In Crohn’s disease and ulcerative colitis, inflammation is not limited to the digestive tract. Extraintestinal manifestations (EIMs), which affect up to 50% of patients, can substantially impair quality of life. EIMs may parallel luminal disease activity or have an independent course. They most commonly involve the musculoskeletal system (e.g., peripheral or axial arthritis) and skin (e.g., erythema nodosum and pyoderma gangrenosum). Less commonly, the hepatobiliary tract (e.g., primary sclerosing cholangitis [PSC]) and the eye (e.g., episcleritis, scleritis, and uveitis) are involved. Although the pathophysiology of EIMs is poorly understood, they are likely either manifestations of a primary systemic immune disease with variable expression amongst organs, or secondary phenomena to bowel inflammation. Additional pathophysiologic mechanisms may include aberrant lymphocyte homing mediated by ectopic expression of gut-specific chemokines and adhesion molecules, cross-reactivity between microbial and self-antigens, autoantibodies against epitopes shared by the intestine and extraintestinal tissues, elevated serum concentrations of cytokines, and alterations in innate immunity. Many EIMs independent of intestinal disease activity can be successfully treated with tumor necrosis factor (TNF) antagonists. The efficacy of vedolizumab-a monoclonal antibody targeting the α4β7 integrin-for the treatment of EIMs is uncertain, but data are emerging from post hoc analyses of randomized controlled trials, prospective and retrospective cohort studies, and case series. Vedolizumab may be effective in treating EIMs related to luminal disease activity (e.g., type 1 peripheral arthritis and erythema nodosum) but has not shown biochemical improvement in PSC. Its postulated role in the development of de novo EIMs is heavily confounded by the high proportion of patients previously exposed to TNF antagonists; new EIMs could result from TNF antagonist treatment cessation rather than being caused by vedolizumab. A common limitation of clinical studies is the lack of multidisciplinary involvement in the diagnosis and monitoring of EIMs, which may lead to misdiagnosis and overreporting. Future studies should rigorously measure EIMs in parallel with objective measures of luminal disease activity to provide more robust data on the relative efficacy of new drugs, especially as increasing numbers of gut-selective compounds enter clinical development.
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