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Crohn Disease: HELP
Articles from Quebec
Based on 133 articles published since 2009
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These are the 133 published articles about Crohn Disease that originated from Quebec during 2009-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
76 Article Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial. 2015

Khanna, Reena / Bressler, Brian / Levesque, Barrett G / Zou, Guangyong / Stitt, Larry W / Greenberg, Gordon R / Panaccione, Remo / Bitton, Alain / Paré, Pierre / Vermeire, Séverine / D'Haens, Geert / MacIntosh, Donald / Sandborn, William J / Donner, Allan / Vandervoort, Margaret K / Morris, Joan C / Feagan, Brian G / Anonymous6910841. ·Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Medicine, University of Western Ontario, London, ON, Canada. · Department of Gastroenterology, St Paul's Hospital, Vancouver, BC, Canada. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada. · Division of Gastroenterology, Mount Sinai Hospital, Toronto, ON, Canada. · Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, Canada. · Division of Gastroenterology, McGill University Health Centre, McGill University, Montreal, QC, Canada. · Laval University, CHAUQ, Hôpital du St-Sacrement, Quebec City, QC, Canada. · Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. · Division of Gastroenterology, Dalhousie University, Halifax, NS, Canada. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Medicine, University of Western Ontario, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. Electronic address: brian.feagan@robartsinc.com. ·Lancet · Pubmed #26342731.

ABSTRACT: BACKGROUND: Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. METHODS: In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. FINDINGS: This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. INTERPRETATION: Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. FUNDING: AbbVie Pharmaceuticals.

77 Article Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans. 2015

Huang, Chengrui / Haritunians, Talin / Okou, David T / Cutler, David J / Zwick, Michael E / Taylor, Kent D / Datta, Lisa W / Maranville, Joseph C / Liu, Zhenqiu / Ellis, Shannon / Chopra, Pankaj / Alexander, Jonathan S / Baldassano, Robert N / Cross, Raymond K / Dassopoulos, Themistocles / Dhere, Tanvi A / Duerr, Richard H / Hanson, John S / Hou, Jason K / Hussain, Sunny Z / Isaacs, Kim L / Kachelries, Kelly E / Kader, Howard / Kappelman, Michael D / Katz, Jeffrey / Kellermayer, Richard / Kirschner, Barbara S / Kuemmerle, John F / Kumar, Archana / Kwon, John H / Lazarev, Mark / Mannon, Peter / Moulton, Dedrick E / Osuntokun, Bankole O / Patel, Ashish / Rioux, John D / Rotter, Jerome I / Saeed, Shehzad / Scherl, Ellen J / Silverberg, Mark S / Silverman, Ann / Targan, Stephan R / Valentine, John F / Wang, Ming-Hsi / Simpson, Claire L / Bridges, S Louis / Kimberly, Robert P / Rich, Stephen S / Cho, Judy H / Rienzo, Anna Di / Kao, Linda W H / McGovern, Dermot P B / Brant, Steven R / Kugathasan, Subra. ·Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21231, USA. · F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90049, USA. · Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA. · Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. · Institute for Translational Genomics and Population Sciences and Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA,90502, USA. · Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Committee on Clinical Pharmacology and Pharmacogenomics, and the Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. · Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. · Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. · Division of Gastroenterology, University of Maryland, Baltimore, MD 21201, USA. · Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. · Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, and Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA. · Charlotte Gastroenterology and Hepatology, PLLC, Charlotte, NC 28207, USA. · Department of Medicine, Baylor College of Medicine; VA HSR&D Center for Innovations in Quality, Effectiveness and Safety , Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA. · Department of Pediatrics, Willis-Knighton Physician Network, Shreveport, LA 71118, USA. · Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA. · Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA. · Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA. · Division of Gastroenterology, Case Western Reserve University, Cleveland, OH 44106, USA. · Section of Pediatric Gastroenterology, Baylor College of Medicine, Houston, TX, 77030. · Department of Pediatrics, University of Chicago Comer Children's Hospital, Chicago, IL 60637, USA. · Departments of Medicine and Physiology and Biophysics, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond VA 23298, USA. · Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. · Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Division of Gastroenterology, Vanderbilt Children's Hospital, Nashville TN 37212, USA. · Department of Pediatrics, Cook Children's Medical Center, Fort Worth, TX 76104, USA. · Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Universite de Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec H1T 1C8, Canada. · Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. · Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. · Departments of Medicine, Surgery, Public Health Sciences, Immunology, and Molecular and Medical Genetics, University of Toronto, Samuel Lunenfeld Research Institute and Mount Sinai Hospital, Toronto General Hospital Research Institute, Toronto, Ontario M5S 2J7, Canada. · Department of Gastroenterology, Henry Ford Health System Detroit, MI 48208, USA. · Division of Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, Utah. · Statistical Genetics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, USA. · Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. · Department of Medicine and Genetics, Yale University, New Haven, CT 06520, USA. ·Gastroenterology · Pubmed #26278503.

ABSTRACT: BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

78 Article Differential accumulation and function of proinflammatory 6-sulfo LacNAc dendritic cells in lymph node and colon of Crohn's versus ulcerative colitis patients. 2015

Bsat, Marwa / Chapuy, Laurence / Baba, Nobuyasu / Rubio, Manuel / Panzini, Benoit / Wassef, Ramses / Richard, Carole / Soucy, Genevieve / Mehta, Heena / Sarfati, Marika. ·*Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Center for Innovative and Translational Medicine, Kochi University Medical School, Kochi, Japan; and Departments of Gastroenterology, Digestive Tract Surgery, and Pathology, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada. · *Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada; Center for Innovative and Translational Medicine, Kochi University Medical School, Kochi, Japan; and Departments of Gastroenterology, Digestive Tract Surgery, and Pathology, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada m.sarfati@umontreal.ca. ·J Leukoc Biol · Pubmed #26162403.

ABSTRACT: Human Slan DCs have been studied in patients with psoriasis, rheumatoid arthritis, cancer, and autoimmune diseases. In this study, we investigated the frequency, phenotype, and function of Slan DCs in blood, colon, as well as mLNs of patients with IBD. We first show that the frequency of circulating CD14(dull)Slan DCs was reduced in CD patients refractory to immunosuppressive drugs or TNF-α blockers relative to untreated CD, UC, and healthy subjects. In blood of CD patients, Slan DCs expressed CD172a, as detected by CD47 fusion protein binding, when compared with its lack of expression in control subjects. Next, we demonstrate that CD172a(+)Slan DCs that produced IL-1β and TNF-α accumulated in mLNs and colons of CD patients. The CD172a(+)Slan DCs up-regulated their expression of CD14 in CD tissues and the proinflammatory cytokines were produced in CD14(bright)CD172a(+)Slan DCs. By contrast, no difference was noted in the frequency of Slan DCs between inflamed, noninflamed colonic mucosa of UC patients and control, non-IBD donors. Finally, the percentage of cytokine-producing Slan DCs also augmented in response to TLR2 and NOD2 in in vitro stimulation in PBMCs of CD, but not UC, patients. In conclusion, we propose that proinflammatory CD14(bright)CD172a(+)Slan DCs are a distinguishing feature between CD and UC, as these cells accumulate uniquely in mLNs and colonic mucosa of CD patients. Thus, Slan DCs may contribute to CD immunopathogenesis.

