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Crohn Disease: HELP
Articles by David C. Wilson
Based on 37 articles published since 2009
(Why 37 articles?)
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Between 2009 and 2019, D. C. Wilson wrote the following 37 articles about Crohn Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN. 2017

Amil-Dias, Jorge / Kolacek, Sanja / Turner, Dan / Pærregaard, Anders / Rintala, Risto / Afzal, Nadeem A / Karolewska-Bochenek, Katarzyna / Bronsky, Jiri / Chong, Sonny / Fell, John / Hojsak, Iva / Hugot, Jean-Pierre / Koletzko, Sibylle / Kumar, Devinder / Lazowska-Przeorek, Izabella / Lillehei, Craig / Lionetti, Paolo / Martin-de-Carpi, Javier / Pakarinen, Mikko / Ruemmele, Frank M / Shaoul, Ron / Spray, Christine / Staiano, Annamaria / Sugarman, Ian / Wilson, David C / Winter, Harland / Kolho, Kaija-Leena / Anonymous611001. ·*Department of Pediatrics, Centro Hospitalar, S. João, Porto, Portugal †Children's Hospital Zagreb, Faculty of Medicine, Zagreb, Croatia ‡The Juliet Keidan Institute of Pediatric Gastroenterology & Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel §Department of Pediatrics, Hvidovre University Hospital, Hvidovre, Denmark ||Pediatric Surgery, Children's Hospital, University of Helsinki, Helsinki, Finland ¶Department of Pediatric Gastroenterology, University Hospital Southampton, Southampton, UK #Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw, Poland **Department of Pediatrics, University Hospital Motol, Prague, Czech Republic ††Queen Mary's Hospital for Children, Epsom and St Helier NHS Trust, Surrey ‡‡Chelsea and Westminster Hospital, London, UK §§Paris-Diderot Sorbonne-Paris-Cité University and Robert Debré Hospital, Paris, France ||||Pediatric Gastroenterology and Hepatology, Dr. von Hauner Children's Hospital, Ludwig Maximilians-University, Munich, Germany ¶¶St George's, University of London, London, UK ##Boston Children's Hospital and Harvard Medical School, Boston, MA ***Department NEUROFARBA, University of Florence - Meyer Hospital, Florence, Italy †††Unit for the Comprehensive Care of Pediatric Inflammatory Bowel Disease, Hospital Sant Joan de Déu, Barcelona, Spain ‡‡‡Department of Pediatric Gastroenterology, Necker Enfants Malades University Hospital, Sorbonne Paris Cité University, Paris Descartes University, Institut IMAGINE - INSERM U1163, Paris, France §§§Pediatric Gastroenterology Institute, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel ||||||Department of Pediatric Gastroenterology, Bristol Royal Hospital for Children, Bristol, UK ¶¶¶Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II," Naples, Italy ###Department of Pediatric Surgery, Leeds Children's Hospital, Leeds General Infirmary, Leeds, UK ****Child Life and Health, University of Edinburgh, Scotland, UK ††††MassGeneral Hospital for Children, Harvard Medical School, Boston, MA ‡‡‡‡Children's Hospital, University of Helsinki, Helsinki, Finland. ·J Pediatr Gastroenterol Nutr · Pubmed #28267075.

ABSTRACT: The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.

2 Guideline ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. 2014

Levine, Arie / Koletzko, Sibylle / Turner, Dan / Escher, Johanna C / Cucchiara, Salvatore / de Ridder, Lissy / Kolho, Kaija-Leena / Veres, Gabor / Russell, Richard K / Paerregaard, Anders / Buderus, Stephan / Greer, Mary-Louise C / Dias, Jorge A / Veereman-Wauters, Gigi / Lionetti, Paolo / Sladek, Malgorzata / Martin de Carpi, Javier / Staiano, Annamaria / Ruemmele, Frank M / Wilson, David C / Anonymous3320775. ·*Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel †Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany ‡Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel §Pediatric Gastroenterology, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands ||Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Italy ¶Children's Hospital, University of Helsinki, Helsinki, Finland #Semmelweis University, Budapest, Hungary **Department of Paediatric Gastroenterology and Nutrition, Yorkhill Children's Hospital, Glasgow, UK ††Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark ‡‡St.-Marien-Hospital, Department of Pediatrics, Bonn, Germany §§Department of Diagnostic Imaging, The Hospital for Sick Children ||||Department of Medical Imaging, University of Toronto, Toronto Canada ¶¶Hospital S. João, Porto, Portugal ##Pediatric Gastroenterology and Nutrition, UZ Brussels, Brussels, Belgium ***Departement Neurofarba, University of Florence, Meyer Children Hospital, Florence, Italy †††Department of Pediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Cracow, Poland ‡‡‡Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona, Spain §§§Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II," Naples, Italy ||||||Université Sorbonne Paris Cité, Université Paris Descartes, INSERM U989, AP-HP, Hôpital Necker Enfants Malades, Service de Gastroentérologie Pédiatrique, Paris, France ¶¶¶Child Life and Health, University of Edinburgh, Edinburgh, UK. ·J Pediatr Gastroenterol Nutr · Pubmed #24231644.

