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Objective: The measure of serum proteome in the preclinical state of Crohn's disease (CD) may provide insight into biological pathways involved in CD pathogenesis. We aimed to assess associations of serum proteins with future CD onset and with other biomarkers predicting CD risk in a healthy at-risk cohort., Design: In a nested case-control study within the Crohn's and Colitis Canada Genetics Environment Microbial Project (CCC-GEM) cohort, which prospectively follows healthy first-degree relatives (FDRs), subjects who developed CD (n=71) were matched with four FDRs remaining healthy (n=284). Using samples at recruitment, serum protein profiles using the Olink Proximity Extension Assay platform was assessed for association with future development of CD and with other baseline biomarkers as follows: serum antimicrobial antibodies (AS: positive antibody sum) (Prometheus); faecal calprotectin (FCP); gut barrier function using the fractional excretion of lactulose-to-mannitol ratio (LMR) assay., Results: We identified 25 of 446 serum proteins significantly associated with future development of CD. C-X-C motif chemokine 9 (CXCL9) had the highest OR with future risk of CD (OR=2.07 per SD, 95% CI 1.58 to 2.73, q=7.9e-5), whereas matrix extracellular phosphoglycoprotein had the lowest OR (OR 0.44, 95% CI 0.29 to 0.66, q=0.02). Notably, CXCL9 was the only analyte significantly associated with all other CD-risk biomarkers with consistent direction of effect (FCP: OR=2.21; LMR: OR=1.67; AS: OR=1.59) (q<0.05 for all)., Conclusion: We identified serum proteomic signatures associated with future CD development, reflecting potential early biological processes of immune and barrier dysfunction., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity., Methods: Using a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies., Results: PHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients' risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy., Conclusions: PHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission., Competing Interests: Competing interests: None declared., (© 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.)

Competing Interests: Competing interests: WJS reports: research grants from Abbvie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, Glaxo Smith Kline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, Theravance Biopharma; consulting fees from Abbvie, Abivax, Admirx, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Meyers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma; and stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Biosciences. Spouse: Iveric Bio—consultant, stock options; Progenity—stock; Oppilan Pharma—consultant, stock options; Prometheus Biosciences—employee, stock, stock options; Ventyx Biosciences—stock, stock options; Vimalan Biosciences—stock, stock options. SS reports speaker, advisory and consulting roles for AbbVie, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Eisai Medical Research, Eli Lilly, Ferring, Genentech, Gilead, Janssen, Merck, Pfizer, Shire Pharmaceuticals, Sandoz, Takeda, Tillotts, RP reports Consultant for: AbbVie, AGI Therapeutics, Alba Therapeutics, Amgen, Astellas, Athersys, Atlantic Healthcare, BioBalance, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eisai Medical Research, Elan, EnGene, Eli Lilly, Enteromedics, Ferring, Flexion Therapeutics, Genentech, Genzyme, Gilead, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood, Janssen, Merck & Co., Merck Research Laboratories, MerckSerono, Nisshin Kyorin, Novo Nordisk, NPS Pharmaceuticals, Optimer, Orexigen, PDL Biopharma, Pfizer, Procter and Gamble, Santarus, Shire Pharmaceuticals, Sigmoid Pharma, Sirtris (a GSK company), Sandoz, S.L.A. Pharma (UK), Targacept, Teva, Therakos, Tillotts, TxCell SA, Speaker’s fees for Abbvie, Amgen, Celgene, Ferring, Janssen, Merck, Novartis, Pfizer, Prometheus, Sandoz, Shire, Takeda Advisory board attendance for Abbvie, Abbott, Allergan, Amgen,Biogen Idec, Eisai, Ferring, Genentech, Janssen, Merck, Shire, Elan, GlaxoSmithKline, Hospira, Pfizer, Bristol-Myers Squibb, Takeda, Cubist, Celgene, Salix, Roche. Research/educational support from Abbvie, Ferring, Janssen, Shire Takeda. SD has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor. LP-B has served as a speaker, consultant and advisory board member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, HAC Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis, Theravance.

