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Ulcerative Colitis: HELP
Articles from King's College
Based on 48 articles published since 2008
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These are the 48 published articles about Colitis, Ulcerative that originated from King's College during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial TPMT Testing Before Starting Azathioprine or Mercaptopurine: Surely Just Do It? 2015

Sanderson, Jeremy D. ·Department of Gastroenterology, Guy's & St. Thomas' Hospitals NHS Foundation Trust, London, United Kingdom. Electronic address: jeremy.sanderson@kcl.ac.uk. ·Gastroenterology · Pubmed #26311276.

ABSTRACT: -- No abstract --

2 Review Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis. 2016

Jairath, Vipul / Zou, Guangyong / Parker, Claire E / Macdonald, John K / Mosli, Mahmoud H / Khanna, Reena / Shackelton, Lisa M / Vandervoort, Margaret K / AlAmeel, Turki / Al Beshir, Mohammad / AlMadi, Majid / Al-Taweel, Talal / Atkinson, Nathan S S / Biswas, Sujata / Chapman, Thomas P / Dulai, Parambir S / Glaire, Mark A / Hoekman, Daniel / Koutsoumpas, Andreas / Minas, Elizabeth / Samaan, Mark A / Travis, Simon / D'Haens, Geert / Levesque, Barrett G / Sandborn, William J / Feagan, Brian G. ·Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada vipul.jairath@robartsinc.com. · Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. · Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada. · Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. · Robarts Research Institute, University of Western Ontario, London, ON, Canada. · Department of Medicine, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia. · Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia. · Haya Al-Habeeb Gastroenterology Center, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait. · Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK. · Robarts Research Institute, University of Western Ontario, London, ON, Canada Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Division of Medical Sciences, University of Oxford, Oxford, UK. · Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands. · Department of Geratology, Oxford University Hospitals NHS Trust, Oxford, UK. · Department of Gastroenterology, Guy's and St Thomas' Hospital NHS Trust, London, UK. · Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands. · Robarts Research Institute, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada Department of Medicine, University of Western Ontario, London, ON, Canada. ·J Crohns Colitis · Pubmed #26746169.

ABSTRACT: BACKGROUND AND AIMS: Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. RESULTS: In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. CONCLUSIONS: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.

3 Review Systematic review: bile acids and intestinal inflammation-luminal aggressors or regulators of mucosal defence? 2015

Pavlidis, P / Powell, N / Vincent, R P / Ehrlich, D / Bjarnason, I / Hayee, B. ·Department of Gastroenterology, King's College Hospital, London, UK. · Division of Transplantation and Mucosal Biology, King's College London, London, UK. · Department of Biochemistry, King's College Hospital, London, UK. · Centre of Host-Microbiome Interactions, King's College London, London, UK. ·Aliment Pharmacol Ther · Pubmed #26223936.

ABSTRACT: BACKGROUND: Inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis (UC), are chronic conditions attributed to an aberrant immune response to luminal triggers. Recently, published work suggests a pathogenic role for bile acids in this context. AIM: To perform a systematic review of studies investigating the role of bile acids in intestinal inflammation and present potentially relevant clinical implications. METHODS: Pubmed search for English language articles published up to May 2015. Terms used were: 'bile', 'bile acid', 'barrier', 'small bowel injury', 'Crohn's' and 'colitis'. RESULTS: Experimental studies support a variable role for bile acids in intestinal barrier homoeostasis. This may be attributed to different physicochemical properties, variable effects on epithelia and immune cells via bile acids-specific receptors, or through a cross-talk with the gut microbiome. A reduction in the bile acids pool, with lower concentrations of secondary forms, has been recognised for some time in Crohn's disease and associated to ileal dysfunction and bile acids malabsorption. Recent work suggests that these changes, including an increase in sulphated forms, are related to inflammatory activity in both Crohn's disease and UC. The detrimental effects of 'western diet' elements such as emulsifiers and fat, which have been implicated in the development of the current IBD and obesity epidemics, may also be bile acid-mediated. CONCLUSIONS: Although there are only a few observational clinical studies to support an interaction, in vivo human and animal studies support an association between bile acids metabolism, the gut microbiome and intestinal inflammation. This may well prove to have significant diagnostic and therapeutic implications.

4 Review Smoking in inflammatory bowel disease: impact on disease course and insights into the aetiology of its effect. 2014

Parkes, Gareth C / Whelan, Kevin / Lindsay, James O. ·Digestive Disease Clinical Academic Unit, Barts Health NHS Trust, London, United Kingdom. Electronic address: gareth.parkes@bartshealth.nhs.uk. · King's College London, School of Medicine, Diabetes and Nutritional Sciences Division, London, United Kingdom. Electronic address: kevin.whelan@kcl.ac.uk. · Digestive Disease Clinical Academic Unit, Barts Health NHS Trust, London, United Kingdom; Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London, United Kingdom. Electronic address: james.lindsay@bartshealth.nhs.uk. ·J Crohns Colitis · Pubmed #24636140.

ABSTRACT: The chronic intestinal inflammation that characterises Crohn's disease and ulcerative colitis arises from a complex interplay between host genotype, the immune system, and the intestinal microbiota. In addition, environmental factors such as smoking impact on disease onset and progression. Individuals who smoke are more likely to develop Crohn's disease, and smoking is associated with recurrence after surgery and a poor response to medical therapy. Conversely, smoking appears protective against ulcerative colitis and smokers are less likely to require colectomy. The mechanism by which smoking exerts its impact on disease and the rational for the dichotomous effect in patients with Crohn's disease and ulcerative colitis is not clear. Recent evidence suggests that smoking induces alterations to both the innate and acquired immune system. In addition, smoking is associated with a distinct alteration in the intestinal microbiota both in patients with active Crohn's disease and healthy subjects.

5 Review Faecal markers of gastrointestinal inflammation. 2012

Sherwood, Roy A. ·Clinical Biochemistry, King's College Hospital, London, UK. roy.sherwood@nhs.net ·J Clin Pathol · Pubmed #22813730.

ABSTRACT: Gastrointestinal (GI) symptoms including abdominal pain, bloating and diarrhoea are a relatively common reason for consulting a physician. They may be due to inflammatory bowel disease (inflammatory bowel disease; Crohn's disease, ulcerative colitis and indeterminate colitis), malignancy (colorectal cancer), infectious colitis or irritable bowel syndrome (IBS). Differentiation between these involves the use of clinical, radiological, endoscopic and serological techniques, which are invasive or involve exposure to radiation. Serological markers include C-reactive protein, erythrocyte sedimentation rate and antibodies (perinuclear antineutrophil cytoplasm antibody and anti-Saccharomyces cerevisiae antibody). Faecal markers that can aid in distinguishing inflammatory disorders from non-inflammatory conditions are non-invasive and generally acceptable to the patient. As IBS accounts for up to 50% of cases presenting to the GI clinic and is a diagnosis of exclusion (Rome III criteria), any test that can reliably distinguish IBS from organic disease could speed diagnosis and reduce endoscopy waiting times. Faecal calprotectin, lactoferrin, M2-PK and S100A12 will be reviewed.

