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Ulcerative Colitis: HELP
Articles by Nicholas A. Kennedy
Based on 26 articles published since 2010
(Why 26 articles?)
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Between 2010 and 2020, N. Kennedy wrote the following 26 articles about Colitis, Ulcerative.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic. 2020

Kennedy, Nicholas A / Jones, Gareth-Rhys / Lamb, Christopher A / Appleby, Richard / Arnott, Ian / Beattie, R Mark / Bloom, Stuart / Brooks, Alenka J / Cooney, Rachel / Dart, Robin J / Edwards, Cathryn / Fraser, Aileen / Gaya, Daniel R / Ghosh, Subrata / Greveson, Kay / Hansen, Richard / Hart, Ailsa / Hawthorne, A Barney / Hayee, Bu'Hussain / Limdi, Jimmy K / Murray, Charles D / Parkes, Gareth C / Parkes, Miles / Patel, Kamal / Pollok, Richard C / Powell, Nick / Probert, Chris S / Raine, Tim / Sebastian, Shaji / Selinger, Christian / Smith, Philip J / Stansfield, Catherine / Younge, Lisa / Lindsay, James O / Irving, Peter M / Lees, Charlie W. ·Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. · University of Exeter, Exeter, UK. · University of Edinburgh, Edinburgh, UK. · Western General Hospital, Edinburgh, UK. · Newcastle University, Newcastle upon Tyne, UK. · Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. · Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. · Southampton Children's Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK. · University College London Hospitals NHS Foundation Trust, London, UK. · Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. · Queen Elizabeth Hospital Birmingham NHS Foundation Trust, Birmingham, UK. · University of Birmingham, Birmingham, UK. · King's College London, London, UK. · The Royal Free Hospital, London, UK. · Torbay and South Devon NHS Foundation Trust, Torquay, UK. · University Hospitals Bristol NHS Foundation Trust, Bristol, UK. · Glasgow Royal Infirmary, Glasgow, UK. · University of Glasgow, Glasgow, UK. · Royal Hospital for Children, Glasgow, UK. · St Mark's Hospital, London, UK. · Imperial College London, London, UK. · University Hospital of Wales, Cardiff, UK. · King's College Hospital NHS Foundation Trust, London, UK. · The Pennine Acute Hospitals NHS Trust, Manchester, UK. · University of Manchester, Manchester, UK. · Barts and the London School of Medicine and Dentistry, London, UK. · The Royal London Hospital, Barts Health NHS Trust, London, UK. · Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · St George's University Hospitals NHS Foundation Trust, London, UK. · St George's, University of London, London, UK. · Imperial College Healthcare NHS Trust, London, UK. · Liverpool University Hospitals NHS Foundation Trusts, Liverpool, UK. · University of Liverpool, Liverpool, UK. · Hull University Teaching Hospitals NHS Trust, Hull, UK. · Leeds Teaching Hospitals NHS Trust, Leeds, UK. · Salford Royal NHS Foundation Trust, Salford, UK. · Crohn's and Colitis UK, St Albans, Hertfordshire, UK. · Guy's and St Thomas' NHS Foundation Trust, London, UK. · University of Edinburgh, Edinburgh, UK charlie.lees@ed.ac.uk. ·Gut · Pubmed #32303607.

ABSTRACT: The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

2 Editorial Editorial: Early corticosteroids in ulcerative colitis. 2014

Kennedy, N A / Satsangi, J. ·Gastrointestinal Unit, Western General Hospital, Edinburgh, EH4 2XU, UK. ·Aliment Pharmacol Ther · Pubmed #25123383.

ABSTRACT: -- No abstract --

3 Review British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. 2019

Lamb, Christopher Andrew / Kennedy, Nicholas A / Raine, Tim / Hendy, Philip Anthony / Smith, Philip J / Limdi, Jimmy K / Hayee, Bu'Hussain / Lomer, Miranda C E / Parkes, Gareth C / Selinger, Christian / Barrett, Kevin J / Davies, R Justin / Bennett, Cathy / Gittens, Stuart / Dunlop, Malcolm G / Faiz, Omar / Fraser, Aileen / Garrick, Vikki / Johnston, Paul D / Parkes, Miles / Sanderson, Jeremy / Terry, Helen / Anonymous7271005 / Gaya, Daniel R / Iqbal, Tariq H / Taylor, Stuart A / Smith, Melissa / Brookes, Matthew / Hansen, Richard / Hawthorne, A Barney. ·Newcastle University, Newcastle upon Tyne, UK. · Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK. · Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. · University of Exeter, Exeter, UK. · Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK. · Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. · Imperial College London, London, UK. · Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. · The Pennine Acute Hospitals NHS Trust, Manchester, UK. · University of Manchester, Manchester, UK. · King's College Hospital NHS Foundation Trust, London, UK. · King's College London, London, UK. · Guy's and St Thomas' NHS Foundation Trust, London, UK. · Barts Health NHS Trust, London, UK. · Barts and the London School of Medicine and Dentistry, London, UK. · Leeds Teaching Hospitals NHS Trust, Leeds, UK. · University of Leeds, Leeds, UK. · New Road Surgery, Rickmansworth, UK. · University of Cambridge, Cambridge, UK. · Systematic Research Ltd, Quorn, UK. · Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland. · ECD Solutions, Bridgetown, Barbados. · University of Edinburgh, Edinburgh, UK. · Western General Hospital, Edinburgh, UK. · St Mark's Hospital, Harrow, UK. · University Hospitals Bristol NHS Foundation Trust, Bristol, UK. · Royal Hospital for Children Glasgow, Glasgow, UK. · Crohn's and Colitis UK, Hatfield, UK. · Glasgow Royal Infirmary, Glasgow, UK. · University of Glasgow, Glasgow, UK. · Queen Elizabeth Hospital Birmingham NHSFoundation Trust, Birmingham, UK. · University of Birmingham, Birmingham, UK. · University College London, London, UK. · University College London Hospitals NHS Foundation Trust, London, UK. · Brighton and Sussex University Hospitals NHS Trust, Brighton, UK. · Brighton and Sussex Medical School, Brighton, UK. · Royal Wolverhampton NHS Trust, Wolverhampton, UK. · University of Wolverhampton, Wolverhampton, UK. · University Hospital of Wales, Cardiff, UK. ·Gut · Pubmed #31562236.