ABSTRACT: BACKGROUND: The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete. METHODS: We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm. RESULTS: The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy. CONCLUSIONS: These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.

3 Review Overview of paediatric IBD. 2017

Wilson, David C / Russell, Richard K. ·Child Life and Health, University of Edinburgh, Edinburgh EH9 1UW, Scotland, UK; Royal Hospital for Sick Children, Edinburgh, Scotland, UK. Electronic address: d.c.wilson@ed.ac.uk. · Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, Scotland, UK. ·Semin Pediatr Surg · Pubmed #29126501.

ABSTRACT: Inflammatory bowel disease (IBD) is a chronic complex disease of children and adults requiring a range of medications and surgical techniques to induce and maintain remission. In common with other immune-mediated inflammatory disorders, it has shown an ever-increasing rise in incidence worldwide over the last 50 years. The cause of IBD arises from interactions between the microbiome in the gut and the gastrointestinal and systemic immune system in genetically susceptible persons, and with environmental triggers to both develop IBD and have relapses of IBD. The burden of IBD in children and adolescents can be high, and treatment needs a multi-disciplinary approach aiming to abolish symptoms, promote growth and development, and support a restriction-free life. Achieving healing of the intestinal mucosa promotes long-term remission and helps to avoid disease complications.

4 Review The diagnostic approach to monogenic very early onset inflammatory bowel disease. 2014

Uhlig, Holm H / Schwerd, Tobias / Koletzko, Sibylle / Shah, Neil / Kammermeier, Jochen / Elkadri, Abdul / Ouahed, Jodie / Wilson, David C / Travis, Simon P / Turner, Dan / Klein, Christoph / Snapper, Scott B / Muise, Aleixo M / Anonymous291012. ·Translational Gastroenterology Unit, University of Oxford, Oxford, England; Department of Pediatrics, University of Oxford, Oxford, England. Electronic address: holm.uhlig@ndm.ox.ac.uk. · Translational Gastroenterology Unit, University of Oxford, Oxford, England. · Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany. · Great Ormond Street Hospital London, London, England; Catholic University, Leuven, Belgium. · Great Ormond Street Hospital London, London, England. · SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. · Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts; Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts. · Child Life and Health, University of Edinburgh, Edinburgh, Scotland; Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Royal Hospital for Sick Children, Edinburgh, Scotland. · Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel. ·Gastroenterology · Pubmed #25058236.

ABSTRACT: Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

5 Review Systematic review: MRI enterography for assessment of small bowel involvement in paediatric Crohn's disease. 2013

Giles, E / Barclay, A R / Chippington, S / Wilson, D C. ·Paediatric Gastroenterology, Barts and the London School of Medicine and Dentistry, London, UK. ·Aliment Pharmacol Ther · Pubmed #23638954.

ABSTRACT: BACKGROUND: Barium meal enteroclysis (BM) is the recommended imaging technique for small bowel inaccessible by ileo-colonoscopy when diagnosing paediatric-onset inflammatory bowel disease, but it has poor sensitivity and involves ionising radiation. MRI enterography (MRE) is an alternative methodology. AIMS: To critically appraise the published evidence on MRE in the assessment of Paediatric inflammatory bowel disease by systematic review. METHODS: Review of all English language data reporting MRE for the investigation of patients <18 years with known or suspected IBD. Primary searches of Medline (Jan 1950-April 2012), Cinahl (1966-April 2012) and Pubmed (Jan 1950-April 2012) were performed using keyword and MeSH terms; IBD; Magnetic resonance imaging; small bowel imaging; EMBASE was then searched. Two authors independently assessed the quality of studies using the quality assessment of diagnostic accuracy studies tool. RESULTS: Searches yielded 930 035 hits, combination word searches limited to 1983 titles. Fifty-two studies were fully reviewed, 41 were excluded due to lack of paediatric data. Eleven studies of 496 children were included. All studies used endoscopy as the reference test. 10/496 patients required jejunal intubation for bowel preparation. Meta-analysis of six comparable studies gave a pooled sensitivity and specificity for MRE detection of active terminal ileal Crohn's disease of 84% and 97% respectively. Studies displayed heterogeneity in bowel preparation, scanning technique, reporting methodology and timing of ileo-colonoscopy in relation to MRE. In three studies comparing BM, MRE had greater sensitivity and specificity. CONCLUSIONS: MRE is a sensitive and specific tool for diagnosis in paediatric inflammatory bowel disease. Technical considerations require refinement and standardisation; however, MRE has no radiation. Current data suggest that MRE should supersede BM as the SB imaging technique in centres with appropriate expertise.

6 Review The genetics of Crohn's disease. 2009

Van Limbergen, Johan / Wilson, David C / Satsangi, Jack. ·Department of Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh EH9 1LF, United Kingdom. johanvanlimbergen@hotmail.com ·Annu Rev Genomics Hum Genet · Pubmed #19453248.

