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ObjectiveA considerable proportion of patients with irritable bowel syndrome (IBS) may be wheat-sensitive and respond to a gluten-free diet (GFD) although they do not have coeliac disease. However, a diagnostic test for wheat sensitivity (WS) is missing. Our study evaluated the diagnostic accuracy (sensitivity and specificity) of confocal laser endomicroscopy (CLE) for the identification of WS as primary outcome.DesignIn this prospective, double-blind diagnostic study 147 non-coeliac patients fulfilling the Rome III criteria for IBS were tested by CLE for duodenal changes after wheat (index test), soy, yeast or milk exposure. Patients with IBS responding to 2 months of GFD were classified as having WS (reference test) using response criteria recommended by regulatory bodies for pharmaceutical trials of patients with IBS. After 2 months, CLE results were unblinded and patients were advised to exclude those food components that had led to a positive CLE reaction. The clinical response was assessed at follow-up after 6 and 12 months.ResultsOf 130 patients who completed the study per protocol, 74 (56.9%) responded to GFD and were classified as WS after 2 months, and 38 of these 74 patients were correctly identified by CLE (sensitivity 51.4%; 97.5% CI: 38.7% to 63.9%). A total of 38 of 56 patients without WS were correctly identified by CLE (specificity 67.9%; 97.5% CI: 52.9% to 79.9%). At 6 months follow-up, CLE correctly identified 49 of 59 food-sensitive patients (sensitivity 83.1%; 97.5% CI: 69.9% to 91.3%) but specificity was only 32% (97.5% CI: 15.7% to 54.3%).ConclusionIn light of the high proportion of patients with IBS responding to GFD, the diagnostic accuracy of CLE is too low to recommend widespread use of this invasive procedure.Trail registration numberThis study was registered as clinical trial in the German Registry for Clinical Studies (DRKS00010123).

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterised by intestinal inflammation limited to the rectum and colonic mucosa.1 At presentation, approximately 30% of patients have inflammation involving the rectum only, termed ulcerative proctitis (UP).2 3 Proximal extension of UP may occur in up to 28% of patients after 5 years follow-up with progression to extensive colitis in 49% of cases.4–8 A population-based study of paediatric-onset UC demonstrated that 25% of patients with paediatric UC had UP at diagnosis and 49% of them presented a colonic extension at maximal follow-up.9 UP is specifically defined by the disease not extending not beyond the rectum (ie, proximal extent of inflammation is distal to the rectosigmoid junction).10 However, there is no universal standard for defining UP. The Montreal classification divides the distribution of UC only into UP (E1: limited to the rectum), left-sided colitis (E2: up to the splenic flexure) and extensive colitis (E3: beyond splenic flexure).11 12 American Gastroenterological Association (AGA) Institute Guidelines defined proctitis as an in inflammation limited to the rectum or

ObjectivesHere, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a pooled analysis of 21 clinical trials.MethodsData from all patients who had received at least one dose of secukinumab were included. Safety analyses were conducted to evaluate cumulative IBD rates as well as per-year rates, by indication. Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) events were analysed using exposure-adjusted incidence rates (patient incidence rates per 100 patient-years (PY)).ResultsA total of 7355 patients with a cumulative exposure of 16 226.9 PY were included in the pooled analysis. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients with PsA, there were 3 cases of UC, 3 cases of CD and 2 cases of IBDU (EAIRs 0.08, 0.08 and 0.05); 7 of these represented new-onset cases. Among 794 patients with AS, there were 4 cases of UC, 8 cases of CD and 1 case of IBDU (EAIRs 0.2, 0.4 and 0.1); 9 were new-onset cases. In the per year analysis, the EAIRs for each indication did not increase over time with secukinumab treatment.ConclusionsIn this pooled secukinumab safety analysis of 7355 patients across 21 clinical trials, cases of IBD events (including CD, UC and IBDU) were uncommon.

ObjectiveThis phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn’s disease (CD).DesignEligible adults were aged 18–75 years, with active moderate-to-severe CD (Crohn’s Disease Activity Index (CDAI) 220–450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12.ResultsIn all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen.ConclusionsClinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β7+ central memory T cells.Trial registration numberNCT01276509; Results.

ObjectivePrimary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

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

Background and aimDisease 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.MethodsUsing 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.ResultsFor 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.ConclusionsBased 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.