Objective: To evaluate the cost-effectiveness of an inflammatory biomarker and clinical symptom directed tight control strategy (TC) compared with symptom-based clinical management (CM) in patients with Crohn's disease (CD) naïve to immunosuppressants and biologics using a UK public payer perspective., Design: A regression model estimated weekly CD Activity Index (CDAI)-based transition matrices (remission: CDAI <150, moderate: CDAI ≥150 to <300, severe: CDAI ≥300 to <450, very severe: CDAI ≥450) based on the Effect of Tight Control Management on Crohn's Disease (CALM) trial. A regression predicted hospitalisations. Health utilities and costs were applied to health states. Work productivity was monetised and included in sensitivity analyses. Remission rate, CD-related hospitalisations, adalimumab injections, other direct medical costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated., Results: Over 48 weeks, TC was associated with a higher clinical remission (CDAI <150) rate (58.2% vs 46.8%), fewer CD-related hospitalisations (0.124 vs 0.297 events per patient) and more injections of adalimumab (40 mg sc) (mean 31.0 vs 24.7) than CM. TC was associated with 0.032 higher QALYs and £593 higher total medical costs. The ICER was £18 656 per QALY. The ICER was cost-effective in 57.9% of simulations. TC became dominant, meaning less costly but more effective, when work productivity was included., Conclusion: A TC strategy as used in the CALM trial is cost-effective compared with CM. Incorporating costs related to work productivity increases the economic value of TC. Cross-national inferences from this analysis should be made with caution given differences in healthcare systems., Trial Registration Number: NCT01235689; Results., Competing Interests: Competing interests: RP has received consultant and/or lecture fees from AbbVie, Amgen, AstraZeneca, Axcan Pharma (now Aptalis), Biogen Idec, Bristol-Myers Squibb, Centocor, ChemoCentryx, Eisai Medical Research Inc, Elan Pharmaceuticals, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck Sharp & Dohme Corp, Millennium Pharmaceuticals Inc (now Takeda), Ocera Therapeutics Inc, Otsuka America Pharmaceutical, Pfizer, Shire Pharmaceuticals, Prometheus Laboratories, Schering-Plough Corporation, Synta Pharmaceuticals Corp, Teva, UCB Pharma and Warner Chilcott. J-FC has been a consultant or advisory board member for AbbVie, Amgen, Boehringer-Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring, Genentech, Janssen and Janssen, Medimmune, Merck & Co, Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda, Theradiag, speaker for AbbVie, Ferring, speaker’s bureau for Amgen, stock options of Intestinal Biotech Development, Genefit. Research Grants: AbbVie, Takeda, Janssen and Janssen. SPLT has been a consultant or advisory board member for AbbVie, Ajinomoto, Amgen, Almirall, Asahi, Atlantic, Bioclinica, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Calcico, Celgene, Chemocentryx, Cosmo, Covance, Enterome, Falk, Ferring, Genentech, Gilead, Giuliani SpA, GlaxoSmithKline, Glenmark, Grunenthal, Immunocore, Immunometabolism, Istesso, Janssen, Lexicon, Lilly, Medarex, Merck, MSD, Napp, Neovacs, NovoNordisk, Novartis, NPS Pharmaceuticals, Ocera, Otsuka, Pfizer, PharmOlam, Phillips, Proximagen, Qunitiles, Receptos, Robarts, Roche, Sandoz, Shire, Sigmoid Pharma, Takeda, Theravance, TiGenix, Topivert, UCB, Warner Chillcott, Vertex, VHsquared, Vifor and Zeria; speaker for AbbVie, Amgen, Biogen, Ferring, Sandoz, Takeda, Zeria; and received research grants from AbbVie, Buhlmann, Lilly, MediAdd, UCB, Vifor and the Norman Collisson