Development of the paris definition of early Crohn's disease for disease-modification trials: results of an international expert opinion process.
; ; et al
in American Journal of Gastroenterology (2012), 107(12), 1770-6
We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen ... [more ▼]
We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen experts on inflammatory bowel diseases held an international expert opinion meeting to discuss and agree on a definition for early CD to be used in disease-modification trials. The process included literature searches for the relevant basic-science and clinical evidence. A published preliminary definition of early CD was used as the basis for development of a proposed definition that was discussed at the expert opinion meeting. The participants then derived a final definition, based on best current knowledge, that it is hoped will be of practical use in disease-modification trials in CD. [less ▲]Detailed reference viewed: 29 (3 ULg)
Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.
; ; et al
in Nature Genetics (2011), 43(3), 246-52
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association ... [more ▼]
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. [less ▲]Detailed reference viewed: 18 (5 ULg)
Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.
Momozawa, Yukihide ; Mni, Myriam ; Nakamura, Kayo et al
in Nature Genetics (2011), 43(1), 43-7
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20 ... [more ▼]
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease. [less ▲]Detailed reference viewed: 76 (30 ULg)
Development of the Crohn's disease digestive damage score, the Lemann score.
; ; et al
in Inflammatory Bowel Diseases (2011), 17(6), 1415-22
Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural ... [more ▼]
Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lemann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lemann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. [less ▲]Detailed reference viewed: 30 (0 ULg)
Familial aggregation and antimicrobial response dose-dependently affect the risk for Crohn's disease.
; Van Steen, Kristel ; et al
in Inflammatory Bowel Diseases (2010), 16(1), 58-67
BACKGROUND:: An increased risk of Crohn's disease (CD) has been reported consistently in first-degree relatives of patients. Our aim was to test whether a combination of CD-associated genes involved in ... [more ▼]
BACKGROUND:: An increased risk of Crohn's disease (CD) has been reported consistently in first-degree relatives of patients. Our aim was to test whether a combination of CD-associated genes involved in innate immunity and/or antibody responses to microbial antigens may be valuable in identifying healthy relatives at risk. METHODS:: We investigated 86 families from Belgium and northern France, 45 with at least 3 first-degree relatives with CD, 24 with a single case, and 17 control families without inflammatory bowel disease (IBD). The cohort consisted of 186 CD patients, 290 healthy relatives, and 142 controls (total 618). Genetic (NOD2, NOD1, TLR4, CARD8) and serologic markers (ASCA, ACMA, ALCA, ACCA, ASigmaMA, OmpC, CBir1, I2) were determined in all subjects. All Belgian families were prospectively followed up for 54 months. RESULTS:: In multiple-affected families, an increment of affected first-degree relatives and of positive antibodies were additive risks factors for CD (P < 0.0001), independent of NOD2 mutations. When comparing subjects from multiple-affected families, having 3 additional first-degree relatives with CD and 1 additional positive antibody increased the odds for CD to 9.19 (95% confidence interval [CI]: 4.07-20.80). After a follow-up of 54 months among all Belgian families, a total of 4 new diagnoses of IBD were confirmed in the multiple-affected families only, resulting in a 57-fold increase in incidence within multiple-affected families compared to the known incidence of IBD in our region. CONCLUSIONS:: We found an additive risk increment for CD in subjects from multicase families per additional affected relative and per additional positive antibody, independent of NOD2. Furthermore, a very high disease incidence was observed in these multiple-affected families. Inflamm Bowel Dis 2010. [less ▲]Detailed reference viewed: 27 (3 ULg)
Severe skin lesions cause patients with inflammatory bowel disease to discontinue anti-tumor necrosis factor therapy.
; ; et al
in Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of The American Gastroenterological Association (2010), 8(12), 1048-55
BACKGROUND & AIMS: Psoriasiform and eczematiform lesions are associated with anti-tumor necrosis factor (TNF)-alpha therapies. We assessed clinical characteristics, risk factors, and outcomes of skin ... [more ▼]
BACKGROUND & AIMS: Psoriasiform and eczematiform lesions are associated with anti-tumor necrosis factor (TNF)-alpha therapies. We assessed clinical characteristics, risk factors, and outcomes of skin disease in patients with inflammatory bowel diseases that presented with psoriasiform and eczematiform lesions induced by anti-TNF-alpha agents. METHODS: We studied 85 patients (69 with Crohn's disease, 15 with ulcerative colitis, and 1 with indeterminate colitis; 62 women) with inflammatory skin lesions (62 psoriasiform and 23 eczematiform lesions). RESULTS: Twenty-four patients had a history of inflammatory skin lesions and 15 had a familial history of inflammatory skin disease. Locations of eczematiform lesions varied whereas scalp and flexural varieties were mostly psoriasiform. Skin lesions emerged but inflammatory bowel disease was quiescent in 69 patients following treatment with any type of anti-TNF-alpha agent (60 with infliximab, 20 with adalimumab, and 5 with certolizumab). Topical therapy resulted in partial or total remission in 41 patients. Patients with psoriasiform lesions that were resistant to topical therapy and that changed anti-TNF-alpha therapies once or twice developed recurring lesions. Overall, uncontrolled skin lesions caused 29 patients to stop taking TNF-alpha inhibitors. CONCLUSIONS: Inflammatory skin lesions following therapy with TNF-alpha inhibitors occurred most frequently among women and patients with a personal or familial history of inflammatory skin disease; lesions did not correlate with intestinal disease activity. Recurring and intense skin lesions caused 34% of patients in this study to discontinue use of anti-TNF-alpha agents. [less ▲]Detailed reference viewed: 16 (2 ULg)
Fibrin glue is effective healing perianal fistulas in patients with Crohn's disease.