Background:Pooled safety data has been reported with secukinumab (SEC) in patients (pts) with Psoriatic arthritis (PsA), Ankylosing Spondylitis (AS) and Psoriasis (PsO).1Objectives:To report longer-term safety data of SEC treatment in PsA, AS, PsO pts up to 5 years.Methods:The integrated clinical trial safety dataset included data pooled from 28 randomised controlled clinical trials of SEC 300 or 150 or 75 mg in PsO (11 Phase 3 and 8 Phase 4 trials), PsA (5 Phase 3 trials), and AS (4 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of 25 December 2018. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 pt-years. Analyses included all pts who received ≥1 dose of SEC.Results:A total of 12637 pts (8819, 2678 and 1140 pts with PsO, PsA and AS, with an exposure of 15063.1, 5984.6 and 3527.2 pt-years, respectively) were included. The most frequent AE was upper respiratory tract infection and EAIR per 100 pt-years for IBD, malignancies and MACE remained low. The EAIR per 100 pt-years for adverse events (AEs) of special interest are reported in Table 1. The cumulative post-marketing exposure to SEC was estimated to be ~285,811 pt-years across the approved indications. Safety data from post-marketing surveillance are reported in Table 2.Table 1.Selected AEs of interest with SEC across pooled clinical trialsVariablePsOPsAASSECN=8819SECN=2678SECN=1140Exposure (Days), Mean (SD)623.9 (567.7)816.2 (580.7)1130.1 (583.0)Death, n (%)15 (0.2)13 (0.5)10 (0.9)Selected AE’s of interest, EAIR (95% CI)Serious infections11.4 (1.2, 1.6)1.8 (1.5, 2.2)1.2 (0.9, 1.6)Candidainfections22.9 (2.7, 3.2)1.5 (1.2, 1.9)0.7 (0.5, 1.1)IBD3Crohn’s disease3Ulcerative colitis30.01 (0.0, 0.05)0.1 (0.05, 0.2)0.1 (0.08, 0.2)0.03 (0.0, 0.1)0.1 (0.04, 0.2)0.1 (0.04, 0.2)0.03 (0.0, 0.2)0.4 (0.24, 0.7)0.2 (0.1, 0.5)MACE40.4 (0.31, 0.5)0.4 (0.3, 0.6)0.7 (0.4, 1.0)Uveitis30.01 (0.0, 0.05)0.1 (0.04, 0.2)1.2 (0.9, 1.7)Malignancy50.9 (0.7, 1.0)1.0 (0.77, 1.3)0.5 (0.3, 0.8)1Rates for system organ class;2Rates for high level term;3Rates for preferred term (PT; IBD for unspecified IBD);4Rates for Novartis MedDRA Query term;5Rates for standardized MedDRA query term – ‘malignancies and unspecified tumour’; EAIR, exposure adjusted incidence rate per 100 pt-years; N, number of pts in the analysisTable 2.Summary of SEC post-marketing safetyExposure (PTY)PSUR126Dec14 -25Jun15PSUR226 Jun - 25Dec15PSUR326Dec15 -25Jun16PSUR426Jun -25Dec16PSUR526Dec16 -25Dec17PSUR626Dec17 -25Dec18Cumulative18387450168712854993744137325285811 n (Reporting rate PTY)Serious infections89 (4.8)149 (2.0)232 (1.4)475 (1.7)649 (0.7)1841 (1.3)3980 (1.4)Malignancy2 (0.1)15 (0.2)21 (0.1)50 (0.2)225 (0.2)422 (0.3)788 (0.3)Total IBD4 (0.2)12 (0.2)37(0.2)46 (0.2)185 (0.2)340 (0.3)693 (0.2)MACE6 (0.3)15 (0.2)16 (0.1)39 (0.1)151 (0.2)238 (0.2)504 (0.2)PSUR, periodic safety update report; PTY, pt-treatment yearsConclusion:In this long-term analysis across clinical trials and post-marketing surveillance, of pts with PsO, PsA and AS, SEC was well tolerated, with a safety profile consistent with previous reports.1Reference:[1]Deodhar et al. Arthritis Research & Therapy (2019) 21:111.Disclosure of Interests:Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Kristian Reich Grant/research support from: Affibody; Almirall; Amgen; Biogen; Boehringer Ingelheim; Celgene; Centocor; Covagen; Eli Lilly; Forward Pharma; Fresenius Medical Care; GlaxoSmithKline; Janssen; Kyowa Kirin; LEO Pharma; Medac; Merck; Novartis; Miltenyi Biotec; Ocean Pharma; Pfizer; Regeneron; Samsung Bioepis; Sanofi Genzyme; Takeda; UCB; Valeant and Xenoport., Consultant of: Affibody; Almirall; Amgen; Biogen; Boehringer Ingelheim; Celgene; Centocor; Covagen; Eli Lilly; Forward Pharma; Fresenius Medical Care; GlaxoSmithKline; Janssen; Kyowa Kirin; LEO Pharma; Medac; Merck; Novartis; Miltenyi Biotec; Ocean Pharma; Pfizer; Regeneron; Samsung Bioepis; Sanofi Genzyme; Takeda; UCB; Valeant and Xenoport., Speakers bureau: Affibody; Almirall; Amgen; Biogen; Boehringer Ingelheim; Celgene; Centocor; Covagen; Eli Lilly; Forward Pharma; Fresenius Medical Care; GlaxoSmithKline; Janssen; Kyowa Kirin; LEO Pharma; Medac; Merck; Novartis; Miltenyi Biotec; Ocean Pharma; Pfizer; Regeneron; Samsung Bioepis; Sanofi Genzyme; Takeda; UCB; Valeant and Xenoport., Alice B Gottlieb Grant/research support from:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Consultant of:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Speakers bureau:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Mark Lebwohl Grant/research support from: AbbVie, Amgen, Arcutis, AstraZeneca, Boehringer Ingelheim, Celgene, Clinuvel, Eli Lilly, Incyte, Janssen Research & Development, LLC, Kadmon Corp., LLC, Leo Pharmaceutucals, Medimmune, Novartis, Ortho Dermatologics, Pfizer, Sciderm, UCB, Inc., and ViDac, Consultant of: Allergan, Almirall, Arcutis, Inc., Avotres Therapeutics, BirchBioMed Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Evelo, Foundation for Research and Education in Dermatology, Inozyme Pharma, LEO Pharma, Meiji Seika Pharma, Menlo, Mitsubishi, Neuroderm, Pfizer, Promius/Dr. Reddy’s Laboratories, Theravance, and Verrica, Stefan Schreiber Consultant of: AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, provention Bio, Protagonist and Falk, Weibin Bao Shareholder of: Novartis, Employee of: Novartis, Kwaku Marfo Shareholder of: Novartis, Employee of: Novartis, Hanno Richards Shareholder of: Novartis, Employee of: Novartis, Luminita Pricop Shareholder of: Novartis, Employee of: Novartis, Abhijit Shete Shareholder of: Novartis, Employee of: Novartis, Jorge Safi Shareholder of: Novartis, Employee of: Novartis, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau

Background:IgG4-related disease (IgG4-RD) is a polymorphic autoimmune disease leading to tumourous swelling and/or fibrosis of affected organs. Riedel’s thyroiditis is – besides chronic periaortitis, Mikulicz Syndrome and many others – an organ manifestation of IgG4-RD that has been thought to be an independent disease for a long time. About 40% of patients have single organ IgG4-RD while the others suffer from multisystemic disease [1].Objectives:Glucocorticoids, sometimes combined with other immunosuppressives are the standard treatment of IgG4-RD, in some situations (e.g. mechanical complications or suspected malignancy) surgery may be necessary but little is known about the management of fully resected single-organ IgG4-RD [1].Methods:We report a case of single-organ IgG4-RD (Riedel’s thyroiditis) after complete resection and perform a brief review of the literature to guide clinical management in this situation.Results:A woman (51 y) with pre-existing Hashimoto’s thyroiditis (thyroid peroxidase antibody positive) developed a rapidly growing struma with very firm consistency (not allowing fine needle biopsy). Besides slightly increased C-reactive protein (5,3 mg/l) there was no laboratory sign suggestive for IgG4-RD (normal serum IgG4, complement, eosinophils and IgE). Within 4 months the patient suffered from hoarseness and progredient dyspnea. Surgical thyroidectomy was performed and histopathology revealed IgG4-related Riedel’s thyroiditis with extensive (storiform) fibrosis, a dense lymphoplasmacytic infiltrate, obliterative phlebitis, eosinophilia and 13 IgG4-positive plasma cells per high power field.After referral to our department a comprehensive work-up showed no signs of other manifestations of IgG4-RD. Treatment with glucocorticoids is clearly recommended for patients with symptomatic IgG4-RD in an international consensus statement, whereas “watchful waiting” may be appropriate in some cases of asymptomatic or mild disease. While some highly fibrotic lesions may not respond well to glucocorticoids and may require surgical intervention, no clear guidance is available for the management of fully resected single organ IgG4-RD [2].A brief review of the literature revealed that few cases of single-organ IgG4-RD remaining in remission after resection without medical treatment have been reported e.g. IgG4-related cholecystitis, autoimmune-pancreatitis, tumours of the intestinal tract, lung, thymus, meninges, paravertebral space and others [3–9].After discussion of the options with the patient no systemic immunosuppression was given under close follow up without signs of relapse in clinical examinations, laboratory or imaging during the first 6 months.Conclusion:Limited evidence from case reports suggests that a “watchful waiting” strategy without systemic immunosuppressive treatment may be reasonable in some cases of single-organ IgG4-RD after the affected organ was completely resected (e.g. due to mechanical complications or suspected malignoma). However, close follow-up monitoring should be applied due to the risk of relapse or development of new organ manifestations.References:[1]Brito-Zerón et al.Best Pract. Res. Clin. Rheumatol.2016[2]Khosroshahi et al.Arthritis Rheumatol.2015[3]Takahashi et al.Surg. Case Rep.2015[4]Akbari et al.ACG Case Rep. J.2018[5]Oda et al.Thorac. Cancer2019[6]Nambirajan et al.Childs Nerv. Syst. ChNS Off. J. Int. Soc. Pediatr. Neurosurg.2019[7]Uchida et al.Asian J. Endosc. Surg.2018[8]Hart et al.Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc2015[9]Kim et al.Tuberc. Respir. Dis.2014Disclosure of Interests:Jan Schirmer: None declared, Marcus Seeger: None declared, Dominik Schulte Paid instructor for: Ferring, Speakers bureau: Amgen, Astra Zeneca, Braun, Fresenius, Ipsen, Johnson & Johnson, Lilly, MSD, Novartis, Novo Nordisk, Sanofi, Matthias Laudes Speakers bureau: Roche, Sanofi, Chugai, Stefan Schreiber Consultant of: AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, provention Bio, Protagonist and Falk, Bimba F. Hoyer: None declared

We read with interest the recent work by Schwerd et al 1 showing yet another example of human monogenic diseases that can present with IBD-like intestinal inflammation. Among the genes and diseases related to these often early onset monogenic IBD cases in humans is also the MEFV gene encoding for pyrin. The DNA sequence of gorillas shows >98% identity to the human genome.2 However, so far, there are only individual case descriptions of severe colitis due to infections3–6 and, to our knowledge, no cases of IBD have been reported in gorillas so far. We here report two closely related female western lowland gorillas living in captivity and showing partly overlapping GI symptoms, following the relocation into new groups in different zoos. The first case Enea (figure 1A) shows the typical clinical signs of a chronic IBD, most likely Crohn’s disease (CD). After a psychological stress situation, the relocation to a new zoo involving minor dietary …

Objective A global increase of IBD has been reported, especially in countries that previously had low incidence rates. Also, the knowledge of the human gut microbiome is steadily increasing, however, limited information regarding its variation on a global scale is available. In the light of the microbial involvement in IBDs, we aimed to (1) identify shared and distinct IBD-associated mucosal microbiota patterns from different geographical regions including Europe (Germany, Lithuania) and South Asia (India) and (2) determine whether profiling based on 16S rRNA transcripts provides additional resolution, both of which may hold important clinical relevance. Design In this study, we analyse a set of 89 mucosal biopsies sampled from individuals of German, Lithuanian and Indian origins, using bacterial community profiling of a roughly equal number of healthy controls, patients with Crohn's disease and UC from each location, and analyse 16S rDNA and rRNA as proxies for standing and active microbial community structure, respectively. Results We find pronounced population-specific as well as general disease patterns in the major phyla and patterns of diversity, which differ between the standing and active communities. The geographical origin of samples dominates the patterns of beta diversity with locally restricted disease clusters and more pronounced effects in the active microbial communities. However, two genera belonging to the Clostridium leptum subgroup, Faecalibacteria and Papillibacter, display consistent patterns with respect to disease status and may thus serve as reliable 'microbiomarkers'. Conclusions These analyses reveal important interactions of patients' geographical origin and disease in the interpretation of disease-associated changes in microbial communities and highlight the added value of analysing communities on both the 16S rRNA gene (DNA) and transcript (RNA) level.