Foundation. PB has received educational grants from AbbVie, Janssens; speaker fees from AbbVie, Takeda and MSD; and advisory board fees from Abbvie, Hospira, Janssen, MSD, Mundipharma, Roche, Pfizer and Dr Falk Benelux. FB has received research grants from Abbvie, Chiesi, Ipsen, MSD, Roche, speakers and consultancy fees from Abbvie, Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, and Vifor. TV has served as advisory member for Hospira, Pfizer and Takeda, has received lecture fees from Takeda. GN has served as a consultant/advisory board member/speaker for AbbVie, MSD, Takeda, Ferring, Vifor, Merck, Janssen and Pfizer. AA has served as a consultant or advisory member for AbbVie, Allergan, Amgen, Biogen, Celgene, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Pfizer, Samsung Bioepis, Sofar and Takeda, has received lecture fees from AbbVie, AstraZeneca, Chiesi, Ferring, Hospira, Medtronic, MSD, Mitsubishi Tanabe, Mundipharma, Nikkiso, Otsuka, Pfizer, Takeda, Tigenix and Zambon, has received research funding from MSD and Takeda. WR has served as a speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult; as a consultant for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, Elan, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, Mallinckrodt, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Schering-Plough, Second Genome, Setpointmedical, Sigmoid, Takeda, Therakos, Tigenix, UCB, Vifor, Zyngenia and 4SC; as an advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zyngenia, and 4SC; and has received research funding from Abbott Laboratories, Abbvie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnsotik, and MSD. SJ and MB are employees of Medicus Economics LLC which was paid fees by AbbVie to conduct the research in the manuscript. EN, JP and W-JL are AbbVie employees and may own AbbVie stock and/or options. GRD’H is a consultant for AbbVie, ActoGeniX NV, AGI Therapeutics, Inc, Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas, Athersys, Inc, Atlantic Healthcare Limited, Aptalis, BioBalance Corporation, Boehringer Ingelheim, Inc, Bristol-Myers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine PharmaSciences, Eagle Pharmaceuticals, Eisai Medical Research Inc, Elan Pharmaceuticals, enGene, Inc, Eli Lilly, EnteroMedics, Exagen Diagnostics, Inc, Ferring Pharmaceuticals, Flexion Therapeutics, Inc, Funxional Therapeutics Limited, Genzyme Corporation, Genentech, Gilead Sciences, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals, Janssen, KaloBios Pharmaceuticals, Inc, Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals, Merck Research Laboratories, Merck Serono, Merck & Co., Millennium, Nisshin Kyorin Pharmaceuticals Co, Ltd, Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL BioPharma, Pfizer, Procter & Gamble, Prometheus Laboratories, ProtAb Limited, PurGenesis Technologies, Inc, Receptos, Relypsa, Inc, Salient Pharmaceuticals, Salix Pharmaceuticals, Inc, Santarus, Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals, Inc (a GSK company), SLA Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG, TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Limited (VBL) and Warner Chilcott UK Limited; has received speaker fees from AbbVie, Bristol-Myers Squibb and Janssen; and has received financial support for research from AbbVie, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Millennium, Novartis, Pfizer, Procter & Gamble Pharmaceuticals, Shire Pharmaceuticals and UCB Pharma., (© 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.)

