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Mucosal kinase activity and inflammatory profiles in inflammatory bowel disease, and in relation to tofacitinib
Eelco C Brand1,2, Britt Roosenboom3, Lisanne Lutter1,2
1Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Background And 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 the 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.
Insights
Inflammatory bowel disease (IBD) involves distinct mucosal kinase activity profiles. Higher baseline activity predicts response to tofacitinib, which significantly reduces kinase activity in responders.
Area of Science:
- Gastroenterology
- Immunology
- Molecular Biology
Background:
- Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), presents challenges in treatment response.
- Understanding the mucosal inflammatory environment is crucial for precise therapeutic interventions.
- Kinase activity modulation is a therapeutic strategy, but not all patients respond.
Purpose of the Study:
- To investigate mucosal kinase activity and cytokine/chemokine profiles in IBD.
- To correlate these profiles with response to tofacitinib treatment.
- To identify potential biomarkers for therapeutic response.
Main Methods:
- Collected paired inflamed and non-inflamed colonic biopsies from CD, UC, and non-IBD controls.
- Assessed IBD-associated kinase activity and cytokine/chemokine profiles.
- Analyzed colonic samples from UC patients before and after 8 weeks of tofacitinib treatment to evaluate response-related kinase activity.
Main Results:
- Significant differences in kinase activity profiles were observed between inflamed and non-inflamed mucosa, particularly in UC.
- Tyrosine kinase families showed the most pronounced increase in activity.
- Responders to tofacitinib exhibited higher baseline mucosal kinase activity, which decreased significantly after treatment.
Conclusions:
- Mucosal kinase activity profiles are linked to IBD inflammation, with distinct patterns in UC and CD.
- Baseline kinase activity may predict tofacitinib response.
- Kinase activity profiling offers potential for optimizing IBD therapeutic strategies.
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