Multidrug Transporters Of Peripheral Lymphocytes Serve As Biomarkers To Bdmard Response In Rheumatoid Arthritis (Ra)

Background: Multidrug resistance transporters (MDR-ABC transporters, namely MDR1, MRP1 and BCRP) play essential role in the homeostasis of a variety of endogenous molecules, proinflammatory mediators among them [1]. When the regulation of this phenomenon is disturbed, cell migration, proliferation and inflammatory processes are over activated which finally results in the pathogenesis of RA. Moreover, enhanced function of MDR proteins leads to multidrug resistance [2]. Objectives: In our multicenter, multinational clinical trial we aimed to assess the predictive value of flow cytometry-based multidrug resistance activity measurement of the previously mentioned MDR proteins for bDMARD response in RA in CD3+ and CD19+ lymphocytes before and as well as 4 to 6 and 12 weeks after initiation of bDMARD therapy. Methods: Peripheral blood samples were collected from 27 bDMARD responders and 12 non-responder RA patients at the indicated time points. Multidrug activity factors (MAFs) were measured from CD3+ and CD19+ lymphocytes by using SOLVO MDQ Kit™. Cut-off values were determined by using ROC curve analysis. Results: Before starting bDMARD therapy, MAFC and MAFMDR1 values of CD3+ cells were higher in non-responders as compared with responders. Six weeks after starting therapy, the same pattern was detected in case of MAFc, MAFMDR1 and MAFMRP1 in both investigated cell types. ROC analysis revealed that when MAFC value is higher than 21.3 in CD3+ cells before starting bDMRAD therapy are likely to be non-responders. At later time points, MAFC values above 20.3 and MAFMRP1 above 6.0 and MAFMDR1 values above 13.9 in CD3+ cells also predict unfavourable treatment response. Of note, these cut-off values are all below the respective reference ranges in healthy individuals established in our earlier study [3]. Conclusion: Importantly, little is known about the relation of MDR activities and therapeutic success to bDMARDs. Proinflammatory mediators and cytokines may serve as an interface between pharmacological activity of bDMARDS and MDR transporters [4-6]. References [1] Fletcher, J.I., et al., ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer, 2010. 10(2): p.147-56. [2] Marki-Zay, J., et al., MDR-ABC transporters: biomarkers in rheumatoid arthritis. Clin Exp Rheumatol, 2013. 31(5): p.779-87. [3] Szeremy, P., et al., Determination of reference values of MDR-ABC transporter activities in CD3+ lymphocytes of healthy volunteers using a flow cytometry based method. Cytometry B Clin Cytom, 2018. [4] Garcia-Carrasco, M., et al., P-glycoprotein in autoimmune rheumatic diseases. Autoimmun Rev, 2015. 14(7): p.594-600. [5] Ghandadi, M. and A. Sahebkar, Interleukin-6: A Critical Cytokine in Cancer Multidrug Resistance. Curr Pharm Des, 2016. 22(5): p.518-26. [6] Ronaldson, P.T., T. Ashraf, and R. Bendayan, Regulation of multidrug resistance protein 1 by tumor necrosis factor alpha in cultured glial cells: involvement of nuclear factor-kappaB and c-Jun N-terminal kinase signaling pathways. Mol Pharmacol, 2010. 77(4): p.644-59. Disclosure of Interests: None declared