79 Article High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. 2015

Goyette, Philippe / Boucher, Gabrielle / Mallon, Dermot / Ellinghaus, Eva / Jostins, Luke / Huang, Hailiang / Ripke, Stephan / Gusareva, Elena S / Annese, Vito / Hauser, Stephen L / Oksenberg, Jorge R / Thomsen, Ingo / Leslie, Stephen / Anonymous5720816 / Anonymous5730816 / Anonymous5740816 / Anonymous5750816 / Anonymous5760816 / Anonymous5770816 / Anonymous5780816 / Anonymous5790816 / Daly, Mark J / Van Steen, Kristel / Duerr, Richard H / Barrett, Jeffrey C / McGovern, Dermot P B / Schumm, L Philip / Traherne, James A / Carrington, Mary N / Kosmoliaptsis, Vasilis / Karlsen, Tom H / Franke, Andre / Rioux, John D. ·Research Center, Montreal Heart Institute, Montreal, Quebec, Canada. · 1] Department of Surgery, University of Cambridge, Cambridge, UK. [2] National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK. · Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany. · 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK. [2] Christ Church, University of Oxford, St Aldates, UK. · 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. · 1] Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium. [2] Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Génoprotéomique Appliquée) Research Center, University of Liege, Liege, Belgium. · 1] Unit of Gastroenterology, IRCCS-CSS (Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza) Hospital, San Giovanni Rotondo, Italy. [2] Unit of Gastroenterology SOD2 (Strutture Organizzative Dipartimentali), Azienda Ospedaliero Universitaria (AOU) Careggi, Florence, Italy. · Department of Neurology, University of California, San Francisco, San Francisco, California, USA. · 1] Murdoch Children's Research Institute, Parkville, Victoria, Australia. [2] Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia. · 1] Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. [2] Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA. · Wellcome Trust Sanger Institute, Hinxton, UK. · F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA. · 1] Cambridge Institute for Medical Research, Cambridge, UK. [2] Department of Pathology, University of Cambridge, Cambridge, UK. · 1] Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. [2] Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachusetts, USA. · 1] Research Institute of Internal Medicine, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway. [2] Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway. [3] K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · 1] Research Center, Montreal Heart Institute, Montreal, Quebec, Canada. [2] Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada. ·Nat Genet · Pubmed #25559196.

ABSTRACT: Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

80 Article Small bowel capsule endoscopy in the management of established Crohn's disease: clinical impact, safety, and correlation with inflammatory biomarkers. 2015

Kopylov, Uri / Nemeth, Artur / Koulaouzidis, Anastasios / Makins, Richard / Wild, Gary / Afif, Waqqas / Bitton, Alain / Johansson, Gabriele Wurm / Bessissow, Talat / Eliakim, Rami / Toth, Ervin / Seidman, Ernest G. ·*Division of Gastroenterology, McGill University Health Center, Montreal, QC, Canada; †Department of Gastroenterology, Skåne University Hospital, Malmö, Lund University, Lund, Sweden; ‡Endoscopy Unit, Centre for Liver and Digestive Disorders, The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; §Department of Gastroenterology, Gloucestershire Hospitals NHS Foundation Trust, Chetlenham, United Kingdom; and ‖Department of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Israel. ·Inflamm Bowel Dis · Pubmed #25517597.

ABSTRACT: BACKGROUND: Multiple studies have established the superior diagnostic accuracy of video capsule endoscopy (VCE) for the diagnosis of small bowel (SB) Crohn's disease (CD). However, data on the clinical impact of VCE in patients with established CD are scarce. The aim of this study was to examine the impact and safety of VCE on the clinical management of patients with established CD. METHODS: A retrospective, multicenter, cross-sectional study. The study cohort included consecutive patients with established SB CD who underwent VCE in 4 tertiary referral centers (1 Canada, 1 Sweden, and 2 United Kingdom) from January 2008 to October 2013. Patients were excluded if VCE was performed as a part of the initial diagnostic workup. The presence of SB mucosal inflammation was quantified using the Lewis score. Inflammatory biomarkers (C-reactive protein and fecal calprotectin) were measured and correlated with the Lewis score. RESULTS: The study included 187 patients. No SB inflammation was observed in 28.4%, mild-to-moderate inflammation in 26.6%, and moderate-to-severe inflammation in 45% of the patients (median Lewis score, 662; range, 0-6400). A change in management was recommended in 52.3% of the patients based on VCE findings. Elevated C-reactive protein, fecal calprotectin, or the combination of both were poorly correlated with significant SB inflammation. SB capsule retention occurred in 4 patients (2.1%). CONCLUSIONS: VCE in patients with established CD is safe, and the results often have a significant clinical impact. VCE should not be limited to CD patients with positive inflammatory markers because their predictive value for significant SB inflammation is poor.

81 Article The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn's disease. 2015

Fedorak, Richard N / Feagan, Brian G / Hotte, Naomi / Leddin, Des / Dieleman, Levinus A / Petrunia, Denis M / Enns, Robert / Bitton, Alain / Chiba, Naoki / Paré, Pierre / Rostom, Alaa / Marshall, John / Depew, William / Bernstein, Charles N / Panaccione, Remo / Aumais, Guy / Steinhart, A Hillary / Cockeram, Alan / Bailey, Robert J / Gionchetti, Paolo / Wong, Cindy / Madsen, Karen. ·Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada. Electronic address: Richard.Fedorak@ualberta.ca. · Robarts Clinical Trials University of Western Ontario, London, Ontario, Canada. · Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada. · Dalhousie University, Halifax, Nova Scotia, Canada. · University of Victoria, Victoria, British Columbia, Canada. · University of British Columbia, Vancouver, British Columbia, Canada. · McGill University, Montreal, Quebec, Canada. · Guelph GI and Surgery Clinic, Guelph, Ontario, Canada; McMaster University, Hamilton, Ontario, Canada. · Université Laval, CHA-Hopitâl du Saint-Sacrement, Quebec City, Quebec, Canada. · University of Ottawa, Ottawa, Ontario, Canada. · McMaster University, Hamilton, Ontario, Canada. · Queen's University, Kingston, Ontario, Canada. · University of Manitoba, Winnipeg, Manitoba, Canada. · University of Calgary, Calgary, Alberta, Canada. · University of Montreal, Montreal, Quebec, Canada. · University of Toronto, Toronto, Ontario, Canada. · St John, New Brunswick, Canada. · DIMEC University of Bologna, Bologna, Italy. ·Clin Gastroenterol Hepatol · Pubmed #25460016.

