A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease

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Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn's disease

Background Adalimumab is an effective treatment in patients with Crohn's disease; as it is a humanized anti-tumour necrosis factor monoclonal antibody, immunogenicity is thought not to be of any significance. Aim To assess whether antibodies to adalimumab (ATAs) affect adalimumab treatment outcome in patients with Crohn's disease previously treated with infliximab. Methods A retrospective study was performed. Patients with active Crohn's disease and who had lost response or were intolerant to infliximab were treated with adalimumab. Clinical response and side effects were assessed as were serum ATAs and antibodies to infliximab (ATIs). Results In total 30 patients [M/F (7/23)], median age 36 years (range 21-73) were treated with adalimumab for 318 days (median range 83-632). Clinical response was 77% (23/30), a dose escalation was necessary in eight (27%) patients and side effects were observed in 47% (14/30). In five patients (17%) ATAs were detected; of these patients, four were nonresponders. The presence of ATAs was related to nonresponse to adalimumab (P = 0.006). ATIs were positive in 57% of patients (17/30) and serum levels were significantly increased in adalimumab nonresponders (P = 0.01). Conclusion Immunogenicity plays a role in adalimumab treatment because of the development of ATAs

Malignant transformation of perianal and enterocutaneous fistulas is rare: results of 17 years of follow-up from The Netherlands

Objective. Malignant transformation of fistulas has been observed, particularly in perianal fistulas in Crohn's disease (CD) patients. The prevalence of adenocarcinoma in enterocutaneous fistulas and non-CD-related fistulas, however, is unknown. We investigated adenocarcinoma originating from perianal and enterocutaneous fistulas in both CD patients and non-CD patients from nine large, mostly tertiary referral, hospitals in The Netherlands. Methods. Patients suffering from fistulizing disease and either dysplasia or adenocarcinoma between January 1990 and January 2007 were identified using the nationwide automated pathology database (PALGA). Clinical and histopathological data were collected and verified using hospital patient-charts and reported by descriptive statistics. The total CD-population comprised 6058 patients. Results. In a study-period of 17 years, 2324 patients with any fistula were reported in PALGA. In 542 patients, dysplasia or adenocarcinoma was also mentioned. After initial review and additional detailed chart review, 538 patients were excluded, mainly because the adenocarcinoma was not related to the fistula. In the remaining four patients, all suffering from CD, adenocarcinoma originating from the fistula-tract was confirmed. The malignancies developed 25 years (IQR 10--38) after CD diagnosis, and 10 years (IQR 6--22) after fistula diagnosis. Median age at time of adenocarcinoma diagnosis was 48.3 years (IQR 43--58). Only one patient had clinical symptoms indicative for adenocarcinoma. In three other patients, the adenocarcinoma was found coincidently. Conclusions. Adenocarcinoma complicating perianal or enterocutaneous fistula-tracts is a rare finding. Only 4 out of 6058 CD patients developed a fistula-associated adenocarcinoma. We could not identify any malignant transformations in non-CD-related fistulas in our 17 years study-period

Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort

Background: Crohn's disease and ulcerative colitis have a complex genetic background. We assessed the risk for both the development and severity of the disease by combining information from genetic variants associated with inflammatory bowel disease (IBD). Methods: We studied 2804 patients (1684 with Crohn's disease and 1120 with ulcerative colitis) and 1350 controls from seven university hospitals. Details of the phenotype were available for 1600 patients with Crohn's disease and for 800 with ulcerative colitis. Genetic association for disease susceptibility was tested for the nucleotide-binding and oligomerisation domain 2 gene (NOD2), the IBD5 locus, the Drosophila discs large homologue 5 and autophagy-related 16-like 1 genes (DLG5 and ATG16L1) and the interleukin 23 receptor gene (IL23R). Interaction analysis was performed for Crohn's disease using the most associated single nucleotide polymorphism (SNP) for each locus. Odds ratios were calculated in an ordinal regression analysis with the number of risk alleles as an independent variable to analyse disease development and severity. Results: Association with Crohn's disease was confirmed for NOD2, IBD5, DLG5, ATG16L1 and IL23R. Patients with Crohn's disease carry more risk alleles than controls (p = 3.85 x 10(-22)). Individuals carrying an increasing number of risk alleles have an increasing risk for Crohn's disease, consistent with an independent effects multiplicative model (trend analysis p = 4.25 x 10(-23)). Patients with Crohn's disease with a more severe disease course, operations or an age of onset below 40 years have more risk alleles compared to non-stricturing, non-penetrating behaviour (p = 0.0008), no operations (p = 0.02) or age of onset above 40 years (p = 0.028). Conclusion: Crohn's disease is a multigenic disorder. An increase in the number of risk alleles is associated with an increased risk for the development of Crohn's disease and with a more severe disease course. Combining information from the known common risk polymorphisms may enable clinicians to predict the course of Crohn's disease