ABSTRACT: Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

4 Review Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease: an observational study, plus systematic review and meta-analysis. 2016

Kennedy, N A / Warner, B / Johnston, E L / Flanders, L / Hendy, P / Ding, N S / Harris, R / Fadra, A S / Basquill, C / Lamb, C A / Cameron, F L / Murray, C D / Parkes, M / Gooding, I / Ahmad, T / Gaya, D R / Mann, S / Lindsay, J O / Gordon, J / Satsangi, J / Hart, A / McCartney, S / Irving, P / Anonymous5810858 / Lees, C W. ·Edinburgh, UK. · London, UK. · Winchester, UK. · Newcastle Upon Tyne, UK. · Glasgow, UK. · Cambridge, UK. · Colchester, UK. · Exeter, UK. ·Aliment Pharmacol Ther · Pubmed #26892328.

ABSTRACT: BACKGROUND: Infliximab and adalimumab have established roles in inflammatory bowel disease (IBD) therapy. UK regulators mandate reassessment after 12 months' anti-TNF therapy for IBD, with consideration of treatment withdrawal. There is a need for more data to establish the relapse rates following treatment cessation. AIM: To establish outcomes following anti-TNF withdrawal for sustained remission using new data from a large UK cohort, and assimilation of all available literature for systematic review and meta-analysis. METHODS: A retrospective observational study was performed on 166 patients with IBD (146 with Crohn's disease (CD) and 20 with ulcerative colitis [UC) and IBD unclassified (IBDU)] withdrawn from anti-TNF for sustained remission. Meta-analysis was undertaken of all published studies incorporating 11 further cohorts totalling 746 patients (624 CD, 122 UC). RESULTS: Relapse rates in the UK cohort were 36% by 1 year and 56% by 2 years for CD, and 42% by 1 year and 47% by 2 years for UC/IBDU. Increased relapse risk in CD was associated with age at diagnosis [hazard ratio (HR) 2.78 for age <22 years], white cell count (HR 3.22 for >5.25 × 10 CONCLUSIONS: Assimilation of all available data reveals remarkable homogeneity. Approximately one-third of patients with IBD flare within 12 months of withdrawal of anti-TNF therapy for sustained remission.

5 Review Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease. 2015

Torres, Joana / Boyapati, Ray K / Kennedy, Nicholas A / Louis, Edouard / Colombel, Jean-Frédéric / Satsangi, Jack. ·Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: joana.torres@mssm.edu. · Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland. Electronic address: ray.boyapati@ed.ac.uk. · Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland. · Department of Gastroenterology, University Hospital CHU of Liège, Liège, Belgium. · Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. ·Gastroenterology · Pubmed #26381892.

ABSTRACT: Little is known about the optimal duration of therapy with an anti-tumor necrosis factor (TNF) agent and/or an immunomodulator for patients with inflammatory bowel disease (IBD). We performed a systematic search of the literature to identify studies reporting after de-escalation (drug cessation or dose reduction) of anti-TNF agents and/or immunomodulators in patients in remission from IBD. Studies were reviewed according to the type of IBD and drug. Rates of relapse, factors associated with relapse, and response to re-treatment were determined. Our search yielded 6315 unique citations; we analyzed findings from 69 studies (18 on de-escalation [drug cessation or dose reduction] of immunomodulator monotherapy, 8 on immunomodulator de-escalation from combination therapy, and 43 on de-escalation of anti-TNF agents, including 3 during pregnancy) comprising 4672 patients. Stopping immunomodulator monotherapy after a period of remission was associated with high rates of relapse in patients with Crohn's disease or ulcerative colitis (approximately 75% of patients experienced a relapse within 5 years after therapy was stopped). Most studies of patients with Crohn's disease who discontinued an immunomodulator after combination therapy found that rates of relapse did not differ from those of patients who continued taking the drug (55%-60% had disease relapse 24 months after they stopped taking the immunomodulator). The only study in patients with ulcerative colitis supported continued immunomodulator use. Approximately 50% of patients who discontinued anti-TNF agents after combination therapy maintained remission 24 months later, but the proportion in remission decreased with time. Markers of disease activity, poor prognostic factors, and complicated or relapsing disease course were associated with future relapse. In conclusion, based on a systematic review, 50% or more of patients with IBD who cease therapy have a disease relapse. Further studies are required to accurately identify subgroups of patients who are good candidates for discontinuation of treatment. The decision to withdraw a drug should be made for each individual based on patient preference, disease markers, consequences of relapse, safety, and cost.

6 Review Predicting outcomes in acute severe ulcerative colitis. 2015

Ventham, Nicholas T / Kalla, Rahul / Kennedy, Nicholas A / Satsangi, Jack / Arnott, Ian D. ·Centre for Genomics and Molecular medicine, Western General Hospital, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK. ·Expert Rev Gastroenterol Hepatol · Pubmed #25494666.

