Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease

Abstract

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.