Objective Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient ( Ctsk −/− ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. Design Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk −/− mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. Results Using Ctsk −/− mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk −/− mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk −/− mice ameliorates the severity of intestinal inflammation. Conclusion These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.

Objective The mammalian commensal gut microbiota is highly diverse and displays an individual-specific composition determined by host genotype and environmental factors. The temporal development of host-microbial homeostasis in the digestive tract is recognised as a major function of the immune system. However, the underlying cellular and molecular mechanisms are just beginning to come to light. Nucleotide-binding, oligomerisation domain 2 (NOD2) recognises bacterial muramyl dipeptide and is regarded as a pivotal sensor molecule of the intestinal barrier. The aim of this study was to investigate its influence on the development and composition of the intestinal microbiota using a Nod2-deficient mouse model. Methods The dynamics of faecal and ileal microbial composition were investigated in Nod2(+/+) and Nod2(-/-) mice on a C57BL/6J background. We assessed microbial diversity and composition using 16S ribosomal RNA gene-based clone library sequencing and high throughput pyrosequencing and quantified the observed changes by real-time PCR. Changes in the major bacterial phyla were investigated in human samples by quantitative real-time PCR. Results We found that adult Nod2-deficient mice display a substantially altered microbial community structure and a significantly elevated bacterial load in their faeces and terminal ileum compared to their wild-type counterparts. Interestingly, we demonstrate that these findings are also present in weaning mice, indicating a profound influence of Nod2 on the early development and composition of the intestinal microbiota. We demonstrate that NOD2 genotypes also influence the microbial composition in humans. Conclusions Our results point to an essential role of Nod2 for the temporal development and composition of the host microbiota, both in mice and in humans, which may contribute to the complex role of NOD2 for the aetiopathogenesis of Crohn's disease.

Background There is a paucity of data on fertility or pregnancy in patients with primary sclerosing cholangitis (PSC). Objective To assess fertility in PSC by comparing the number of children in a large cohort of PSC patients to healthy controls and to investigate the outcome of pregnancy, as well as the influence of pregnancy on the disease course. Design Case series. Setting Germany. Participants 229 PSC patients and 569 healthy controls were evaluated for the number of children. 17 patients with PSC and at least one pregnancy, or who received a diagnosis of PSC within 6 months after delivery, were included in the more detailed analysis. Main outcome measures Number of children per patient and control; disease activity during pregnancy and after delivery including maternal complications; long-term development of live births, fetal loss rate and the influence of medication on fetal and maternal outcome. Results Fertility did not seem to be reduced in PSC since the number of children did not differ between PSC patients and healthy controls. 25 pregnancies in 17 female PSC patients (median age at conception 31 years) were investigated in detail. An increase in liver enzymes was documented during five pregnancies (20%) and eight times (32%) post-partum. There were no serious maternal complications. All 21 live births presented with a normal perinatal and postnatal development over a median observation time of 50 months. Two pregnancies were delivered pre-term and four fetal losses occurred early in pregnancy (

Aim: Maintenance treatment in ulcerative colitis should be as convenient as possible, to increase the chance of compliance. MMX mesalazine is a once-daily, high-strength (1.2 g/tablet) formulation of 5-aminosalicylic acid. This study evaluated the safety and efficacy of MMX mesalazine dosed once or twice daily as maintenance therapy in patients with ulcerative colitis. Methods: This multicentre, randomised, open-label trial enrolled patients with strictly defined clinical and endoscopic remission, immediately following an episode of mild to moderate ulcerative colitis. Patients were randomised to MMX mesalazine 2.4 g/day as a single (2×1.2 g tablet) or divided dose (1×1.2 g tablet twice daily) for 12 months. Results: 174 patients (37.9%; safety population n = 459) experienced 384 adverse events, the majority of which were mild or moderate in intensity. Eighteen patients (3.9%), nine in each group, experienced a total of 22 serious adverse events (10 in the once-daily and 12 in the twice-daily group). Most serious adverse events were gastrointestinal, experienced by 5 patients in the once-daily and 4 in the twice-daily group. At month 12, 64.4% (efficacy population, n = 451) of patients in the once-daily and 68.5% of patients in the twice-daily group were in clinical and endoscopic remission (p = 0.351). At month 12, 88.9% and 93.2% in each group, respectively, had maintained clinical remission (were relapse free). Conclusions: MMX mesalazine 2.4 g/day administered as a single or divided dose demonstrated a good safety profile, was well tolerated and was effective as maintenance treatment. High clinical and endoscopic remission rates can be achieved with once-daily dosing. Trial registration number: NCT00151944.

