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Background and Objectives: Primary objectives: to compare the rates of sustained clinical remission at 12 months in patients treated with antitumour necrosis factor (anti-TNF) and immunomodulators who withdraw anti-TNF treatment versus those who maintain it., Secondary Objectives: to evaluate the effect of anti-TNF withdrawal on relapse-free time, endoscopic and radiological activity, safety, quality of life and work productivity; and to identify predictive factors for relapse., Design: Prospective, quadruple-blind, multicentre, randomised, controlled trial. Patients with ulcerative colitis or Crohn's disease in clinical remission for >6 months and absence of severe endoscopic (and radiological in Crohn's disease) lesions were randomised to maintain anti-TNF treatment (maintenance arm (MA)) or to withdraw it (withdrawal arm (WA)). All patients maintained immunomodulators. Patients were followed-up until month 12 or up to clinical relapse., Results: One-hundred forty patients were randomised: 70 were allocated to the MA and 70 to the WA. The proportion of patients with sustained clinical remission at 12 months was similar in the MA and WA: 59/70 (84%), 95% CI=74% to 92% versus 53/70 (76%), 95% CI=64% to 85%. The proportion of patients with significant endoscopic lesions at the end of follow-up was 8.5% in the MA and 19% in the WA (p=0.1); a higher proportion of patients had faecal calprotectin >250 µg/g at the end of follow-up in the WA (p=0.01). The same percentage of patients in both groups had at least one adverse event (69%). The proportion of patients with serious adverse events was also similar in both groups (4% in MA vs 7% in WA)., Conclusion: Anti-TNF withdrawal in selected patients with IBD in clinical, endoscopic and radiological remission has no impact on sustained clinical remission at 1 year although objective markers of activity were higher in patients who withdrew treatment., Trial Registration Number: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-001410-10 https://clinicaltrials.gov/study/NCT02994836., Competing Interests: Competing interests: MBdA has served as a speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, GALAPAGOS, Pfizer, Sandoz, Biogen, Fresenius, Lilly, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma. MCh has served as speaker, consultant or research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Biogen, Gilead and Lilly. ED has served as a speaker, or has received research or education funding or advisory fees from AbbVie, Adacyte Therapeutics, Biogen, Celltrion, Galapagos, Gilead, GoodGut, Imidomics, Janssen, Kern Pharma, MSD, Pfizer, Roche, Samsung, Takeda, Tillots. JPG has served as speaker, consultant, and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos, Lilly, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine and Vifor Pharma.Marisa Iborra reports grants and personal fees from MSD, Janssen, Abbvie, Takeda, Kern and Chiesi, during the conduct of the study.Eduardo Leo has received grants or honoraria for scientific activities, presentations or as a scientific advisor for MSD, Pfizer, Abbvie, Takeda, Janssen, Tillotts Pharma, Shire Pharmaceuticals, Ferring, Dr. Falk Pharma, Adacyte and Otsuka Pharmaceutical. PNM reports grants and personal fees from MSD, grants from Otsuka, AbbVie; personal fees from Takeda, Kern, Biogen, Ferring. JP received financial support for research from AbbVie and Pfizer; consultancy fees/honorarium from AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celsius, Celltrion, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Morphic, Pandion, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Robarts, Sanofi, Takeda, Theravance and Wasserman; reports payment for lectures including service on speaker bureau from Abbott, Ferring, Janssen, Pfizer and Takeda; and reports payment for development of educational presentations from Abbott, Janssen, Pfizer Roche and Takeda. MR has served as a speaker or advisory member from TaKeda, Janssen, Galapagos, Ferring and Pfizer. MV has received educational funding from Janssen, Kern Pharma and Takeda. Rest of authors have nothing to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with Crohn's disease commonly develop ileal and less commonly colonic strictures, containing various degrees of inflammation and fibrosis. While predominantly inflammatory strictures may benefit from a medical anti-inflammatory treatment, predominantly fibrotic strictures currently require endoscopic balloon dilation or surgery. Therefore, differentiation of the main components of a stricturing lesion is key for defining the therapeutic