ABSTRACT: From epidemiological data, based on concordance data in family studies, via linkage analysis to genome-wide association studies, we and others have accumulated robust evidence implicating more than 30 distinct genomic loci involved in the genetic susceptibility to Crohn's disease (CD). These loci encode genes involved in a number of homeostatic mechanisms: innate pattern recognition receptors (NOD2/CARD15, TLR4, CARD9), the differentiation of Th17-lymphocytes (IL-23R, JAK2, STAT3, CCR6, ICOSLG), autophagy (ATG16L1, IRGM, LRRK2), maintenance of epithelial barrier integrity (IBD5, DLG5, PTGER4, ITLN1, DMBT1, XBP1), and the orchestration of the secondary immune response (HLA-region, TNFSF15/TL1A, IRF5, PTPN2, PTPN22, NKX2-3, IL-12B, IL-18RAP, MST1). While many of these loci also predispose to pediatric CD, an additional number of childhood-onset loci have been identified recently (e.g., TNFRSF6B). Not only has the identification of these loci improved our understanding of the pathophysiology of CD, this knowledge also holds real promise for clinical practice.

7 Article Development and Validation of Diagnostic Criteria for IBD Subtypes Including IBD-unclassified in Children: a Multicentre Study From the Pediatric IBD Porto Group of ESPGHAN. 2017

Birimberg-Schwartz, Liron / Zucker, David M / Akriv, Amichay / Cucchiara, Salvatore / Cameron, Fiona L / Wilson, David C / Lazowska, Iza / Yianni, Lambri / Paul, Siba Prosad / Romano, Claudio / Kolacek, Sanja / Buderus, Stephan / Pærregaard, Anders / Russell, Richard K / Escher, Johanna C / Turner, Dan / Anonymous960904. ·Institute of Pediatric Gastroenterology, Shaare Zedek Medical Centre, Jerusalem, Israel. · Department of Statistics, Hebrew University of Jerusalem, Jerusalem, Israel. · Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy. · Child Life and Health, University of Edinburgh and Royal Hospital for Children, Edinburgh, UK. · Paediatric Gastroenterology Unit, Medical University of Warsaw, Warsaw, Poland. · University Hospital Southampton NHS Foundation Trust, Child Health, Southampton,UK. · Paediatric Gastroenterology, Bristol Royal Hospital for Children,Bristol, UK. · Pediatric Gastroenterology and Endoscopy, University of Messina, Messina, Italy. · Paediatric Gastroenterology Unit, Children's Hospital Zagreb, University Medical School, Zagreb, Croatia. · St.-Marien-Hospital, Department of Pediatrics, Bonn, Germany. · Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark. · Paediatric Gastroenterology Unit, Royal Hospital for Children, Glasgow, UK. · Pediatric Gastroenterology, Erasmus MC-Sophia, Rotterdam, The Netherlands. ·J Crohns Colitis · Pubmed #28430891.

ABSTRACT: Background: The revised Porto criteria identify subtypes of paediatric inflammatory bowel diseases: ulcerative colitis [UC], atypical UC, inflammatory bowel disease unclassified [IBDU], and Crohn's disease [CD]. Others have proposed another subclassifiction of Crohn's colitis. In continuation of the Porto criteria, we aimed to derive and validate criteria, termed "PIBD-classes," for standardising the classification of the different IBD subtypes. Methods: This was a multicentre retrospective longitudinal study from 23 centres affiliated with the Port -group of ESPGHAN. Both a hypothesis-driven judgmental approach and mathematical classification and regression tree [CART] modelling were used for creating a diagnostic algorithm. Since small bowel inflammation is easily recognised as CD, we focused here primarily on the phenotype of colitis. Results: In all, 749 IBD children were enrolled: 236 [32%] Crohn's colitis, 272 [36%] UC and 241 [32%] IBDU [age 10.9 ± 3.6 years] with a median follow-up of 2.8 years (interquartile range [IQR] 1.7-4.3). A total of 23 features were clustered in three classes according to their prevalence in UC: six class-1 features [0% prevalence in UC], 12 class-2 features [< 5% prevalence], and five class-3 features [5-10% prevalence]. According to the algorithm, the disease should be classified as UC if no features exist in any of the classes. When at least one feature exists, different combinations classify the disease into atypical UC, IBDU or CD. The algorithm differentiated UC from CD and IBDU with 80% sensitivity (95% confidence interval [CI] 71-88%) and 84% specificity [77-89%], and CD from IBDU and UC with 78% sensitivity [67-87%] and 94% specificity [89-97%]. Conclusions: The validated PIBD-classes algorithm can adequately classify children with IBD into small bowel CD, colonic CD, IBDU, atypical UC, and UC.