6 Review The mycobiome: influencing IBD severity. 2012

Moyes, David L / Naglik, Julian R. ·Clinical & Diagnostic Sciences Group, King's College London Dental Institute, King's College London, London, UK. ·Cell Host Microbe · Pubmed #22704612.

ABSTRACT: The etiology and maintenance of inflammatory bowel disease (IBD) is the subject of much speculation. Iliev et al. (2012) impose a change in our views of the gut microbiome and catapult the fungal "mycobiome" center-stage in the exploration of IBD.

7 Review Diagnostic value, clinical utility and pathogenic significance of reactivity to the molecular targets of Crohn's disease specific-pancreatic autoantibodies. 2011

Bogdanos, Dimitrios P / Rigopoulou, Eirini I / Smyk, Daniel S / Roggenbuck, Dirk / Reinhold, Dirk / Forbes, Alastair / Laass, Martin W / Conrad, Karsten. ·Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine at King's College Hospital, London, UK. dimitrios.bogdanos@kcl.ac.uk ·Autoimmun Rev · Pubmed #21983481.

ABSTRACT: Pancreatic autoantibodies (PAB) giving characteristic staining patterns of the exocrine pancreas by indirect immunoflourescence appear to be specific markers of Crohn's disease (CrD), being present in approximately 30% of patients with CrD and in less than 5% of patients with ulcerative colitis (UC). Some studies have suggested that PAB are associated with specific disease phenotypes and that their detection may be of clinical significance. Thorough investigation of the role of PAB in the immunopathogenesis of inflammatory bowel diseases (IBD) has been hampered due to the lack of identity of their antigenic targets. The recent identification of the pancreatic zymogen granule protein 2 (GP2) as the major target of PAB has led to the development of an enzyme immunoassay that helps determine the diagnostic and clinical relevance of antigen-specific immune responses. Recent studies have demonstrated that GP2 is expressed on the apical surface of intestinal membranous cells of the follicle-associated epithelium, and is essential for host-microbial interaction and the initiation of bacteria-specific mucosal immune responses. This review critically discusses recent reports investigating the diagnostic and clinical utility of GP2-specific autoantibody responses in patients with IBD. Hints towards a better understanding of the immunogenicity of GP2 are also provided.

8 Article A retrospective observational study of early experiences of vedolizumab treatment for inflammatory bowel disease in the UK: The REVIVE study. 2019

Cummings, Fraser / Gaya, Daniel R / Levison, Scott / Subramanian, Sreedhar / Owen, Glynn / Rathmell, Anna / Glen, Fiona / Demuth, Dirk / Meadowcroft, Simon / Irving, Peter M. ·Department of Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton. · Gastroenterology Unit, Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow. · Department of Gastroenterology, Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust, Manchester. · Department of Gastroenterology, Royal Liverpool University Hospital, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool. · Takeda UK Ltd, High Wycombe, UK. Current address: Takeda Pharmaceuticals International AG, Zurich, Switzerland. · pH Associates, Marlow. · Evidence and Value Generation, Takeda Development Centre Europe Ltd. · IBD Unit, St Thomas' Hospital, Guys and St Thomas' NHS Foundation Trust, London, UK. ·Medicine (Baltimore) · Pubmed #30817598.

ABSTRACT: Results from clinical trials show that vedolizumab is an efficacious treatment for inflammatory bowel disease, namely Crohn's disease (CD) and ulcerative colitis (UC). However, there is limited evidence from real-world clinical practice, especially on early clinical experiences in the UK.To describe real-world early experiences of vedolizumab to treat CD and UC in the UK.A retrospective, chart review study of patients with CD or UC treated with vedolizumab across 5 UK hospitals. All eligible adults (≥18 years at initiation) with a diagnosis of CD and ≥14 weeks of data or UC and ≥10 weeks of data available following vedolizumab initiation were included.Data were analyzed for 112 patients (CD: 66; UC: 46). Patients with CD had a median of 7.4 (interquartile range 5.7-9.4) months follow-up and patients with UC had a median of 7.4 (5.6-10.2) months follow-up post-vedolizumab initiation. Most patients, 80% (53/66) with CD and 89% (41/46) with UC, remained on vedolizumab treatment at the time of data collection. No new safety signals were identified during the study.These results add to the body of evidence supporting vedolizumab as an effective and well-tolerated treatment for CD and UC in real-world clinical practice.

9 Article Oral Adjuvant Curcumin Therapy for Attaining Clinical Remission in Ulcerative Colitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. 2018

Grammatikopoulou, Maria G / Gkiouras, Konstantinos / Theodoridis, Xenophon / Asteriou, Eleni / Forbes, Alastair / Bogdanos, Dimitrios P. ·Faculty of Medicine, School of Health Sciences, University of Thessaly, Mezourlo, GR41110 Larissa, Greece. maria@nutr.teithe.gr. · Department of Nutrition & Dietetics, Alexander Technological Educational Institute, Sindos, P.O. Box 141, GR57400 Thessaloniki, Greece. maria@nutr.teithe.gr. · Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, GR54124 Thessaloniki, Greece. maria@nutr.teithe.gr. · Laboratory of Clinical Pharmacology, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, GR54124 Thessaloniki, Greece. kostasgkiouras@hotmail.com. · Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, GR41110 Larissa, Greece. kostasgkiouras@hotmail.com. · Faculty of Medicine, School of Health Sciences, University of Thessaly, Mezourlo, GR41110 Larissa, Greece. xenofontheodoridis@gmail.com. · Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, GR54124 Thessaloniki, Greece. xenofontheodoridis@gmail.com. · Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, GR41110 Larissa, Greece. eleniaster91@gmail.com. · Norwich Medical School, University of East Anglia, Bob Champion Building, James Watson Road, Norwich NR4 7UQ, UK. alastair.forbes@uea.ac.uk. · Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, GR41110 Larissa, Greece. bogdanos@med.uth.gr. · Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London Medical School, London SE5 9RS, UK. bogdanos@med.uth.gr. ·Nutrients · Pubmed #30424514.