management. The role of endoscopy to diagnose the nature of strictures is limited by the superficial inspection of the intestinal mucosa, the lack of depth of mucosal biopsies and by the risk of sampling error due to a heterogeneous distribution of inflammation and fibrosis within a stricturing lesion. These limitations may be in part overcome by cross-sectional imaging techniques such as ultrasound, CT and MRI, allowing for a full thickness evaluation of the bowel wall and associated abnormalities. This systematic literature review provides a comprehensive summary of currently used radiologic definitions of strictures. It discusses, by assessing only manuscripts with histopathology as a gold standard, the accuracy for diagnosis of the respective modalities as well as their capability to characterise strictures in terms of inflammation and fibrosis. Definitions for strictures on cross-sectional imaging are heterogeneous; however, accuracy for stricture diagnosis is very high. Although conventional cross-sectional imaging techniques have been reported to distinguish inflammation from fibrosis and grade their severity, they are not sufficiently accurate for use in routine clinical practice. Finally, we present recent consensus recommendations and highlight experimental techniques that may overcome the limitations of current technologies., Competing Interests: Competing interests: DB is on the advisory board or consultant for AbbVie, Dr Falk Foundation, Ferring, MSD, Pharmacosmos, Roche, Takeda, Tillotts Pharma and Vifor. MB receives support from Siemens Healthineers in the form of salary support, hardware and software for investigating the effect of lower exposure CT in detecting active Crohn’s disease. CEP is an employee of Robarts Clinical Trials. JP has received consultancy fees from AbbVie, Arena, Boehringer Ingelheim, Galapagos, Genentech, Janssen, MSD, Novartis, Pfizer, Robarts, Second Genome, Takeda, Theravance, TiGenix and Topivert. JR is on the advisory board or consultant for Robarts Clinical Trials, Takeda and TiGenix and received research grant from AbbVie and Genentech. JGF receives grants to his institution from Siemens Healthineers and Medtronic. VJ receives salary support from the John and Susan McDonald Endowed IBD Chair at Western University, London, Ontario, Canada; consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genentech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert and Celltrion; speaker fees from Takeda, Janssen, Shire, Ferring, AbbVie and Pfizer. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma, AbbVie, Novartis Pharmaceuticals, Centocor, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix and Wyeth Pharmaceuticals; consulting fees from Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, AstraZeneca, Serono, Genentech, Tillotts Pharma, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals, Novonordisk, GSK, ActoGenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma and Sigmoid Pharma; and speaker’s bureau fees from UCB, AbbVie and J&J/Janssen. FR is on the advisory board or consultant for AbbVie, Allergan, Celgene, Gossamer, Receptos, Thetis, UCB, Samsung, Pliant, Boehringer Ingelheim, Metacrine, Takeda, Allergan, Helmsley, RedX and Roche. RM has no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: UC is a chronic inflammatory disease of the colonic mucosa. Growing evidence supports a role for epithelial cell defects in driving pathology. Moreover, long-lasting changes in the epithelial barrier have been reported in quiescent UC. Our aim was to investigate whether epithelial cell defects could originate from changes in the epithelial compartment imprinted by the disease., Design: Epithelial organoid cultures (EpOCs) were expanded ex vivo from the intestinal crypts of non-IBD controls and patients with UC. EpOCs were induced to differentiate (d-EpOCs), and the total RNA was extracted for microarray and quantitative real-time PCR (qPCR) analyses. Whole intestinal samples were used to determine mRNA expression by qPCR, or protein localisation by immunostaining., Results: EpOCs from patients with UC maintained self-renewal potential and the capability to give rise to differentiated epithelial cell lineages comparable with control EpOCs. Nonetheless, a group of genes was differentially regulated in the EpOCs and d-EpOCs of patients with UC, including genes associated with antimicrobial defence (ie, LYZ , PLA2G2A ), with secretory (ie, ZG16 , CLCA1 ) and absorptive (ie, AQP8 , MUC12 ) functions, and with a gastric phenotype (ie, ANXA10 , CLDN18 and LYZ ). A high rate of concordance was found in the expression profiles of the organoid