8 Article Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. 2017

Lee, James C / Biasci, Daniele / Roberts, Rebecca / Gearry, Richard B / Mansfield, John C / Ahmad, Tariq / Prescott, Natalie J / Satsangi, Jack / Wilson, David C / Jostins, Luke / Anderson, Carl A / Anonymous8260892 / Traherne, James A / Lyons, Paul A / Parkes, Miles / Smith, Kenneth G C. ·Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK. · Department of Medicine, University of Otago, Christchurch, New Zealand. · Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK. · University of Exeter Medical School, Exeter, UK. · Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, London, UK. · Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. · Paediatric Gastroenterology and Nutrition, Child Life and Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Royal Hospital for Sick Children, Edinburgh, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. · Department of Pathology, University of Cambridge, Cambridge, UK. ·Nat Genet · Pubmed #28067912.

ABSTRACT: For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.

9 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.

10 Article Disease Status and Pubertal Stage Predict Improved Growth in Antitumor Necrosis Factor Therapy for Pediatric Inflammatory Bowel Disease. 2017

Cameron, Fiona L / Altowati, Mabrouka A / Rogers, Pamela / McGrogan, Paraic / Anderson, Niall / Bisset, William Michael / Ahmed, Syed Faisal / Wilson, David C / Russell, Richard K. ·*Child Life and Health, University of Edinburgh, Edinburgh †Developmental Endocrinology Research Group, Royal Hospital for Sick Children, University of Glasgow, Glasgow ‡Department of Pediatric Gastroenterology, Royal Hospital for Sick Children, Edinburgh §Department of Pediatric Gastroenterology, Hospital for Sick Children, Glasgow ||Usher Institute for Population Health Sciences & Informatics, University of Edinburgh, Edinburgh ¶Department of Pediatric Gastroenterology, Royal Aberdeen Children's Hospital, Aberdeen, UK. ·J Pediatr Gastroenterol Nutr · Pubmed #27657882.

ABSTRACT: BACKGROUND: Growth failure is well-recognized in pediatric inflammatory bowel disease (PIBD; <18 years). We aimed to examine whether antitumor necrosis factor (TNF) therapy improves growth in a PIBD population-based cohort. METHODS: A retrospective review of all Scottish children receiving anti-TNF (infliximab [IFX] and adalimumab [ADA]) from 2000 to 2012 was performed; height was collected at 12 months before anti-TNF (T-12), start (T0), and 12 (T+12) months after anti-TNF. RESULTS: Ninety-three of 201 treated with IFX and 28 of 49 with ADA had satisfactory growth data; 66 had full pubertal data. Univariate analysis demonstrated early pubertal stages (Tanner 1-3 n = 44 vs T4-5 n = 22), disease remission, disease duration ≥2 years, and duration of IFX ≥12 months were associated with improved linear growth for IFX; for ADA only improvement was seen in Tanner 1-3. For IFX, Tanner 1-3 median Δ standard deviation scores for height (Ht SDS) -0.3 (-0.7, 0.2) at T0 changed to 0.04 (-0.5, 0.7) at T+12 (P < 0.001) versus -0.01 (-0.5, 0.9) at T0 in T4-5 changed to -0.01 (-0.4, 0.2) at T+12 (P > 0.05). For IFX disease duration ≥2 year, median Δ Ht SDS was -0.13 (-0.6, 0.3) at T0 then 0.07 (-0.3, 0.6) at T+12 (P < 0.001). Remission improved Δ Ht SDS (median Δ Ht SDS -0.14 [-0.6, 0.3] at T0 to 0.17 [-0.2, 0.7] at T+12 [P < 0.001]). Multiple regression analysis demonstrated corticosteroid usage at T0 predicted improved Δ Ht SDS at T+12 for IFX and ADA. CONCLUSIONS: Anti-TNF therapy is more likely to be associated with growth improvement when used at earlier stages of puberty with remission a key growth-promoting strategy in pediatric Crohn disease.

11 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 / Anonymous5360888 / Anonymous5370888 / 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

12 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.

13 Article pANCA and ASCA in Children with IBD-Unclassified, Crohn's Colitis, and Ulcerative Colitis-A Longitudinal Report from the IBD Porto Group of ESPGHAN. 2016

Birimberg-Schwartz, Liron / Wilson, David C / Kolho, Kaija-Leena / Karolewska-Bochenek, Katarzyna / Afzal, Nadeem Ahmad / Spray, Christine / Romano, Claudio / Lionetti, Paolo / Hauer, Almuthe C / Martinez-Vinson, Christine / Veres, Gabor / Escher, Johanna C / Turner, Dan / Anonymous5370866. ·1Shaare Zedek Medical Center, Jerusalem, Israel;2Child Life and Health, University of Edinburgh, United Kingdom;3University of Helsinki, Finland;4Department of Pediatric Gastroenterology, Medical University, Warsaw, Poland;5University Hospital Southampton, United Kingdom;6University Hospitals Bristol, Scotland, United Kingdom;7University of Messina, Italy;8University of Florence, Italy;9University Hospital for Pediatrics and Adolescent Medicine of the Medical University of Graz, Austria;10Department of Pediatric Gastroenterology and Nutrition, Robert Debré Hospital, Paris, France;11Semmelweis University, Budapest, Hungary;12Erasmus MC, Rotterdam, Zuid Holland, Netherlands; and13The Hebrew University of Jerusalem, Israel. ·Inflamm Bowel Dis · Pubmed #27135480.