ABSTRACT: Curcumin has demonstrated anti-inflammatory properties and has been investigated as an adjuvant therapy of ulcerative colitis (UC). The scope of this study was to systematically review and meta-analyze the efficacy of oral curcumin administration as an adjuvant therapy of UC. MEDLINE, Cochrane/CENTRAL, ClinicalTrials.gov, WHO-ICT Registry, EMBASE and grey literature were searched for relevant randomized controlled trials (RCTs). The primary outcome was clinical remission (attainment) and the secondary outcome was clinical response (maintenance/failure). Risk of bias was assessed with the Cochrane tool. Odds ratios (OR) were calculated with a Mantel-Haenszel (M-H) random effects model and with a beta-binomial (B-B) random effects model when zero events/cells occurred. Four RCTs met the criteria, but one was removed from the analyses due to inconsistency in protocol details. With the M-H method, treatment with curcumin was significantly superior to placebo in attaining remission in the per-protocol (PP) analysis (OR = 5.83, 95%CI = 1.24⁻27.43), but not in the intention-to-treat (ITT) analysis (OR = 4.33, 95%CI = 0.78⁻24.00). However, with the more accurate B-B method, both analyses were insignificant (for PP OR = 4.26, 95%CI = 0.59⁻31.00, for ITT OR = 3.80, 95%CI = 0.55⁻26.28). Based on the current available evidence, oral curcumin administration does not seem superior to placebo in attaining remission in patients with UC. Future RCTs should be planned more cautiously with sufficient size and adhere to the ITT analysis in all outcomes.

10 Article Exome Sequencing and Genotyping Identify a Rare Variant in NLRP7 Gene Associated With Ulcerative Colitis. 2018

Onoufriadis, Alexandros / Stone, Kristina / Katsiamides, Antreas / Amar, Ariella / Omar, Yasmin / de Lange, Katrina M / Taylor, Kirstin / Barrett, Jeffrey C / Pollok, Richard / Hayee, Bu'Hussain / Mansfield, John C / Sanderson, Jeremy D / Simpson, Michael A / Mathew, Christopher G / Prescott, Natalie J. ·Department of Medical and Molecular Genetics, King's College London, London, UK. · Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. · Department Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, UK. · IBD Service, King's College Hospital NHS Foundation Trust, London, UK. · Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. · Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK. · Sydney Brenner Institute for Molecular Bioscience, University of Witwatersrand, Johannesburg, South Africa. ·J Crohns Colitis · Pubmed #29211899.

ABSTRACT: Background and Aims: Although genome-wide association studies [GWAS] in inflammatory bowel disease [IBD] have identified a large number of common disease susceptibility alleles for both Crohn's disease [CD] and ulcerative colitis [UC], a substantial fraction of IBD heritability remains unexplained, suggesting that rare coding genetic variants may also have a role in pathogenesis. We used high-throughput sequencing in families with multiple cases of IBD, followed by genotyping of cases and controls, to investigate whether rare protein-altering genetic variants are associated with susceptibility to IBD. Methods: Whole-exome sequencing was carried out in 10 families in whom three or more individuals were affected with IBD. A stepwise filtering approach was applied to exome variants, to identify potential causal variants. Follow-up genotyping was performed in 6025 IBD cases [2948 CD; 3077 UC] and 7238 controls. Results: Our exome variant analysis revealed coding variants in the NLRP7 gene that were present in affected individuals in two distinct families. Genotyping of the two variants, p.S361L and p.R801H, in IBD cases and controls showed that the p.S361L variant was significantly associated with an increased risk of ulcerative colitis [odds ratio 4.79, p = 0.0039] and IBD [odds ratio 3.17, p = 0.037]. A combined analysis of both variants showed suggestive association with an increased risk of IBD [odds ratio 2.77, p = 0.018]. Conclusions: The results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD.

11 Article Anti-TNFα Treatment in Children and Adolescents With Combined Inflammatory Bowel Disease and Autoimmune Liver Disease. 2018

Nedelkopoulou, Natalia / Vadamalayan, Babu / Vergani, Diego / Mieli-Vergani, Giorgina. ·Paediatric Liver, GI and Nutrition Centre, Mowat Labs and Institute of Liver Studies, King's College Hospital, London, UK. ·J Pediatr Gastroenterol Nutr · Pubmed #28953529.

ABSTRACT: OBJECTIVES: Inflammatory bowel disease (IBD) and autoimmune liver disease (AILD) are closely associated, the former often dictating progression of the latter. Antibodies to tumor necrosis factor alpha (anti-TNFα) are effective in the management of IBD, but may cause liver injury. METHODS: Retrospective review of medical records of patients with juvenile AILD who received anti-TNFα for IBD to evaluate the safety and efficacy of anti-TNFα. RESULTS: Eleven patients (6 boys), ages 9 to 15 years (median 13 years) were identified. Ten had ulcerative colitis and 1 Crohn disease; 2 had autoimmune hepatitis type 1 and 9 autoimmune hepatitis-sclerosing cholangitis variant. All patients were started on infliximab (IFX, 5 mg/kg) and 2 required dose increase (10 mg/kg); 3 of 11 switched to adalimumab due to allergic reaction or nonresponse. Three received adalimumab after losing response or developing antibodies to IFX. Liver function tests (LFTs) improved in 5, 1 continued to have stably abnormal LFTs and 2 maintained normal LFTs. Patients on adalimumab showed stable or improved liver function compared to pretreatment status. Six of 8 treated with a full course of IFX maintained clinical remission of IBD for 6 months to 2.5 years; of the 6 patients treated with adalimumab, 1 sustained IBD clinical remission for 24 months, 2 achieved remission only after tacrolimus addition and 3 did not respond. CONCLUSIONS: IBD in patients with AILD can be aggressive, requiring escalation to anti-TNFα or switching to other biologics. In this series, anti-TNFα did not impair liver function and improved gut disease in most of the patients, indicating that it can be beneficial and safe.

12 Article Establishing Key Performance Indicators [KPIs] and Their Importance for the Surgical Management of Inflammatory Bowel Disease-Results From a Pan-European, Delphi Consensus Study. 2017

Morar, Pritesh S / Hollingshead, James / Bemelman, Willem / Sevdalis, Nick / Pinkney, Thomas / Wilson, Graeme / Dunlop, Malcolm / Davies, R Justin / Guy, Richard / Fearnhead, Nicola / Brown, Steven / Warusavitarne, Janindra / Edwards, Cathryn / Faiz, Omar. ·Surgical Epidemiology, Trials and Outcome Centre (SETOC), St. Mark's Hospital and Academic Institute, London, United Kingdom. · Department of Surgery and Cancer, Imperial College, London, United Kingdom. · Department of Surgery, Amsterdam Medical Centre, Amsterdam, Netherlands. · Centre for Implementation Science, King's College, London, United Kingdom. · Inflammatory Bowel Disease (IBD) subcommittee of Association of Coloproctology of Great Britain and Ireland (ACPGBI), London, United Kingdom. · Inflammatory Bowel Disease (IBD) Clinical Advisory Group (CAG), Association of Coloproctology of Great Britain and Ireland (ACPGBI), London, United Kingdom. · South Devon NHS Foundation Trust, Torbay. ·J Crohns Colitis · Pubmed #28961891.

