Crohn Disease: Bitton A

Sadowski DC, Bernstein CN, Bitton A, Croitoru K, Fedorak RN, Griffiths A, Anonymous00036. · Royal Alexandra Hospital, Edmonton, Canada. · Can J Gastroenterol. · Pubmed #19319383 No free full text.

Abstract: BACKGROUND: Guidelines regarding the use of infliximab in Crohn's disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines. OBJECTIVE: To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn's disease. METHODS: A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement). OUTCOME: The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication. CONCLUSION: In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn's disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn's disease is substantial and strengthened by results from longterm clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated.

Panaccione R, Fedorak RN, Aumais G, Bernstein CN, Bitton A, Croitoru K, Enns R, Feagan B, Fishman M, Greenberg G, Griffiths A, Marshall JK, Rasul I, Sadowski D, Seidman E, Steinhart H, Sutherland L, Walli E, Wild G, Williams CN, Zachos M, Anonymous00234. · University of Calgary, Calgary, Canada. · Can J Gastroenterol. · Pubmed #15372114 links to  free full text

This publication has no abstract.

Steinhart AH, Feagan BG, Wong CJ, Vandervoort M, Mikolainis S, Croitoru K, Seidman E, Leddin DJ, Bitton A, Drouin E, Cohen A, Greenberg GR. · Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. · Gastroenterology. · Pubmed #12105831 No free full text.

Abstract: BACKGROUND & AIMS: Although antibiotics are frequently used to treat Crohn's disease, this practice is not supported by strong evidence from randomized trials. METHODS: We conducted a double-blind multicenter study of patients with active Crohn's disease of the ileum, right colon, or both. Patients were randomized to receive oral ciprofloxacin and metronidazole, both 500 mg twice daily, or placebo for 8 weeks. All patients received oral budesonide 9 mg once daily. The primary efficacy measure was the proportion of patients in remission at week 8. RESULTS: Of the 134 patients who were randomized, 130 were evaluated for efficacy; 66 received placebo, and 64 received antibiotics. At week 8, 21 patients (33%) assigned to antibiotics were in remission as compared with 25 patients (38%) in the placebo group (P = 0.55; absolute difference, -5%; 95% confidence interval, -21% to 11%). An interaction (P = 0.025) between treatment allocation and disease location on treatment response was identified. Among patients with disease of the colon, 9 of 17 (53%) were in remission after treatment with antibiotics, compared with 4 of 16 (25%) of those who received placebo (P = 0.10). Discontinuation of therapy because of adverse events occurred in 13 of 66 (20%) patients treated with antibiotics, compared with 0 of 68 in the group who received placebo (P < 0.001). CONCLUSIONS: In patients with active Crohn's disease of the ileum, the addition of ciprofloxacin and metronidazole to budesonide is an ineffective intervention, but this antibiotic combination may improve outcome when there is involvement of the colon.

Villani AC, Lemire M, Fortin G, Louis E, Silverberg MS, Collette C, Baba N, Libioulle C, Belaiche J, Bitton A, Gaudet D, Cohen A, Langelier D, Fortin PR, Wither JE, Sarfati M, Rutgeerts P, Rioux JD, Vermeire S, Hudson TJ, Franchimont D. · Division of Gastroenterology, McGill University Health Centre, Montreal General Hospital, Montréal, Québec, Canada. · Nat Genet. · Pubmed #19098911 No free full text.

Abstract: We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (P(combined) = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1beta production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.

Lowe AM, Roy PO, B-Poulin M, Michel P, Bitton A, St-Onge L, Brassard P. · Faculty of Medicine, University of Montréal, Montréal, Québec, Canada. · Inflamm Bowel Dis. · Pubmed #18942744 No free full text.

