Mucosal Kinase Activity and Inflammatory Profiles in Inflammatory Bowel Disease, and in Relation with Tofacitinib Response.

Abstract

Background & aims: Not all patients, as with other inflammatory bowel disease (IBD) treatments, respond to modulation of kinase activity. To improve the precision of therapeutic interventions, a better understanding of the mucosal inflammatory environment is essential. This study investigates mucosal kinase activity and cytokine/chemokine profiles in IBD and in relation to tofacitinib response.

Methods: Paired inflamed and non-inflamed colonic biopsies were collected from patients with Crohn's disease (CD, N = 16), ulcerative colitis (UC, N = 16), and non-IBD controls (N = 4) to assess IBD-associated kinase activity and cytokine/chemokine profiles. Additionally, colonic samples were collected from UC patients before start of tofacitinib treatment (cohort 1, N = 12) and both before and after 8 weeks of treatment (cohort 2, N = 16), to assess tofacitinib response-related kinase activity profiles.

Results: The kinase activity profiles exhibited significant differences between inflamed and non-inflamed mucosa, with more pronounced alterations observed in UC compared to CD. The increase in kinase activity was most pronounced in the tyrosine kinase families. Responders to tofacitinib demonstrated higher baseline mucosal kinase activity, although only two predicted kinases (DCLK1 and ATR) were consistently identified. In responders, mucosal kinase activity significantly decreased after 8 weeks of treatment.

Conclusion: Mucosal kinase activity profiles are associated with inflammation in IBD, with distinct differences between UC and CD. Baseline kinase activity appears to predict response to tofacitinib, with a marked reduction in kinase activity observed after 8 weeks of treatment in responders. These findings highlight the potential of kinase activity profiling in optimizing therapeutic strategies for IBD.