ABSTRACT: Response to corticosteroid treatment in acute severe ulcerative colitis (ASUC) has changed very little in the past 50 years. Predicting those at risk at an early stage helps stratify patients into those who may require second line therapy or early surgical treatment. Traditionally, risk scores have used a combination of clinical, radiological and biochemical parameters; established indices include the 'Travis' and 'Ho' scores. Recently, inflammatory bowel disease genetic risk alleles have been built into models to predict outcome in ASUC. Given the multifactorial nature of inflammatory bowel disease pathogenesis, in the future, composite scores integrating clinical, biochemical, serological, genetic and other '-omic' data will be increasingly investigated. Although these new genetic prediction models are promising, they have yet to supplant traditional scores, which remain the best practice. In this modern era of rescue therapies in ASUC, robust scoring systems to predict failure of ciclosporine and infliximab must be devised.

7 Review MicroRNAs: new players in IBD. 2015

Kalla, R / Ventham, N T / Kennedy, N A / Quintana, J F / Nimmo, E R / Buck, A H / Satsangi, J. ·Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK. · Centre for Immunity, Infection and Evolution, Ashworth laboratories, University of Edinburgh, Edinburgh, UK. ·Gut · Pubmed #25475103.

ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs, 18-23 nucleotides long, which act as post-transcriptional regulators of gene expression. miRNAs are strongly implicated in the pathogenesis of many common diseases, including IBDs. This review aims to outline the history, biogenesis and regulation of miRNAs. The role of miRNAs in the development and regulation of the innate and adaptive immune system is discussed, with a particular focus on mechanisms pertinent to IBD and the potential translational applications.

8 Review A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis. 2013

Kennedy, N A / Rhatigan, E / Arnott, I D R / Noble, C L / Shand, A G / Satsangi, J / Lees, C W. ·Gastrointestinal Unit, Western General Hospital, Edinburgh, UK; Gastrointestinal research, Centre for molecular medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. ·Aliment Pharmacol Ther · Pubmed #24117596.

ABSTRACT: BACKGROUND: Thiopurines maintain remission and modify disease course in inflammatory bowel disease. Use is limited by intolerance and subsequent drug withdrawal in approximately 17% of patients treated with azathioprine. Previous case series have addressed the success rates of re-treatment with mercaptopurine in these individuals. AIMS: To determine the rate of tolerance when trialling mercaptopurine in azathioprine-intolerant patients and the factors predictive of success, and to perform a systematic review and meta-analysis of these data with other published data sets. METHODS: A retrospective observational study of 149 patients with IBD (82 with Crohn's disease and 67 with ulcerative colitis) previously intolerant of azathioprine subsequently treated with mercaptopurine was performed. A meta-analysis was undertaken of all published studies of mercaptopurine use in azathioprine-intolerant patients (455 patients in 11 included studies). RESULTS: Mercaptopurine was tolerated by 58% of azathioprine-intolerant patients in the Edinburgh cohort. In the meta-analysis, 68% tolerated mercaptopurine. A higher proportion of those in the meta-analysis with GI toxicity (62%) or hepatotoxicity (81%) were able to tolerate mercaptopurine than those with flu-like illness (36%). Among those patients who ceased mercaptopurine for further adverse effects, 59% experienced the same adverse effect as they had with azathioprine. CONCLUSIONS: This meta-analysis shows that switching to mercaptopurine is a safe therapeutic strategy for over two-thirds of azathioprine-intolerant patients and may help optimise immunomodulatory therapy in inflammatory bowel disease. A trial of mercaptopurine should be attempted in IBD patients (except those with acute pancreatitis or bone marrow aplasia) before considering thiopurine intolerance.

9 Review Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. 2013

Ventham, Nicholas T / Kennedy, Nicholas A / Nimmo, Elaine R / Satsangi, Jack. ·Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland. nventham@staffmail.ed.ac.uk ·Gastroenterology · Pubmed #23751777.

ABSTRACT: In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD.

10 Article Real-World Effectiveness of Tofacitinib for Moderate to Severe Ulcerative Colitis: A Multi-Centre UK Experience. 2020

Honap, Sailish / Chee, Desmond / Chapman, Thomas P / Patel, Mehul / Kent, Alexandra J / Ray, Shuvra / Sharma, Esha / Kennedy, James / Cripps, Sarah / Walsh, Alissa / Goodhand, James R / Ahmad, Tariq / Satsangi, Jack / Irving, Peter M / Kennedy, Nicholas A / Anonymous3411163. ·IBD Centre, Guy's and St. Thomas' Hospitals NHS Foundation Trust, London, UK. · Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK. · Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK. · Department of Gastroenterology, King's College Hospital NHS Foundation Trust, London, UK. · Department of Pharmacy, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK. · School of Immunology and Microbial Sciences, King's College London, London, UK. ·J Crohns Colitis · Pubmed #32280965.

ABSTRACT: BACKGROUND: Tofacitinib is a partially selective Janus kinase inhibitor approved for the treatment of refractory moderate to severe ulcerative colitis (UC). We sought to define the effectiveness and adverse effects of tofacitinib in a real-world cohort. METHODS: We conducted a retrospective observational cohort study of 134 patients with UC (64% male; median age 37 years [range 16-81]; 83% patients had previously received at least one biologic) treated with tofacitinib from October 2018 to October 2019 in four UK centres. Disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI) or Partial Mayo Score (PMS) depending on study site. Response and remission were defined as a reduction in SCCAI or PMS of ≥3, and SCCAI ≤2 or a PMS ≤1, respectively. FINDINGS: Overall, 74% (88/119; 95 CI 65-81%) patients responded to tofacitinib at week 8 and steroid free remission was observed in 44% (47/108; 95% CI 34%-53%) patients at week 26. Primary non-response was independently associated with younger age (p = 0.014) and higher CRP levels at baseline (p = 0.004). Only 23% (3/13) of patients who continued tofacitinib in the setting of primary non-response were in steroid free remission at week 26. Prior biologic exposure did not influence response or remission rates. Dose escalation, however, recaptured response in approximately half of patients who lost response. Dyslipidaemia was observed in 20% (27/134; 95% CI 14%-28%) of patients but adverse events necessitating drug withdrawal were uncommon and no venous thromboembolic events occurred. CONCLUSION: In this multi-centre real-world cohort, tofacitinib was well tolerated and clinically effective in a treatment refractory UC population.

