D2 | Abstract 04
Annual NUTRIM Symposium 18 November 2020
APPLIED SCIENCE
Rac1/pSTAT3 expression in lymphocytes as a pharmaco-dynamic marker for thiopurine therapy in IBD-patients
Debbie S. Deben1, Rob H. Creemers2,4, Dennis R. Wong1, Roosmarie Drent3, Arjan J. van Adrichem3, Mathie P.G. Leers3, Adriaan A. van Bodegraven2,5
1 Zuyderland Medical Centre, Department of Clinical Pharmacy, Clinical pharmacology and Toxicology, Sittard-Geleen-Heerlen, The Netherlands
2 Zuyderland Medical Centre, Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Sittard-Geleen-Heerlen, The Netherlands
3 Zuyderland Medical Centre, Department of Clinical and Haematological Chemistry, Sittard-Geleen-Heerlen, The Netherlands
4 School for Nutrition and Translational Research in Metabolism(NUTRIM), Maastricht University Medical Centre+, Maastricht, The Netherlands
5 Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands
Thiopurine derivatives remain standard treatment of Inflammatory Bowel Disease (IBD). Indirect pharmacokinetic markers are being used to optimize therapeutic outcome. However, a direct pharmacodynamic marker in lymphocytes may be more useful. The aim of this study is to explore whether expression of Rac1 and activated STAT3 (pSTAT3) in lymphocytes can be used as a pharmacodynamic marker to predict therapeutic outcome of thiopurine therapy.
Method:
We performed a single centre pilot study. A flow cytometric assay on blood derived leukocytes was used to determine expression of Rac1 and activated pSTAT3 in 3 parallel group. Per group six patients were included; 1) IBD patients with active disease without systemic immunomodulating therapy, 2) IBD patients on AZA or MP monotherapy, and 3) healthy controls.
Results:
Compared to healthy controls (1.01 Arbitrary Units (AU), range 0.67-1.29), Rac1 expression in lymphocytes was increased in IBD-patients using thiopurine therapy (1.30 AU, range 1.07-2.07). This upregulation was not found in therapy-naïve IBD patients (1.00 AU, range 0.60-1.98). An increase in absolute pSTAT3 expression compared to healthy controls (0.67 AU, range 0.58-2.89) was found in both therapy-naïve IBD patients (2.40 AU, range 0.64-3.37) and patients on thiopurine therapy (2.09 AU, range 1.68-2.40). Furthermore, pSTAT3 expression corrected for Rac1 expression was decreased in IBD patients treated with thiopurines (1.34 AU, range 1.10-2.20) compared to therapy-naive IBD patient (2.93 AU, range 0.60-4.23).
Discussion:
This is the first study which examines whether expression of Rac1 and pSTAT3 in lymphocytes can be used as a pharmacodynamic marker to predict therapeutic outcome of thiopurine therapy. We found that the absolute expression of the pSTAT3 was comparable between IBD-patients with or without thiopurine therapy, Rac1-corrected pSTAT3 expression was decreased in IBD patients on thiopurine therapy. In conclusion, Rac1 expression in combination with pSTAT3 expression may serve as a potential pharmacodynamic marker for thiopurine therapy.
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