposure and evaluate temporal trends in diagnostic imaging over a 20-year period., Methods: This was a retrospective cohort study whereby IBD patients were recruited from the outpatient clinic and evaluated retrospectively. The total cumulative effective dose (CED) received from tests was calculated for each subject. Cox regression was performed to assess factors associated with potentially harmful levels of ionising radiation defined as total CED > 50 milli-sieverts (mSv; equivalent to five CT abdomen scans)., Results: The cohort included 415 patients. Median total CED was 7.2 mSv (IQR: 3.0-22.7) in Crohn's disease and 2.8 mSv (IQR: 0.8-8.9) in ulcerative colitis patients, respectively. A total of 32 patients (8%) received a CED > 50 mSv. A history of IBD-related surgery was associated with high exposure (HR 7.7). During the study period, usage of abdominal CT increased by 310%., Conclusion: Approximately 1 in 13 patients in the study cohort were exposed to potentially harmful levels of ionising radiation. Strategies to minimise exposure to diagnostic medical radiation in IBD patients are required., (© 2013 John Wiley & Sons Ltd.)

Objective: The aim of this study was to determine the prevalence of vitamin D deficiency in a multicultural inflammatory bowel disease (IBD) cohort and determine predictors of deficiency including ethnicity., Design: Patients with IBD were recruited into a dedicated database over a 6-month period and evaluated retrospectively., Setting: Department of Gastroenterology, St George's University Hospital, London, UK., Outcomes Measured: Clinical data including demographics, ethnic group, disease phenotype by the Montreal classification, vitamin D level and season tested were recorded from clinical and electronic medical records. Vitamin D levels were classified as normal (≥50 nmol/l) and deficient (<50 nmol/l)., Results: 168 patients had a vitamin D level measured subsequent to diagnosis. There was no significant difference in the median vitamin D level between patients with Crohn's disease (CD) and ulcerative colitis (UC) (39 nmol/l (IQR 23-56) vs 28 nmol/l (IQR 17-51), p=0.35). Overall the median vitamin D level was significantly lower in non-Caucasians (Asian and Black) versus Caucasians (28 nmol/l (IQR 17-41) vs 41 nmol/l (IQR 25-63), p<0.0001). Multiple regression analysis revealed IBD related surgery (OR 2.9) and ethnicity (OR 6.0 non-Caucasian vs Caucasian) in CD and ethnicity (OR 5.0 non-Caucasian vs Caucasian) in UC were independently associated with vitamin D deficiency., Conclusions: Vitamin D deficiency is common in IBD patients; therefore, we suggest monitoring of vitamin D levels and correction with supplements especially in non-Caucasians and those with a history of IBD related surgery.

Background: Diagnostic imaging plays a pivotal role in the diagnosis and management of inflammatory bowel disease (IBD); however, increasing use has led to concerns about the malignant potential of ionising radiation. Several studies have demonstrated that diagnostic imaging can result in exposure to potentially harmful levels of ionising radiation in IBD patients., Aim: To determine the pooled prevalence of increased exposure and pooled odds ratio of risk factors associated with exposure to potentially harmful levels of diagnostic medical radiation., Methods: We searched Medline, EMBASE, CINHAL and reference lists of identified articles, without language restrictions in October 2011., Results: Six studies with 1704 participants provided data on the proportion of patients receiving potentially harmful levels of radiation defined as ≥50 milli-sieverts (mSv)-equivalent to 5 CT abdomen scans. The pooled prevalence was 8.8% (95% CI 4.4-16.8) for IBD patients and 11.1% (95% CI 5.7-20.5%) and 2% (95% CI 0.8-4.9%) for Crohn's disease and ulcerative colitis patients respectively. Five studies involving 2627 participants provided data for risk factors. IBD-related surgery and corticosteroid use were significant with pooled adjusted odds ratio of 5.4 (95% CI 2.6-11.2) and 2.4 (95% CI 1.7-3.4) respectively., Conclusions: About 1 in 10 patients may be exposed to potentially harmful levels of diagnostic medical radiation. Corticosteroid use and IBD related surgery increased this risk. Strategies to reduce radiation exposure while assessing disease activity need to be considered., (© 2012 Blackwell Publishing Ltd.)