Abstract: BACKGROUND: Crohn's disease (CD) is an idiopathic inflammatory bowel disease (IBD). We aimed to determine the prevalence and incidence of CD in Québec and characterize the demographic and health-related factors associated with this disease. METHODS: We identified CD cases in the provincial administrative databases for the years 1993-2002. The CD prevalence and incidence rates were estimated respectively for the periods 1993-2002 and 1998-2000. We validated the identified cases using clinically confirmed IBD cases. Predictor variables of CD were analyzed using the Poisson regression model to explain the variation in CD incidence rates across Québec. RESULTS: In all, 21,172 patients fulfilled the CD case definition for the period. The age and sex standardized average prevalence rate for 1993-2002 was 189.7 cases / 100,000 population and the age and sex standardized incidence rate of CD for the 1998-2000 period was 20.2 cases / 100,000 person-years. The female/male cases ratio among incident cases was 0.74 for the 0-14-year-old group, 1.30 for the 15-64-year-old group, and 1.77 for the cases older than 65 years old. After adjustment, independent predictors of CD incidence were: incidence of 5 reportable enteric diseases, proportion of individuals of Jewish ethnicity, and proportion of immigrant people. CONCLUSIONS: The identified predictors of CD explained 20% of the regional variance in the incidence rate of CD in the Québec population. Other factors such as genetic susceptibility to CD or the effect of an environmental cause should be taken into consideration in the models to explain the residual variance.

Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JW, Cohen A, Bitton A, Baker J, Dubé R, Landau SB, Vandervoort MK, Parikh A. · Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada. · Clin Gastroenterol Hepatol. · Pubmed #18829392 No free full text.

Abstract: BACKGROUND & AIMS: Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the alpha4beta7 integrin, in patients with active Crohn's disease. METHODS: Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (>or=70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score <or=150) and with an enhanced clinical response (>or=100-point decrement in CDAI). Human anti-human antibody levels were measured. RESULTS: Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease. CONCLUSIONS: This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.

Thia KT, Mahadevan U, Feagan BG, Wong C, Cockeram A, Bitton A, Bernstein CN, Sandborn WJ. · Miles & Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA. · Inflamm Bowel Dis. · Pubmed #18668682 No free full text.

Abstract: BACKGROUND: Although metronidazole and ciprofloxacin are used to treat perianal Crohn's disease (CD), no placebo-controlled trials have been performed. METHODS: We performed a placebo-controlled pilot trial to evaluate the efficacy and safety of metronidazole and ciprofloxacin in patients with perianal CD. Twenty-five patients with CD and actively draining perianal fistulas were randomized to receive ciprofloxacin 500 mg, metronidazole 500 mg, or placebo twice daily for 10 weeks. Remission and response of perianal fistulas were defined as closure of all fistulas and closure of at least 50% of fistulas that were draining at baseline, respectively. The primary endpoint was remission at 10 weeks. RESULTS: Ten patients were randomized to ciprofloxacin, 7 to metronidazole, and 8 to placebo. Remission at week 10 occurred in 3 patients (30%) treated with ciprofloxacin, no patients (0%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.41). Response at week 10 occurred in 4 patients (40%) treated with ciprofloxacin, 1 patient (14.3%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.43). Termination of the trial prior to week 10 occurred in 1 patient (10%) treated with ciprofloxacin, 5 patients (71.4%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P < 0.02). No serious adverse events occurred. CONCLUSION: Remission and response occurred more frequently in patients treated with ciprofloxacin but the differences were not significant in this pilot study. Ciprofloxacin was well tolerated.

Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Anonymous00002, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Anonymous00003, Anonymous00004, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ. · Bioinformatics and Statistical Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. · Nat Genet. · Pubmed #18587394 links to  free full text

Abstract: Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

Bitton A, Dobkin PL, Edwardes MD, Sewitch MJ, Meddings JB, Rawal S, Cohen A, Vermeire S, Dufresne L, Franchimont D, Wild GE. · McGill University Health Centre, 687 Pine Avenue West, Montreal, Quebec, Canada, H3A 1A1. · Gut. · Pubmed #18390994 No free full text.