11 Article Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis. 2019

Green, Harry D / Beaumont, Robin N / Thomas, Amanda / Hamilton, Benjamin / Wood, Andrew R / Sharp, Seth / Jones, Samuel E / Tyrrell, Jessica / Walker, Gareth / Goodhand, James / Kennedy, Nicholas A / Ahmad, Tariq / Weedon, Michael N. ·Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK. · IBD Pharmacogenetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. ·J Crohns Colitis · Pubmed #31125052.

ABSTRACT: BACKGROUND AND AIMS: The causes of microscopic colitis are currently poorly understood. Previous reports have found clinical associations with coeliac disease and genetic associations at the human leukocyte antigen [HLA] locus on the ancestral 8.1 haplotype. We investigated pharmacological and genetic factors associated with microscopic colitis in the UK Biobank. METHODS: In total, 483 European UK Biobank participants were identified by ICD10 coding, and a genome-wide association study was performed using BOLT-LMM, with a sensitivity analysis performed excluding potential confounders. The HLA*IMP:02 algorithm was used to estimate allele frequency at 11 classical HLA genes, and downstream analysis was performed using FUMA. Genetic overlap with inflammatory bowel disease [Crohn's disease and ulcerative colitis] was investigated using genetic risk scores. RESULTS: We found significant phenotypic associations with smoking status, coeliac disease and the use of proton-pump inhibitors but not with other commonly reported pharmacological risk factors. Using the largest sample size to date, we confirmed a recently reported association with the MHC Ancestral 8.1 Haplotype. Downstream analysis suggests association with digestive tract morphogenesis. By calculating genetic risk scores, we also report suggestive evidence of shared genetic risk with Crohn's disease, but not with ulcerative colitis. CONCLUSIONS: This report confirms the role of genetic determinants in the HLA in the pathogenesis of microscopic colitis. The genetic overlap with Crohn's disease suggests a common underlying mechanism of disease.

12 Article Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease. 2019

Walker, Gareth J / Harrison, James W / Heap, Graham A / Voskuil, Michiel D / Andersen, Vibeke / Anderson, Carl A / Ananthakrishnan, Ashwin N / Barrett, Jeffrey C / Beaugerie, Laurent / Bewshea, Claire M / Cole, Andy T / Cummings, Fraser R / Daly, Mark J / Ellul, Pierre / Fedorak, Richard N / Festen, Eleonora A M / Florin, Timothy H / Gaya, Daniel R / Halfvarson, Jonas / Hart, Ailsa L / Heerasing, Neel M / Hendy, Peter / Irving, Peter M / Jones, Samuel E / Koskela, Jukka / Lindsay, James O / Mansfield, John C / McGovern, Dermot / Parkes, Miles / Pollok, Richard C G / Ramakrishnan, Subramaniam / Rampton, David S / Rivas, Manuel A / Russell, Richard K / Schultz, Michael / Sebastian, Shaji / Seksik, Philippe / Singh, Abhey / So, Kenji / Sokol, Harry / Subramaniam, Kavitha / Todd, Anthony / Annese, Vito / Weersma, Rinse K / Xavier, Ramnik / Ward, Rebecca / Weedon, Michael N / Goodhand, James R / Kennedy, Nicholas A / Ahmad, Tariq / Anonymous3751117. ·Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England. · IBD Pharmacogenetics Group, University of Exeter, Exeter, England. · University of Exeter Medical School, Exeter, England. · Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands. · Medical Department, Regional Hospital Viborg, Viborg, Denmark. · Wellcome Trust Sanger Institute, Hinxton, England. · Department of Gastroenterology, Massachusetts General Hospital, Boston. · Department of Gastroenterology, Saint-Antoine Hospital and Sorbonne Universite, Paris, France. · Derby Digestive Diseases Centre, Royal Derby Hospital, Derby Teaching Hospitals NHS Foundation Trust, Derby, England. · Department of Gastroenterology, Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, England. · Broad Institute, Harvard University, Cambridge, Massachusetts. · Department of Gastroenterology, Mater Dei Hospital, Msida, Malta. · Division of Gastroenterology, University of Alberta, Edmonton, Canada. · Mater Research Institute, University of Queensland, South Brisbane, Australia. · Department of Gastroenterology, Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, Scotland. · Division of Gastroenterology, Örebro University, Örebro, Sweden. · Department of Gastroenterology, St Mark's Hospital, London North West Healthcare NHS Trust, Harrow, England. · Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, England. · Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, England. · Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, England. · F. Widjaja Foundation Inflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California. · Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England. · Department of Gastroenterology, St George's Healthcare NHS Trust, Tooting, England. · Gastrointestinal and Liver Services, Warrington and Halton Hospitals NHS Foundation Trust, Warrington, England. · Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, England. · Department of Paediatric Gastroenterology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, Scotland. · Dunedin Hospital, Dunedin, New Zealand. · Gastroenterology and Hepatology, Hull and East Yorkshire Hospitals NHS Trust, Hull, England. · Canberra Hospital, Canberra, Australia. · Department of Haematology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England. · Division of Gastroenterology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy. ·JAMA · Pubmed #30806694.