Background: Clostridium difficile (C. difficile) infection in hospitals in developed countries continues to be a major public health hazard despite increased control measures including review of antibiotic policies and hygiene measures. Patients with colitis are thought to be particularly vulnerable to C. difficile associated diarrhoea (CDAD). Identifying the clinical burden among hospitalised patients admitted with inflammatory bowel disease is an essential first step towards identifying and treating severe C. difficile infection in such individuals., Aim: To determine excess morbidity and in-hospital mortality associated with hospital acquired CDAD in patients with inflammatory bowel disease (IBD-CDAD-HAI) admitted to NHS hospitals in England compared with those admitted for inflammatory bowel disease alone., Methods: Time trends study of all admissions to NHS hospitals between 2002/03 and 2007/08. We developed case definitions for IBD-CDAD-HAI patients. The primary outcomes were in-hospital mortality and length of stay. The secondary outcome was gastrointestinal surgery., Results: Patients in the IBD-CDAD-HAI group were more likely to die in hospital (adjusted OR 6.32), had 27.9 days longer in-patient stays and higher gastrointestinal surgery rates (adjusted OR 1.87) than patients admitted for inflammatory bowel disease alone., Conclusion: Patients with inflammatory bowel disease admitted to NHS hospitals in England with co-existent C. difficile infection are at risk of greater in-hospital mortality and morbidity than patients admitted for inflammatory bowel disease alone., (© 2011 Blackwell Publishing Ltd.)

Context: Corticosteroids are the mainstay of medical therapies to induce remission in acute episodes of inflammatory bowel disease (IBD). However, evidence suggests that this may increase the risk of postoperative complications among patients with IBD who go on to have abdominal surgery., Objective: To estimate the risk of postoperative complications following abdominal surgery in patients with IBD on steroids at the time of abdominal surgery., Design: Meta-analysis of observational studies., Methods: We searched medical electronic databases for full journal articles published after 1965 reporting on postoperative complications in patients with IBD undergoing abdominal surgery provided they compared patients treated with steroids with those not on steroids. We hand searched the reference lists of all retrieved articles. Two independent reviewers extracted data from studies meeting the inclusion criteria and any discrepancies were resolved by discussion. We carried out fixed effects meta-analysis, funnel plot and sensitivity analyses., Results: A total of seven observational studies involving 1,532 patients met the inclusion criteria for risk of total complications, and five observational studies involving 1,714 patients met the inclusion criteria for risk of infectious complications. Pooled analysis showed an increased risk of all postoperative complications (OR 1.41, 95% confidence interval 1.07-1.87), as well as an increased risk of postoperative infectious complications (OR 1.68, 95% confidence interval 1.24-2.28) among patients on steroids. Patients who received higher doses of perioperative oral steroids (>40 mg) had a higher risk of total complications (OR 2.04 (95% CI 1.28-3.26)., Conclusions: There is an increased risk of total as well as infectious complications following the use of steroids in patients with IBD.

Background: Assessing the extent of ulcerative colitis determines therapeutic strategies and provides prognostic information. Colonoscopy with mucosal biopsy is considered unsafe in patients with severe disease., Aim: To assess the correlation between proximal extent of ulcerative colitis as determined by Technitium-99-m hexamethylpropylene amine oxime labelled leucocyte scan (white cell scan) with that determined by histological assessment., Methods: One hundred and thirty-five patients, with histologically-confirmed ulcerative colitis, who had a white cell scan and histological assessment of colonic inflammation within 6 months of each other, during the years 1991-2004, were included. Overall agreement, quadratic-weighted kappa (kappa) and polychoric correlations (rho) were calculated to estimate the inter-rater reliability., Results: The correlation between white cell scan and histological extent was excellent (kappa = 0.7 rho = 0.8). Macroscopic appearance on colonoscopy did not correlate as well with histological extent (kappa = 0.62 and rho = 0.67). White cell scans correlated significantly better in patients with extensive disease (P = 0.02). Colonoscopy predicted disease extent more accurately in patients with limited colitis (P = 0.002)., Conclusions: Proximal extent of ulcerative colitis determined by white cell scans correlates well with histological assessment especially in patients with more extensive disease. White cell scans offer a reasonable alternative to colonoscopy with mucosal biopsies in determining the proximal extent of colitis.