ABSTRACT: Background and Aims: Key performance indicators [KPIs] exist across a range of areas in medicine. They help to monitor outcomes, reduce variation, and drive up standards across services. KPIs exist for inflammatory bowel disease [IBD] care, but none specifically cover inflammatory bowel disease [IBD] surgical service provision. Methods: This was a consensus-based study using a panel of expert IBD clinicians from across Europe. Items were developed and fed through a Delphi process to achieve consensus. Items were ranked on a Likert scale from 1 [not important] to 5 [very important]. Consensus was defined when the inter quartile range was ≤ 1, and items with a median score > 3 were considered for inclusion. Results: A panel of 21 experts [14 surgeons and 7 gastroenterologists] was recruited. Consensus was achieved on procedure-specific KPIs for ileocaecal and perianal surgery for Crohn's disease, [N = 10] with themes relating to morbidity [N = 7], multidisciplinary input [N = 2], and quality of life [N = 1]; and for subtotal colectomy, proctocolectomy and ileoanal pouch surgery for ulcerative colitis [N = 11], with themes relating to mortality [N = 2], morbidity [N = 8], and service provision [N = 1]. Consensus was also achieved for measures of the quality of IBD surgical service provision and quality assurance in IBD surgery. Conclusions: This study has provided measurable KPIs for the provision of surgical services in IBD. These indicators cover IBD surgery in general, the governance and structures of the surgical services, and separate indicators for specific subareas of surgery. Monitoring of IBD services with these KPIs may reduce variation across services and improve quality.

13 Article A multi-centre audit of excess steroid use in 1176 patients with inflammatory bowel disease. 2017

Selinger, C P / Parkes, G C / Bassi, A / Fogden, E / Hayee, B / Limdi, J K / Ludlow, H / McLaughlin, S / Patel, P / Smith, M / Raine, T. ·Leeds Teaching Hospitals NHS Trust, Leeds, UK. · Royal London Hospital, Barts Heath, London, UK. · St Helens and Knowsley Teaching Hospitals NHS Trust, St Helens, UK. · Sandwell and West Birmingham Hospitals, Birmingham, UK. · King's College Hospital NHS Foundation Trust, London, UK. · Pennine Acute Hospitals NHS Trust, Manchester, UK. · Cardiff and Vale University Health Board, Cardiff, UK. · The Royal Bournemouth and Christchurch Hospitals NHS Trust, Bournemouth, UK. · Epsom and St Helier University Hospitals NHS, Epsom, UK. · Brighton and Sussex University Hospitals, Brighton, UK. · Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. ·Aliment Pharmacol Ther · Pubmed #28949018.

ABSTRACT: BACKGROUND: Corticosteroids are central to inducing remission in inflammatory bowel disease (IBD) but are ineffective maintenance agents. AIM: To benchmark steroid usage in British outpatients and assess factors associated with excess exposure. METHODS: We recorded steroid use in unselected IBD outpatients. Cases meeting criteria for steroid dependency or excess were blind peer reviewed to determine whether steroid prescriptions were avoidable. Associations between steroid use and patient/institutional factors were analysed. RESULTS: Of 1176 patients, 30% received steroids in the prior 12 months. 14.9% had steroid dependency or excess, which was more common in moderate/severe ulcerative colitis (UC) than Crohn's disease (CD) (42.6% vs 28.1%; P = .027). Steroid dependency or excess was deemed avoidable in 49.1%. The annual incidence of inappropriate steroid excess was 7.1%. Mixed-effects logistic regression analysis revealed independent predictors of inappropriate steroid excess. The odds ratio (OR, 95%CI) for moderate/severe compared to mild/quiescent disease activity was 4.59 (1.53-20.64) for UC and 4.60 (2.21-12.00) for CD. In CD, lower rates of inappropriate steroid excess were found in centres with an IBD multi-disciplinary team (OR 0.62 [0.46-0.91]), whilst dedicated IBD clinics protected against inappropriate steroid excess in UC (OR 0.64, 95% CI 0.21-0.94). The total number of GI trainees was associated with rates of inappropriate steroid excess. CONCLUSIONS: Steroid dependency or excess occurred in 14.9% of British IBD patients (in 7.1% potentially avoidable). We demonstrated positive effects of service configurations (IBD multi-disciplinary team, dedicated IBD clinics). Routine recording of steroid dependency or excess is feasible and should be considered a quality metric.

14 Article Regulation of epithelial cell expressed C3 in the intestine - Relevance for the pathophysiology of inflammatory bowel disease? 2017

Sünderhauf, Annika / Skibbe, Kerstin / Preisker, Sophie / Ebbert, Karen / Verschoor, Admar / Karsten, Christian M / Kemper, Claudia / Huber-Lang, Markus / Basic, Marijana / Bleich, André / Büning, Jürgen / Fellermann, Klaus / Sina, Christian / Derer, Stefanie. ·Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. · Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany. · Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany; Division of Transplant Immunology and Mucosal Biology, Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. · Institute for Clinical and Experimental Trauma-Immunology, University Hospital Ulm, Ulm, Germany. · Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany. · 1st Department of Medicine, Gastroenterology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. · Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; 1st Department of Medicine, Gastroenterology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; 1st Department of Medicine, Section of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. · Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. Electronic address: Stefanie.derer@uksh.de. ·Mol Immunol · Pubmed #28843904.

ABSTRACT: The complement system not only plays a critical role in efficient detection and clearance of bacteria, but also in intestinal immune homeostasis as mice deficient for key complement components display enhanced intestinal inflammation upon experimental colitis. Because underlying molecular mechanisms for this observation are unclear, we investigated the crosstalk between intestinal epithelial cells (IEC), bacteria and the complement system in the course of chronic colitis. Surprisingly, mouse intestinal epithelial cell lines constitutively express high mRNA levels of complement component 3 (C3), Toll-like receptor 2 (Tlr2) and Tlr4. Stimulation of these cells with lipopolysaccharide (LPS), but not with flagellin, LD-muramyldipeptide or peptidoglycan, triggered increased C3 expression, secretion and activation. Stimulation of the C3aR on these cell lines with C3a resulted in an increase of LPS-triggered pro-inflammatory response. Tissue biopsies from C57BL/6J mice revealed higher expression of C3, Tlr1, Tlr2 and Tlr4 in colonic primary IECs (pIECs) compared to ileal pIECs, while in germ-free mice no differences in C3 protein expression was observed. In DSS-induced chronic colitis mouse models, C3 mRNA expression was upregulated in colonic biopsies and ileal pIECs with elevated C3 protein in the lamina propria, IECs and the mucus. Notably, increased C3b opsonization of mucosa-attached bacteria and decreased fecal full-length C3 protein was observed in DSS-treated compared to untreated mice. Of significant interest, non-inflamed and inflamed colonic biopsy samples from CD but not UC patients displayed exacerbated C3 expression compared to controls. These findings suggest that a novel TLR4-C3 axis could control the intestinal immune response during chronic colitis.