cultures and whole colonic tissues from patients with UC., Conclusions: Permanent changes in the colonic epithelium of patients with UC could be promoted by alterations imprinted in the stem cell compartment. These changes may contribute to perpetuation of the disease., Competing Interests: Competing interests: None declared., (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: To evaluate the feasibility and toxicity of autologous haematopoietic stem cell transplantation (HSCT) for the treatment of refractory Crohn's disease (CD)., Design: In this prospective study, patients with refractory CD suffering an aggressive disease course despite medical treatment, impaired quality of life and in whom surgery was not an acceptable option underwent HSCT. Toxicity and complications during the procedure and within the first year following transplantation were evaluated, along with the impact of the introduction of supportive measures on safety outcomes., Results: 26 patients were enrolled. During mobilisation, 16 patients (62%) presented febrile neutropaenia, including one bacteraemia and two septic shocks. Neutropaenia median time after mobilisation was 5 days. 5 patients withdrew from the study after mobilisation and 21 patients entered the conditioning phase. Haematopoietic recovery median time for neutrophils (>0.5×10(9)/L) was 11 days and for platelets (>20×10(9)/L) 4 days. Twenty patients (95%) suffered febrile neutropaenia and three patients (27%) presented worsening of the perianal CD activity during conditioning. Among non-infectious complications, 6 patients (28.5%) presented antithymocyte globulin reaction, 12 patients (57%) developed mucositis and 2 patients (9.5%) had haemorrhagic complications. Changes in supportive measures over the study, particularly antibiotic prophylaxis regimes during mobilisation and conditioning, markedly diminished the incidence of severe complications. During the first 12-month follow-up, viral infections were the most commonly observed complications, and one patient died due to systemic cytomegalovirus infection., Conclusions: Autologous HSCT for patients with refractory CD is feasible, but extraordinary supportive measures need to be implemented. We suggest that this procedure should only be performed in highly experienced centres., (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: Severe endoscopic lesions (SEL) in patients with colonic Crohn's disease (CD) have been linked to higher risk of colectomy. The aims of this study were to reassess the predictive value of colonoscopy compared against MRI for requirement of resection surgery in patients with CD and determine the influence of current therapeutic options., Design: In this single-centre, observational, prospective, longitudinal study, patients with an established diagnosis of CD and suspected activity were included. After baseline assessment, including colonoscopy and MRI, patients were followed until resection surgery or the end of study., Results: 112 patients were eligible for analysis. Ulcers were present in 94/112 (84%) of patients at colonoscopy (SELs in 51/112 (46%)) and stenosis in 38/112 (34%). MRI identified ulcers in 79/112 (71%) of patients, stenosis in 36/112 (32%) and intra-abdominal fistulae in 20/112 (18%). Surgical resection requirements (29/112 (26%)) were not associated with the presence of SELs at colonoscopy. The presence of stenosis (p<0.001) or intra-abdominal fistulae (p<0.001) at MRI correlated with a higher risk of surgery. In the multivariate analysis, perianal disease (OR 9 (2 to 39), p=0.003), stenosis (OR 3.4 (1 to 11), p=0.04) and fistulae at MRI (OR 10.6 (2 to 46), p=0.002) increased the risk of abdominal resection surgery, while months under immunomodulators (OR 0.94 (0.90 to 0.98), p=0.002) and/or antitumor necrosis factor (anti-TNF) therapy (OR 0.97 (0.94 to 1), p=0.04) during follow-up decreased this risk., Conclusions: Perianal disease, stenosis and/or intra-abdominal fistulae at MRI independently predict an increased risk of resection surgery in patients with CD, whereas immunosuppressants and/or anti-TNF therapy reduce such risk. Under current therapeutic strategies, the presence of SELs is not a predictor of resection surgery in patients with CD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC., Design: In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels., Results: The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups., Conclusions: A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13., Trial Registration Number: ClinicalTrials.gov number NCT01284062., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Anti-tumour necrosis factor α (TNFα) therapy effectively induces and maintains remission in Crohn's disease (CD). Up to 40% of patients, however, fail to respond to anti-TNFα., Objective: To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNFα therapy., Design: An observational study based on whole-genome transcriptional analysis was carried out using intestinal biopsy specimens from patients with CD receiving (n=12) or not (n=10) anti-TNFα therapy. The transcriptional signature of responders was compared with that of non-responders after anti-TNFα therapy. Controls with non-inflammatory bowel disease (non-IBD) (n=17) were used for comparisons. Genes of interest were validated by real-time RT-PCR in an independent cohort of patients with CD receiving (n=17) or not (n=16) anti-TNFα and non-IBD controls (n=7)., Results: We confirmed that response to anti-TNFα is accompanied by significant regulation of a large number of genes, including IL1B, S100A8, CXCL1, which correlated with endoscopic activity. Remarkably, patients who failed to respond to anti-TNFα showed a mixed signature, maintaining increased expression of IL1B, IL17A and S100A8, while showing significant modulation of other genes commonly upregulated in active CD, including IL6 and IL23p19., Conclusions: Our results show that anti-TNFα therapy significantly downregulates a subset of inflammatory genes even in patients who fail to achieve endoscopic remission, suggesting that these genes may not be dominant in driving inflammation in non-responders. On the other hand, we identified IL1B and IL17A as genes that remained altered in non-responders, pointing to potentially more relevant targets for modulating mucosal damage in refractory patients., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To develop a consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease (pCD), based on best available evidence., Methods: Based on a systematic literature review, statements were formed, discussed and approved in multiple rounds by the 20 working group participants. Consensus was defined as at least 80% agreement among voters. Evidence was assessed using the modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria., Results: Highest diagnostic accuracy can only be established if a combination of modalities is used. Drainage of sepsis is always first line therapy before initiating immunosuppressive treatment. Mucosal healing is the goal in the presence of proctitis. Whereas antibiotics and thiopurines have a role as adjunctive treatments in pCD, anti-tumour necrosis factor (anti-TNF) is the current gold standard. The efficacy of infliximab is best documented although adalimumab and certolizumab pegol are moderately effective. Oral tacrolimus could be used in patients failing anti-TNF therapy. Definite surgical repair is only of consideration in the absence of luminal inflammation., Conclusions: Based on a multidisciplinary approach, items relevant for fistula management were identified and algorithms on diagnosis and treatment of pCD were developed., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: The aim of this study was to determine the diagnostic accuracy of magnetic resonance colonography (MRC) for the evaluation of disease activity and severity in patients with ulcerative colitis (UC) using endoscopy as the reference standard., Methods: Fifty patients with UC underwent colonoscopy and MRC for the evaluation of disease activity. All patients were prospectively and consecutively included. Endoscopic activity was evaluated globally and on a segment basis using the modified Baron score (MBS), and also classified as absent, mild to moderate (inflammation without ulcers) or severe (presence of ulceration). MRC parameters evaluated in each segment were: wall thickness, pre- and post-contrast wall signal intensity, relative contrast enhancement (RCE), mural oedema, ulcers, enlarged lymph nodes and the comb sign., Results: Independent predictors for endoscopic activity on a segment basis were RCE (p=0.006), presence of oedema (p=0.003), enlarged lymph nodes (p<0.001) and the comb sign (p<0.001). A segmental simplified MRC index (MRC-S) ≥ 1 detected endoscopic inflammation with high diagnostic accuracy (sensitivity 87%, specificity 88%, area under the curve (AUC) 0.95; p<0.001). MRC-S index ≥ 2 detected severe lesions with high sensitivity (83%) and specificity (82%) with an AUC of 0.91 (p<0.001). The MRC-S index strongly correlated with the MBS (r=0.81, p<0.001) and with the subjective assessment of the radiologists for the evaluation of disease severity (r=0.77, p<0.001)., Conclusions: MRC has a high accuracy for the diagnosis of disease activity and severity in UC.