ABSTRACT: BACKGROUND & AIMS: Probiotic formulations of single species of bacteria have not been effective in preventing the recurrence of Crohn's disease after surgery. We investigated the ability of VSL#3, a mixture of 8 different bacterial probiotic species, to prevent Crohn's disease recurrence after surgery in a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Within 30 days of ileocolonic resection and re-anastomosis, patients with Crohn's disease were randomly assigned to groups given 1 sachet of VSL#3 (900 billion viable bacteria, comprising 4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus) (n = 59) or matching placebo (n = 60). Colonoscopy was performed at days 90 and 365 to evaluate the neoterminal ileum for disease recurrence and obtain mucosal biopsies for cytokine analysis. Patients from both groups with either no or mild endoscopic recurrence at day 90 received VSL#3 until day 365. The primary outcome was the proportion of patients with severe endoscopic recurrence at day 90. RESULTS: At day 90, the proportion of patients with severe endoscopic lesions did not differ significantly between VSL#3 (9.3%) and placebo (15.7%, P = .19). The proportions of patients with non-severe lesions at day 90 who had severe endoscopic recurrence at day 365 were 10.0% in the early VSL#3 group (given VSL#3 for the entire 365 days) and 26.7% in the late VSL#3 group (given VSL#3 from days 90 through 365) (P = .09). Aggregate rates of severe recurrence (on days 90 and 365) were not statistically different, 20.5% of subjects in the early VSL#3 group and 42.1% in the late VSL#3 group. Patients receiving VSL#3 had reduced mucosal inflammatory cytokine levels compared with placebo at day 90 (P < .05). Crohn's disease activity index and inflammatory bowel disease quality of life scores were similar in the 2 groups. CONCLUSIONS: There were no statistical differences in endoscopic recurrence rates at day 90 between patients who received VSL#3 and patients who received placebo. Lower mucosal levels of inflammatory cytokines and a lower rate of recurrence among patients who received early VSL#3 (for the entire 365 days) indicate that this probiotic should be further investigated for prevention of Crohn's disease recurrence. Clinical trials.gov number: NCT00175292.

82 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.

83 Article Increased incidence of inflammatory bowel disease in Québec residents with airway diseases. 2015

Brassard, Paul / Vutcovici, Maria / Ernst, Pierre / Patenaude, Valérie / Sewitch, Maida / Suissa, Samy / Bitton, Alain. ·Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada McGill University, Faculty of Medicine, Montreal, QC, Canada paul.brassard@mcgill.ca. · McGill University Health Centre, Division of Gastroenterology, Montreal, QC, Canada. · Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada McGill University, Faculty of Medicine, Montreal, QC, Canada. · Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada. · McGill University, Faculty of Medicine, Montreal, QC, Canada McGill University Health Centre, Division of Clinical Epidemiology, Montreal, QC, Canada. · McGill University, Faculty of Medicine, Montreal, QC, Canada McGill University Health Centre, Division of Gastroenterology, Montreal, QC, Canada. ·Eur Respir J · Pubmed #25406447.

ABSTRACT: The objective of the study was to assess whether the incidences of Crohn's disease and ulcerative colitis are increased in patients with asthma and chronic obstructive pulmonary disease (COPD) compared to the general population. A population-based retrospective cohort study was conducted using the administrative health databases of Québec, Canada. Incidences of Crohn's disease and ulcerative colitis among patients with asthma and COPD were assessed for the 2001-2006 period. In total, 136 178 subjects with asthma and 143 904 subjects with COPD were identified. The average incidence of Crohn's disease and ulcerative colitis was 23.1 and 8.8 per 100 000 person-years among asthmatic patients; in the COPD cohort there were 26.2 Crohn's disease cases and 17 ulcerative colitis cases per 100 000 person-years. The incidence of Crohn's disease in asthma and COPD patients was 27% and 55% higher than in the general population of Québec; the incidence of ulcerative colitis was 30% higher among COPD patients compared to the general population. Incidence of inflammatory bowel disease was significantly increased in asthma and COPD patients compared to the general population of Québec. Incidence rates were particularly high in patients with COPD. Awareness of an association between airway diseases and inflammatory bowel disease in older age groups may play an important role in earlier detection of bowel disease and in the therapeutic management of such patients.

84 Article Hematologic indices as surrogate markers for monitoring thiopurine therapy in IBD. 2015

Kopylov, Uri / Battat, Robert / Benmassaoud, Amine / Paradis-Surprenant, Laurence / Seidman, Ernest G. ·Division of Gastroenterology, McGill University Health Centre, Montreal, QC, Canada, ukopylov@gmail.com. ·Dig Dis Sci · Pubmed #25236422.

ABSTRACT: BACKGROUND: Clinical efficacy and risk of complications are associated with intracellular levels of thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurines (6-MMP) in patients with Crohn's disease. Therapeutic monitoring of thiopurine metabolites is not widely available. Surrogate markers such as hematologic indices (MCV, leukopenia) have been proposed. AIMS: To evaluate accuracy of hematologic indices for prediction of therapeutic levels of thiopurine metabolites. METHODS: A retrospective cross-sectional study. We included patients treated with thiopurines for IBD between February 2008 and November 2013. Hematologic indices were correlated with thiopurine metabolites and compared to pre-treatment levels. RESULTS: A total of 168 patients with 608 measurements were included. Macrocytosis was observed in 4.5 % of the patients. On multivariate analysis, macrocytosis was associated with 6-TGN levels >235 pmol/8 × 10(8) erythrocytes and 6-mmp levels >5,700 pmol/8 × 10(8) erythrocytes. Therapeutic 6-TGN levels were associated with MCV, ΔMCV, macrocytosis and lymphocyte count. Sensitivity and Spearman's r correlation for prediction of therapeutic metabolite levels were poor for all hematologic indices. CONCLUSION: Although macrocytosis and an elevated MCV are associated with therapeutic 6-TGN levels, the correlation is weak. None of the evaluated hematologic indices is a reliable surrogate marker for thiopurine metabolite levels.