15 Article Fine-mapping inflammatory bowel disease loci to single-variant resolution. 2017

Huang, Hailiang / Fang, Ming / Jostins, Luke / Umićević Mirkov, Maša / Boucher, Gabrielle / Anderson, Carl A / Andersen, Vibeke / Cleynen, Isabelle / Cortes, Adrian / Crins, François / D'Amato, Mauro / Deffontaine, Valérie / Dmitrieva, Julia / Docampo, Elisa / Elansary, Mahmoud / Farh, Kyle Kai-How / Franke, Andre / Gori, Ann-Stephan / Goyette, Philippe / Halfvarson, Jonas / Haritunians, Talin / Knight, Jo / Lawrance, Ian C / Lees, Charlie W / Louis, Edouard / Mariman, Rob / Meuwissen, Theo / Mni, Myriam / Momozawa, Yukihide / Parkes, Miles / Spain, Sarah L / Théâtre, Emilie / Trynka, Gosia / Satsangi, Jack / van Sommeren, Suzanne / Vermeire, Severine / Xavier, Ramnik J / Anonymous3570911 / Weersma, Rinse K / Duerr, Richard H / Mathew, Christopher G / Rioux, John D / McGovern, Dermot P B / Cho, Judy H / Georges, Michel / Daly, Mark J / Barrett, Jeffrey C. ·Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. · Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA. · Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège, 4000 Liège, Belgium. · Faculty of Veterinary Medicine, University of Liège, 4000 Liège, Belgium. · Wellcome Trust Centre for Human Genetics, University of Oxford, Headington OX3 7BN, UK. · Christ Church, University of Oxford, St Aldates OX1 1DP, UK. · Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. · Research Center, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada. · Focused research unit for Molecular Diagnostic and Clinical Research (MOK), IRS-Center Sonderjylland, Hospital of Southern Jutland, 6200 Åbenrå, Denmark. · Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark. · Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium. · Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK. · Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden. · Department of Gastrointestinal and Liver Diseases, BioDonostia Health Research Institute, 20014 San Sebastián, Spain. · IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain. · Illumina, San Diego, California 92122, USA. · Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany. · Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE-70182 Örebro, Sweden. · F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Data Science Institute and Lancaster Medical School, Lancaster University, Lancaster LA1 4YG, UK. · Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, Western Australia 6008, Australia. · Harry Perkins Institute for Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch, Western Australia 6150, Australia. · Gastrointestinal Unit, Western General Hospital University of Edinburgh, Edinburgh, UK. · Division of Gastroenterology, Centre Hospitalier Universitaire (CHU) de Liège, 4000 Liège, Belgium. · Institute of Livestock and Aquacultural Sciences, Norwegian University of Life Sciences, 1430 Ås, Norway. · Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa 230-0045, Japan. · Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. · Open Targets, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK. · Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9700RB Groningen, The Netherlands. · Division of Gastroenterology, University Hospital Gasthuisberg, 3000 Leuven, Belgium. · Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. · Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA. · Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK. · Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg 2193, South Africa. · Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada. · Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA. ·Nature · Pubmed #28658209.

ABSTRACT: Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

16 Article Fermentable Carbohydrates [FODMAPs] Exacerbate Functional Gastrointestinal Symptoms in Patients With Inflammatory Bowel Disease: A Randomised, Double-blind, Placebo-controlled, Cross-over, Re-challenge Trial. 2017

Cox, Selina R / Prince, Alexis C / Myers, Clio E / Irving, Peter M / Lindsay, James O / Lomer, Miranda C / Whelan, Kevin. ·King's College London, Diabetes and Nutritional Sciences Division, UK. · King's College Hospital NHS Foundation Trust, Department of Nutrition and Dietetics, UK. · Royal Surrey County Hospital NHS Trust, Department of Nutrition and Dietetics, UK. · Guy's and St Thomas' NHS Foundation Trust, Department of Gastroenterology, UK. · Barts Health NHS Trust, Department of Gastroenterology, Royal London Hospital, UK. · Queen Mary University of London, Blizard Institute, UK. ·J Crohns Colitis · Pubmed #28525543.

ABSTRACT: Background and Aims: Preliminary evidence suggests that fermentable carbohydrate restriction might ameliorate functional gastrointestinal symptoms [FGS] in inflammatory bowel disease [IBD]. Our aim was to determine whether fermentable carbohydrates exacerbate FGS in IBD using a randomised, double-blinded, placebo-controlled, re-challenge trial. Methods: Patients with quiescent IBD and FGS responsive to a low FODMAP diet were allocated to a series of 3-day [d] fermentable carbohydrate challenges in random order [fructan, 12 g/d; galacto-oligosaccharides [GOS] 6 g/d; sorbitol, 6 g/d; and glucose placebo, 12 g/d], each separated by a washout period. Symptoms and stool output were measured daily during the challenges. Results: Thirty-two patients with IBD, fulfilling criteria for irritable bowel syndrome, functional bloating, or functional diarrhoea, were recruited and data were available for 29 patients completing all arms [12 Crohn's disease, 17 ulcerative colitis]. Significantly fewer patients reported adequate relief of FGS on the final day day of the fructan challenge [18/29, 62.1%] compared with glucose [26/29, 89.7%] [p = 0.033]. There was greater severity of pain [1.1 vs 0.5, p = 0.004], bloating [1.3 vs 0.6, p = 0.002], flatulence [1.5 vs 0.7, p = 0.004], and faecal urgency [0.9 vs 0.4, p = 0.014] on the final day of fructan challenge compared with glucose. Conclusions: At the relatively high doses used, fructans, but not GOS or sorbitol, exacerbated FGS in quiescent IBD. Further research is required to determine whether a low FODMAP diet reduces FGS in IBD and the degree of FODMAP restriction required for symptom improvement.

17 Article αEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis. 2017

Lamb, Christopher A / Mansfield, John C / Tew, Gaik W / Gibbons, Deena / Long, Anna K / Irving, Peter / Diehl, Lauri / Eastham-Anderson, Jeff / Price, Maria B / O'Boyle, Graeme / Jones, David E J / O'Byrne, Sharon / Hayday, Adrian / Keir, Mary E / Egen, Jackson G / Kirby, John A. ·Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. · Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK. · Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK. · Research & Early Development, Genentech, South San Francisco, CA 94080, USA. · Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, UK. · London Research Institute, Cancer Research UK, London WC2, UK. · Department of Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK. · Department of Gastroenterology, Guys and St Thomas' NHS Foundation Trust, London SE1 7EH, UK. ·J Crohns Colitis · Pubmed #28453768.