Background: Increased expression of proinflammatory cytokines, including tumour necrosis factor α, interleukin 6, and interferon γ, as well as activation of proinflammatory signalling molecules such as nuclear factor kappa B, is characteristic of inflammatory bowel disease (IBD). Aims: To investigate expression and activation of signal transducer and activator of transcription (STAT) 1 in patients with IBD. Patients: Patients with active IBD (n=42), disease specificity controls (n=8), and normal controls (n=12) were investigated. Methods: Expression and activation of STAT1 were assessed by western blotting and electrophoretic mobility shift assays in extracts of endoscopic colonic biopsies. Cellular localisation was determined by immunohistochemistry. Results: Western blots and immunohistochemical staining revealed an increase in STAT1 expression and activation in mucosal samples from ulcerative colitis and to a lesser extend in Crohn9s disease patients. High levels of suppressor of cytokine signalling (SOCS)-3 expression, an inhibitor of STAT activation, were observed in Crohn9s disease patients and normal controls in western blot experiments whereas no differences were observed for SOCS-1 expression. Phosphorylated (p) STAT1 was mainly detected in monocytic cells and neutrophils in the inflamed mucosa. Induction of remission by systemic glucocorticoids led to a decrease in levels of pSTAT1. In vitro studies indicated a direct effect of steroid treatment on STAT1 activation. Conclusions: Expression and activation of STAT1 are predominantly heightened in ulcerative colitis and may therefore play an important role in the pathophysiology of colonic inflammation.

Inflammatory bowel disease is frequently associated with spondylarthritis (SpA). It has been discussed that α4/β7 expressing lymphocytes are involved in the aetiology of SpA. We report a case of a successful combination therapy of vedolizumab (VDZ) and etanercept (ETA) in a patient with ulcerative colitis with pouchitis and SpA. In our case VDZ was effective for pouchitis and ineffective for SpA. The combination with ETA might be a useful treatment strategy to control both diseases and first indications suggest that it is safe. α4/β7 Expressing lymphocytes are most likely not associated in the aetiology of SpA.

BACKGROUND AND AIMS—Genetic predisposition for inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic linkage studies. Genetic linkage of IBD to chromosome 3 has been observed previously. A high density analysis of chromosome 3p was performed to confirm prior linkages and elucidate potential genetic associations. METHODS—Forty three microsatellite markers on chromosome 3 were genotyped in 353 affected sibling pairs of North European Caucasian extraction (average marker density 2 cM in the linkage interval). Marker order was defined by genetic and radiation hybrid techniques. RESULTS—The maximum single point logarithm of odds (LOD) score was observed for Crohn's disease at D3S3591. Peak multipoint LOD scores of 1.65 and 1.40 for the IBD phenotype were observed near D3S1304 (distal 3p) and near D3S1283 in the linkage region previously reported. Crohn's disease contributed predominantly to the linkage. The transmission disequilibrium test showed significant evidence of association (p=0.009) between allele 4 of D3S1076 and the IBD phenotype (51 transmitted v 28 non-transmitted). Two known polymorphisms in the CCR2 and CCR5 genes were analysed, neither of which showed significant association with IBD. Additional haplotype associations were observed in the vicinity of D3S1076. CONCLUSIONS—This study provides confirmatory linkage evidence for an IBD susceptibility locus on chromosome 3p and suggests that CCR2 and CCR5 are unlikely to be major susceptibility loci for IBD. The association findings in this region warrant further investigation. Keywords: inflammatory bowel disease; fine mapping; chromosome 3

Identification of the DNA structure as a double stranded helix consisting of two nucleotide chain molecules was a milestone in modern molecular biology. This discovery has lead to a rapidly accumulating body of genomic information. The dramatic developments in genetic analysis during the past decade have placed genomics at the forefront of life science research. Large multinational projects (for example, the human genome project) have generated a host of sequence, mapping, and expression data. At the same time, new technologies for automated sequencing, data analysis, genotyping, expression, and protein analysis have been developed. An important result is identification of the genetic aetiology of many monogenic diseases and the enormous progress in the exploration of polygenic disorders. This article reviews the possible applications and future developments of genomic technologies in disorders of the gastrointestinal tract. In recent years, significant progress in the elucidation of the pathophysiology and aetiology of gastrointestinal disorders has been made. Novel experimental therapies which specifically target single steps in disease relevant regulatory pathways have been designed and are in different stages of clinical development. Examples are inhibition of the gastric proton pump in peptic ulcer disease1 and anti-tumour necrosis factor α therapy which has been developed for Crohn's disease and rheumatoid arthritis.2-4 This process was made possible by technological advances in cell biology, biochemistry, and microbiology and their application to disorders of the gastrointestinal tract. While this methodological approach has produced substantial advances in our understanding of gastrointestinal pathophysiology and increased available treatment options, there are currently several new challenges that call for the development of novel research techniques. (i) : The pursuit of hypothesis driven functional research limits the scope of discovery to known genes and pathways and may therefore hamper the elucidation of novel genes and regulatory mechanisms. (ii) : Exploration of signalling cascades and their role in disease pathophysiology has reached an enormous degree of complexity. Therefore, distinction between primary and secondary events is impossible in most cases. Even the exact mechanisms of a successful therapeutic application of targeted immune therapies (for example, therapy of Crohn's disease with tumour necrosis factor binding monoclonal antibodies) are not completely clear.5 6 Application of exploratory techniques based on a hypothesis free approach using high throughput (“parallel”) methodologies may help to establish a hierarchy of known and new players in signalling pathways and to identify key events in the mechanism of anti-inflammatory therapeutics. (iii) : A genetic—or familial—component has been identified in many gastrointestinal disorders, including gastrointestinal malignancies, inflammatory bowel disease, susceptibility to Helicobacter pylori related pathology, pancreatitis, bile stone formation, and others.7 8 Progress in the different fields outlined above may rely to different extents on the availability of genomic information and technology. Taking a cell biological hypothesis to a specific test has for a long time been the …