Abstract: BACKGROUND: Crohn's disease (CD) is a chronic relapsing inflammatory bowel disorder. Both biological and psychosocial factors may modulate the illness experience. AIM: The aim of this study was to identify clinical, biological and psychosocial parameters as predictors of clinical relapse in quiescent CD. METHODS: Patients in medically induced remission were followed prospectively for 1 year, or less if they relapsed. Disease characteristics were determined at baseline. Serum cytokines, anti-Saccharomyces cerevisiae antibodies, C-reactive protein (CRP), erythrocyte sedimentation rate and intestinal permeability were measured every 3 months. Psychological distress, perceived stress, minor life stressors and coping strategies were measured monthly. A time-dependent multivariate Cox regression model determined predictors of time to relapse. RESULTS: 101 patients (60 females, 41 males) were recruited. Fourteen withdrew and 37 relapsed. CRP (HR = 1.5 per 10 mg/l, 95% CI 1.1 to 1.9, p = 0.007), fistulising disease (HR = 3.2, 95% CI, 1.1 to 9.4, p = 0.04), colitis (HR = 3.5 95% CI 1.2 to 9.9, p = 0.02) and the interaction between perceived stress and avoidance coping (HR = 7.0 per 5 unit increase for both scales, 95% CI 2.3 to 21.8, p = 0.003) were predictors of earlier relapse. CONCLUSIONS: In quiescent CD, a higher CRP, fistulising disease behaviour and disease confined to the colon were independent predictors of relapse. Moreover, patients under conditions of low stress and who scored low on avoidance coping (ie, did not engage in social diversion or distraction) were least likely to relapse. This study supports a biopsychosocial model of CD exacerbation.

Shugart YY, Silverberg MS, Duerr RH, Taylor KD, Wang MH, Zarfas K, Schumm LP, Bromfield G, Steinhart AH, Griffiths AM, Kane SV, Barmada MM, Rotter JI, Mei L, Bernstein CN, Bayless TM, Langelier D, Cohen A, Bitton A, Rioux JD, Cho JH, Brant SR. · Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21231, USA. · Genes Immun. · Pubmed #18246054 No free full text.

Abstract: Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Jeyanathan M, Boutros-Tadros O, Radhi J, Semret M, Bitton A, Behr MA. · Department of Medicine, McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada. · Microbes Infect. · Pubmed #18062905 No free full text.

Abstract: Studies seeking Mycobacterium avium subsp. paratuberculosis in Crohn's disease by PCR have generated inconsistent findings. As an alternative, microscopy offers a number of advantages, including direct visualization of organisms in tissue. Experimental infections have demonstrated that M. avium organisms can be seen by both acid-fast staining and species-specific in situ hybridization, but because they are smaller than M. tuberculosis, oil-immersion microscopy (x 1,000 magnification) is needed. We performed a blinded search for M. avium in paraffin-embedded surgical resections from Crohn's and control subjects at two centres. Specimens were coded and subjected to acid-fast staining and ribosomal RNA in situ hybridization for M. avium rRNA. Agreement between these two methods was good (42/52 patients, kappa=0.60) and similar results were observed for patients from two centers. Together, both methods provided positive results in 10 of 17 Crohn's subjects (59%, 95% CI: 36-78), contrasting with only 5 of 35 control subjects (Odds ratio for Crohn's vs. controls=8.6, p=0.002). M. avium organisms had an intracellular localization within inflammatory lesions, but were often observed as lone organisms outside of granulomas. Using two assays in two settings, presence of M. avium organisms was strongly associated with Crohn's disease.