ABSTRACT: Background and Aims: The αEβ7 integrin is crucial for retention of T lymphocytes at mucosal surfaces through its interaction with E-cadherin. Pathogenic or protective functions of these cells during human intestinal inflammation, such as ulcerative colitis [UC], have not previously been defined, with understanding largely derived from animal model data. Defining this phenotype in human samples is important for understanding UC pathogenesis and is of translational importance for therapeutic targeting of αEβ7-E-cadherin interactions. Methods: αEβ7+ and αEβ7- colonic T cell localization, inflammatory cytokine production and expression of regulatory T cell-associated markers were evaluated in cohorts of control subjects and patients with active UC by immunohistochemistry, flow cytometry and real-time PCR of FACS-purified cell populations. Results: CD4+αEβ7+ T lymphocytes from both healthy controls and UC patients had lower expression of regulatory T cell-associated genes, including FOXP3, IL-10, CTLA-4 and ICOS in comparison with CD4+αEβ7- T lymphocytes. In UC, CD4+αEβ7+ lymphocytes expressed higher levels of IFNγ and TNFα in comparison with CD4+αEβ7- lymphocytes. Additionally the CD4+αEβ7+ subset was enriched for Th17 cells and the recently described Th17/Th1 subset co-expressing both IL-17A and IFNγ, both of which were found at higher frequencies in UC compared to control. Conclusion: αEβ7 integrin expression on human colonic CD4+ T cells was associated with increased production of pro-inflammatory Th1, Th17 and Th17/Th1 cytokines, with reduced expression of regulatory T cell-associated markers. These data suggest colonic CD4+αEβ7+ T cells are pro-inflammatory and may play a role in UC pathobiology.

18 Article Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. 2017

Soderquest, Katrina / Hertweck, Arnulf / Giambartolomei, Claudia / Henderson, Stephen / Mohamed, Rami / Goldberg, Rimma / Perucha, Esperanza / Franke, Lude / Herrero, Javier / Plagnol, Vincent / Jenner, Richard G / Lord, Graham M. ·Department of Experimental Immunobiology, King's College London, London, United Kingdom. · NIHR Biomedical Research Centre at Guy's and St Thomas' Hospital and King's College London, London, United Kingdom. · UCL Cancer Institute, University College London, London, United Kingdom. · UCL Genetics Institute, University College London, London, United Kingdom. · The Francis Crick Institute, London, United Kingdom. · Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. ·PLoS Genet · Pubmed #28187197.

ABSTRACT: The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn's disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.

19 Article Do Thiopurines Reduce the Risk of Surgery in Elderly Onset Inflammatory Bowel Disease? A 20-Year National Population-Based Cohort Study. 2017

Alexakis, Christopher / Saxena, Sonia / Chhaya, Vivek / Cecil, Elizabeth / Curcin, Vasa / Pollok, Richard. ·*Department of Gastroenterology, St George's Hospital NHS Trust, London, United Kingdom; †Department of Primary Care and Public Health, Charing Cross Campus, Imperial College London, London, United Kingdom; and ‡Division of Health and Social Care Research, King's College London, London, United Kingdom. ·Inflamm Bowel Dis · Pubmed #28151735.

ABSTRACT: BACKGROUND: Evidence that thiopurines impact on the risk of surgery in elderly onset inflammatory bowel disease (EO-IBD) is lacking. We aimed to compare the rates of surgery in EO-IBD (>60 years at diagnosis) with adult-onset IBD (18-59 yrs), and examine the impact of thiopurines on surgical risk in EO-IBD. METHODS: Using a U.K. database between 1990 and 2010, we compared rates of surgery between adult-onset IBD and EO-IBD using survival analysis. Ulcerative colitis (UC) and Crohn's disease (CD) were analyzed separately. Cox proportional hazard modeling was used to determine the adjusted relative risk of surgery. We further assessed the impact of duration of thiopurine treatment on risk of surgery. RESULTS: We identified 2758 of 9515 patients with UC and 1349 of 6490 patients with CD, with EO-IBD. Cumulative 1, 5, and 10 years risk of colectomy was similar in EO-UC (2.2, 4.5, and 5.8%, respectively) and AO-UC (2.2, 5.0, and 7.3%, respectively; P = 0.15). Cumulative 1, 5, and 10 years risk of first intestinal surgery was lower in EO-CD (9.5, 14.6, and 17.9%, respectively) than AO-CD (12.2, 19.0, and 24.4%, respectively; P < 0.001). Early steroid use, steroid dependency, and thiopurine use was associated with higher risk of colectomy in EO-UC. Among EO-UC receiving thiopurines for >12 months, there was a 70% reduction in risk of colectomy (hazard ratio. 0.30; 95% confidence interval, 0.15-0.58). Thiopurines were not associated with a reduced risk of surgery in EO-CD. CONCLUSIONS: Risk of colectomy in EO-UC does not differ from AO-UC, but the risk of surgery in EO-CD is significantly lower than in AO-CD. Sustained thiopurine use of 12 months or more duration in EO-UC reduces the risk colectomy, but does not impact on the risk of surgery in EO-CD. These findings are important given the greater risk of thiopurine-associated lymphoma in the elderly.

20 Article Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7. 2017

Luo, Yang / de Lange, Katrina M / Jostins, Luke / Moutsianas, Loukas / Randall, Joshua / Kennedy, Nicholas A / Lamb, Christopher A / McCarthy, Shane / Ahmad, Tariq / Edwards, Cathryn / Serra, Eva Goncalves / Hart, Ailsa / Hawkey, Chris / Mansfield, John C / Mowat, Craig / Newman, William G / Nichols, Sam / Pollard, Martin / Satsangi, Jack / Simmons, Alison / Tremelling, Mark / Uhlig, Holm / Wilson, David C / Lee, James C / Prescott, Natalie J / Lees, Charlie W / Mathew, Christopher G / Parkes, Miles / Barrett, Jeffrey C / Anderson, Carl A. ·Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. · Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK. · Christ Church, University of Oxford, St Aldates, UK. · Precision Medicine Exeter, University of Exeter, Exeter, UK. · IBD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK. · Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne. · Department of Gastroenterology, Torbay Hospital, Torbay, Devon, UK. · Department of Medicine, St Mark's Hospital, Harrow, Middlesex, UK. · Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK. · Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK. · Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK. · Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK. · The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK. · Gastrointestinal Unit, Wester General Hospital University of Edinburgh, Edinburgh, UK. · Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK. · Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. · Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK. · Translational Gastroenterology Unit and the Department of Paediatrics, University of Oxford, Oxford, United Kingdom. · Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK. · Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK. · Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK. · Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK. · Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of Witwatersrand, South Africa. ·Nat Genet · Pubmed #28067910.