Background Secukinumab (SEC), a fully human anti–interleukin-17A monoclonal antibody, has been evaluated and approved for the treatment of moderate to severe psoriasis (PsO), active psoriatic arthritis (PsA) and active ankylosing spondylitis (AS). Inflammatory bowel disease (IBD), including Crohn9s disease (CD) and ulcerative colitis (UC), is commonly associated with PsO, PsA and AS. 1,2 The risk of CD in PsO pts is ∼4-fold higher than that in the general population; this risk is even higher among PsO pts with PsA, reported at a rate of 0.05 cases per 100 pt-years. 1 The rate of CD among placebo (Pbo) treated pts in AS trials has been reported as 0.7 cases per 100 pt-years. 3 Endoscopic subclinical inflammation occurs in up to 50% of AS patients. 2 Objectives To assess the incidence of CD and ulcerative colitis (UC) among SEC-treated pts in the PsO, PsA, and AS clinical trial programs. Methods This analysis included data from 10 Phase 2 and Phase 3 studies in moderate to severe PsO, 2 Phase 3 studies in active PsA, and 2 Phase 3 studies in active AS, pooled per indication. Most studies included short-term, Pbo treatment arms; 1 PsO study included an etanercept (ETN) active comparator arm. Pts with prior history of, but not active, IBD could be enrolled. Study durations varied; data from all pts receiving ≥1 SEC dose up to Week (Wk) 52 (PsO studies) or Wk 112 visit were included. Data are reported as crude frequency rates (%) in the short-term (Wk 12 in PsO studies and Wk 16 in the PsA/AS studies) and exposure adjusted incidence rates (EAIR; per 100 pt-years) over the entire treatment period. Results Overall, 3430, 974, and 571 pts received ≥1 SEC dose in the PsO, PsA, and AS studies, respectively. AEs of CD or UC were reported infrequently amongst SEC-treated pts in both the short- and long-term treatment periods (Table). Rates of CD and UC were similar across the PsO and PsA cohort, and rates with SEC were similar to those seen with ETN in PsO pts. Across all indications, there was no dose dependency with respect to the incidence of CD or UC with SEC, and no pattern in time-to-onset (data not shown). Conclusions Events of CD and UC in the 14 clinical studies were reported infrequently in SEC-treated pts with PsO, PsA, or AS; rates were similar across the PsO and PsA cohorts. EAIR rates of CD and UC observed in SEC-treated patients are consistent with those reported in the literature in PsO, PsA, and AS pts. References Li et al. Ann Rheum Dis 2013;72:1200–5; Rudwaleit et al. Best Pract Res Clin Rheumatol 2006;20:451–71; Braun et al. Arthritis Rheum 2007;57:639–47; Ward et al. AAD 2014. Poster presentation #8233; Secukinumab US Prescribing Information Acknowledgement The study was sponsored by Novartis Pharma AG. Disclosure of Interest S. Schreiber Grant/research support from: Abbvie, AstraZeneca/Medimmune, Boehringer, Celltrion, Ferring, Jansen, Novartis, MSD, Pfizer, Sanofi, Takeda, UCB, Consultant for: Abbvie, Celltrion, Ferring, MSD, Takeda, B. Sands: None declared, A. Deodhar Grant/research support from: AbbVie, Amgen, Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Consultant for: AbbVie, Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, D. Baeten Grant/research support from: Boehringer Ingelheim, Janssen, MSD, Novartis, Pfizer, Consultant for: AbbVie, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, UCB, J. Huang Shareholder of: Novartis, Employee of: Novartis, K. Gandhi Shareholder of: Novartis, Employee of: Novartis, C. Karyekar Shareholder of: Novartis, Employee of: Novartis, T. Fox Shareholder of: Novartis, Employee of: Novartis, C. Gaillez Shareholder of: Novartis, Employee of: Novartis

4-Aminosalicylic acid (4-ASA) has been suggested as an effective treatment for both active and quiescent ulcerative colitis. 5-Aminosalicylic acid (5-ASA) is well accepted for the maintenance treatment of inactive ulcerative colitis. Moreover, recent studies suggest that 5-ASA may also be effective in maintaining remission in Crohn's colitis. As treatment with 4-ASA may result in less side effects, the efficacy of a one year's maintenance treatment with oral 4-ASA (1.5 g/d, slow release tablets, n = 19) and oral 5-ASA (1.5 g/d, slow release tablets, n = 21) was compared in a double blind, randomised trial in patients with quiescent Crohn's ileocolitis. Patients with ileocolonic or colonic involvement were enrolled if in stable remission for more than two months but less than one year. Baseline demography and clinical severity were similar in both groups. Total colonoscopy and ileoscopy were performed at enrollment and at the end of the study. After one year seven of 19 patients receiving 4-ASA (36%) and 8 of 21 receiving 5-ASA (38%) had developed a clinical relapse, as defined by a rise in the Crohn's disease activity index (CDAI) of more than 100 points to values higher than 150. The relapse rates between the 4-ASA and the 5-ASA groups were not statistically different although no comparison with the spontaneous relapse rate in a placebo group could be made. Clinical relapse was accompanied by a statistically significant rise in serum concentrations of soluble interleukin 2 receptor and by an increased percentage of activated peripheral blood T cells. There were no statistical differences between the 4-ASA and the 5-ASA groups regarding the height of rise in CDAI or of soluble interleukin 2 receptor concentrations during relapse, thus showing a similar severity relapsed disease activity. In conclusion, 4-ASA maybe as effective as 5-ASA in the maintenance treatment of quiescent Crohn's disease and there were no differences in the severity of relapse between both treatment groups.