85 Article Bacterial bile metabolising gene abundance in Crohn's, ulcerative colitis and type 2 diabetes metagenomes. 2014

Labbé, Alain / Ganopolsky, Jorge G / Martoni, Christopher J / Prakash, Satya / Jones, Mitchell L. ·Micropharma Limited, Montreal, Quebec, Canada. · Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, Montreal, Quebec, Canada; Micropharma Limited, Montreal, Quebec, Canada. ·PLoS One · Pubmed #25517115.

ABSTRACT: We performed an analysis to determine the importance of bile acid modification genes in the gut microbiome of inflammatory bowel disease and type 2 diabetic patients. We used publicly available metagenomic datasets from the Human Microbiome Project and the MetaHIT consortium, and determined the abundance of bile salt hydrolase gene (bsh), 7 alpha-dehydroxylase gene (adh) and 7-alpha hydroxysteroid dehydrogenase gene (hsdh) in fecal bacteria in diseased populations of Crohn's disease (CD), Ulcerative Colitis (UC) and Type 2 diabetes mellitus (T2DM). Phylum level abundance analysis showed a significant reduction in Firmicute-derived bsh in UC and T2DM patients but not in CD patients, relative to healthy controls. Reduction of adh and hsdh genes was also seen in UC and T2DM patients, while an increase was observed in the CD population as compared to healthy controls. A further analysis of the bsh genes showed significant differences in the correlations of certain Firmicutes families with disease or healthy populations. From this observation we proceeded to analyse BSH protein sequences and identified BSH proteins clusters representing the most abundant strains in our analysis of Firmicute bsh genes. The abundance of the bsh genes corresponding to one of these protein clusters was significantly reduced in all disease states relative to healthy controls. This cluster includes bsh genes derived from Lachospiraceae, Clostridiaceae, Erysipelotrichaceae and Ruminococcaceae families. This metagenomic analysis provides evidence of the importance of bile acid modifying enzymes in health and disease. It further highlights the importance of identifying gene and protein clusters, as the same gene may be associated with health or disease, depending on the strains expressing the enzyme, and differences in the enzymes themselves.

86 Article Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms: New data and a meta-analysis. 2014

Senhaji, Nezha / Diakité, Brehima / Serbati, Nadia / Zaid, Younes / Badre, Wafaa / Nadifi, Sellama. ·Laboratory of Genetic and Molecular Pathology (LGPM), Medical School, Hassan II University, Casablanca, Morocco. nezha.senhaji@gmail.com. · Laboratory of Genetic and Molecular Pathology (LGPM), Medical School, Hassan II University, Casablanca, Morocco. br.diakite@yahoo.fr. · Laboratory of Genetic and Molecular Pathology (LGPM), Medical School, Hassan II University, Casablanca, Morocco. nadiaserbati@yahoo.fr. · Laboratory of Thrombosis and Haemostasis Research Centre, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada. younes_zaid@yahoo.ca. · Gastroenterology Department, CHU Ibn Rochd, Casablanca, Morocco. wafaa6badre6dr@gmail.com. · Laboratory of Genetic and Molecular Pathology (LGPM), Medical School, Hassan II University, Casablanca, Morocco. nadifisel@yahoo.fr. ·BMC Gastroenterol · Pubmed #25492126.

ABSTRACT: BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) involves interactions between the host genetic susceptibility, intestinal microflora and mucosal immune responses through the pattern recognition receptor. Polymorphisms in toll-like receptor 4 (TLR4) induce an aberrant immune response to indigenous intestinal flora, which might favor IBD development. In this study, we aimed to determine whether TLR4 gene was associated with Crohn's disease (CD) and ulcerative colitis (UC) among Moroccan patients, and evaluated its correlation with clinical manifestation of the disease. METHODS: The study population comprised 117 patients with IBD and 112 healthy unrelated blood donors. TLR4 polymorphisms: Asp299Gly and Thr399Ile were genotyped by polymerase chain reaction-restriction fragment length polymorphism. PCR products were cleaved with Nco I for the Asp299Gly polymorphism and Hinf I for the Thr399Ile polymorphism. Meta-analysis was performed to test the association of 299Gly and 399Ileu carriage with CD, UC and the overall IBD risk. RESULTS: Our study revealed that the frequency of Asp299Gly and Thr399Ile did not differ significantly between patients and controls in the Moroccan population. However, meta-analysis demonstrated significantly higher frequencies of both Asp299Gly and Thr399Ile SNPs in IBD and CD and for 399Ileu carriage in UC patients. CONCLUSION: The meta-analysis provides evidence that TLR4 polymorphisms confer a significant increased risk for the overall IBD development.

87 Article Rasmussen encephalitis and comorbid autoimmune diseases: A window into disease mechanism? 2014

Amrom, Dina / Kinay, Demet / Hart, Yvonne / Berkovic, Samuel F / Laxer, Ken / Andermann, Frederick / Andermann, Eva / Bar-Or, Amit. ·From the Neurogenetics Unit (D.A., E.A.), Epilepsy Clinic (F.A.), and Neuroimmunology Unit (A.B.-O.), Montreal Neurological Hospital and Institute, Quebec, Canada · Departments of Neurology & Neurosurgery (D.A., F.A., E.A., A.B.-O.), Pediatrics (F.A.), and Human Genetics (E.A.), McGill University, Montreal, Quebec, Canada · Okmeydani Education and Research Hospital (D.K.), Istanbul, Turkey · Royal Victoria Infirmary (Y.H.), Newcastle-upon-Tyne, UK · Epilepsy Research Center (S.F.B.), Department of Medicine (Neurology), University of Melbourne, Australia · and Department of Neurology (K.L.), University of California at San Francisco. ·Neurology · Pubmed #25142901.

ABSTRACT: OBJECTIVE: To describe a potential association between comorbid autoimmune disease and Rasmussen encephalitis (RE) and discuss potential insights into underlying RE pathogenesis. METHODS: We report a case series of 4 patients with RE in whom a comorbid autoimmune disease was subsequently diagnosed and review the literature on possible common susceptibility factors. RESULTS: In 4 patients who presented with typical clinical features of RE, a comorbid autoimmune disease was subsequently diagnosed: Hashimoto thyroiditis, ulcerative colitis, Crohn disease, and systemic lupus erythematosus. We discuss the possible common predisposing factors. CONCLUSIONS: The association of RE, a rare entity, with a comorbid autoimmune disease raises the possibility of shared mechanisms of susceptibility, including common immunogenetic and/or environmental risk factors.

