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Background The most common complication after ileal pouch anal anastomosis in up to 50% of patients is an acute pouchitis. The majority of patients respond to antibiotic treatment. However, 10%-15% develops chronic antibiotic-dependent or refractory pouchitis which is usually hard to treat. Aim To evaluate the effectiveness of vedolizumab in patients with chronic pouchitis. Methods Patients with chronic antibiotic-dependent or refractory pouchitis were treated with vedolizumab (300 mg at week 0, 2, 6 and 10) in 10 IBD centres and retrospectively registered. Data were recorded until week 14 of vedolizumab treatment. In total 20 patients (12 male, median age 43 years) were included for analysis. The effectiveness was measured using the Oresland Score (OS) at week 2, 6, 10 and 14 and the pouch disease activity index (PDAI) at week 0 and 14. Results The mean OS declined from 6.8 (range 2-12) to 3.4 (range 0-11). Concordantly, the mean PDAI after 14 weeks of treatment dropped from 10 (range 5-18) to 3 (range 0-10). Only three patients reported moderate side effects. No serious side effects were recorded. In addition, symptomatic co-medication such as loperamide and tincture of opium could be terminated in 8 out of 12 patients as well as antibiotic treatment could be stopped in 17 out of 19 patients. Conclusion Our data indicate that vedolizumab could be an option in the treatment of patients with chronic, antibiotic-dependent or refractory pouchitis.

Objective: Pancreatic autoantibodies (PABs), comprising antibodies against glycoprotein 2 (anti-GP2), are typically associated with complicated phenotypes in Crohn's disease, but have also been observed with variable frequencies in patients with UC. In a previous study, we observed a high frequency of primary sclerosing cholangitis (PSC) in patients with anti-GP2-positive UC. We therefore aimed to characterise the role of anti-GP2 in PSC. Design: In an evaluation phase, sera from 138 well-characterised Norwegian patients with PSC were compared with healthy controls (n=52), and patients with UC without PSC (n=62) for the presence of PABs by indirect immunofluorescence. Further, 180 German patients with PSC served as a validation cohort together with 56 cases of cholangiocarcinoma without PSC, 20 of secondary sclerosing cholangitis (SSC) and 18 of autoimmune hepatitis. Results: Anti-GP2 IgA specifically occurred at considerable rates in large bile duct diseases (cholangiocarcinoma=36%, PSC and SSC about 50%). In PSC, anti-GP2 IgA consistently identified patients with poor survival during follow-up (Norwegian/German cohort: p Log Rank=0.016/0.018). Anti-GP2 IgA was associated with the development of cholangiocarcinoma in both PSC cohorts, yielding an overall OR of cholangiocarcinoma in patients with anti-GP2 IgA-positive PSC of 5.0 (p=0.001). Importantly, this association remained independent of disease duration, bilirubin level and age. Conclusions: Anti-GP2 IgA can be hypothesised as a novel marker in large bile duct diseases. In particular, in PSC, anti-GP2 IgA identified a subgroup of patients with severe phenotype and poor survival due to cholangiocarcinoma. Anti-GP2 IgA may therefore be a clinically valuable tool for risk stratification in PSC. The final version of this research has been published in Hepatology. © 2016 Wiley

Background and Aims: In Crohn's disease (CD) patients still remain refractory to current regimens, including biologicals. Previous data from small single-center studies indicated cyclophosphamide pulse therapy (CPT) to be effective for induction of remission at least in steroid-refractory cases. The aim of the present study was to study the efficacy and safety of CPT in mainly tumor necrosis factor (TNF)-refractory complicated CD patients. Methods: Patients with refractory CD undergoing CPT were identified in 13 centers of the German IBD Study Group and retrospectively registered. In total, 41 patients (12 male, 29 female, median age 36 years, range 18-72 years) were included for analysis. Seventy-eight percent of these had previously been treated with thiopurines and 90% had previously received anti-TNF antibodies. Former steroid treatment was found throughout the cohort. Results: Patients received a median number of 5 (1-13) pulses every 28 (13-54) days in a period of 120 (12-411) days. A median dose of 766 (600-1,200) mg and a median cumulative dose of 4,500 (750-9,750) mg was given. A clinical response (reduction in the Harvey-Bradshaw Index [HBI] ≥2 points) was found in 68% of the patients and clinical remission (HBI n = 29) of the patients. Three patients terminated CPT due to side effects. No patient died. Conclusion: Our data point to CPT as a therapeutic alternative for induction of remission in patients with severe refractory courses of CD including TNF antagonists. CPT might serve as bridging for maintenance treatment.

Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far, a definite cure of the disease is still out of scope. An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy. Thiopurines comprising azathioprine and its active metabolite mercaptopurine as well as tioguanine, are widely used in the therapy of chronic active inflammatory bowel disease (IBD). Their steroid sparing potential and efficacy in remission maintenance are out of doubt. Unfortunately, untoward adverse events are frequently observed and may preclude further administration or be life threatening. This review will focus on new aspects of thiopurine therapy in IBD, its efficacy and safety.

Background: In the last years, the interest of circadian rhythms as regulators of intestinal inflammation has increased substantially. Consisting of a range of clock genes including Per1 and Per2, the molecular clock machinery is thought to be engaged in modulating intestinal barrier function and gut homeostasis, features which are highly disturbed in inflammatory bowel disease (IBD). Elucidating the precise role of clock genes in the intestine may therefore highlight new pathophysiological mechanisms and new therapeutic approaches. Methods: Here, we used Per1/Per2 mutant mice and wildtype controls to investigate the functional consequence of circadian disruption on gastrointestinal tract morphology and intestinal inflammation. Small and large intestines were evaluated histologically at basal conditions. Experimental chronic colitis was induced by cyclic administration of 2% dextran sulphate sodium (DSS) in the drinking water, and colitis severity was determined by mouse endoscopy and clinical scores (murine endoscopic index of colitis severity, disease activity index). Biopsies were taken and further investigated via RT-PCR, western blotting and immunofluorescence staining. Results: At baseline, Per1/2 mice displayed mucosal alterations in the small and large intestines, characterized by a diminished crypt length-to-width ratio and reduced numbers of goblet and Paneth cells. Strikingly, mutant mice exhibited severely increased clinical symptoms of colitis (e.g. body weight loss, rectal bleeding, and diarrhea) and gross lethality in response to DSS. BrdU labeling revealed increased numbers of proliferative intestinal epithelial cells (IEC) in Per1/2 mice, but a restricted migratory capacity along the crypt axis. Analyzing the fate of individual IEC, we detected elevated protein level of RIP3, a marker of necroptotic cell death, in IEC at the crypt base, indicating that aberrant cell death in the proliferative region of intestinal crypts is responsible for the observed morphological changes in Per1/2 mice. Together, these data suggest that Per1/Per2 deficiency modulates cell death events, and thus influences intestinal homeostasis. Conclusions: Our data render intact circadian rhythm crucially important for intestinal barrier function and maintenance. Thus, therapeutic interventions stabilizing circadian rhythm may be promising options for the treatment of IBD. OP004 Early combined immunosuppression for the management of Crohn’s disease: A community-based cluster randomized trial R. Khanna1, B.G. Levesque1,2, B. Bressler3, G. Zou1,4, L. Stitt1, G.R. Greenberg5, R. Panaccione6, A. Bitton7, P. Pare8, S. Vermeire9, G. D’Haens1,10, D. MacIntosh11, W.J. Sandborn1,2, M.K. Vandervoort1, J.C. Morris1, B.G. Feagan1,12 *. 1Robarts Clinical Trials Inc., Robarts Research Institute, Western University, London, Ontario, Canada, 2University of California, San Diego, Division of Gastroenterology, La Jolla, United States, 3St. Paul’s Hospital, Department of Gastroenterology, Vancouver, British Columbia, Canada, 4Western University, Department of Epidemiology and Biostatistics, London Ontario, Canada, 5Mount Sinai Hospital, Division of Gastroenterology, Toronto Ontario, Canada, 6University of Calgary, Division of Gastroenterology & Hepatology, Calgary Alberta, Canada, 7McGill University, Division of Gastroenterology, Montreal Quebec, Canada, 8Laval University, Hopital du St-Sacrement, Quebec City, Quebec, Canada, 9Department of Clinical and Experimental Medicine, KU Leuven, Translational Research in GastroIntestinal Disorders, Leuven, Belgium, 10University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands, 11Dalhousie University, Division of Gastroenterology, Halifax, Canada, 12Western University, Department of Epidemiology and Biostatistics, Department of Medicine, London Ontario, Canada