Dassopoulos T, Nguyen GC, Bitton A, Bromfield GP, Schumm LP, Wu Y, Elkadri A, Regueiro M, Siemanowski B, Torres EA, Gregory FJ, Kane SV, Harrell LE, Franchimont D, Achkar JP, Griffiths A, Brant SR, Rioux JD, Taylor KD, Duerr RH, Silverberg MS, Cho JH, Steinhart AH. · Johns Hopkins University Meyerhoff Inflammatory Bowel Disease Center, Baltimore MD, USA. · Inflamm Bowel Dis. · Pubmed #17427244 links to  free full text

Abstract: BACKGROUND: The NIDDK IBD Genetics Consortium (IBDGC) collects DNA and phenotypic data from inflammatory bowel disease (IBD) subjects to provide a resource for genetic studies. No previous studies have been performed on the reliability and validity of phenotypic determinations in either Crohn's disease (CD) or ulcerative colitis (UC) using primary records. Our aim was to determine the reliability and validity of these phenotypic assessments. METHODS: The de-identified records of 30 IBD patients were reviewed by 2 phenotypers per center using a standard protocol for phenotypic assessment. Each phenotyper evaluated 10 charts on 2 occasions 5 months apart. Reliability was expressed as the kappa (kappa) statistic. Performance characteristics were determined by comparison to a consensus-derived "gold standard" and by generation of receiver operating characteristic (ROC) curves. RESULTS: Agreement for diagnosis was excellent (kappa = 0.82; 95% confidence interval [CI]: 0.71-0.92). Agreement for CD location was good for jejunal, ileal, colorectal, and perianal disease with kappa between 0.60 and 0.74 but was fair for esophagogastroduodenal (kappa = 0.36). Agreement for UC extent (kappa = 0.67; 95% CI: 0.48-0.85), and CD behavior (kappa = 0.67; 95% CI: 0.49-0.83) were very good. Area under the ROC curves was greater than 0.84 for diagnosis, CD behavior, UC extent, and ileal and colonic CD location. CONCLUSIONS: IBD phenotype classification using a standard protocol exhibited very good to excellent inter- and intrarater agreement and validity. This study highlights the importance of standard protocols in generating reliable and valid phenotypic assessments. The data will facilitate estimates of phenotyping misclassification rates that should be considered when making inferences from IBD genotype-phenotype studies.

Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian, Mezzanine Level, C-Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA. · Science. · Pubmed #17068223 links to  free full text

Abstract: The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

Nguyen GC, Torres EA, Regueiro M, Bromfield G, Bitton A, Stempak J, Dassopoulos T, Schumm P, Gregory FJ, Griffiths AM, Hanauer SB, Hanson J, Harris ML, Kane SV, Orkwis HK, Lahaie R, Oliva-Hemker M, Pare P, Wild GE, Rioux JD, Yang H, Duerr RH, Cho JH, Steinhart AH, Brant SR, Silverberg MS. · Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Am J Gastroenterol. · Pubmed #16696785 No free full text.

Abstract: OBJECTIVES: Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population. METHODS: Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions. RESULTS: African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32-0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3-13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55-10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8-4.6) and erythema nodosum (3.3; 95% CI: 1.7-6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts. CONCLUSIONS: There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.

De Jager PL, Sawcer S, Waliszewska A, Farwell L, Wild G, Cohen A, Langelier D, Bitton A, Compston A, Hafler DA, Rioux JD. · Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. · Eur J Hum Genet. · Pubmed #16391555 links to  free full text

Abstract: The 620W allele of PTPN22 has been associated with susceptibility to several different forms of chronic inflammatory disease, including Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroiditis (AIT). We set out to explore its possible role in two other inflammatory diseases: multiple sclerosis (MS) and Crohn's disease (CD). In our cohort of 496 MS trios from the United Kingdom, we observed reduced transmission of the PTPN22 620W allele. The CD sample consisted of 169 trios as well as 249 cases of CD with their 207 matched control subjects collected in the province of Québec, Canada; there was also no evidence of association between the PTPN22 620W allele and susceptibility for CD. Pooled analyses combining our data with published data assessed a total of 1496 cases of MS and 1019 cases of CD but demonstrated no evidence of association with either disease. Given the modest odds ratios of known risk alleles for inflammatory diseases, these analyses do not exclude a role for the PTPN22 allele in susceptibility to CD or MS, but they do suggest that such a putative role would probably be more modest than that reported so far in T1D, RA, SLE, and AIT.