; ; et al
in Gastroenterology (2010), 138(7), 2275-8122811
BACKGROUND & AIMS: Fibrin glue is a therapeutic for fistulas that activates thrombin to form a fibrin clot, which mechanically seals the fistula tract. We assessed the efficacy and safety of a ... [more ▼]
BACKGROUND & AIMS: Fibrin glue is a therapeutic for fistulas that activates thrombin to form a fibrin clot, which mechanically seals the fistula tract. We assessed the efficacy and safety of a heterologous fibrin glue that was injected into the fistula tracts of patients with Crohn's disease (ClinicalTrials.gov No. NCT00723047). METHODS: This multicenter, open-label, randomized controlled trial included patients with a Crohn's disease activity index < or =250 and fistulas between the anus (or low rectum) and perineum, vulva, or vagina, that drained for more than 2 months. Magnetic resonance imaging or endosonography was performed to assess fistula tracts and the absence of abscesses. Patients were stratified into groups with simple or complex fistulas and randomly assigned to receive fibrin glue injections (n = 36) or only observation (n = 41) after removal of setons. The primary end point was clinical remission at week 8, defined as the absence of draining, perianal pain, or abscesses. At week 8, a fibrin glue injection was offered to patients who were not in remission. RESULTS: Clinical remission was observed in 13 of the 34 patients (38%) of the fibrin glue group compared with 6 of the 37 (16%) in the observation group; these findings demonstrate the benefit of fibrin glue (odds ratio, 3.2; 95% confidence interval: 1.1-9.8; P = .04). The benefit seemed to be greater in patients with simple fistulas. Four patients in the fibrin glue group and 6 in the observation group had adverse events. CONCLUSIONS: Fibrin glue injection is a simple, effective, and well-tolerated therapeutic option for patients with Crohn's disease and perianal fistula tracts. [less ▲]Detailed reference viewed: 12 (0 ULg)
Efficacy and safety of a third anti-TNF monoclonal antibody in Crohn's disease after failure of two other anti-TNF.
; ; et al
in Alimentary Pharmacology & Therapeutics (2009)
Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn's disease (CD) patients previously treated with infliximab (IFX). Aim: To assess the efficacy and tolerability of a third ... [more ▼]
Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn's disease (CD) patients previously treated with infliximab (IFX). Aim: To assess the efficacy and tolerability of a third anti-TNF in CD after failure of and/or intolerance to two different anti-TNF. Methods: CD patients who received ADA or CZP after loss of response and/or intolerance to two anti-TNF were included in this retrospective study. Data were collected using a standardized questionnaire. Clinical response, duration, safety and reasons for discontinuation were assessed. Results: Sixty-seven patients treated with CZP (n=40) or ADA (n=27) were included. A clinical response was observed in 41 (61%) at week 6 and 34 patients (51%) at week 20. The probability of remaining under treatment at 3 months, 6 months and 9 months was 68%, 60% and 45%, respectively. At the end of follow-up, the third anti-TNF had been stopped in 36 patients for intolerance (n=13), or failure (n=23). Two deaths were observed. Conclusion: Treatment, with a third anti-TNF (CZP or ADA) agent, of CD patients who have experienced loss of response and/or intolerance to two anti-TNF antibodies, has favorable short- and long-term efficacy and is an option to be considered in patients with no other therapeutic options. [less ▲]Detailed reference viewed: 35 (5 ULg)
Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn's disease: a subanalysis of the ACCENT I study.
Louis, Edouard ; ; et al
in Pharmacogenetics and Genomics (2006), 16(12), 911-4
Recently, it has been shown that FCGR3A-158 gene polymorphism is associated with biological and possibly clinical response to infliximab in Crohn's disease. We further assessed this association in a ... [more ▼]
Recently, it has been shown that FCGR3A-158 gene polymorphism is associated with biological and possibly clinical response to infliximab in Crohn's disease. We further assessed this association in a subset of 344 patients from the large and well-defined cohort of 573 patients with Crohn's disease from the ACCENT I study. No association could be observed between FCGR3A-158 gene polymorphism and the clinical response to infliximab, which was primarily defined as a decrease of >or=70 points in the Crohn's disease activity index or clinical remission (Crohn's disease activity index <150). We did, however, confirm a trend towards a greater decrease in C-reactive protein after infliximab in V/V homozygotes as compared with V/F heterozygotes and F/F homozygotes (-79.4, -76.5, and -64.3%, respectively, at week 6; P=0.085; one-tailed P=0.043). This finding has no immediate clinical impact but may enhance the understanding of the complex mechanisms of action of anti-tumor necrosis factor agents in Crohn's disease. [less ▲]Detailed reference viewed: 16 (0 ULg)