ABSTRACT: To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ∼12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.

21 Article Identification of Research Priorities for Inflammatory Bowel Disease Nursing in Europe: a Nurses-European Crohn's and Colitis Organisation Delphi Survey. 2017

Dibley, Lesley / Bager, Palle / Czuber-Dochan, Wladyslawa / Farrell, Dawn / Jelsness-Jørgensen, Lars-Petter / Kemp, Karen / Norton, Christine. ·Florence Nightingale Faculty of Nursing and Midwifery, King's College London, London, UK. · Department of Gastroenterology and Hepatology, Aarhus University Hospital, Aarhus, Denmark. · Institute of Technology Tralee, Ireland. · Østfold University College, Halden, Norway. · Østfold Hospital Trust, Fredrikstad, Moss, Sarpsborg and Halden, Norway. · Department of Gastroenterology, Manchester Royal Infirmary/University of Manchester, Manchester, UK. ·J Crohns Colitis · Pubmed #27664273.

ABSTRACT: Background: Robust research evidence should inform clinical practice of inflammatory bowel disease [IBD] specialist nurses, but such research is currently very limited. With no current agreement on research priorities for IBD nursing, this survey aimed to establish topics to guide future IBD nursing research across Europe. Methods: An online modified Delphi survey with nurse and allied health professional members of the Nurses European Crohn's and Colitis Organisation [n = 303] was conducted. In Round One, participants proposed topics for research. In Round Two, research topics were rated on a 1-9 scale and subsequently synthesised to create composite research questions. In Round Three, participants selected their top five research questions, rating these on a 1-5 scale. Results: Representing 13 European countries, 88, 90 and 58 non-medical professionals, predominantly nurses, responded to Rounds One, Two and Three, respectively. In Round One, 173 potential research topics were suggested. In Rounds Two And Three, responders voted for and prioritised 125 and 44 questions, respectively. Round Three votes were weighted [rank of 1 = score of 5], reflecting rank order. The top five research priorities were: interventions to improve self-management of IBD; interventions for symptoms of frequency, urgency and incontinence; the role of the IBD nurse in improving patient outcomes and quality of life; interventions to improve IBD fatigue; and care pathways to optimise clinical outcomes and patient satisfaction. Conclusions: The prioritised list of topics gives clear direction for future IBD nursing research. Conducting this research has potential to improve clinical practice and patient-reported outcomes.

22 Article A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. 2016

Rivas, Manuel A / Graham, Daniel / Sulem, Patrick / Stevens, Christine / Desch, A Nicole / Goyette, Philippe / Gudbjartsson, Daniel / Jonsdottir, Ingileif / Thorsteinsdottir, Unnur / Degenhardt, Frauke / Mucha, Sören / Kurki, Mitja I / Li, Dalin / D'Amato, Mauro / Annese, Vito / Vermeire, Severine / Weersma, Rinse K / Halfvarson, Jonas / Paavola-Sakki, Paulina / Lappalainen, Maarit / Lek, Monkol / Cummings, Beryl / Tukiainen, Taru / Haritunians, Talin / Halme, Leena / Koskinen, Lotta L E / Ananthakrishnan, Ashwin N / Luo, Yang / Heap, Graham A / Visschedijk, Marijn C / Anonymous5010877 / Anonymous5020877 / MacArthur, Daniel G / Neale, Benjamin M / Ahmad, Tariq / Anderson, Carl A / Brant, Steven R / Duerr, Richard H / Silverberg, Mark S / Cho, Judy H / Palotie, Aarno / Saavalainen, Päivi / Kontula, Kimmo / Färkkilä, Martti / McGovern, Dermot P B / Franke, Andre / Stefansson, Kari / Rioux, John D / Xavier, Ramnik J / Daly, Mark J / Barrett, J / de Lane, K / Edwards, C / Hart, A / Hawkey, C / Jostins, L / Kennedy, N / Lamb, C / Lee, J / Lees, C / Mansfield, J / Mathew, C / Mowatt, C / Newman, B / Nimmo, E / Parkes, M / Pollard, M / Prescott, N / Randall, J / Rice, D / Satsangi, J / Simmons, A / Tremelling, M / Uhlig, H / Wilson, D / Abraham, C / Achkar, J P / Bitton, A / Boucher, G / Croitoru, K / Fleshner, P / Glas, J / Kugathasan, S / Limbergen, J V / Milgrom, R / Proctor, D / Regueiro, M / Schumm, P L / Sharma, Y / Stempak, J M / Targan, S R / Wang, M H. ·Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. · Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. · deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland. · Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8. · School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland. · Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland. · Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland. · Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany. · F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA. · Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden. · BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain. · Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy. · Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy. · Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium. · Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium. · Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands. · Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden. · Department of Medicine, University of Helsinki, 00100 Helsinki, Finland. · Helsinki University Hospital, 00100 Helsinki, Finland. · Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland. · Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland. · Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland. · Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland. · Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. · Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. · IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK. · Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK. · Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA. · Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. · Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA. · Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5. · Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA. · Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland. · Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA. · Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland. · Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4. · Department of Gastroenterology, Torbay Hospital, Devon, UK. · Department of Medicine, St. Mark's Hospital, Middlesex, UK. · Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK. · Christ Church, University of Oxford, Oxford, UK. · Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK. · Newcastle University, Newcastle upon Tyne, UK. · Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK. · Department of Medical and Molecular Genetics, Guy's Hospital, London, UK. · Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK. · Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK. · Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK. · The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK. · Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK. · Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK. · Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. · Gastroenterology &General Medicine, Norfolk and Norwich University Hospital, Norwich, UK. · Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK. · Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK. · Child Life and Health, University of Edinburgh, Edinburgh, UK. · Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA. · Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA. · Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. · Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada. · Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. · Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA. · Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada. · Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA. · Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. ·Nat Commun · Pubmed #27503255.

ABSTRACT: Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

23 Article Steroid dependency and trends in prescribing for inflammatory bowel disease - a 20-year national population-based study. 2016

Chhaya, V / Saxena, S / Cecil, E / Subramanian, V / Curcin, V / Majeed, A / Pollok, R C. ·Department of Gastroenterology, St George's University Hospital, London, UK. · Department of Primary Care and Public Health, Imperial College, London, UK. · Department of Gastroenterology, St James University Hospital, Leeds, UK. · Department of Health and Social Care Research, King's College London, London, UK. ·Aliment Pharmacol Ther · Pubmed #27375210.