ABSTRACT: INTRODUCTION: No study to date has evaluated perinuclear antineutrophil cytoplasmic antibody (pANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) in pediatric inflammatory bowel disease-unclassified (IBDU) as compared with Crohn's colitis (CC) and ulcerative colitis (UC), which represent the diagnostic challenge. We aimed to explore the diagnostic utility of serology and to assess whether serology can predict disease severity in these subgroups. METHODS: This was a multicenter retrospective longitudinal study including 406 children with inflammatory bowel diseases (IBD) from 23 centers affiliated with the Porto group of European Society of Pediatric Gastroenterology, Hepatology and Nutrition (mean age 10.5 ± 3.9, 54% males); 117 (29%) with CC, 143 (35%) with UC, and 146 (36%) with IBDU. Median follow-up period was 2.8 years (interquartile range, 1.6-4.2). RESULTS: The most prevalent serologic profile in IBDU was pANCA-/ASCA- (41%), followed by pANCA+/ASCA- (34%) and pANCA-/ASCA+ (17%). pANCA-/ASCA+ differentiated well between CC versus IBDU (83% specificity, 96% positive predictive value [PPV]) and UC (97% specificity, 90% PPV) patients, albeit with a low negative predictive value (13% and 40%, respectively). pANCA+/ASCA- did not differentiate as well between IBD subgroups, but UC children with pANCA+/ASCA- had more often severe disease at diagnosis (36 [62%] versus 22 [38%], P = 0.033) and needed more often calcineurin inhibitors, biologics, or colectomy (25 [80%] versus 6 [20%], P = 0.026). In CC, double positivity for ASCA and not pANCA-/ASCA+ profile was associated with disease severity. CONCLUSIONS: Serology may have some role in predicting disease course and outcomes in colonic IBD, but its routine use needs to be supported by more studies. Serology cannot routinely be recommended for differentiating between IBDU versus CC or UC as a sole diagnostic criterion given its low diagnostic utility.

14 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 / Anonymous4370846 / 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).

15 Article Anti-TNF therapy for paediatric IBD: the Scottish national experience. 2015

Cameron, F L / Wilson, M L / Basheer, N / Jamison, A / McGrogan, P / Bisset, W M / Gillett, P M / Russell, R K / Wilson, D C. ·Child Life and Health, University of Edinburgh, Edinburgh, UK. · University of Glasgow, Glasgow, UK. · Department of Paediatric Gastroenterology, Royal Hospital for Sick Children, Glasgow, UK. · Department of Paediatric Gastroenterology, Royal Aberdeen Children's Hospital, Aberdeen, UK. · Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK. · Child Life and Health, University of Edinburgh, Edinburgh, UK Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK. ·Arch Dis Child · Pubmed #25678594.

ABSTRACT: BACKGROUND AND AIMS: Biological agents are being increasingly used in the UK for paediatric-onset inflammatory bowel disease (PIBD) despite limited evidence and safety concerns. We evaluated effectiveness and safety in the clinical setting, highlighting drug cost pressures, using our national Scottish PIBD biological registry. METHODS: Complete usage of the biological agents, infliximab (IFX) and adalimumab (ADA) for treatment of PIBD (in those aged <18 years) from 1 January 2000 to 30 September 2010 was collated from all treatments administered within the Scottish Paediatric Gastroenterology, Hepatology and Nutrition (PGHAN) national managed service network (all regional PGHAN centres and paediatric units within their associated district general hospitals). RESULTS: 132 children had biological therapy; 24 required both agents; 114 had Crohn's disease (CD), 16 had ulcerative colitis (UC) and 2 had IBD Unclassified (IBDU). 127 children received IFX to induce remission; 61 entered remission, 49 had partial response and 17 had no response. 72 were given maintenance IFX and 23 required dose escalation. 18 had infusion reactions and 27 had adverse events (infections/other adverse events). 29 had ADA to induce remission (28 CD and 1 UC), 24 after IFX; 10 entered remission, 12 had partial response and 7 had no response. All had maintenance; 19 required dose escalation. 12 children overall required hospitalisation due to drug toxicity. No deaths occurred with either IFX or ADA. CONCLUSIONS: Complete accrual of the Scottish nationwide 'real-life' experience demonstrates moderate effectiveness of anti tumour necrosis factor agents in severe PIBD but duration of effect is limited; significant financial issues (drug cost-need for dose escalation and/or multiple biological usage) and safety issues exist.

16 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.

