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BACKGROUND AND AIMS: Patients with IBD frequently develop extraintestinal manifestations (EIM) that significantly contribute to morbidity. We assembled the largest multi-cohort dataset to-date to investigate the clinical, serological, and genetic factors associated with EIM complications in IBD.METHODS: Data were available in 12,083 unrelated European ancestry IBD cases with presence/absence of EIMs (ankylosing spondylitis (AS-SI), primary sclerosing cholangitis (PSC), peripheral arthritis, and skin and ocular manifestations) across four cohorts (Cedars-Sinai Medical Center, NIDDK IBD Genetics Consortium, SHARE Consortium, and RISK cohort). Clinical and serological parameters were analyzed by univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations.RESULTS: Most EIMs occurred more commonly in patients with female sex (overall EIM: P=9.0E-05, OR=1.2 [1.1-1.4]), CD (especially colonic disease location; P=9.8E-09, OR=1.7 [1.4-2.0]), and in subjects who required surgery (both CD and UC; P=3.6E-19, OR=1.7 [1.5-1.9]). Smoking increased risk of EIMs except for PSC where there was a 'protective' effect. Multiple serological associations were observed including with PSC (ANCA, ASCA, anti-CBir1) and any EIM (ANCA, ASCA, anti-I2). We identified genome-wide significant associations within MHC (AS-SI P=1.4E-15, OR=2.5 [2.0-3.1]; PSC P=2.7E-10, OR=2.8 [2.0-3.8]; ocular P=2E-08, OR=3.6 [2.3-5.6]; and overall EIM P=8.4E-09, OR=2.2 [1.7-2.9]) and CPEB4 (SKIN P=2.7E-08, OR=1.5 [1.3-1.8]). Genetic associations implicated TNF, JAK-STAT and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated.CONCLUSION: We have identified demographic, clinical and genetic associations with EIMs that reveal underlying mechanisms and implicate novel and existing drug targets: important steps towards more personalized approach to IBD management.