Objective: Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn's disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported., Design: Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study : 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study : PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up., Results: 247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn's Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis., Conclusions: PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development., Trial Registration Number: NCT01287897 and NCT01345318., Competing Interests: Competing interests: SD is a speaker, consultant and advisory board member for Abbott Laboratories, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Hospira, Johnson and Johnson, Merck & Co, Millennium Takeda, Mundipharma, Novo Nordisk, Nycomed, Pharmacosmos, Pfizer, Schering-Plough, UCB Pharma and Vifor. SV received research support from AbbVie, MSD and Takeda and received consultancy and/or speaker honoraria from AbbVie, Celgene, Centocor, Ferring, Galapagos, Genentech/Roche, Hospira, MSD, Mundipharma, Pfizer, Shire and Takeda. PH is a consultant and/or advisory board participant for, and/or has received speaker honoraria, research support and/or educational grants from, Cubist, Evoke, Ferring, Forest, Furiex, Gilead, GlaxoSmithKline, Intercept, Ironwood, Menarini, Nature Coast Clinical Research, Pfizer, Rhythm, Salix, Synergy, Takeda, Theravance and Vivus. RP is a consultant for and/or received lecture fees from Abbott, AbbVie, Allergan, Amgen, AstraZeneca, Axcan Pharma, Biogen Idec, Bristol-Myers Squibb, Centocor, ChemoCentryx, Eisai Medical Research, ELAN, Ferring, Genentech, GlaxoSmithKline, Janssen, Millennium, MSD, Ocera Therapeutics, Otsuka America Pharmaceuticals, Pfizer, Shire Pharmaceuticals, Prometheus, Robarts Clinical Trials, Schering-Plough, Synta Pharmaceuticals, Takeda, Teva, UCB Pharma and Warner Chilcott. GR is a consultant for Abbott, AbbVie, Augurix, Boehringer, Calypso, FALK, Ferring, Fisher, Genentech, Essex/MSD, Novartis, Pfizer, Phadia, Roche, Takeda, Tillots, UCB, Vifor, Vital Solutions and Zeller; received speaker honoraria from AstraZeneca, Abbott, AbbVie, FALK, MSD, Phadia, Tillots, UCB and Vifor; and received educational grants and research grants from Abbot, AbbVie, Ardeypharm, Augurix, Calypso, Essex/MSD, FALK, Flamentera, Novartis, Roche, Takeda, Tillots, UCB and Zeller. AK received educational grants from AbbVie, MSD and Takeda. PD participated in advisory boards for, and received fees and grants from, AbbVie, Biofortis, BioMérieux Danone, Ferring, Genfit, Intralytix, Kitozyme, Lesaffre, MSD, Norgine, OmegaPharma International, Pileje, PPM, Roquette, Takeda and TxCell. RWL participated in advisory boards for AbbVie, Aspen, Ferring, Janssen, Hospira and Takeda and received research support from Janssen, NHMRC Career Development Fellowship and Shire. SS received consultancy fees from AbbVie, Bristol-Myers Squibb, Boehringer, Ferring, Genentech/Roche, Pfizer, MSD/Janssen, Takeda and UCB and lecture fees from AbbVie, MSD/Janssen, Takeda and UCB. AB, MKM, CL, NR and JB are all employees of Pfizer Inc and hold stock or options in Pfizer Inc. GMC and FC are former employees of Pfizer Inc and FC is a current employee of Shire Pharmaceuticals. GF has no conflicts of interest to report. GMC has been a consultant for Adare, Albireo, AstraZeneca, CinRx, Cutis, OrphoMed, Second Genome, Strongbridge and Zealand., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Perianal fistulae in patients with Crohn's disease (CD) can be associated with significant morbidity resulting in negative impact on quality of life. The last two decades have seen significant advancements in the management of perianal fistulas in CD, which has evolved into a multidisciplinary approach that includes gastroenterologists, colorectal surgeons, endoscopists and radiologists. Despite the introduction of new medical therapies such as antitumour necrosis factor and novel models of care delivery, the best fistula healing rates reported with combined medical and surgical approaches are approximately 50%. More recently, newer biologics, cell-based therapies as well as novel endoscopic and surgical techniques have been introduced raising new hopes that outcomes can be improved upon. In this review, we describe the modern management and the most recent advances in the management of complex perianal fistulising CD, which will likely impact clinical practice. We will explore optimal use of both older and newer biological agents, as well as new data on cell-based therapies. In