17 Article Efficacy of oral methotrexate in paediatric Crohn's disease: a multicentre propensity score study. 2015

Turner, Dan / Doveh, Etti / Cohen, Ayala / Wilson, Michelle L / Grossman, Andrew B / Rosh, Joel R / Lu, Ying / Bousvaros, Athos / Deslandres, Colette / Noble, Angela / Baldassano, Robert N / Levine, Arie / Lerner, Aaron / Wilson, David C / Griffiths, Anne M. ·The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel. · The Technion Institute of Technology, Haifa, Israel. · Department of Child Life and Health, University of Edinburgh, Scotland, UK. · Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, USA. · Goryeb Children's Hospital/Atlantic Health, Icahn School of Medicine at Mount Sinai, USA. · Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts. · Gastroenterology, Hepatology and Nutrition Service, CHU Sainte-Justine and Research Center, Montreal, Quebec. · Pediatric Gastroenterology Unit, Wolfson Medical Center, Tel Aviv University, Holon, Israel. · Pediatric Gastroenterology and Nutrition Unit, Carmel Medical Center, Technion-Israel Institute of Technology, Haifa, Israel. · Division of GI/Hepatology/Nutrition, SickKids Hospital, University of Toronto, Toronto, Ontario, Canada. ·Gut · Pubmed #25416066.

ABSTRACT: BACKGROUND: Oral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn's disease (CD), especially children. Routes of administration have never been systematically compared in CD. We aimed to compare effectiveness and safety of orally (PO) versus subcutaneously (SC) administered MTX in paediatric CD. METHODS: 226 children with CD treated with oral or subcutaneous MTX were included in a multicentre, retrospective 1-year cohort study (62% boys, mean age 13.8±2.8 years, 88% previous thiopurines). 38 (17%) were initially commenced on oral, 98 (43%) started subcutaneous and switched to oral and 90 (40%) were treated with subcutaneous only. Matching and 'doubly robust' weighted regression models were based on the propensity score method, controlling for confounding-by-indication bias. 11/23 pretreatment variables were different between the groups, but the propensity score modelling successfully balanced the treatment groups. RESULTS: 76 children (34%) had sustained steroid-free remission with a difference that did not reach significance between the PO and the SC groups (weighted OR=1.72 (95% CI 0.5 to 5.9); p=0.52). There were no differences in need for treatment escalation (p=0.24), elevated liver enzymes (p=0.59) or nausea (p=0.85). Height velocity was lower in the PO group (p=0.006) and time to remission was delayed in the PO group (p=0.036; Fleming (0, 1) test). CONCLUSIONS: In this largest paediatric CD cohort to date, SC administered MTX was superior to PO, but only in some of the outcomes and with a modest effect size. Therefore, it may be reasonable to consider switching children in complete remission treated with subcutaneous MTX to the oral route with close monitoring of inflammatory markers and growth.

18 Article Two-stage genome-wide methylation profiling in childhood-onset Crohn's Disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci. 2014

Adams, Alex T / Kennedy, Nicholas A / Hansen, Richard / Ventham, Nicholas T / OʼLeary, Kate R / Drummond, Hazel E / Noble, Colin L / El-Omar, Emad / Russell, Richard K / Wilson, David C / Nimmo, Elaine R / Hold, Georgina L / Satsangi, Jack. ·*Gastrointestinal Unit, Centre for Genetics and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom; †Gastrointestinal Research Group, Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom; ‡Department of Paediatric Gastroenterology, Royal Hospital for Sick Children, Glasgow, United Kingdom; and §Paediatric Gastroenterology and Nutrition, Child Life and Health, University of Edinburgh, Royal Hospital for Sick Children, Edinburgh, United Kingdom. ·Inflamm Bowel Dis · Pubmed #25144570.

ABSTRACT: BACKGROUND: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease. METHODS: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa. RESULTS: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10(-7)), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10(-7)), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10(-15)) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10(-5), n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10(-6), n = 99). CONCLUSIONS: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.

19 Article The intermediate filament protein, vimentin, is a regulator of NOD2 activity. 2013

Stevens, Craig / Henderson, Paul / Nimmo, Elaine R / Soares, Dinesh C / Dogan, Belgin / Simpson, Kenneth W / Barrett, Jeffrey C / Anonymous6330728 / Wilson, David C / Satsangi, Jack. ·Centre for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. craig.stevens@ed.ac.uk ·Gut · Pubmed #22684479.

ABSTRACT: OBJECTIVE: Mutations in the nucleotide-binding oligomerisation domain-containing protein 2 (NOD2) gene remain the strongest genetic determinants for Crohn's disease (CD). Having previously identified vimentin as a novel NOD2-interacting protein, the authors aimed to investigate the regulatory effects of vimentin on NOD2 function and the association of variants in Vim with CD susceptibility. DESIGN: Coimmunoprecipitation, fluorescent microscopy and fractionation were used to confirm the interaction between NOD2 and vimentin. HEK293 cells stably expressing wild-type NOD2 or a NOD2 frameshift variant (L1007fs) and SW480 colonic epithelial cells were used alongside the vimentin inhibitor, withaferin A (WFA), to assess effects on NOD2 function using the nuclear factor-kappaB (NF-κB) reporter gene, green fluorescent protein-LC3-based autophagy, and bacterial gentamicin protection assays. International genome-wide association meta-analysis data were used to test for associations of single-nucleotide polymorphisms in Vim with CD susceptibility. RESULTS: The leucine-rich repeat domain of NOD2 contained the elements required for vimentin binding; CD-associated polymorphisms disrupted this interaction. NOD2 and vimentin colocalised at the cell plasma membrane, and cytosolic mislocalisation of the L1007fs and R702W variants correlated with an inability to interact with vimentin. Use of WFA demonstrated that vimentin was required for NOD2-dependent NF-κB activation and muramyl dipeptide-induced autophagy induction, and that NOD2 and vimentin regulated the invasion and survival properties of a CD-associated adherent-invasive Escherichia coli strain. Genetic analysis revealed an association signal across the haplotype block containing Vim. CONCLUSION: Vimentin is an important regulator of NOD2 function and a potential novel therapeutic target in the treatment of CD. In addition, Vim is a candidate susceptibility gene for CD, supporting the functional data.