Increased concentrations of the soluble form of the interleukin 2 receptor have been observed in the sera of Crohn's disease and ulcerative colitis patients. In this study we have observed the spontaneous release of soluble interleukin 2 receptor by unstimulated, isolated normal and inflammatory bowel disease colonic lamina propria mononuclear cells. Lamina propria mononuclear cells from Crohn's disease patients (median = 204 U/ml (interquartile range 126-396, n 17) secreted significantly (p less than 0.01) more soluble interleukin 2 receptor than normal controls (median = 124.5 U/ml (108-131), n 12). No statistically significant differences were seen between ulcerative colitis (median = 135 U/ml (92-196), n 20) and normal controls. Moreover, significantly (p less than 0.01) increased amounts of soluble interleukin 2 receptor were secreted by colonic diverticulitis lamina propria mononuclear cells (median = 259 U/ml (149-282), n 15) which were used as disease specificity controls. Time course experiments showed that the majority of soluble interleukin 2 receptor was released by isolated lamina propria mononuclear cells in the first six days of culture. Upon stimulation with pokeweed mitogen, Crohn's disease (median = 2258 U/ml (1435-3584), n 14), normal control (median = 2622 U/ml (2030-3180), n 14) and diverticulitis lamina propria mononuclear cells (median = 2745 U/ml (1733-3192), n 10) reached similar maximal soluble interleukin 2 receptor secretion levels, while ulcerative colitis lamina propria mononuclear cells secreted significantly (p less than 0.005) less soluble interleukin 2 receptor (median = 912 U/ml (494-1259), n 17). These results suggest that enhanced shedding/secretion of soluble interleukin 2 receptor by intestinal lymphocytes may account in part for increased serum soluble interleukin 2 receptor concentrations during chronic intestinal inflammatory reactions.

INTRODUCTION: Peroxiredoxins are a family of highly conserved antioxidant proteins. Beside its role in the reduction of peroxides, Peroxiredoxin-4 (Prdx4) has been shown to play a role in the modulation of pro-inflammatory signalling cascades. Our group has previously demonstrated that Prdx4 is expressed in the intestinal mucosa and upregulated upon stimulation with the bacterial cell wall component muramyl-dipeptide (MDP). In addition, siRNA-mediated downregulation of Prdx4 increased MDP-induced NF-kappaB signalling. We therefore generated a murine Prdx4-knockout model to address the relevance of Prdx4 in the intestinal immune response in vivo . METHODS: In this study, two different Prdx4-knockout mouse lines were used: A constitutive Prdx4(‑/-) knockout strain, in which global Prdx4 expression was deleted and a conditional mouse line that specifically lacked Prdx4 in the intestinal epithelium (Prdx4 (DeltaIEC/DeltaIEC)). Intestinal inflammation was induced by administration of dextran-sodium-sulfate (DSS) in the drinking water of Prdx4 (-/-), Prdx4 (DeltaIEC/DeltaIEC) and respective littermate control mice. Mice were assessed for weight loss, disease severity, histopathology and endoscopic appearance. RESULTS: We found that during DSS-induced colitis Prdx4 (-/-) mice lost significantly more weight and had a more pronounced disease activity than their wild-type littermates. However, no such differences were observed in Prdx4 (DeltaIEC/DeltaIEC) mice, compared to their Prdx4 (floxed/floxed) littermates. Likewise, colon histopathology and endoscopy did not reveal significant differences. We next examined Prdx4 expression in dissociated intestinal segments and found that Prdx4 levels in the lamina propria exceeded those of the intestinal epithelium (foldchange >2). In addition, already under basal conditions, lamina propria immune cell composition differed significantly between Prdx4 (-/-) and wild-type mice. CONCLUSION: Our data assign a protective role of Peroxiredoxin-4 in intestinal inflammation which does not arise from the intestinal epithelium but presumably from the lamina propria. Further studies will be needed to determine the functional basis and molecular mechanisms of the observed effects. DISCLOSURE OF INTEREST: None Declared.

Currently, decisions regarding patient care in Crohn’s disease are largely dictated by clinical phenotypes, incorporating disease localisation and behaviour. In this context, a molecular classification based on genetic susceptibility can provide a far more meaningful stratification for biologically relevant genotype–phenotype associations, and ultimately, the individualisation of patient treatment.1 The IBD5 risk haplotype (IBD5risk) located within the 5q31 cytokine gene cluster has been unequivocally associated with Crohn’s disease.2 Specific clinical phenotypes have not been firmly established for IBD5risk, although an association with perianal and with fistulising Crohn’s disease has been proposed.3–8 We performed genotype–phenotype correlations for IBD5risk and Crohn’s disease in a cohort of 325 German patients, described elsewhere,3 to determine whether IBD5risk is associated with specific localisation phenotypic features and, in particular, with an extensive disease feature. Disease characteristics and age of onset were also analysed. Phenotyping procedures have been …

Challenging our understanding of the role of nuclear factor κB activation in the pathophysiology of intestinal inflammation in human inflammatory bowel disease Nuclear factor kappa B (NFκB) was discovered as a transcription factor some 15 years ago.1 Since then the protein has been linked to early pathophysiological events in a host of inflammatory conditions. NFκB, in most instances, is a heterodimer composed of a p50 and p65 subunit. In most mammalian cells NFκB is found in the resting state in the cytoplasm where it is bound in a complex to a protein that is a member of a family of specific inhibitors (IKK). Following phosphorylation, the inhibitor is rapidly degraded and the released NFκB migrates within minutes into the nucleus where it can specifically induce gene expression by binding to sequence defined DNA elements in gene promoter regions. Even after more than a decade of mechanistic and clinical studies, the role of NFκB in intestinal inflammation is not fully …