addition, new techniques in endoscopic and surgical approaches will be discussed., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background and Aim: Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC., Methods: Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute., Results: For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities., Conclusions: Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD., Competing Interests: Competing interests: Phase 1 was funded thanks to an unrestricted educational grant to IOIBD from AbbVie and Tillotts. CAS has served as a consultant on advisory boards for AbbVie, Amgen, Lilly, Janssen, Sandoz, Pfizer, Prometheus, Takeda, Theradiag and UCB; as a speaker for American Regent, AbbVie, Janssen, Pfizer and Takeda; and receives grant support from AbbVie, Janssen and Takeda. BMRS has research grants from Shire and Takeda. BF has served as a consultant for Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics, Avir Pharma, Axcan, Baxter Healthcare, Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging, GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma, Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared, Warner-Chilcott, Wyeth, Zealand and Zyngenia; has been a speaker for Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott and UCB Pharma; has served on advisory boards for Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics, Bristol-Myers Squibb, Celgene, Centocor, Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG and UCB Pharma; receives research funding from Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts and UCB Pharma; and serves on the board of directors for Robarts Clinical Trials. BS has served as a consultant for AbbVie, Celgene, Janssen Biotech, MedImmune, Takeda, Pfizer, TiGenix, Bristol-Myers Squibb, Receptos, Akros Pharma, Arena Pharmaceuticals, Theravance Biopharma R&D, Boehringer-Ingelheim, Synergy Pharmaceuticals, Toplvert Pharma, UCB and Lilly; has served on scientific advisory boards for Celgene, Janssen Biotech, MedImmune, Takeda, Pfizer, TiGenix and Lily; and he receives research funding from Celgene, Janssen Biotech, MedImmune, Takeda and Pfizer. EVL has consulted for UCB Pharma, Takeda, Janssen, AbbVie, Genentech, Celgene, Amgen, Mesoblast, Theradiag, Sun Pharma and Seres Health; has received research support from UCB Pharma, Takeda, Janssen, AbbVie, Genentech, Celgene, Amgen, Pfizer, Receptos, Gilead and Robarts Clinical Trials. RP has served as a consultant for Abbvie/Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Eisai, Ferring, Janssen, Merck, Schering-Plough, Shire, Centocor, Elan, Glaxo-Smith Kline, UCB, Pfizer, Bristol-Myers Squibb, Warmer Chilcot, Takeda, Cubist and Celgene; on speaker's bureaus for Abbvie/Abbott, AstraZeneca, Janssen, Schering-Plough, Shire, Centocor, Elan, Prometheus, Warner Chilcott and Takeda; on advisory boards for Abbvie/Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Eisai, Ferring, Genentech, Janssen, Merck, Schering-Plough, Shire, Centocor, Elan, Glaxo-Smith Kline, UCB, Pfizer, Bristol-Myers Squibb, Warner Chilcott, Takeda, Cubist, Celgene and Salix; and receives research/educational support from Abbvie, Abbott, Ferring, Janssen, Schering-Plough, Centocor, Millenium, Elan, Proctor and Gamble and Bristol-Myers Squibb. GD has served as advisor for Abbvie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Bristol-Meyers Squibb, Boerhinger Ingelheim, Celgene, Celltrion, Cosmo, Covidien, Ferring, DrFALK Pharma, Engene, Galapagos, Gilead, Glaxo Smith Kline, Hospira, Johnson & Johnson, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Novonordisk, Pfizer, Prometheus laboratories/Nestle, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor; and received speaker fees from Abbvie, Ferring, Johnson & Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Shire, Millenium/Takeda, Tillotts and Vifor. CNB is supported in part by the Bingham Chair in Gastroenterology. He has served on advisory boards to Abbvie Canada, Janssen Canada, Shire Canada, Takeda Canada and Pfizer Canada and has