T cell and cytokine signatures as early predictors of response to IL-12/IL-23 inhibition in Crohn's disease

Abstract

Crohn’s disease (CD) is a disabling inflammatory disorder with highly variable response to biologic therapies. Despite the availability of multiple biologic agents, a significant proportion of patients experience primary non-response, while others initially respond but subsequently develop secondary loss of response, leading to sequential treatment failures and increased healthcare burden. The disease course and response to treatment are remarkably heterogeneous among patients, and a better understanding of the personalised pathways affected is required. Identifying early biomarkers of treatment efficacy is crucial for improving patient outcomes and reducing unnecessary healthcare costs. In this study, we comprehensively analysed T cell subpopulations in blood and lamina propria, together with serum cytokine profiles, in CD patients receiving the IL-12/IL-23 inhibitor ustekinumab. The most remarkable findings were observed in peripheral blood. At week 24, good responders showed decreased Th1, increased Th2, and reduced IL-17A serum levels compared with non-responders. Importantly, elevated IL-12/IL-23 serum levels at week 8 associated with strongly correlated with favorable clinical and endoscopic outcomes, suggesting effective pathway blockade. These findings support the measurement of serum IL-12/IL-23 at week 8 as a simple, early predictor of ustekinumab response in CD, potentially guiding personalised treatment strategies and ultimately long-term response.