Objective: Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course., Design: This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied., Results: Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02 × 10(-06), OR=1.90), stenosing (p=3.16 × 10(-06), OR=1.82) and penetrating (p=1.26 × 10(-02), OR=1.25) CD behaviours, and need for surgery (p=2.28 × e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86 × 10(-06), OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48 × 10(-06), OR=0.35) and surgical rate (p=1.71 × 10(-07), OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12 × 10(-03), HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01 × 10(-02), HR=1.29) among patients with low and high score., Conclusions: This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.

Objective: Genome-wide association studies (GWAS) have identified multiple risk loci for Crohn's disease (CD). However, the cumulative risk exerted by these loci is low, and the likelihood that additional, as-yet undiscovered loci contribute to the risk of CD is very high. We performed a GWAS on a southern European population to identify new CD risk loci., Design: We genotyped 620 901 genome markers on 1341 CD patients and 1518 controls from Spain. The top association signals representing new candidate risk loci were subsequently analysed in an independent replication cohort of 1365 CD patients and 1396 controls., Results: We identified a genome-wide significant association on chromosome 22q13.2 in the intergenic region between the RBX1 and EP300 genes (single nucleotide polymorphism rs4820425, OR 1.27, 95% CI 1.17 to 1.38, p=3.42E-8). We also found suggestive evidence for the association of the IFNGR2 (21q22.11), FOXP2 (7q31), MACROD2 (20p12.1) and AIF1 (6p21.3) loci with CD risk., Conclusions: In this GWAS performed on a southern European cohort, we have identified a new risk locus for CD between RBX1 and EP300. This study demonstrates that using populations of different ancestry is a useful strategy to identify new risk loci for CD.

Objective: Ulcerative colitis (UC) is a chronic condition characterised by the relapsing inflammation despite previous endoscopic and histological healing. Our objective was to identify the molecular signature associated with UC remission., Design: We performed whole-genome transcriptional analysis of colonic biopsies from patients with histologically active and inactive UC, and non-inflammatory bowel disease (non-IBD) controls. Real-time reverse transcriptase-PCR and immunostaining were used for validating selected genes in independent cohorts of patients., Results: Microarray analysis (n=43) demonstrates that UC patients in remission present an intestinal transcriptional signature that significantly differs from that of non-IBD controls and active patients. Fifty-four selected genes were validated in an independent cohort of patients (n=30). Twenty-nine of these genes were significantly regulated in UC-in-remission subjects compared with non-IBD controls, including a large number of epithelial cell-expressed genes such as REG4, S100P, SERPINB5, SLC16A1, DEFB1, AQP3 and AQP8, which modulate epithelial cell growth, sensitivity to apoptosis and immune function. Expression of inflammation-related genes such as REG1A and IL8 returned to control levels during remission. REG4, S100P, SERPINB5 and REG1A protein expression was confirmed by immunohistochemistry (n=23)., Conclusions: Analysis of the gene signature associated with remission allowed us to unravel pathways permanently deregulated in UC despite histological recovery. Given the strong link between the regulation of some of these genes and the growth and dissemination of gastrointestinal cancers, we believe their aberrant expression in UC may provide a mechanism for epithelial hyper-proliferation and, in the context of malignant transformation, for tumour growth.