88 Article Timing, frequency and type of physician-diagnosed infections in childhood and risk for Crohn's disease in children and young adults. 2014

Springmann, Vicky / Brassard, Paul / Krupoves, Alfreda / Amre, Devendra. ·*Department of Gastroenterology & Hepatology, Ste-Justine Hospital Research Centre, Montreal, QC, Canada; †Department of Social and Preventive Medicine, University of Montreal, Montreal, QC, Canada; ‡Department of Clinical Epidemiology and Community Studies, Jewish General Hospital, Montreal, QC, Canada; §Division of Occupational & Environmental Health, Institut national de santé publique du Québec, Montreal, QC, Canada; and ‖Department of Pediatrics, University of Montreal, Montreal, QC, Canada. ·Inflamm Bowel Dis · Pubmed #25046007.

ABSTRACT: BACKGROUND: Recent experimental data show that exposure to microbes during early childhood can confer immunological tolerance and protect against Crohn's disease (CD). Epidemiological evidence for this link, however, remains controversial. Using prospective data, we examined the link between this hypothesis and risk for CD in children and young adults. METHODS: A case-control study design was used. CD cases (diagnosed before age 20 years) were recruited from a tertiary-care pediatric hospital in Montreal, and population-based controls matched for age, gender and, geographical location were selected. Infection data were ascertained from physician-billing records. These records, which use International Classification of Diseases, Ninth Revision diagnostic codes, were consulted retrospectively but provide prospectively collected diagnostic information. Conditional logistic regression analysis was used to study potential associations. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated. RESULTS: Four hundred nine cases and 1621 controls were included. Regression analysis adjusting for potential confounding variables suggested that any recorded infection before the diagnosis of CD was associated with reduced risk of CD (OR, 0.67; 95% CI, 0.48-0.93). The protective effect was restricted to infections occurring mainly before 5 years of age, with increasing number of infections resulting in greater protection (1-5 infections: OR, 0.74; ≥6 infections: OR, 0.61; P value for trend = 0.039). Infections affecting the oral and upper respiratory tracts, cellulitis, and, enteric infections seemed most protective. CONCLUSIONS: Our study provides support for the hygiene hypothesis, whereby exposure to infections in early childhood could potentially reduce risks of CD.

89 Article Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease--the McGill experience. 2014

Kopylov, U / Afif, W / Cohen, A / Bitton, A / Wild, G / Bessissow, T / Wyse, J / Al-Taweel, T / Szilagyi, A / Seidman, E. ·Division of Gastroenterology, McGill University Health Center, Montreal, Quebec, Canada. Electronic address: ukopylov@gmail.com. · Division of Gastroenterology, McGill University Health Center, Montreal, Quebec, Canada. · Division of Gastroenterology, Jewish General Hospital, Montreal, Quebec, Canada. ·J Crohns Colitis · Pubmed #24996483.

ABSTRACT: BACKGROUND: Ustekinumab is a fully human IgG1κ monoclonal antibody that blocks the biologic activity of interleukin-12/23. Ustekinumab is approved for treatment of plaque psoriasis and has been shown to be effective for induction and maintenance of clinical response in anti-TNF resistant Crohn's disease (CD). The aim of the study was to describe the real-life experience with open-label use of ustekinumab in anti-TNF resistant CD patients. METHODS: A retrospective observational open-label study. Clinical response was defined by physician's global assessment combined with decision to continue therapy. The clinical response was evaluated at 3, 6, 12months and last follow-up. RESULTS: Thirty-eight patients were included in the study. Initial clinical response was achieved in 28/38 (73.7%) of the patients. Among the initial responders, 80% with follow-up data maintained their response for 6months. At 12months of follow-up, 88.9% of patients responding at 6months maintained their response. At the last follow-up (7.9±5.2 mo) 27/38 (71%) of the patients were responding, and 73.3% were able to discontinue corticosteroids. Dose escalation was required in 47.7% of the patients and was successful in 61.1% of them. SUMMARY: In this real-life cohort of severe anti-TNF resistant CD, an initial clinical response to subcutaneous ustekinumab was observed in 73.7% of the patients. The initial response was successfully maintained in the majority of patients for up to 12months. Subcutaneous ustekinumab is an effective therapeutic option in this challenging patient cohort. The optimal dosing and injection schedule remain to be established in future studies.

90 Article Basophils increase in Crohn disease and ulcerative colitis and favor mesenteric lymph node memory TH17/TH1 response. 2014

Chapuy, Laurence / Bsat, Marwa / Mehta, Heena / Rubio, Manuel / Wakahara, Keiko / Van, Vu Quang / Baba, Nobuyasu / Cheong, Cheolho / Yun, Tae Jin / Panzini, Benoît / Wassef, Ramses / Richard, Carole / Tamaz, Raja / Soucy, Geneviève / Delespesse, Guy / Sarfati, Marika. ·Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada. · Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Center for Innovative and Translational Medicine, Kochi University Medical School, Kochi, Japan. · Cellular Physiology and Immunology Research Unit, Institut de recherches cliniques de Montréal, Montreal, Quebec, Canada. · Department of Gastroenterology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada. · Department of Digestive Tract Surgery, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada. · Department of Pathology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada. · Allergy Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada. · Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada. Electronic address: m.sarfati@umontreal.ca. ·J Allergy Clin Immunol · Pubmed #24996262.

ABSTRACT: -- No abstract --

91 Article Thiopurine metabolite ratios for monitoring therapy in pediatric Crohn disease. 2014

Kopylov, U / Amre, D / Theoret, Y / Deslandres, C / Seidman, E G. ·*Division of Gastroenterology, McGill University Health Center †Department of Pediatrics, Research Center, Sainte Justine Hospital, University of Montreal, Quebec, Canada. ·J Pediatr Gastroenterol Nutr · Pubmed #24918978.