ABSTRACT: Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

13 Article Promoter methylation of the 2018

Klasić, Marija / Markulin, Dora / Vojta, Aleksandar / Samaržija, Ivana / Biruš, Ivan / Dobrinić, Paula / Ventham, Nicholas T / Trbojević-Akmačić, Irena / Šimurina, Mirna / Štambuk, Jerko / Razdorov, Genadij / Kennedy, Nicholas A / Satsangi, Jack / Dias, Ana M / Pinho, Salome / Annese, Vito / Latiano, Anna / D'Inca, Renata / Anonymous3990954 / Lauc, Gordan / Zoldoš, Vlatka. ·1Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia. · 2Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 6XU UK. · Genos Glycoscience Research Laboratory, Borongajska cesta 83h, 10000 Zagreb, Croatia. · 5IBD Pharmacogenetics, University of Exeter, Exeter, UK. · 10Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. · 6Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal. · 7Department of Medical and Surgical Sciences, Division of Gastroenterology, University Hospital Careggi, Florence, Italy. · Department of Medical Sciences, Division of Gastroenterology, IRCCS-CSS Hospital, Viale Cappuccini, Rotondo, Italy. · 9Gastrointestinal Unit, University of Padua, Padua, Italy. · 4Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia. ·Clin Epigenetics · Pubmed #29991969.

ABSTRACT: Background: Many genome- and epigenome-wide association studies (GWAS and EWAS) and studies of promoter methylation of candidate genes for inflammatory bowel disease (IBD) have demonstrated significant associations between genetic and epigenetic changes and IBD. Independent GWA studies have identified genetic variants in the Methods: Using bisulfite pyrosequencing, we analyzed CpG methylation in promoter regions of these five genes from peripheral blood of several hundred IBD patients and healthy controls (HCs) from two independent cohorts, respectively. Results: We found significant differences in the methylation levels in the Conclusions: Our results suggest that epigenetic deregulation of key glycosylation genes might lead to an increase in pro-inflammatory properties of IgG in IBD through a decrease in galactosylation and sialylation and an increase of bisecting GlcNAc on digalactosylated glycan structures. Finally, we showed that CpG methylation in the promoter of the

14 Article Glycosylation of Immunoglobulin G Associates With Clinical Features of Inflammatory Bowel Diseases. 2018

Šimurina, Mirna / de Haan, Noortje / Vučković, Frano / Kennedy, Nicholas A / Štambuk, Jerko / Falck, David / Trbojević-Akmačić, Irena / Clerc, Florent / Razdorov, Genadij / Khon, Anna / Latiano, Anna / D'Incà, Renata / Danese, Silvio / Targan, Stephan / Landers, Carol / Dubinsky, Marla / Anonymous1631133 / McGovern, Dermot P B / Annese, Vito / Wuhrer, Manfred / Lauc, Gordan. ·Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia. · Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands. · Genos Glycoscience Research Laboratory, BIOCentar, Zagreb, Croatia. · University of Exeter, Exeter, UK. · Division of Gastroenterology, S. Camillo-Forlanini Hospital, Circonvallazione Gianicolense, Rome, Italy. · Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy. · Division of Gastroenterology, University Hospital, Padua, Italy. · Humanitas University, Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Clinical and Research Hospital, Milan, Italy. · F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California. · Division of Gastroenterology, University Hospital Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; Valiant Clinic, Dubai, United Arab Emirates. · Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia; Genos Glycoscience Research Laboratory, BIOCentar, Zagreb, Croatia. Electronic address: glauc@pharma.hr. ·Gastroenterology · Pubmed #29309774.

ABSTRACT: BACKGROUND AND AIMS: Causes of inflammatory bowel diseases are not well understood and the most prominent forms, Crohn's disease (CD) and ulcerative colitis (UC), are sometimes hard to distinguish. Glycosylation of IgG has been associated with CD and UC. IgG Fc-glycosylation affects IgG effector functions. We evaluated changes in IgG Fc-glycosylation associated with UC and CD, as well as with disease characteristics in different patient groups. METHODS: We analyzed 3441 plasma samples obtained from 2 independent cohorts of patients with CD (874 patients from Italy and 391 from the United States) or UC (1056 from Italy and 253 from the US and healthy individuals [controls]; 427 in Italy and 440 from the United States). IgG Fc-glycosylation (tryptic glycopeptides) was analyzed by liquid chromatography coupled to mass spectrometry. We analyzed associations between disease status (UC vs controls, CD vs controls, and UC vs CD) and glycopeptide traits, and associations between clinical characteristics and glycopeptide traits, using a logistic regression model with age and sex included as covariates. RESULTS: Patients with CD or UC had lower levels of IgG galactosylation than controls. For example, the odds ratio (OR) for IgG1 galactosylation in patients with CD was 0.59 (95% confidence interval [CI], 0.51-0.69) and for patients with UC was 0.81 (95% CI, 0.71-0.92). Fucosylation of IgG was increased in patients with CD vs controls (for IgG1: OR, 1.27; 95% CI, 1.12-1.44), but decreased in patients with UC vs controls (for IgG23: OR, 0.72; 95% CI, 0.63-0.82). Decreased galactosylation associated with more severe CD or UC, including the need for surgery in patients with UC vs controls (for IgG1: OR, 0.69; 95% CI, 0.54-0.89) and in patients with CD vs controls (for IgG23: OR, 0.78; 95% CI, 0.66-0.91). CONCLUSIONS: In a retrospective analysis of plasma samples from patients with CD or UC, we associated levels of IgG Fc-glycosylation with disease (compared to controls) and its clinical features. These findings could increase our understanding of mechanisms of CD and UC pathogenesis and be used to develop diagnostics or guide treatment.