consulted to Mylan Pharmaceuticals; he has received unrestricted educational grants from Abbvie Canada, Janssen Canada, Shire Canada and Takeda Canada. RG has received consulting and speaking fees from AbbVie, Janssen, MSD, Ferring, Takeda and Baxter; and research grants from AbbVie. GJM has served as speaker or advisory board member for AbbVie, Angelini, Astellas, Danone, MSD, Falk Pharma, Ferring, Hospira, Janssen, Omega Pharma, Otsuka, Pharmacosmos, Pfizer, Sandoz and Takeda; as consultant for Janssen, MSD, Takeda and Omega Pharma; and has received research grants in the last 3 years from Menarini, AbbVie, and MSD. BS has served on advisory boards for Dann and Yakult North American Probiotic Council, Second Genome, Lilly and Enterome; and receives grant support from Janssen, Salix and GSK. MSS has received consulting and speaker fees from AbbVie, Amgen, Ferring, Janssen, Merck, Pfizer, Prometheus, Shire and Takeda; and research funding from AbbVie, Janssen, Prometheus and Takeda. IEK has served as a consultant and on advisory boards for AbbVie and MSD. CO is the principal investigator for Redhill Pharma. DPBM is a consultant for UCB, Jannsen, Merck and Second Genome. WR has served as a speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor and Yakult; as a consultant for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Vifor, Zyngenia and 4SC; as an advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zyngenia and 4SC; and has received research funding from Abbott Laboratories, Abbvie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnsotik and MSD. GR has consulted to Abbot, Abbvie, Augurix, Boehringer, Calypso, FALK, Ferring, Fisher, Genentech, Essex/MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions and Zeller; has received speaker's honoraria from Astra Zeneca, Abbott, Abbvie, FALK, MSD, Phadia, Tillots, UCB and Vifor; has received educational grants and research grants from Abbott/Abbvie, Ardeypharm, Augurix, Calypso, Essex/MSD, FALK, Flamentera, Novartis, Roche, Takeda, Tillots, UCB and Zeller. WK has received fees for advising from Dr. Falk Pharma GmbH, Ferring International, GA-Analysis; support for research from Dr. Falk Pharma GmbH and GA-Analysis; grants for lectures from Abbvie, Ardeypharm, Falk Foundation, Ferring Arzneimittel, GA-Analysis, Institut Allergosan, Nikkiso, Otsuka and Recordati. CT has served as a speaker for Dr. Falk Pharma, Tillotts Pharma, Ferring, MSD and AstraZeneca. SS has received consulting fees from AbbVie, Boehringer; Celltrion/Mundipharma, Jansen, Novartis, Merck, Pfizer/Hospira, Sanofi, Takeda and UCB; and speaking fees from AbbVie Ferring, Falk, Merck, Takeda and Shire. SD has served as a speaker, a consultant and an advisory board member for Abbvie, Ferring, Hospira, Johnson & Johnson, Merck, Millennium Takeda, Mundipharma, Pfizer, Tigenix, UCB Pharma and Vifor. WS reports grant support from Receptos, Exact Sciences, Amgen, the American College of Gastroenterology and the Broad Foundation; grant support and personal fees from Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer and Nutrition Science Partners; and personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast, Shire, Ardelyx, Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries, Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx, Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen and the University of Western Ontario (owner of Robarts Clinical Trials). AG has served as a consultant for AbbVie, Janssen, Merck and Takeda; a speaker for Janssen; and received research and clinical programme support from AbbVie and Janssen. ST has received Grants/Research Support from AbbVie, IOIBD, Lilly, UCB, Vifor and Norman Collison Foundation; consulting fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chemocentryx, Cosmo, Ferring, Giuliani SpA, GlaxoSmithKline, Lilly, MSD, Neovacs, NovoNordisk, Norman Collison Foundation, Novartis, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Shire, Sigmoid Pharma, Takeda, Topivert, UCB, VHsquared and Vifor; speaker fees from AbbVie, Ferring