20 Article Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. 2012

Jostins, Luke / Ripke, Stephan / Weersma, Rinse K / Duerr, Richard H / McGovern, Dermot P / Hui, Ken Y / Lee, James C / Schumm, L Philip / Sharma, Yashoda / Anderson, Carl A / Essers, Jonah / Mitrovic, Mitja / Ning, Kaida / Cleynen, Isabelle / Theatre, Emilie / Spain, Sarah L / Raychaudhuri, Soumya / Goyette, Philippe / Wei, Zhi / Abraham, Clara / Achkar, Jean-Paul / Ahmad, Tariq / Amininejad, Leila / Ananthakrishnan, Ashwin N / Andersen, Vibeke / Andrews, Jane M / Baidoo, Leonard / Balschun, Tobias / Bampton, Peter A / Bitton, Alain / Boucher, Gabrielle / Brand, Stephan / Büning, Carsten / Cohain, Ariella / Cichon, Sven / D'Amato, Mauro / De Jong, Dirk / Devaney, Kathy L / Dubinsky, Marla / Edwards, Cathryn / Ellinghaus, David / Ferguson, Lynnette R / Franchimont, Denis / Fransen, Karin / Gearry, Richard / Georges, Michel / Gieger, Christian / Glas, Jürgen / Haritunians, Talin / Hart, Ailsa / Hawkey, Chris / Hedl, Matija / Hu, Xinli / Karlsen, Tom H / Kupcinskas, Limas / Kugathasan, Subra / Latiano, Anna / Laukens, Debby / Lawrance, Ian C / Lees, Charlie W / Louis, Edouard / Mahy, Gillian / Mansfield, John / Morgan, Angharad R / Mowat, Craig / Newman, William / Palmieri, Orazio / Ponsioen, Cyriel Y / Potocnik, Uros / Prescott, Natalie J / Regueiro, Miguel / Rotter, Jerome I / Russell, Richard K / Sanderson, Jeremy D / Sans, Miquel / Satsangi, Jack / Schreiber, Stefan / Simms, Lisa A / Sventoraityte, Jurgita / Targan, Stephan R / Taylor, Kent D / Tremelling, Mark / Verspaget, Hein W / De Vos, Martine / Wijmenga, Cisca / Wilson, David C / Winkelmann, Juliane / Xavier, Ramnik J / Zeissig, Sebastian / Zhang, Bin / Zhang, Clarence K / Zhao, Hongyu / Anonymous2970741 / Silverberg, Mark S / Annese, Vito / Hakonarson, Hakon / Brant, Steven R / Radford-Smith, Graham / Mathew, Christopher G / Rioux, John D / Schadt, Eric E / Daly, Mark J / Franke, Andre / Parkes, Miles / Vermeire, Severine / Barrett, Jeffrey C / Cho, Judy H. ·Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK. ·Nature · Pubmed #23128233.

ABSTRACT: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

21 Article A role for vimentin in Crohn disease. 2012

Henderson, Paul / Wilson, David C / Satsangi, Jack / Stevens, Craig. ·Department of Child Life and Health, University of Edinburgh, Edinburgh, UK. ·Autophagy · Pubmed #22929019.

ABSTRACT: Crohn disease (CD), one of the major chronic inflammatory bowel diseases, occurs anywhere in the gastrointestinal tract with discontinuous transmural inflammation. A number of studies have now demonstrated that genetic predisposition, environmental influences and a dysregulated immune response to the intestinal microflora are involved. Major CD susceptibility pathways uncovered through genome-wide association studies strongly implicate the innate immune response (NOD2), in addition to the more specific acquired T cell response (IL23R, ICOSLG) and autophagy (ATG16L1, IRGM). Examination of the disease-associated microbiome, although complex, has identified several potentially contributory microorganisms, most notably adherent-invasive E.coli strains (AIEC), which have been isolated by independent investigators in both adult and pediatric CD patients. Here we discuss our recent finding that the type-III intermediate filament (IF) protein VIM/vimentin is a novel NOD2 interacting protein that regulates NOD2 activities including inflammatory NFKB1 signaling, autophagy and bacterial handling.