ABSTRACT: OBJECTIVES: Thiopurines (azathioprine, 6-mercaptopurine) are a mainstay of treatment in Crohn disease (CD). Monitoring intracellular metabolite (6-thioguanine nucleotides [6-TGN] and 6-methylmercaptopurine [6-MMP]) levels can help optimize therapeutic efficacy and minimize potential toxicity. Determination of 6-MMP/6-TGN ratios may provide additional useful information, such as the identification of individuals with excessive thiopurine methyltransferase activity and disadvantageous 6-MMP overproduction. These patients are at increased risk of therapeutic failure and hepatotoxicity. The aim of the study was to evaluate the correlation of 6-MMP/6-TGN ratios with therapeutic efficacy and risk of hepatotoxicity in CD. METHODS: The present study was a single-center cross-sectional study including pediatric patients with CD studied prospectively with clinical and laboratory assessments along with serial measurements of 6-MMP and 6-TGN. Clinical response was determined using established clinical indices. RESULTS: The study included 238 pediatric patients with CD with a total of 1648 evaluation points. The patients were in steroid-free remission at 59.1% of the evaluation points. 6-MMP/6-TGN ratios of 4 to 24 were protective against relapse (odds ratio [OR] 0.52, 95% confidence interval [CI] -0.39 to 0.69, P = 0.001). Hepatotoxicity was associated with high 6-MMP levels (>3919  pmol/8 × 10 red blood cell count: OR 7.65, 95% CI 3.7-15.9, P = 0.001) and high 6-MMP/6-TGN ratios (>24: OR 5.35, 95% CI -3.43 to 8.43, P = 0.001). CONCLUSIONS: We observed significant associations between 6-MMP/6-TGN ratios and clinical response, and risk of hepatotoxicity. Our results suggest that determination of thiopurine metabolite ratios is a valuable tool for identification of patients at increased risk of therapeutic failure and hepatotoxicity.

92 Article Host defense peptide resistance contributes to colonization and maximal intestinal pathology by Crohn's disease-associated adherent-invasive Escherichia coli. 2014

McPhee, Joseph B / Small, Cherrie L / Reid-Yu, Sarah A / Brannon, John R / Le Moual, Hervé / Coombes, Brian K. ·Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. · Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada. · Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada coombes@mcmaster.ca. ·Infect Immun · Pubmed #24866805.

ABSTRACT: Host defense peptides secreted by colonocytes and Paneth cells play a key role in innate host defenses in the gut. In Crohn's disease, the burden of tissue-associated Escherichia coli commonly increases at epithelial surfaces where host defense peptides concentrate, suggesting that this bacterial population might actively resist this mechanism of bacterial killing. Adherent-invasive E. coli (AIEC) is associated with Crohn's disease; however, the colonization determinants of AIEC in the inflamed gut are undefined. Here, we establish that host defense peptide resistance contributes to host colonization by Crohn's-associated AIEC. We identified a plasmid-encoded genomic island (called PI-6) in AIEC strain NRG857c that confers high-level resistance to α-helical cationic peptides and α- and β-defensins. Deletion of PI-6 sensitized strain NRG857c to these host defense molecules, reduced its competitive fitness in a mouse model of infection, and attenuated its ability to induce cecal pathology. This phenotype is due to two genes in PI-6, arlA, which encodes a Mig-14 family protein implicated in defensin resistance, and arlC, an OmpT family outer membrane protease. Implicit in these findings are new bacterial targets whose inhibition might limit AIEC burden and disease in the gut.

93 Article Differential effect of vitamin D on NOD2- and TLR-induced cytokines in Crohn's disease. 2014

Dionne, S / Calderon, M R / White, J H / Memari, B / Elimrani, I / Adelson, B / Piccirillo, C / Seidman, E G. ·McGill Center for IBD Research, Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada. · Department of Physiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. ·Mucosal Immunol · Pubmed #24781050.

ABSTRACT: Accumulating evidence implicates defective innate immunity in the pathogenesis of Crohn's disease (CD). Ineffectual NOD2 (nucleotide-binding oligomerization domain 2) is the most common susceptibility gene contributing to CD. Vitamin D (vD), a potent modulator of innate and adaptive immunity, induces NOD2 gene expression and its downstream function. We hypothesized that the hormonal form of vD (1,25D) could beneficially modulate innate immune function in CD. Using peripheral mononuclear cells and monocyte-derived dendritic cells (Mo-DCs) from CD, it was found that 1,25D decreased Toll-like receptor (TLR)-induced cytokine production and enhanced cytokine levels induced by muramyl dipeptide (MDP), the NOD2 ligand. 1,25D increased the synergistic effect provided by NOD2 and TLR co-activation on interleukin (IL)-10, IL-23, and tumor necrosis factor-alpha (TNF-α). Whereas 1,25D inhibits Mo-DC TLR-induced cytokines, co-stimulation of NOD2 results in increased IL-10 and IL-23. IL-12p70 was completely abrogated by 1,25D. 1,25D similarly modulated cytokine production by immune cells in ulcerative colitis patients and healthy controls. Mo-DCs from CD patients heterozygous for NOD2 mutations had a response similar to those from patients without NOD2 mutations. Immune cells from patients homozygous for the 1007 fs mutation were unresponsive to MDP and 1,25D. Our in vitro data support 1,25D as a potential modulator of immunity. However, these results cannot be extrapolated to CD patients without further controlled studies.

94 Article 25-Hydroxyvitamin D concentrations in children with Crohn's disease supplemented with either 2000 or 400 IU daily for 6 months: a randomized controlled study. 2014

Wingate, Kirstin E / Jacobson, Kevan / Issenman, Robert / Carroll, Matthew / Barker, Collin / Israel, David / Brill, Herbert / Weiler, Hope / Barr, Susan I / Li, Wangyang / Lyon, Michael R / Green, Timothy J. ·Food, Nutrition, and Health, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada. · Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada. · Canadian Center for Functional Medicine, Coquitlam, British Columbia, Canada. · Food, Nutrition, and Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: tim.green@ubc.ca. ·J Pediatr · Pubmed #24423431.

ABSTRACT: OBJECTIVES: To assess vitamin D status of pediatric patients with Crohn's disease (CD) and to compare their serum 25-hydroxyvitamin D (s-25OHD) with established cutoffs and assess whether 6 months of supplementation with 2000 IU/d, vs 400 IU/d, would reduce the group prevalence of vitamin D below these cutoffs. STUDY DESIGN: Subjects 8-18 years (n = 83) with quiescent CD were randomized to either 400 or 2000 IU vitamin D3/d for 6 months. RESULTS: Baseline mean ± SD s-25OHD was 24 ± 8 ng/mL; 13 subjects (16%) had an s-25OHD <16 ng/mL, 27 (33%) < 20 ng/mL, and 65 (79%) < 30 ng/mL. There was no significant difference between groups in achieving the cutoffs of 16 ng/mL or 20 ng/mL at 6 months; however, only 35% of the 400 IU group achieved the greater cutoff of 30 ng/mL compared with 74% in the 2000 IU group (P < .001). Baseline adjusted mean s-25OHD concentrations at 6 months were 9.6 ng/mL (95% CI 6.0-13.2, P < .001) greater in the 2000 IU than the 400 IU group. Disease activity was not affected by supplement dose. Few subjects exceeded safety marker cutoffs, and this did not differ by dose. CONCLUSIONS: At baseline, a high proportion of patients had a mean s-25OHD >20 ng/mL. 2000 IU vitamin D3/d is more effective in raising s-25OHD concentrations to > 30 ng/mL in children with CD than 400 IU/d, but both treatments were equally effective at achieving 16 or 20 ng/mL.

