Rac1/pSTAT3 expression in T lymphocytes: A potential pharmacodynamic marker for thiopurines in the treatment of Inflammatory Bowel Disease patients?

Abstract Background The thiopurine derivatives, azathioprine (AZA), mercaptopurine (MP) and tioguanine (TG), remain standard treatment of Inflammatory Bowel Diseases (IBD). To date, therapeutic drug monitoring (TDM) is used to optimize thiopurine therapy. However, since this provides mainly pharmacokinetic information, TDM is of limited use to predict clinical effectiveness or to explain therapeutic failure. A specific pharmacodynamic marker would therefore be of more beneficial use. The immune suppressive mechanism of thiopurines, by the active thiopurine metabolite 6-thioguanine triphosphate, is primarily based on blocking the Ras-related C3 botulinum toxin substrate 1 (Rac1) causing T-cell apoptosis by inhibition of the phosphorylated downstream transcription factor signal transducer and activator of transcription 3 (pSTAT3) (Figure 1). The aim of this study was to explore whether expression of Rac1 and pSTAT3 in T-cells may be used as a pharmacodynamic marker for the therapeutic effect of thiopurine therapy in IBD patients. Methods To assess feasibility, T-cell Rac1 and pSTAT3 expression was evaluated in six parallel IBD groups: patients with active disease (1) and patients in remission on AZA/MP (2), TG (3), infliximab (IFX) (4), thiopurine and IFX (5) or without medication (6). Data of healthy subjects were used as reference values. Rac1 and pSTAT3 expression of patients in remission on AZA/MP or TG were compared to all other IBD groups and healthy subjects. Results Absolute Rac1 expression in T-cells did not differ between any of the IBD patient groups (Figure 2). A decrease in absolute pSTAT3 expression was found in IBD patients in remission on AZA/MP or TG, when compared to active disease patients, although not statistically significant. Notably, Rac1-corrected pSTAT3 expression was decreased in IBD patients in remission on AZA/MP or TG compared to active disease patients (p<0.01). This effect was not observed in the IBD groups in remission on other immunosuppressive therapy. Conclusion Rac1-corrected pSTAT3 expression in T-cells was significantly decreased in IBD patients in remission on thiopurine monotherapy compared to IBD patients with active disease, resulting in comparable values to healthy subjects. Rac1/pSTAT3 expression may serve as a potential, class specific pharmacodynamic marker to assess therapeutic efficacy of thiopurine monotherapy or as a marker to explain thiopurine resistance.