Waschke KA, Villani AC, Vermeire S, Dufresne L, Chen TC, Bitton A, Cohen A, Thomson AB, Wild GE. · Department of Medicine, Division of Gastroenterology, McGill University Inflammatory Bowel Disease Program, Montreal, Canada. · Am J Gastroenterol. · Pubmed #15842589 No free full text.

Abstract: OBJECTIVES: Crohn's disease (CD) is a chronic multifactorial disorder with diverse clinical features that are influenced by a heterogeneous set of genetic factors. TNF-alpha/TNF receptor interactions play a pivotal role in the pathogenesis of the inflammatory response. Our purpose was to determine whether single nucleotide polymorphisms (SNPs) in the TNF receptors confer susceptibility to Crohn's disease and whether they are associated with clinical phenotype. METHODS: A cohort of 205 consecutively identified and unrelated patients with CD and 106 controls were recruited. Subjects were genotyped for polymorphisms in TNFRSF1A (position +36, -609), TNFRSF1B (+196, +1466), along with the three common CARD15 variants and phenotyped for disease behavior. Genotypic and allelic frequencies were compared between CD and controls and a logistic regression model was constructed to determine independent associations with specific clinical phenotypes. RESULTS: Only the TNFRSF1A +36 and TNFRSF1B +196 SNPs were associated with CD (p= 0.0019 and 0.034, respectively). The TNFRSF1A +36 mutation was negatively associated with stricturing disease phenotype (OR = 0.384; CI = 0.166-0.887). In contrast, the TNFRSF1B +196 was negatively associated with colitis (OR = 0.410; CI = 0.191-0.880). These associations were independent of CARD15 mutation status. Finally, TNFRSF1B +196 was negatively associated with surgery in CARD15 negative patients. CONCLUSIONS: These data constitute the first report of an association of TNFRSF1A and TNFRSF1B polymorphisms with CD in a Caucasian population and address the role of TNFR mutations in determining clinical heterogeneity in CD.

Daly MJ, Pearce AV, Farwell L, Fisher SA, Latiano A, Prescott NJ, Forbes A, Mansfield J, Sanderson J, Langelier D, Cohen A, Bitton A, Wild G, Lewis CM, Annese V, Mathew CG, Rioux JD. · The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. · Eur J Hum Genet. · Pubmed #15841097 links to  free full text

Abstract: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal system known as the inflammatory bowel diseases (IBD). Recently, Stoll and colleagues reported a novel finding of genetic variation in the DLG5 gene that is associated with IBD (CD and UC combined). We present here a study of the genetic variation described in that report in two well-powered, independent case-control cohorts and one family-based collection, and confirm the proposed association between IBD and the R30Q variant of DLG5 in two of the three studies. We are, however, unable to replicate the other proposed association to the common haplotype described in Stoll et al and suggest that this other finding could conceivably have been partially a statistical fluctuation and partially a result of LD with the replicated R30Q association. This study provides support for the hypothesis that DLG5 constitutes a true IBD risk factor of modest effect.

Wild GE, Waschke KA, Bitton A, Thomson AB. · Department of Medicine, Division of Gastroenterology, McGill University, Montreal, Canada. · Aliment Pharmacol Ther. · Pubmed #12895215 links to  free full text

Abstract: BACKGROUND: The clinical course of Crohn's disease after the induction of remission with medical therapy is characterized by unpredictable relapse. AIM: To evaluate three surrogate markers, intestinal permeability, mucosal TNFalpha and nuclear factor (NF)-kappaB/IkappaBalpha expression, in order to determine the relationship of these parameters to clinical relapse. METHODS: Thirty patients with active Crohn's disease were treated with a 10 week course of prednisone using a tapering dosing regimen. Intestinal permeability (lactulose/mannitol [L/M ratio]) was determined at baseline and at the end of prednisone tapering. TNFalpha production and the levels of expression of NF-kappaB/IkappaBalpha were measured in colonic mucosal biopsies obtained after the induction of remission. RESULTS: Twenty-two patients (73%) achieved remission and 50% of patients experienced a clinical relapse during the ensuing 12 months. Treatment with prednisone resulted in a significant decrease in the L/M ratio. Of the patients that relapsed, 75% had a raised L/M ratio at the time of remission compared with 20% of patients with a normal L/M ratio (P < 0.008; hazard ratio = 6.094; CI 1.55, 17.43). Mucosal TNFalpha production was greater in relapsers compared with those who remained in remission. The levels of NF-kappaB in relapsers were significantly greater and levels of cytosolic IkappaBalpha were significantly lower compared with those measured in patients who remained in remission. CONCLUSIONS: These findings underscore the importance of incorporating biological parameters of inflammation in determining the clinical course of Crohn's disease.