95 Article Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease. 2014

Costea, Irina / Mack, David R / Lemaitre, Rozenn N / Israel, David / Marcil, Valerie / Ahmad, Ali / Amre, Devendra K. ·Public Health Agency of Canada, Montreal, Canada. · Division of Gastroenterology, Children's Hospital of Eastern Ontario, Ottawa, Canada. · Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington. · Division of Gastroenterology, Hepatology and Nutrition, British Columbia's Children's Hospital, Vancouver, Canada. · Research Institute, McGill University, Montreal, Quebec, Canada. · Department of Microbiology and Immunology, University of Montreal, Quebec, Canada; Research Centre, Le Centre Hospitalier Universitaire-Ste-Justine, Montreal, Canada. · Research Centre, Le Centre Hospitalier Universitaire-Ste-Justine, Montreal, Canada; Department of Pediatrics, University of Montreal, Quebec, Canada. Electronic address: devendra.amre@gmail.com. ·Gastroenterology · Pubmed #24406470.

ABSTRACT: Increased dietary ratios of ω6/ω3 polyunsaturated fatty acids have been implicated in the pathogenesis of Crohn's disease (CD), but epidemiologic data are limited. We investigated whether variants of genes that control polyunsaturated fatty acid metabolism (CYP4F3, FADS1, and FADS2), along with the dietary ratio of ω6/ω3, confers susceptibility to CD. Based on data from 182 children newly diagnosed with CD and 250 controls, we found that children who consumed a higher dietary ratio of ω6/ω3 were susceptible for CD if they were also carriers of specific variants of CYP4F3 and FADS2 genes. Our findings implicate diet-gene interactions in the pathogenesis of CD.

96 Article Crohn's disease susceptibility variants in Colombian tuberculosis patients. 2014

Sánchez, D / Lefebvre, C / García, L F / Rioux, J / Barrera, L F. ·Grupo de Inmunología Celular e Inmunogenética, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia; Centro Colombiano de Investigación en Tuberculosis, Medellin, Colombia; Health Sciences Center, Louisiana Cancer Research Center, Louisiana State University, New Orleans, Louisiana, USA. · Laboratory in Genetics and Genomic Medicine of Inflammation, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; ECOGENE-21 Clinical Trial Center, Centre de Médecine Génique Communautaire de l'Université de Montréal, Centre Hospitalier Affilié Universitaire Régional de Chicoutimi, Chicoutimi, Québec, Canada. · Grupo de Inmunología Celular e Inmunogenética, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia; Centro Colombiano de Investigación en Tuberculosis, Medellin, Colombia. · Laboratory in Genetics and Genomic Medicine of Inflammation, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada. ·Int J Tuberc Lung Dis · Pubmed #24365559.

ABSTRACT: BACKGROUND: The molecular basis of genetic predisposition to pulmonary tuberculosis (PTB) in adults remains largely elusive. A chronic granulomatous inflammatory reaction is one of the main characteristics of the immune response to TB; however, a similar reaction is observed in other diseases, such as Crohn's disease. OBJECTIVE: To assess the association of genetic polymorphisms previously associated with Crohn's disease and PTB in a Colombian population of PTB patients and controls. DESIGN: A case-control study was performed among 500 newly diagnosed PTB patients and 320 healthy control subjects. Thirty-one single nucleotide polymorphisms (SNPs) identified in a previous meta-analysis of genome-wide association studies of Crohn's disease were used for genotyping using MassARRAY technology. RESULTS: In this study, we identified an association with borderline significance (P = 0.0009433 and P = 0.029 after multiple testing by Bonferroni's correction) of SNP rs10995271 with PTB. SNP rs10995271 is in linkage disequilibrium with SNPs belonging to the zinc finger protein (ZNF365) gene. CONCLUSIONS: Our results suggest that human PTB shares a genetic basis with Crohn's disease, and that SNPs in the ZNF365 gene would have a role in the occurrence of chronic granulomatous inflammatory reaction in TB as well as Crohn's disease.

97 Article Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease. 2014

Feagan, Brian G / McDonald, John W D / Panaccione, Remo / Enns, Robert A / Bernstein, Charles N / Ponich, Terry P / Bourdages, Raymond / Macintosh, Donald G / Dallaire, Chrystian / Cohen, Albert / Fedorak, Richard N / Paré, Pierre / Bitton, Alain / Saibil, Fred / Anderson, Frank / Donner, Allan / Wong, Cindy J / Zou, Guangyong / Vandervoort, Margaret K / Hopkins, Marybeth / Greenberg, Gordon R. ·Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. Electronic address: brian.feagan@robartsinc.com. · Robarts Clinical Trials, Western University, London, Ontario, Canada. · Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Alberta, Canada. · St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada. · Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada. · Department of Medicine, Western University, London, Ontario, Canada; London Health Sciences Centre, South Street Hospital, London, Ontario, Canada. · Hôtel-Dieu de Lévis, Lévis, Quebec, Canada. · Dalhousie University, Halifax, Nova Scotia, Canada. · Centre Hospitalier Universitaire de Québec-Pavillon St. François d'Assise, Quebec City, Quebec, Canada. · Jewish General Hospital, Montreal, Quebec, Canada. · University of Alberta, Edmonton, Alberta, Canada. · Hôpital St. Sacrement, Quebec City, Quebec, Canada. · McGill University Health Centre, Montreal, Quebec, Canada. · Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. · The Liver and Intestinal Research Centre, Vancouver, British Columbia, Canada. · Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. · Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. ·Gastroenterology · Pubmed #24269926.

ABSTRACT: BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. METHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. RESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. CONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

98 Article High residential sun exposure is associated with a low risk of incident Crohn's disease in the prospective E3N cohort. 2014

Jantchou, Prévost / Clavel-Chapelon, Francoise / Racine, Antoine / Kvaskoff, Marina / Carbonnel, Franck / Boutron-Ruault, Marie-Christine. ·*Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, France; †Univ Paris Sud, UMRS 1018, Villejuif, France; ‡Inserm U1018, Institut Gustave Roussy, Villejuif, France; §Sainte Justine University Hospital, Montréal, Canada; and ‖Service de Gastroentérologie, Hôpitaux Universitaires Paris Sud, CHU de Bicêtre, APHP, Le Kremlin Bicêtre, France. ·Inflamm Bowel Dis · Pubmed #24247650.