Accumulating evidence suggests that intestinal epithelial cells (IECs) constitutively express the immunoregulatory cytokine interleukin (IL)-18. IECs also serve as the host cell for the intracellular parasitic protozoan Cryptosporidium parvum. In the present study, C. parvum infection of a human enterocyte cell-line HCT-8 resulted in increased expression of IL-18 mRNA as measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). IL-18 protein was detected in control uninfected cells and following infection there was increased expression as measured by enzyme-linked immunosorbent assay (ELISA). Gene expression revealed the presence of the IL-18 receptor subunits not only in cell-lines but also in freshly isolated IECs, suggesting that IL-18-mediated signalling events may contribute to epithelial host defence during infection. Recombinant IL-18 inhibited intracellular development of the parasite in HCT-8 and HT-29 cells. Increased expression of bactericidal antibiotic peptides LL-37 and alpha-defensin 2 by IL-18 in HCT-8 and HT-29 cells may represent one mode of action by which this pluripotent cytokine aids in limiting the development of intracellular pathogens such as C. parvum in the gastrointestinal tract.

Background: This systematic review examined the use of immunomodulators and the risk of postoperative complications after abdominal surgery in patients with inflammatory bowel disease., Methods: Electronic databases (PubMed, Embase, Ingenta, Zetoc and Ovid) were searched and the reference lists in all articles identified were hand-searched for further relevant papers. Studies were included if they evaluated postoperative complications and defined exposure to individual immunomodulators., Results: All 11 studies that met the inclusion criteria were observational studies; two were reported only in abstract form. Five studies reported risks associated with azathioprine, five reported risks associated with cyclosporin and three reported risks associated with infliximab. None showed an increased risk of either total or infectious complications associated with immunomodulator use. However, subgroup analysis in one study, published as an abstract, suggested increased rates of anastomotic complications and reoperation associated with azathioprine., Conclusion: Available evidence does not suggest an increased rate of postoperative complications associated with immunomodulator use., (Copyright 2006 British Journal of Surgery Society Ltd.)

We present four cases of acute mesenteric infarction in patients with active ulcerative colitis: one presenting prior to the diagnosis of ulcerative colitis, two at the time of diagnosis, and one many years after the diagnosis had been made. Intestinal ischaemia is an important part of the differential diagnosis in patients with ulcerative colitis presenting with abdominal pain. Conversely, in patients presenting with bloody diarrhoea after mesenteric ischaemia, ulcerative colitis should be considered.

Protozoa infections are an important cause of chronic diarrhea in patients infected with HIV. The introduction of highly active antiretroviral treatment to the management of HIV in the mid 1990s has led to a dramatic reduction in the incidence of these opportunistic infections in Europe and America. In contrast, in the developing world where such treatments are not readily affordable, protozoa-related diarrhea remains a major cause of morbidity and mortality in HIV-infected individuals. In this review, the optimum investigations required to diagnose these pathogens in HIV-related diarrhea, as well as current treatment options, will be discussed.

It was shown previously that enterocytes activated by gamma interferon (IFN-gamma) are efficient effector cells in the killing of Cryptosporidium parvum. How this function is regulated is not clearly understood, but transforming growth factor beta (TGF-beta) and the Th2 regulatory cytokines may play a role. Using an in vitro cell culture system, we investigated how the key regulatory cytokines interleukin-4 (IL-4), IL-10, IL-13, and TGF-beta might modulate the effect of IFN-gamma in inducing resistance to infection in enterocyte cell lines. The results showed that TGF-beta can abolish the inhibitory effect on C. parvum development and that neither IL-13 nor IL-10 influenced the action of IFN-gamma. In contrast, IL-4 cooperated with low concentrations of IFN-gamma (1 and 10 U/ml) to enhance parasite killing. One mechanism that appeared to be involved in the combined activity of IFN-gamma and IL-4 was intracellular Fe(2+) deprivation, but induction of nitric oxide production was not involved. In one cell line, the extents and durations of phosphorylation of STAT1, a transcription factor involved in IFN-gamma signaling, were similar when cells were stimulated with IFN-gamma alone and with IFN-gamma and IL-4 gamma, suggesting that the cooperative effect of the cytokines was not related to STAT1 activation. The effects of the presence of TGF-beta and IL-4 on IFN-gamma function did not appear to involve any alteration in the level of expression of IFN-gamma receptors.