22 Article The effects of anti-TNF-α treatment with adalimumab on growth in children with Crohn's disease (CD). 2012

Malik, S / Ahmed, S F / Wilson, M L / Shah, N / Loganathan, S / Naik, S / Bourke, B / Thomas, A / Akobeng, A K / Fagbemi, A / Wilson, D C / Russell, R K. ·Bone & Endocrine Research Group Royal Hospital for Sick Children, Yorkhill, Glasgow, UK. ·J Crohns Colitis · Pubmed #22405171.

ABSTRACT: INTRODUCTION: Adalimumab is used to treat children with Crohn's disease (CD), but the effects of adalimumab on growth in CD have not been studied. AIM: To study growth and disease activity over 12 months (6 months prior to (T-6), baseline (T0) and for 6 months following (T+6) adalimumab). SUBJECTS AND METHODS: Growth and treatment details of 36 children (M: 22) who started adalimumab at a median (10th, 90th) age of 14.7 years (11.3, 16.8) were reviewed. RESULTS: Of 36 cases, 28 (78%) went into remission. Overall 42% of children showed catch up growth, which was more likely in: (i) those who achieved remission (median change in height SDS (ΔHtSDS) increased from -0.2 (-0.9, 1.0) at T0 to 0.2 (-0.6, 1.6) at T+6, (p=0.007)), (ii) in those who were on immunosuppression ΔHtSDS increased from -0.2 (-0.9, 1.0) at T0 to 0.1 (-0.8, 1.3) at T+6, (p=0.03) and (iii) in those whose indication for using adalimumab therapy was an allergic reaction to infliximab, median ΔHtSDS increased significantly from -0.3 (-0.9, 1.0) at T0 to 0.3 (-0.5, 1.6) at T+6, (p=0.02). Median ΔHtSDS also increased from -0.4 (-0.8, 0.7) at T0 to 0.0 (-0.6, 1.6) at T+6, (p=0.04) in 15 children who were on prednisolone therapy when starting adalimumab. CONCLUSION: Clinical response to adalimumab therapy is associated with an improvement in linear growth in a proportion of children with CD. Improved growth is more likely in patients entering remission and on immunosuppression but is not solely due to a steroid sparing effect.

23 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.

24 Article Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease. 2012

Henderson, P / Wilson, D C / Satsangi, J. ·Department of Child Life and Health, University of Edinburgh, UK. paul.henderson2@nhs.net ·Aliment Pharmacol Ther · Pubmed #22221081.

ABSTRACT: -- No abstract --

25 Article Genome-wide methylation profiling in Crohn's disease identifies altered epigenetic regulation of key host defense mechanisms including the Th17 pathway. 2012

Nimmo, Elaine R / Prendergast, James G / Aldhous, Marian C / Kennedy, Nicholas A / Henderson, Paul / Drummond, Hazel E / Ramsahoye, Bernard H / Wilson, David C / Semple, Colin A / Satsangi, Jack. ·Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK. ·Inflamm Bowel Dis · Pubmed #22021194.

ABSTRACT: BACKGROUND: Germline variation in the 71 Crohn's disease (CD) loci implicated by genome-wide association studies (GWAS) only accounts for approximately 25% of estimated heritability. The contribution of epigenetic alterations to disease pathogenesis is emerging as a research priority. MATERIALS AND METHODS: The methylation status of 27,578 CpG sites across the genome was analyzed using the Illumina Human Methylation27 assay in DNA extracted from whole blood samples from 40 adult females (21 ileal CD, 19 healthy controls) and 16 girls with childhood-onset CD, all nonsmokers. Our primary analysis compared methylation profiles in adult cases and controls. RESULTS: Our data define a global methylation profile characteristic of ileal CD. In all, 1117 sites were differentially methylated (corrected P < 0.01); 50 showed significantly altered methylation in cases compared with controls (uncorrected P < 10(-6), corrected P < 0.0006), including genes altering immune activation: MAPK13, FASLG, PRF1, S100A13, RIPK3, and IL-21R. Gene ontology analyses implicated immunity-related pathways as targets of epigenetic modification (immune system processes [P = 1.3 × 10(-22)], immune response [P = 8.1 × 10(-16)], defense responses to bacteria [P = 1.8 × 10(-15)]). Ingenuity canonical pathway analyses implicated dendritic cell activity (P = 2.4 × 10(-8)) and differential regulation of cytokines by interleukin (IL)-17A and IL-17F (P = 5.8 × 10(-7)). We identified a significant enrichment of methylation changes within 50 kb of CD GWAS loci (8.6-fold [P = 0.021] in adults; 2.4-fold [P = 0.009] in adults and children combined), including IL-27, IL-19, TNF, MST1, and NOD2. Methylation status was predictive of disease status (sensitivity 0.71, specificity 0.83). Disease activity, drug therapy, NOD2 and DNMT3A genotypes were not associated with methylation changes. CONCLUSIONS: These data provide an important insight into the impact of epigenetic mechanisms in the pathogenesis of CD.

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