ABSTRACT: BACKGROUND: Vitamin D insufficiency has been suggested to be associated with high risk of Crohn's disease (CD). In France, where food fortification is limited, the major source of vitamin D is through sun exposure. The aim of this work was to analyze the relationship between residential sun exposure and the risk of incident CD or ulcerative colitis (UC). METHODS: The E3N cohort consists of women living in France, aged 40 to 65 years and free of major diseases at inclusion in 1990. Among the 91,870 women included in the study, we identified 123 incident cases (45 CD, 71 UC, and 7 indeterminate colitis). To assess residential sun exposure, we used a database containing mean daily ultraviolet radiation (UVR) dose for each French county. The relationship between residential sun exposure and risk of incident inflammatory bowel diseases was explored using Cox models. RESULTS: Higher levels of residential sun exposure were associated with a significant decreased risk of CD (hazard ratio [HR] for the third versus the first tertile of UVR dose, 0.49; 95% confidence interval (CI), 0.23-1.01; P for trend = 0.04), but not of UC (HR, 1.21; CI, 0.61-2.11). In women with available data on dietary vitamin D intake, we observed a lower risk of CD with higher residential UVR (HR, 0.29; 95% CI, 0.11-0.80; P for trend = 0.01). Dietary vitamin D intake was neither associated with the risk of CD (HR, 0.41; 95% CI, 0.14-1.24; P for trend = 0.14) nor UC (HR, 1.61; CI, 0.61-4.23). CONCLUSIONS: In this prospective cohort of women, high residential sunlight exposure was associated with decreased incidence of CD, but not UC.

99 Article Capsule endoscopy is superior to small-bowel follow-through and equivalent to ileocolonoscopy in suspected Crohn's disease. 2014

Leighton, Jonathan A / Gralnek, Ian M / Cohen, Stanley A / Toth, Ervin / Cave, David R / Wolf, Douglas C / Mullin, Gerard E / Ketover, Scott R / Legnani, Peter E / Seidman, Ernest G / Crowell, Michael D / Bergwerk, Ari J / Peled, Ravit / Eliakim, Rami. ·Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona. Electronic address: leighton.jonathan@mayo.edu. · Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel. · Children Center for Digestive Health Care, Children Healthcare of Atlanta, Atlanta, Georgia. · Department of Gastroenterology, Skane University Hospital, Malmö, Sweden. · University of Massachusetts Medical School, Worcester, Massachusetts. · Atlanta Gastroenterology Associates, Atlanta, Georgia. · Johns Hopkins Hospital, Baltimore, Maryland. · Minnesota Gastroenterology PA, Minneapolis, Minnesota. · Mount Sinai School of Medicine, New York, New York. · Research Institute of McGill University Health Center, Montreal General Hospital, Montreal, Quebec, Canada. · Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona. · Shaare Zedek Medical Center, Jerusalem, Israel. · Given Imaging Ltd, Yoqneam, Israel. · Department of Gastroenterology, Sheba Medical Center, Tel-Aviv, Israel. ·Clin Gastroenterol Hepatol · Pubmed #24075891.

ABSTRACT: BACKGROUND & AIMS: Evaluation of the small intestine for inflammation has traditionally relied on small-bowel follow-through (SBFT), but multiple studies have demonstrated its low diagnostic accuracy. Capsule endoscopy (CE) transmits high-quality images of the small intestinal mucosa; it can be used to visualize the entire length of the small bowel and much of the mucosa. We compared the diagnostic yields of CE vs SBFT in a prospective study of patients with suspected small-bowel Crohn's disease. METHODS: Eighty patients with signs and/or symptoms of small-bowel Crohn's disease (age, 10-65 years) underwent CE, followed by SBFT and ileocolonoscopy. Readers were blinded to other test results. The primary outcome was the diagnostic yield for inflammatory lesions found with CE before ileocolonoscopy compared with SBFT and ileocolonoscopy. A secondary outcome was the incremental diagnostic yield of CE compared with ileocolonoscopy and CE compared with SBFT. RESULTS: The combination of CE and ileocolonoscopy detected 107 of 110 inflammatory lesions (97.3%), whereas the combination of SBFT and ileocolonoscopy detected only 63 lesions (57.3%) (P < .001). The diagnostic yield of CE compared with ileocolonoscopy was not different (P = .09). The diagnostic yield was higher for CE than for SBFT (P < .001). Of the 80 patients with suspected Crohn's disease, 25 (31.3%) had the diagnosis confirmed. Eleven were diagnosed by CE findings alone and 5 by ileocolonoscopy findings alone. In the remaining 9 patients, diagnostic findings were identified by at least 2 of the 3 modalities. No diagnoses were made on the basis of SBFT findings alone. CONCLUSIONS: CE was better than SBFT and equivalent to ileocolonoscopy in detecting small-bowel inflammation. Although ileocolonoscopy remains the initial diagnostic test of choice, CE is safe and can establish the diagnosis of Crohn's disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated. ClinicalTrials.gov Number: NCT00487396.

100 Article Characterization of PTPN2 and its use as a biomarker. 2014

Bussières-Marmen, Stéphanie / Hutchins, Andrew P / Schirbel, Anja / Rebert, Nancy / Tiganis, Tony / Fiocchi, Claudio / Miranda-Saavedra, Diego / Tremblay, Michel L. ·Goodman Cancer Research Center, McGill University, Montreal, QC, Canada; Department of Biochemistry, McGill University, Montreal, QC, Canada. · Bioinformatics and Genomics Laboratory, World Premier International (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan. · Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin, Berlin, Germany. · Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. · Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. · Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. · Goodman Cancer Research Center, McGill University, Montreal, QC, Canada; Department of Biochemistry, McGill University, Montreal, QC, Canada. Electronic address: Michel.tremblay@mcgill.ca. ·Methods · Pubmed #23994241.

ABSTRACT: For years, the two main isoforms of PTPN2 have been an interesting yet academic topic of debate for researchers working on this phosphatase. In recent years, several studies were published in which these isoforms were attributed specific functions. Most importantly, differences in their stoichiometry have been reported to be associated with certain diseases such as inflammatory bowel diseases (IBDs). Hence, understanding the evolutionary ontogeny of the main transcripts and the physiological consequences of their expression have now become clinically relevant issues. Herein we describe the genomic controls placed upon PTPN2, the identified splice variants, the encoded PTPN2 proteins, and both the known and putative post-translational modifications that have been reported. Moreover, we examine the expression of PTPN2 isoforms in specific tissues as well as in a disease setting. PTPN2 is an important negative regulator of inflammation. Therefore, the following protocols are effective approaches for its adequate monitoring in inflammatory diseases' progression and outcome.

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