Sewitch MJ, Abrahamowicz M, Barkun A, Bitton A, Wild GE, Cohen A, Dobkin PL. · Groupe de Recherche Interdisciplinaire en Santé, University of Montreal, Montreal, Quebec, Canada. · Am J Gastroenterol. · Pubmed #12873575 No free full text.

Abstract: OBJECTIVE: The aim of this study was to identify determinants of nonadherence to medication in outpatients with established inflammatory bowel disease (IBD). METHODS: Ten gastroenterologists and 153 of their IBD patients participated in this prospective study. Demographic, clinical, and psychosocial characteristics, as well as patient-physician discordance, were assessed at an office visit. Nonadherence to medication was assessed 2 wk later. Separate generalized estimating equations were used to identify determinants of nonadherence. RESULTS: Physicians averaged 47.9 yr in age (range 30.1-57.5 yr), and 90% were male. Patients averaged 37.0 yr (SD = 15.1), and 87 (56.9%) were female. In all, 63 patients (41.2%) were nonadherent to medication; of these, 51 (81.0%) indicated unintentional nonadherence, 23 (36.5%) intentional nonadherence, and 11 (17.5%) both. Overall nonadherence was predicted by disease activity (OR = 0.55, p = 0.0022), new patient status (OR = 2.14, p = 0.0394), disease duration (OR = 0.50, p = 0.0001), and scheduling a follow-up appointment (OR = 0.30, p = 0.0059), whereas higher discordance on well-being was predictive only in psychologically nondistressed patients (p = 0.0026 for interaction). Unintentional nonadherence was predicted by age (OR = 0.97, p = 0.0072), new patient status (OR = 2.80, p = 0239), and higher discordance on well-being in psychologically nondistressed patients (p = 0.0504). Intentional nonadherence was predicted by disease duration (OR = 0.55, p = 0032), scheduling a follow-up appointment (OR = 0.12, p = 0.0001), certainty that medication would be helpful (OR = 0.99, p = 0.0409), and total patient-physician discordance (OR = 1.59, p =.0120). CONCLUSIONS: These findings suggest that the therapeutic relationship, as well as individual clinical and psychosocial characteristics, influence adherence to medication.

Vermeire S, Wild G, Kocher K, Cousineau J, Dufresne L, Bitton A, Langelier D, Pare P, Lapointe G, Cohen A, Daly MJ, Rioux JD. · Department of Gastroenterology, McGill University Health Centre, McGill University, Montreal, Canada. · Am J Hum Genet. · Pubmed #12019468 links to  free full text

Abstract: The caspase recruitment domain gene (CARD15) was recently identified as the underlying gene associated with the IBD1 locus that confers susceptibility to Crohn disease (CD). CARD15 is related to the NOD1/Apaf-1 family of apoptosis regulators, and three sequence variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) in the gene were demonstrated to be associated with CD. We collected a cohort of 231 patients with CD and 71 healthy control individuals from the Canadian province of Quebec, to determine the prevalence of these sequence variants in an independent population. Clinical records of all patients were systematically reviewed, and detailed phenotypic information was obtained. All patient DNA samples were genotyped for the three variants, thus enabling an analysis of genotype-phenotype correlations. In this cohort, 45.0% of patients with CD carried at least one variant in the CARD15 gene, compared with 9.0% of control individuals (P<10-7). Allele frequencies of Arg702Trp, Gly908Arg, and Leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with CD, compared with 4.2%, 0.7%, and 0.7% in control individuals, respectively. Importantly, CARD15 mutants were seen with equal frequency in patients with familial and sporadic CD. Analysis of the relationship between genotype and phenotype convincingly demonstrates that CARD15 variants are significantly associated with ileal disease involvement, as opposed to strictly colonic disease (P<.001). Moreover, we were able to determine the haplotype structure surrounding this disease gene by genotyping 45 single-nucleotide polymorphisms (SNPs) in a 177-kb region that contained the CARD15 gene. This structure helps clarify the history of these causal mutations. Finally, this analysis shows that CARD15 involvement with CD is detectable by use of publicly available SNPs alone.

Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z, Delmonte T, Kocher K, Miller K, Guschwan S, Kulbokas EJ, O'Leary S, Winchester E, Dewar K, Green T, Stone V, Chow C, Cohen A, Langelier D, Lapointe G, Gaudet D, Faith J, Branco N, Bull SB, McLeod RS, Griffiths AM, Bitton A, Greenberg GR, Lander ES, Siminovitch KA, Hudson TJ. · Whitehead Institute/Massachusetts Institute of Technology, Center for Genome Research, Cambridge, Massachusetts, USA. · Nat Genet. · Pubmed #11586304 No free full text.

Abstract: Linkage disequilibrium (LD) mapping provides a powerful method for fine-structure localization of rare disease genes, but has not yet been widely applied to common disease. We sought to design a systematic approach for LD mapping and apply it to the localization of a gene (IBD5) conferring susceptibility to Crohn disease. The key issues are: (i) to detect a significant LD signal (ii) to rigorously bound the critical region and (iii) to identify the causal genetic variant within this region. We previously mapped the IBD5 locus to a large region spanning 18 cM of chromosome 5q31 (P<10(-4)). Using dense genetic maps of microsatellite markers and single-nucleotide polymorphisms (SNPs) across the entire region, we found strong evidence of LD. We bound the region to a common haplotype spanning 250 kb that shows strong association with the disease (P< 2 x 10(-7)) and contains the cytokine gene cluster. This finding provides overwhelming evidence that a specific common haplotype of the cytokine region in 5q31 confers susceptibility to Crohn disease. However, genetic evidence alone is not sufficient to identify the causal mutation within this region, as strong LD across the region results in multiple SNPs having equivalent genetic evidence-each consistent with the expected properties of the IBD5 locus. These results have important implications for Crohn disease in particular and LD mapping in general.

Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, McLeod RS, Griffiths AM, Green T, Brettin TS, Stone V, Bull SB, Bitton A, Williams CN, Greenberg GR, Cohen Z, Lander ES, Hudson TJ, Siminovitch KA. · Whitehead Institute/Massachusetts Institute of Technology, Center for Genome Research, Cambridge, MA 02139, USA. · Am J Hum Genet. · Pubmed #10777714 links to  free full text

Abstract: The chronic inflammatory bowel diseases (IBDs)-Crohn disease (CD) and ulcerative colitis (UC)-are idiopathic, inflammatory disorders of the gastrointestinal tract. These conditions have a peak incidence in early adulthood and a combined prevalence of approximately 100-200/100,000. Although the etiology of IBD is multifactorial, a significant genetic contribution to disease susceptibility is implied by epidemiological data revealing a sibling risk of approximately 35-fold for CD and approximately 15-fold for UC. To elucidate the genetic basis for these disorders, we undertook a genomewide scan in 158 Canadian sib-pair families and identified three regions of suggestive linkage (3p, 5q31-33, and 6p) and one region of significant linkage to 19p13 (LOD score 4.6). Higher-density mapping in the 5q31-q33 region revealed a locus of genomewide significance (LOD score 3.9) that contributes to CD susceptibility in families with early-onset disease. Both of these genomic regions contain numerous genes that are important to the immune and inflammatory systems and that provide good targets for future candidate-gene studies.