Introduction
Modulation of kinase activity is part of the therapeutic armamentarium for inflammatory bowel disease (IBD). However, as with other IBD treatments, not all patients respond to treatment. To improve the precision of therapeutic interventions, a better understanding of the mucosal inflammatory environment is essential. This study investigates mucosal kinase activity, along with mucosal cytokine and chemokine profiles in IBD and in relation to tofacitinib response.
Aims & 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 kinase activity profiles in relation to tofacitinib response.
Results
The mucosal kinase activity and cytokine/chemokine 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 across two cohorts. In responders, mucosal kinase activity significantly decreased after 8 weeks of treatment.
Conclusion
Mucosal kinase activity and cytokine/chemokine 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.
Disclosure
The presented research was funded by an unrestricted investigator initiated research grant of Pfizer (ASPIRE 2017). The funding party did not have any role in the design, conduct, analyses or reporting of the study.
Conflicts of interest
ECB is supported by the Alexandre Suerman program for MD and PhD students of the University Medical Center Utrecht, Netherlands, and was co-applicant on an unrestricted Investigator Initiated Research Grant of Pfizer.
BR no conflicts of interest
LL no conflicts of interest
BMF no conflicts of interest
SR no conflicts of interest
EvK no conflicts of interest
SvG no conflicts of interest
GRD has served as advisor and/or received speaker fees from Abbvie, Agomab Therapeutics, Alimentiv, AstraZeneca, Bristol Meiers Squibb, Cytoki, Celltrion, Eli Lilly, Exeliom Biosciences, Ferring, Galapagos, Glaxo Smith Kline, Pfizer, Polpharm, Immunic, Index Pharmacueticals, Johnson and Johnson, Merck, ProciseDx, Roivant, Seres Health, Takeda, Tillotts and Ventyx.
EGvL no conflicts of interest
CSHTH no conflicts of interest
KAR was co-applicant on an unrestricted Investigator Initiated Research Grant of Pfizer.
FvW is a speaker and/or consultant for Janssen, Johnson & Johnson, and Takeda. She has received research funding from Leo Pharma, Takeda, Galapagos, Sanofi, and Bristol-Myers Squibb, all unrelated to this research. She was co-applicant on an unrestricted Investigator Initiated Research Grant of Pfizer.
BO has received research support from Pfizer, Galapagos, Abbvie, Takeda, Ferring and consulting and speaker fees from Galapagos, Takeda, Janssen, BMS, Pfizer, Abbvie and Ferring.