and Takeda. JP has received consultant fees from Abbvie, Boehringer Ingelheim, Celltrion, Galapagos, Genentech-Roche, Janssen, Pfizer, Takeda, TiGenix and Topivert; speaker fees from Abbvie, Celltrion, Janssen, MSD and Pfizer. JFC has served as a consultant or advisory board member for AbbVie, Amgen, Boehringer-Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring, Genentech, Janssen and Janssen, Medimmune, Merck & Co., Pfizer, Protagonist, Second Genome, Seres, Takeda and Theradiag; a speaker for AbbVie, Ferring, Takeda and Shire; receives research support from Abbvie, Janssen and Janssen, Genentech and Takeda; and has stock options for Intestinal Biotech Development and Genfit. SH is a consultant for AbbVie, Actavis, Amgen, Arena, Astellas Pharma Global, Astra Zeneca, Baxter, Boehringer Ingelheim, Bristol Myers Squibb, Catabasis, Cellgene, Celltrion, Cubist, Ferring, Forest Labs, Genentech, Glenmark, GSK, Hospira, Janssen, Lilly, Lutipold/American Regent, Meda, Nestle, Novartis, Novo Nordisk, Pfizer, Prometheus, Receptos, Salix, Sanofi-Avantis, Seattle-Genetics, Seres Health, Shire, Takeda, Theradiag, Tigenex, UCB Pharma and VHsquared; does clinical research with Abbvie, Amgen, Genentech, GSK, Janssen, Lilly, Lutipold/American Regent, Novartis, Novo Nordisk, Pfizer, Prometheus, Receptos, Sanofi-Avantis, Takeda and UCB Pharma; is a speaker for AbbVie, Janssen and Takeda; and serves on a DSMB for Bristol Myers Squibb. LPB reports consulting fees from Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer, HAC-Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera and Samsung Bioepis; and lecture fees from Merck, Abbvie, Takeda, Janssen, Takeda, Ferring, Norgine, Tillots, Vifor, Therakos, Mitsubishi and HAC-pharma., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD)., Design: We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study., Results: 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments., Conclusions: Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib., Trial Registration Numbers: NCT01393626 and NCT01393899., Competing Interests: Competing interests: JP: received consulting fees from AbbVie, Boehringer Ingelheim, Galapagos, GlaxoSmithKline, Janssen, MSD, Pfizer, Second Genome, Takeda, TiGenics and Topivert Pharma; received lectures and/or speaker bureau fees from AbbVie, Janssen, MSD, Pfizer and Takeda. WJS: received grant support from Receptos, Exact Sciences, Amgen, the American College of Gastroenterology and the Broad Foundation; received grant support and personal fees from Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer and Nutrition Science Partners; and personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr. August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast, Shire, Ardelyx, Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics GmbH, Eisai, Qu Biologics, Toray Industries, Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx, Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen and the University of Western Ontario (owner of Robarts Clinical Trials). SS: received consulting fees from Ferring, AbbVie, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Janssen, Galapagos, MedImmune, MSD, Pfizer/Hospira, Shire, Takeda and UCB; received lectures and/or speaker bureau fees from Ferring, AbbVie, MSD, Takeda, UCB and Falk. BES: received consulting fees from AbbVie, Akros Pharma, Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, Forest Research Institute, Lilly, MedImmune, Puretech Ventures, LLC, Receptos, Salix, Shire, Takeda, Topivert Pharma, Vedanta Biosciences, Bristol-Myers Squibb, Janssen R&D, Luitpold Pharmaceuticals, Pfizer, Prometheus Laboratories, Synergy Pharmaceuticals, Takeda, Theravance Biopharma and Tigenix; received research grants from AbbVie, Celgene, GlaxoSmithKline, Janssen R&D, Pfizer, Prometheus Laboratories and Takeda. SV: received consulting fees from Takeda, Roche/Genentech, Merck, Centocor, AbbVie, UCB, Pfizer, Ferring, Second Genome and Galapagos; received research grants from Centocor, AbbVie, Takeda and Merck; received