15 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.

16 Article Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease. 2016

Ventham, N T / Kennedy, N A / Adams, A T / Kalla, R / Heath, S / O'Leary, K R / Drummond, H / Anonymous1771111 / Anonymous1781111 / Wilson, D C / Gut, I G / Nimmo, E R / Satsangi, J. ·Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 6XU, UK. · CNAG-CRG, Centro Nacional de Análisis Genómico, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, Barcelona 08028, Spain. · Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain. · Department of Child Life and Health, University of Edinburgh, Edinburgh EH9 1UW, UK. ·Nat Commun · Pubmed #27886173.

ABSTRACT: Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8

17 Article Serum Calprotectin: A Novel Diagnostic and Prognostic Marker in Inflammatory Bowel Diseases. 2016

Kalla, Rahul / Kennedy, Nicholas A / Ventham, Nicholas T / Boyapati, Ray K / Adams, Alex T / Nimmo, Elaine R / Visconti, Micaela R / Drummond, Hazel / Ho, Gwo-Tzer / Pattenden, Rebecca J / Wilson, David C / Satsangi, Jack. ·Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK. · Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK. · Metabolic Bone Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK. · Department of Clinical Chemistry, Western General Hospital, NHS Lothian, Edinburgh, UK. · Child Life and Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK. ·Am J Gastroenterol · Pubmed #27596694.

ABSTRACT: OBJECTIVES: There is an unmet need for novel blood-based biomarkers that offer timely and accurate diagnostic and prognostic testing in inflammatory bowel diseases (IBD). We aimed to investigate the diagnostic and prognostic utility of serum calprotectin (SC) in IBD. METHODS: A total of 171 patients (n=96 IBD, n=75 non-IBD) were prospectively recruited. A multi-biomarker model was derived using multivariable logistic regression analysis. Cox proportional hazards model was derived to assess the contribution of each variable to disease outcomes. RESULTS: SC correlated strongly with current biomarkers, including fecal calprotectin (FC) (n=50, ρ=0.50, P=1.6 × 10 CONCLUSIONS: A diagnostic and prognostic model that combines SC and other blood-based biomarkers accurately predicts the inflammatory burden in IBD and has the potential to predict disease and its outcomes. Our data warrant further detailed exploration and validation in large multicenter cohorts.

18 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 / Anonymous4110877 / Anonymous4120877 / 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.

19 Article Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. 2016

Cleynen, Isabelle / Boucher, Gabrielle / Jostins, Luke / Schumm, L Philip / Zeissig, Sebastian / Ahmad, Tariq / Andersen, Vibeke / Andrews, Jane M / Annese, Vito / Brand, Stephan / Brant, Steven R / Cho, Judy H / Daly, Mark J / Dubinsky, Marla / Duerr, Richard H / Ferguson, Lynnette R / Franke, Andre / Gearry, Richard B / Goyette, Philippe / Hakonarson, Hakon / Halfvarson, Jonas / Hov, Johannes R / Huang, Hailang / Kennedy, Nicholas A / Kupcinskas, Limas / Lawrance, Ian C / Lee, James C / Satsangi, Jack / Schreiber, Stephan / Théâtre, Emilie / van der Meulen-de Jong, Andrea E / Weersma, Rinse K / Wilson, David C / Anonymous4340846 / Parkes, Miles / Vermeire, Severine / Rioux, John D / Mansfield, John / Silverberg, Mark S / Radford-Smith, Graham / McGovern, Dermot P B / Barrett, Jeffrey C / Lees, Charlie W. ·Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium. · Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Christ Church, University of Oxford, St Aldates, UK. · Department of Public Health Sciences, University of Chicago, Chicago, IL, USA. · Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany. · Peninsula College of Medicine and Dentistry, Exeter, UK. · Medical Department, Viborg Regional Hospital, Viborg, Denmark; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark. · Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia. · Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy; Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy. · Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany. · Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. · Department of Genetics, Yale School of Medicine, New Haven, CT, USA. · Broad Institute of MIT and Harvard, Cambridge, MA, USA. · Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA. · School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. · Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany. · Department of Medicine, University of Otago, Christchurch, New Zealand; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand. · Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. · Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Sweden; School of Health and Medical Sciences, Örebro University, Örebro, Sweden. · Norwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway. · Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco WA and School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute for Medical Research, Murdoch, WA, Australia. · Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. · Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany. · Unit of Animal Genomics, Groupe Interdisciplinaire de Genoproteomique Appliquee (GIGA-R) and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium; Division of Gastroenterology, Centre Hospitalier Universitaire, Universite de Liege, Liege, Belgium. · Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands. · Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands. · Child Life and Health, University of Edinburgh, Edinburgh, UK; Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK. · Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium; Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. · Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK. · Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, ON, Canada. · Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, and School of Medicine, University of Queensland, Brisbane, Australia. · F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. Electronic address: barrett@sanger.ac.uk. · Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. Electronic address: Charlie.lees@ed.ac.uk. ·Lancet · Pubmed #26490195.

ABSTRACT: BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). INTERPRETATION: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

20 Article Serum C-reactive protein and CRP genotype in pediatric inflammatory bowel disease: influence on phenotype, natural history, and response to therapy. 2015

Henderson, Paul / Kennedy, Nicholas A / Van Limbergen, Johan E / Cameron, Fiona L / Satsangi, Jack / Russell, Richard K / Wilson, David C. ·*Department of Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom; †Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom; ‡Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; §IBD Center, Division of Pediatric Gastroenterology and Nutrition, IWK Health Center, Dalhousie University, Halifax, NS, Canada; and ‖Department of Pediatric Gastroenterology, Royal Hospital for Sick Children, Glasgow, United Kingdom. ·Inflamm Bowel Dis · Pubmed #25636121.

