Rheumatoid Arthritis Disease Activity Is Determinant for ABCB1 and ABCG2 Drug-Efflux Transporters Function

Abstract

ObjectiveTo compare drug efflux function of ABCB1 and ABCG2 transporters in rheumatoid arthritis (RA) patients with active disease and in remission.MethodsTwenty two active RA patients (DAS28 ≥3.2) and 22 patients in remission (DAS28<2.6) were selected from an early RA clinic. All patients were evaluated at study inclusion and six months later. ABCB1 and ABCG2 functional activity was measured in peripheral lymphocytes by flow cytometry. The percentage of cells able to extrude substrates for ABCB1 and ABCG2 was recorded.ResultsActive patients had higher ABCB1 and ABCG2 activity compared with patients in remission (median [interquartile range]): 3.9% (1.4–22.2) vs (1.3% (0.6–3.2), p = 0.003 and 3.9% (1.1–13.3) vs 0.9% (0.5–1.9) p = 0.006 respectively. Both transporters correlated with disease activity assessed by DAS28, rho = 0.45, p = 0.002 and rho = 0.47, p = 0.001 respectively. Correlation was observed between the time from the beginning of treatment and transporter activity: rho = 0.34, p = 0.025 for ABCB1 and rho = 0.35, p = 0.018 for ABCG2. The linear regression model showed that DAS28 and the time from the onset of treatment are predictors of ABCB1 and ABCG2 functional activity, even after adjustment for treatment. After six months we calculated the correlation between change in DAS28 and change in the functional activity in both transporters and found a moderate and significant correlation for ABCG2 (rho = 0.28, p = 0.04) and a non-significant correlation for ABCB1 (rho = 0.22, p = 0.11).ConclusionsPatients with active RA have an increased function of ABCB1 and ABCG2, and disease activity is the main determinant of this phenomena.

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“…As an efflux transporter, BCRP is highly expressed in apical epithelium of small intestine and colon, which can restrict the absorption of its substrates 42 . Recent studies have shown the importance of BCRP in diabetes 43 , rheumatoid arthritis 44 and various cancers 45 , 46 .…”

Reverse Microbiomics: A New Reverse Dysbiosis Analysis Strategy and Its Usage in Prediction of Autoantigens and Virulent Factors in Dysbiotic Gut Microbiomes From Rheumatoid Arthritis Patients

“…In humans, over 20 ABC transporters, covering all sub-families, have been found to associate with human diseases (Theodoulou and Kerr, 2015). Several ABC transporters also play an important role in drug metabolism and resistance (Atisha-Fregoso et al, 2016). The role of eukaryotic ABC transporters in RA has been studied for almost two decades (Marki-Zay et al, 2013).…”

“…with drug resistance, disease activity, and progressive destructive arthritis with extra-articular involvement in RA (Atisha-Fregoso et al, 2016;Pascual-Ramos et al, 2016). P-glycoprotein (Pgp), a member of the eukaryotic ABC transporter superfamily, can stimulate CXCR4-overexpressing B cells, and produce rheumatoid factor and various inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin (IL)-6, and present antigens to T cells in RA (Tsujimura et al, 2018).…”

Rationales for discontinuation of disease-modifying antirheumatic drugs, biologic agents, and tofacitinib in rheumatoid arthritis

“…К сожалению, не так много работ, в которых анализируются детерминанты функциональной активности этих транспортеров при РА, в большинстве из них изучали ABCB1. Специальное исследование показало, что у больных активным РА повышена функция ABCB1 и ABCG2 и активность болезни тесно связана с этим феноменом [29].…”