Background: There is no information about the frequency of liver dysfunction in patients with inflammatory bowel disease (IBD) treated with immunosuppressants and infected with hepatitis B (HBV) and/or C virus (HCV)., Aim: To assess the influence of immunosuppressants on the course of HBV and HCV infection in IBD., Methods: Patients with IBD with HBV and/or HCV infection from 19 Spanish hospitals were included. Clinical records were reviewed for the type of immunosuppressant used, treatment duration, liver function tests and viral markers before, during and after each immunosuppressant. Logistic and Cox regression analysis were used to identify predictors of outcome., Results: 162 patients were included; 104 had HBV markers (25 HBsAg positive) and 74 had HCV markers (51 HCV-RNA positive), and 16 patients had markers of both infections. Liver dysfunction was observed in 9 of 25 HBsAg positive patients (36%), 6 of whom developed hepatic failure. Liver dysfunction in HCV was observed in 8 of 51 HCV-RNA positive patients (15.7%), and only one developed hepatic failure. The frequency and severity of liver dysfunction was significantly higher in HBV-infected patients than in HCV-infected patients (p=0.045 and p=0.049, respectively). Treatment with ≥2 immunosuppressants was an independent predictor of HBV reactivation (OR 8.75; 95% CI 1.16 to 65.66). The majority of patients without reactivation received only one immunosuppressant for a short period and/or prophylactic antiviral treatment. No definite HBV reactivations were found in anti-HBc positive patients lacking HBsAg., Conclusion: Liver dysfunction in patients with IBD treated with immunosuppressants is more frequent and severe in those with HBV than in HCV carriers and is associated with combined immunosuppression.

Objective: Assessment of disease extension and activity is crucial to guide treatment in Crohn's disease. The objective of the current cross-sectional study was to determine the accuracy of MR for this assessment., Design: 50 patients with clinically active (n = 35) or inactive (n = 15) Crohn's disease underwent ileocolonoscopy (reference standard) and MR. T2-weighted and precontrast and postcontrast-enhanced T1-weighted sequences were acquired. Endoscopic activity was evaluated by CDEIS (Crohn's Disease Endoscopic Index of Severity); in addition endoscopic lesions were classified as absent, mild (inflammation without ulcers) or severe (presence of ulceration)., Results: The comparison of intestinal segments with absent, mild and severe inflammation demonstrated a progressive and significant (p<0.001) increase in the following MR parameters: wall thickness, postcontrast wall signal intensity, relative contrast enhancement, presence of oedema, ulcers, pseudopolyps and lymph node enlargement. Independent predictors for CDEIS in a segment were wall thickness (p = 0.007), relative contrast enhancement (p = 0.01), presence of oedema (p = 0.02) and presence of ulcers at MR (p = 0.003). There was a significant correlation (r = 0.82, p<0.001) between the CDEIS of the segment and the MR index calculated according to the logistic regression analysis coefficients. The MR index had a high accuracy for the detection of disease activity (area under the receiver operating characteristic (ROC) curve 0.891, sensitivity 0.81, specificity 0.89) and for the detection of ulcerative lesions (area under the ROC curve 0.978, sensitivity 0.95, specificity 0.91) in the colon and terminal ileum., Conclusion: The accuracy of MR for detecting disease activity and assessing severity brings about the possibility of using MR as an alternative to endoscopy in the evaluation of ileocolonic Crohn's disease.

Background and Aims: Increased pancreatitis associated protein (PAP) mRNA has been reported in active inflammatory bowel disease (IBD). The aims of the current study were to characterise PAP production in IBD and the effects of PAP on inflammation., Patients and Methods: Serum PAP levels were determined in healthy controls (n = 29), inflammatory controls (n = 14), and IBD patients (n = 171). Ex vivo PAP secretion in intestinal tissue was measured in 56 IBD patients and 13 healthy controls. Cellular origin of PAP was determined by immunohistochemistry. The effects of exogenous PAP on nuclear factor kappaB (NFkappaB) activation, proinflammatory cytokine production, and endothelial adhesion molecule expression were also analysed ex vivo., Results: Patients with active IBD had increased serum PAP levels compared with controls, and these levels correlated with clinical and endoscopic disease severity. Ex vivo intestinal PAP synthesis was increased in active IBD and correlated with endoscopic and histological severity of inflammatory lesions. PAP localised to colonic Paneth cells. Incubation of mucosa from active Crohn's disease with PAP dose dependently reduced proinflammatory cytokines secretion. PAP prevented TNF-alpha induced NFkappaB activation in monocytic, epithelial, and endothelial cells and reduced proinflammatory cytokine mRNA levels and adhesion molecule expression., Conclusions: PAP is synthesised by Paneth cells and is overexpressed in colonic tissue of active IBD. PAP inhibits NFkappaB activation and downregulates cytokine production and adhesion molecule expression in inflamed tissue. It may represent an anti-inflammatory mechanism and new therapeutic strategy in IBD.