ABSTRACT: BACKGROUND: C-reactive protein (CRP) is an acute phase reactant. Patients with pediatric inflammatory bowel disease (PIBD) differ from adult patients with inflammatory bowel disease with regard to phenotype, inflammatory profile, and treatment response. We hypothesized that variations in CRP and CRP genotype influence PIBD phenotype, natural history, and remission after anti-tumor necrosis factor alpha therapy. METHODS: Six single nucleotide polymorphisms tagging CRP (rs1935193, rs1130864, rs1205, rs1417938, rs11265263, and rs1800947) were genotyped in 465 patients with PIBD (diagnosed <17 yr). Phenotyping was serially performed until last follow-up and serum CRP levels recorded at diagnosis and before biological therapy in a subgroup. RESULTS: CRP haplotype (ATGCTC) differed in those diagnosed <10 years, with rs1205T more frequent in Crohn's disease (CD) than ulcerative colitis (UC) (P = 0.009); the haplotype ATGCTC was less frequent in UC (P = 0.002). Three single nucleotide polymorphisms (rs1205, rs1130864, and rs1417938) showed association with elevated CRP levels at diagnosis. CRP genotype had no association with CD phenotype or natural history. CRP was more frequently raised at diagnosis in CD than UC (63% versus 22%, P < 0.0001). Elevated CRP at diagnosis was associated with a higher risk of progression to surgery in patients with CD (P < 0.0001) and the need for azathioprine in the overall PIBD cohort (P = 0.002). There was no effect of CRP genotype or serum CRP on the achievement of remission using anti-tumor necrosis factor alpha therapy. CONCLUSIONS: CRP and CRP genotype differ between pediatric patients with CD and UC with a high inflammatory burden at diagnosis suggesting a worse prognosis. Additional evaluation of CRP in inflammatory bowel disease pathogenesis and natural history is now warranted.

21 Article Clinical utility and diagnostic accuracy of faecal calprotectin for IBD at first presentation to gastroenterology services in adults aged 16-50 years. 2015

Kennedy, Nicholas A / Clark, Annalie / Walkden, Andrew / Chang, Jeff C W / Fascí-Spurio, Federica / Muscat, Martina / Gordon, Brydon W / Kingstone, Kathleen / Satsangi, Jack / Arnott, Ian D R / Lees, Charlie W. ·Gastrointestinal Unit, Western General Hospital, Edinburgh, UK. · Department of Clinical Biochemistry, Western General Hospital, Edinburgh, UK. · Gastrointestinal Unit, Western General Hospital, Edinburgh, UK charlie.lees@ed.ac.uk. ·J Crohns Colitis · Pubmed #25135754.

ABSTRACT: BACKGROUND: Distinguishing inflammatory bowel disease (IBD) from functional gastrointestinal (GI) disease remains an important issue for gastroenterologists and primary care physicians, and may be difficult on the basis of symptoms alone. Faecal calprotectin (FC) is a surrogate marker for intestinal inflammation but not cancer. AIM: This large retrospective study aimed to determine the most effective use of FC in patients aged 16-50 presenting with GI symptoms. METHODS: FC results were obtained for patients presenting to the GI clinics in Edinburgh between 2005 and 2009 from the Edinburgh Faecal Calprotectin Registry containing FCs from >16,000 patients. Case notes were interrogated to identify demographics, subsequent investigations and diagnoses. RESULTS: 895 patients were included in the main analysis, 65% female and with a median age of 33 years. 10.2% were diagnosed with IBD, 7.3% with another GI condition associated with an abnormal GI tract and 63.2% had functional GI disease. Median FC in these three groups were 1251, 50 and 20 μg/g (p < 0.0001). On ROC analysis, the AUC for FC as a predictor of IBD vs. functional disease was 0.97. Using a threshold of ≥ 50 μg/g for IBD vs. functional disease yielded a sensitivity of 0.97, specificity of 0.74, positive predictive value of 0.37 and negative predictive value of 0.99. Combined with alarm symptoms, the sensitivity was 1.00. CONCLUSIONS: Implementation of FC in the initial diagnostic workup of young patients with GI symptoms, particularly those without alarm symptoms, is highly accurate in the exclusion of IBD, and can provide reassurance to patients and physicians.

22 Article Thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease: relapse and recapture rates, with predictive factors in 237 patients. 2014

Kennedy, N A / Kalla, R / Warner, B / Gambles, C J / Musy, R / Reynolds, S / Dattani, R / Nayee, H / Felwick, R / Harris, R / Marriott, S / Senanayake, S M / Lamb, C A / Al-Hilou, H / Gaya, D R / Irving, P M / Mansfield, J / Parkes, M / Ahmad, T / Cummings, J R F / Arnott, I D / Satsangi, J / Lobo, A J / Smith, M / Lindsay, J O / Lees, C W. ·Gastrointestinal Unit, Western General Hospital, Edinburgh, UK. ·Aliment Pharmacol Ther · Pubmed #25284134.