Background & Aims Dysregulated energy homeostasis in the intestinal mucosa frequently is observed in patients with ulcerative colitis (UC). Intestinal tissues from these patients have reduced activity of the mitochondrial oxidative phosphorylation (OXPHOS) complex, so mitochondrial dysfunction could contribute to the pathogenesis of UC. However, little is known about the mechanisms by which OXPHOS activity could be altered. We used conplastic mice, which have identical nuclear but different mitochondrial genomes, to investigate activities of the OXPHOS complex. Methods Colitis was induced in C57BL/6J wild-type (B6.B6) and 3 strains of conplastic mice (B6.NZB, B6.NOD, and B6.AKR) by administration of dextran sodium sulfate or rectal application of trinitrobenzene sulfonate. Colon tissues were collected and analyzed by histopathology, immunohistochemical analysis, and immunoblot analysis; we also measured mucosal levels of adenosine triphosphate (ATP) and reactive oxygen species, OXPHOS complex activity, and epithelial cell proliferation and apoptosis. Results We identified mice with increased mucosal OXPHOS complex activities and levels of ATP. These mice developed less-severe colitis after administration of dextran sodium sulfate or trinitrobenzene sulfonate than mice with lower mucosal levels of ATP. Colon tissues from these mice also had increased enterocyte proliferation and transcription factor nuclear factor-κB activity, which have been shown to protect the mucosal barrier—defects in these processes have been associated with inflammatory bowel disease. Conclusions Variants in mitochondrial DNA that increase mucosal levels of ATP protect mice from colitis. Increasing mitochondrial ATP synthesis in intestinal epithelial cells could be a therapeutic approach for UC.

Background Ulcerative colitis (UC) is a chronic inflammatory disorder of still unknown pathogenesis. Increasing evidence indicates that alterations in mitochondrial respiration and thus adenosine triphosphate (ATP) production are involved. This may contribute to mucosal energy deficiency and subsequently intestinal barrier malfunction, which is accepted to be a major hallmark of UC. Genetic alterations of the mitochondrial genome are one cause of mitochondrial dysfunction. However, less is known about mitochondrial gene polymorphisms in UC. Therefore, we aimed at identifying genetic associations between mitochondrial polymorphisms and UC. Methods German UC cases (n = 1062) and German healthy controls (n = 3030) were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. The primary association analysis was to test for associations between mitochondrial single nucleotide polymorphisms (SNPs) and UC using Fisher’s exact test in the total sample and stratified by sex. In addition, we tested for associations between mitochondrial haplogroups and UC and for interactions between the most promising mitochondrial SNPs and nuclear SNPs. An independent set of German subjects with 1625 UC cases and 3575 controls was used for replication. Results We identified a genetic association between the MT-ND4 11719 A/G polymorphism and UC in the subgroup of males (rs2853495; odds ratio, 1.40; 95 % confidence interval, 1.13 to 1.73; p = 0.002). This association was replicated in the second independent cohort. In the association analysis based on mitochondrial haplogroups the lowest p values were reached for haplogroups HV and T (p = 0.029 and 0.035). Haplogroup HV is determined by the mitochondrial 11719 A/G polymorphism. Accordingly, this association was only found in the subgroup of males (p = 0.009). Conclusions For the first time, we observed an association between the MT-ND4 11719 A/G polymorphism and UC. The gene MT-ND4 encodes for a subunit of the mitochondrial electron transport chain complex I, which is pivotal for ATP production and might therefore contribute to mucosal energy deficiency. The male-specific association indicates differences between males and females concerning the impact of mitochondrial gene polymorphisms on the development of UC. Further investigations of the functional mechanism underlying this association and the relevance of the gender-specificity are highly warranted. Electronic supplementary material The online version of this article (doi:10.1186/s12876-016-0509-1) contains supplementary material, which is available to authorized users.