ABSTRACT: BACKGROUND: It is unclear whether adherence to prescribing standards has been achieved in inflammatory bowel disease (IBD). AIM: To determine how prescribing of 5-aminosalicylates (5-ASAs), steroids and thiopurines has changed in response to emerging evidence. METHODS: We examined trends in oral and topical therapies in 23 509 incident IBD cases (6997 with Crohn's disease and 16 512 with ulcerative colitis) using a nationally representative sample between 1990 and 2010. We created five eras according to the year of diagnosis: era 1 (1990-1993), era 2 (1994-1997), era 3 (1998-2001), era 4 (2002-2005) and era 5 (2006-2010). We calculated the proportion of patients treated with prolonged 5-ASAs (>12 months) and steroid dependency, defined as prolonged steroids (>3 months) or recurrent (restarting within 3 months) steroid exposure. We calculated the cumulative probability of receiving each medication using survival analysis. RESULTS: Half of the Crohn's disease patients were prescribed prolonged oral 5-ASAs during the study, although this decreased between era 3 and 5 from 61.8% to 56.4% (P = 0.002). Thiopurine use increased from 14.0% to 47.1% (P < 0.001) between era 1 and 5. This coincided with a decrease in steroid dependency from 36.5% to 26.8% (P < 0.001) between era 1 and 2 and era 4 and 5 respectively. In ulcerative colitis, 49% of patients were maintained on prolonged oral 5-ASAs. Despite increasing thiopurine use, repeated steroid exposure increased from 15.3% to 17.8% (P = 0.02) between era 1 and 2 and era 4 and 5 respectively. CONCLUSIONS: Prescribing in clinical practice insufficiently mirrors the evidence base. Physicians should direct management towards reducing steroid dependency and optimising 5-ASA use in patients with IBD.

24 Article Adverse Pregnancy Outcomes Among Women with Inflammatory Bowel Disease: A Population-Based Study from England. 2016

Abdul Sultan, Alyshah / West, Joe / Ban, Lu / Humes, David / Tata, Laila J / Fleming, Kate M / Nelson-Piercy, Catherine / Card, Timothy. ·*Division of Epidemiology and Public Health, The University of Nottingham, Nottingham, United Kingdom; †NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases, Nottingham University Hospitals NHS Trust, The University of Nottingham, Nottingham, United Kingdom; and ‡Women's Health Academic Centre, Guy's and St Thomas' Foundation Trust, St Thomas' Hospital, London, United Kingdom. ·Inflamm Bowel Dis · Pubmed #27306070.

ABSTRACT: BACKGROUND: There is limited contemporary population-based evidence on adverse birth outcomes and pregnancy-related complications for women with inflammatory bowel disease (IBD). This study provides such estimates of these risks and assesses variation by IBD type and surgical interventions. METHODS: We calculated the proportion of pregnancies in women with and without IBD between 1997 and 2012 throughout England using linked primary (Clinical Practice Research Datalink) and secondary care (Hospital Episode Statistics) data. Risk of pregnancy-related complications and adverse birth outcomes in women with Crohn's disease and ulcerative colitis were compared with risks in women without IBD using odds ratios (ORs). RESULTS: Of 364,363 singleton pregnancies resulting in live or stillbirths, 1969 (0.5%) were in women with IBD. Women with Crohn's disease were more likely to have preterm births (OR = 1.42; 95% confidence interval, 1.12-1.79), babies with low birth weights (OR = 1.39; 95% confidence interval, 1.05-1.83), and postpartum hemorrhage (OR = 1.27; 95% confidence interval, 1.04-1.55), whereas women with ulcerative colitis were only at increased risk of preterm births with an absolute risk difference of <2.7%. These risks remained independent of caesarean section. Prior surgery for IBD did not increase the risk of adverse birth outcomes or pregnancy-related complications compared with cases without surgery, however, women with IBD were more likely to have an elective caesarean section. CONCLUSIONS: Women with Crohn's disease have increased risks of some specific pregnancy-related complications and adverse birth outcomes which are independent of caesarean section, however, the absolute risk differences are small, indicating that most women with IBD will have an uncomplicated pregnancy.

25 Article Long-term Safety and Efficacy of Low-dose Azathioprine and Allopurinol Cotherapy in Inflammatory Bowel Disease: A Large Observational Study. 2016

Pavlidis, Polychronis / Stamoulos, Panagiotis / Abdulrehman, Answar / Kerr, Patrick / Bull, Claire / Duley, John / Ansari, Azhar. ·*Surrey and Sussex Healthcare NHS Trust, East Surrey Hospital, Redhill, United Kingdom; †Department of Gastroenterology, King's College Hospital NHS Foundation Trust, King's Health Partners; ‡East Surrey Clinical Commissioning Group Assistant Chair; and §School of Pharmacy and Mater Research Institute, The University of Queensland, Brisbane, Australia. ·Inflamm Bowel Dis · Pubmed #27271488.

ABSTRACT: BACKGROUND: Low-dose azathioprine with allopurinol (LDAA) has been proposed as a potent therapy in inflammatory bowel disease (IBD) with the benefit of overcoming side effects regularly associated with thiopurine monotherapy and poor responses. Concerns regarding safety remain, while a layer of complexity has been added by the trend toward treatment directed by red cell thioguanine nucleotide (TGN) profiling. We report on the clinical efficacy and safety of LDAA use in IBD undirected by metabolite profiling. METHODS: Observational study of clinical practice from a single IBD center. Patient outcomes were defined clinically based on established activity scores and corticosteroid withdrawal. Red cell TGN was monitored only for suspected nonadherence. RESULTS: Overall, 113/164 (69%) patients with Crohn's disease and 83/136 (61%) patients with ulcerative/unclassified colitis had a clinical response by the end of follow-up (median 19 months), while 85 (52%) patients with Crohn's disease and 74 (54%) patients with ulcerative/unclassified colitis were in clinical remission. Clinical response was seen in 45/57 (79%) patients with Crohn's disease and 34/53 (64%) patients with ulcerative/unclassified colitis who were thiopurine naive, had active IBD, and received LDAA as the first line immunomodulator, while in 35 (61%) and 28 (53%), respectively, remission was achieved. LDAA was stopped in 20/300 (7%) patients because of side effects, all of which resolved on drug cessation. CONCLUSIONS: This is the largest cohort supporting the favorable safety profile and high efficacy of LDAA in IBD. It presents 2 advances in therapy: prescribing LDAA for thiopurine-naive patients, and bypassing TGN monitoring in favor of clinical monitoring (blood counts, etc.), which will make it more accessible for clinics without access to TGN assays.

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