Introduction Differing perceptions between pts and physicians on the experience of living with and managing UC have been reported; the perspective of nurse specialists treating UC has not been fully explored. An international online survey of pts with UC and healthcare professionals (HCPs) treating UC was conducted in 6 countries to explore these differences; results from the UK are reported. Methods Structured, cross-sectional, Web-based questionnaires assessing multiple aspects of UC and its management were administered to pts with UC, and nurses and physicians treating pts with UC. Participants were identified via access panels or “phone-to-Web” recruitment. Statistical comparisons among the 3 groups were not conducted. Results In the UK, 150 pts, 50 nurses and 100 physicians completed the survey. Overall, the majority of pts (55%) described their UC severity as moderate. In contrast, HCPs estimated that their UC caseloads were primarily composed of mild compared with moderate pts (nurses: 49% vs 37%; physicians: 52% vs 35%). Pts reported experiencing a mean of 6.5 flares/year, but only discussed 3.4 flares with their HCP. Nurses and physicians, respectively, estimated that UC pts experienced a mean of 3.8 and 2.6 flares/year. Pts listed stress (41%) and natural disease course (35%) as the most common causes of flare. Both nurses and physicians, respectively, listed natural disease course (44% and 59%) followed by not taking preventive therapy (32% and 29%) as the most common flare causes. Most pts (58%) defined remission as “living with some symptoms”. A similar proportion of nurses (62%) and physicians (53%) defined remission as the “complete absence of symptoms”. Pts ranked urgency (43%) and pain (23%) as the most bothersome UC symptoms; while urgency was also rated most bothersome by a majority of nurses (58%) and physicians (51%), pain was rated most bothersome by the fewest nurses (6%) and physicians (1%). A total of 48% of pts reported that UC symptoms disrupted their quality of life (QoL); nurses and physicians estimated that 37% and 35% of pts, respectively, had their QoL disrupted by UC symptoms. Conclusion In the UK, nurses’ perception of UC was more aligned with physicians’ rather than pts’ perceptions. Both nurses and physicians may underestimate the burden of UC perceived by pts. Disclosure of Interest S. Bloom Consultant for: MSD, Abbott, Shire, Warner Chillcott, Employee of: UCL Hospitals NHS foundation trust, S. Schreiber Grant/Research Support from: Shire Development LLC, Speaker bureau with: Shire Development LLC, J. Panes Grant/Research Support from: Shire Development LLC, Consultant for: Abbott, BMS, MSD, Pfizer, Tygenix, Speaker bureau with: Shire Development LLC, Abbott, MSD, E. Louis Grant/Research Support from: Shire Development LLC, MSD, Schering Plough, Astra Zeneca, Abbott, Consultant for: Schering Plough, Abbott, MSD, Ferring, Shire Development LLC, Millenium, UCB, Speaker bureau with: Abbott, Astra Zeneca, Ferring, MSD, Schering Plough, Falk, Menarini, Chiesi, Nycomed, D. Holley Grant/Research Support from: Shire Development LLC, Employee of: GfK HealthCare, contracted by Shire to perform this research

Objective To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome. Design Multicentre retrospective case-control study. Setting 23 hospitals in northern Germany. Participants 298 adults with enterohaemorrhagic E coli induced haemolytic uraemic syndrome. Main outcome measures Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death. Results 160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% v 15%, P=0.03),fewer deaths (0% v 5%, p=0.029), required no abdominal surgery, and excreted E coli for a shorter duration. Conclusions Enterohaemorrhagic E coli induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial.

See article on page 795 Interleukin (IL)-16 was first described in 1982 under the name “lymphocyte chemoattractant factor”.1 Since its cloning in 1994,2 the complex structure and biological function of this cytokine has been extensively explored. In 1999, the IL-16 gene was localised to chromosome 15q26.33 but the role of genetic variants of this gene have yet to be explored in human disease. IL-16 can be produced by a variety of inflammatory cells, including mast cells, eosinophils, mononuclear phagocytes, and CD4+ and CD8+ T cells.4 IL-16 is expressed as an 80 kDa precursor molecule,5 which is processed to active IL-16 by caspase 3.6 Most interestingly, the main receptor for IL-16 appears to be the CD4 molecule (which identifies T helper cells but is also present on monocytes and other phagocytes). It is assumed that interaction with the CD4 molecule is the …

Transcription factors are small proteins which specifically regulate the expression of genes. A pivotal step in transcriptional regulation is the physical binding of these regulatory proteins to DNA sites in gene promoter regions. Binding specificity is determined by the nucleotide sequence of the binding site. Nuclear factor κB (NF-κB) was defined by its ability to bind to a 10 base pair oligonucleotide motif first identified in the enhancer region of the immunoglobulin κ light chain gene. NF-κB, which has recently been shown to regulate most inflammation genes, was originally described as a heterodimeric complex of two subunits, p65 and p50.1 2 Proteins of the NF-κB family are found constitutively in the cytoplasm of most mammalian cells. In resting cells, they are sequestered in the cytoplasm by inactivating molecules which are mainly members of the inhibitor κB family (IκB).1 2Activation of NF-κB …

Helicobacter pylori infection is one of the most common bacterial infections. The prevalence varies from 25–50% in developed countries to 70–90% in the third world.1 Despite improved treatment modalities, H pylori related gastrointestinal pathology, in common with gastritis, peptic ulcers and consecutive bleeding events, gastric MALT lymphoma, or carcinoma, remains a major burden on Western health systems. In the USA, approximately four million people have active peptic ulcers and about 350 000 new cases are diagnosed each year. Four times as many duodenal ulcers as gastric ulcers are diagnosed.2 Epidemiological evidence suggests that both infection with H pylori and the consecutive development of clinically relevant pathology are influenced by genetic predisposition as only a fraction of exposed individuals develop infection and likewise a fraction …