ABSTRACT: BACKGROUND: Thiopurines (azathioprine and mercaptopurine) remain integral to most medical strategies for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Indefinite use of these drugs is tempered by long-term risks. While clinical relapse is noted frequently following drug withdrawal, there are few published data on predictive factors. AIM: To investigate the success of planned thiopurine withdrawal in patients in sustained clinical remission to identify rates and predictors of relapse. METHODS: This was a multicentre retrospective cohort study from 11 centres across the UK. Patients included had a definitive diagnosis of IBD, continuous thiopurine use ≥3 years and withdrawal when in sustained clinical remission. All patients had a minimum of 12 months follow-up post drug withdrawal. Primary and secondary end points were relapse at 12 and 24 months respectively. RESULTS: 237 patients were included in the study (129 CD; 108 UC). Median duration of thiopurine use prior to withdrawal was 6.0 years (interquartile range 4.4-8.4). At follow-up, moderate/severe relapse was observed in 23% CD and 12% UC patients at 12 months, 39% CD and 26% UC at 24 months. Relapse rate at 12 months was significantly higher in CD than UC (P = 0.035). Elevated CRP at withdrawal was associated with higher relapse rates at 12 months for CD (P = 0.005), while an elevated white cell count was predictive at 12 months for UC (P = 0.007). CONCLUSION: Thiopurine withdrawal in the context of sustained remission is associated with a 1-year moderate-to-severe relapse rate of 23% in Crohn's disease and 12% in ulcerative colitis.

23 Article Comparison of mortality following hospitalisation for ulcerative colitis in Scotland between 1998-2000 and 2007-2009. 2014

Ventham, N T / Kennedy, N A / Duffy, A / Clark, D N / Crowe, A M / Knight, A D / Nicholls, R J / Satsangi, J. ·GI Unit, Centre for Genomics and Molecular Medicine, Western General Hospital, Edinburgh, UK. ·Aliment Pharmacol Ther · Pubmed #24749792.

ABSTRACT: BACKGROUND: Scottish nationwide linkage data from 1998 to 2000 demonstrated high 3-year mortality in patients hospitalised with ulcerative colitis (UC). AIM: To compare 3-year mortality, and factors related to mortality, in Scottish patients hospitalised with UC between 1998-2000 and 2007-2009. METHODS: The Scottish Morbidity Records and linked datasets were used to assess 3-year mortality, standardised mortality ratio (SMR) and multivariate analyses of factors associated with 3-year mortality. The 3-year mortality was determined after four admission types: surgery-elective or emergency; medical-elective or emergency. Age-standardised mortality rates (ASR) were used to compare mortality rates between periods. RESULTS: Ulcerative colitis admissions increased from 10.6 in Period 1 to 11.6 per 100 000 population per year in Period 2 (P = 0.046). Crude and adjusted 3-year mortality fell between time periods (crude 12.2% to 8.3%; adjusted OR 0.59, CI 0.42-0.81, P = 0.04). Adjusted 3-year mortality following emergency medical admission (OR 0.58, CI 0.39-0.87, P = 0.003) and in patients >65 years (38.8% to 28.7%, P = 0.02) was lower in Period 2. The SMR in period 1 was 3.04 and 2.96 in Period 2. Directly age-standardised mortality decreased from 373 (CI 309-437) to 264 (CI 212-316) per 10 000 person-years. On multivariate analysis, increasing age (50-64 years OR 7.11 (CI 2.77-18.27, P < 0.05); 65-74 years OR 14.70 (CI 5.65-38.25 P < 0.05); >75 years OR 46.42 (CI 18.29-117.78, P < 0.001) and co-morbidity (OR 3.02, CI 1.72-5.28, P < 0.001) were significantly associated with 3-year mortality in Period 2. CONCLUSIONS: Comparisons of crude and adjusted mortality rates suggest significant improvement in outcome over the last decade - however, mortality remains high, and older age and co-morbidity are important predictors of outcome.

24 Article The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease. 2012

Henderson, Paul / Casey, Aoife / Lawrence, Sally J / Kennedy, Nicholas A / Kingstone, Kathleen / Rogers, Pam / Gillett, Peter M / Wilson, David C. ·Child Life and Health, University of Edinburgh, UK. paul.henderson2@nhs.net ·Am J Gastroenterol · Pubmed #22370604.

ABSTRACT: OBJECTIVES: Fecal calprotectin (FC) is elevated in patients with inflammatory bowel disease (IBD). Studies evaluating FC during the initial investigation of children with suspected IBD have been limited, especially with regard to their small patient groups. We aimed to evaluate the diagnostic accuracy of FC in a large regional cohort of children undergoing full upper and lower endoscopy for suspected IBD, comparing FC with six common blood parameters. METHODS: Using a retrospective case-control design all FC measurements carried out between 2005 and 2010 in children <18 years old were obtained. All IBD and non-IBD patients who had a FC measurement available before full endoscopic evaluation for suspected bowel inflammation were examined. FC was measured using the PhiCal Test. Multivariate analyzes and receiver operating characteristic curve generation were used to derive significance. RESULTS: A total of 190 patients (91 IBD and 99 non-IBD controls) met the inclusion criteria. Median FC at diagnosis for the IBD group was 1,265 μg/g (interquartile range (IQR) 734-2,024 μg/g), compared with 65 μg/g (IQR 20-235 μg/g) in controls (P<0.001). FC levels did not vary significantly between patients with Crohn's disease, ulcerative colitis, and IBD unclassified and were not influenced by age or disease location. FC was found to be far superior to commonly utilized blood parameters such as C-reactive protein and white cell count (both P<0.01), with an area under the curve of 0.93 (95% confidence interval 0.89-0.97). CONCLUSIONS: This study demonstrates that FC is an invaluable tool in determining those children who may require endoscopy for suspected IBD, and elevated values should prompt further investigation.

25 Article Exploring the hidden heritability of inflammatory bowel disease. 2011

Satsangi, J / Kennedy, N A / Henderson, P / Wilson, D C / Nimmo, E R. ·Centre for Molecular Medicine, University of Edinburgh, Edinburgh, UK. j.satsangi@ed.ac.uk ·Gut · Pubmed #21896637.

ABSTRACT: -- No abstract --

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