Background: In addition to its anticoagulant properties, heparin has anti-inflammatory effects, the molecular and mechanistic bases of which are incompletely defined., Aims: The current studies were designed to test the hypothesis that heparin abrogates the expression or function of leucocyte-endothelial adherence molecules which are fundamental to the acute inflammatory response., Methods: The effects of heparin on tumour necrosis factor alpha (TNF-alpha) induced leucocyte rolling, adhesion, and migration as well as vascular permeability were assessed in rat mesenteric venules using intravital microscopy. Expression of adhesion molecules was quantitated using a double radiolabelled monoclonal antibody (mAb) binding technique in vivo (P-selectin, intercellular cell adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1)) or flow cytometry (CD11a, CD11b, and L-selectin). Ex vivo binding of heparin to neutrophils was assessed by flow cytometry., Results: TNF-alpha induced a significant increase in leucocyte rolling, adhesion, and migration, and vascular permeability, coincident with a significant increase in expression of P-selectin, ICAM-1, and VCAM-1. Ex vivo assessment of blood neutrophils showed significant upregulation of CD11a and CD11b and significant downregulation of L-selectin within five hours of TNF-alpha administration. Heparin pretreatment significantly attenuated leucocyte rolling, adhesion, and migration but did not affect expression of cell adhesion molecules or vascular permeability elicited by TNF-alpha administration. Binding of heparin was significantly increased on blood neutrophils obtained five hours after TNF-alpha administration. Preincubation with an anti-CD11b mAb but not with an anti-CD11a or anti-L-selectin antibody significantly diminished heparin binding ex vivo., Conclusions: Our results support the concept that the anti-inflammatory effects of heparin involve attenuation of a CD11b dependent adherent mechanism.

Background: A previous study showed that the glucocorticoid dexamethasone, at doses of 100 microg/kg and above, inhibited leucocyte adhesion to rat mesenteric postcapillary venules activated with interleukin 1beta (IL-1beta), as assessed by videomicroscopy., Aims: To identify whether the adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), or the chemokine KC could be targeted by the steroid to mediate its antiadhesive effect., Methods: Rat mesenteries were treated with IL-1beta (20 ng intraperitoneally) and the extent of leucocyte adhesion measured at two and four hours using intravital microscopy. Rats were treated with dexamethasone, and passively immunised against ICAM-1 or KC. Endogenous expression of these two mediators was validated by immunohistochemistry, ELISA, and the injection of specific radiolabelled antibodies., Results: Dexamethasone greatly reduced IL-1beta induced leucocyte adhesion, endothelial expression of ICAM-1 in the postcapillary venule, and release of the mast cell derived chemokine KC. Injection of specific antibodies to the latter mediators was also extremely effective in downregulating (>80%) IL-1beta induced leucocyte adhesion., Conclusions: Induction by IL-1beta of endogenous ICAM-1 and KC contributes to leucocyte adhesion to inflamed mesenteric vessels. Without excluding other possible mediators, these data clearly show that dexamethasone interferes with ICAM-1 expression and KC release from mast cells, resulting in suppression of leucocyte accumulation in the bowel wall, which is a prominent feature of several gastrointestinal pathologies.