lectures and/or speaker bureau fees from Merck, AbbVie, Takeda, Pfizer, Ferring, Falk and Centocor. GD: received consulting fees from AbbVie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmo, Covidien/Medtronics, Ferring, DrFALK Pharma, Engene, Galapagos, Gilead, GlaxoSmithKline, Hospira, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millennium/Takeda, Mitsubishi Pharma, MSD, Mundipharma, Novo Nordisk, Pfizer, Prometheus laboratories/Nestle, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor; received research grants from MSD, AbbVie, Takeda, Mundipharma, Ferring and Falk; received lectures and/or speaker bureau fees from AbbVie, Ferring, Johnson and Johnson, MSD, Mundipharma, Norgine, Pfizer, Shire, Millennium/Takeda, Tillotts and Vifor. RP: received consulting fees from AbbVie, Amgen, Aptalis, AstraZeneca, Baxter, Biogen, Bristol-Myers Squibb, Celgene, Cubist, Eisai, Ferring, Gilead, Janssen, Merck, Robarts Clinical Trials, Salix, Samsung Bioepis, Shire, Centocor, Elan, GlaxoSmithKline, UCB, Pfizer and Takeda; received research grants from AbbVie, Ferring, Janssen and Takeda; received lectures and/or speaker bureau fees from AbbVie, Aptalis, AstraZeneca, Ferring, Janssen, Merck, Prometheus, Shire and Takeda; received advisory board fees from AbbVie, Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Eisai, Ferring, Genentech, Jansen, Merck, Schering-Plough, Shire, Centocor, Elan, GlaxoSmithKline, UCB, Pfizer, Bristol-Myers Squibb, Takeda, Cubist, Celgene and Salix. PDRH: received consulting fees from AbbVie, Amgen, Genentech, JBR Pharma and Lycera. J-FC: received consulting fees from Abbott Laboratories, ActoGeniX, Albireo Pharma, Amgen, AstraZeneca, Bayer AG, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Centocor, Chemocentryx, Cosmo Technologies, Danone Research, Elan Pharmaceuticals, Genentech, Giuliani SpA, Given Imaging, GlaxoSmithKline, Hutchison MediPharma, MSD, Millennium Pharmaceuticals (now Takeda), Neovacs, Ocera Therapeutics, Pfizer, Shire Pharmaceuticals, Schering-Plough, Prometheus Laboratories, Sanofi-Aventis, Synta Pharmaceuticals Corp, Teva, Therakos, UCB Pharma and Wyeth; received research grants from AstraZeneca, Ferring, Schering-Plough and UCB Pharma; received lectures and/or speaker bureau fees from Abbott Laboratories, Centocor, Elan Pharmaceuticals, Given Imaging, Otsuka America Pharmaceutical, MSD, Schering-Plough, Shire Pharmaceuticals, Tillotts Pharma and UCB Pharma; received advisory board fees from Abbott Laboratories, Centocor, Danone, Elan, MSD, Millennium Pharmaceuticals (now Takeda), Schering-Plough and UCB Pharma. BGF: received consulting fees from Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging, GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestle, Novo Nordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma, Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, VHsquared Ltd., Warner-Chilcott, Wyeth, Zealand, Zyngenia; received research grants from Abbott/AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts and UCB Pharma; received lectures and/or speaker bureau fees from Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott and UCB Pharma; received advisory board fees from Abbott/AbbVie, Amgen, AstraZeneca, Avaxia Biologics, Bristol-Myers Squibb, Celgene, Centocor, Elan/Biogen, Ferring, JnJ/Janssen, Merck, Nestle, Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma; is a board of directors member of Robarts Clinical Trials. GC, MM, WW, WN, AM, PH and EM are all employees and stockholders of Pfizer Inc., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: Vedolizumab is a gut-selective antibody to α 4 β 7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab., Design: Safety data (May 2009-June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model., Results: In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1-1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy., Conclusions: Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period., Trial Registration Number: NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)