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

Abstract

Objective: To compare drug efflux function of ABCB1 and ABCG2 transporters in rheumatoid arthritis (RA) patients with active disease and in remission.

Methods: Twenty 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.

Results: Active 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).

Conclusions: Patients with active RA have an increased function of ABCB1 and ABCG2, and disease activity is the main determinant of this phenomena.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Representative flow cytometric analyses of daunorubicin and mitoxantrone extruding lymphocytes.

Panel A. Representative flow cytometric analyses of DNR extruding lymphocytes. The figure displays representative cytograms and their corresponding histograms obtained by cells incubated at 4°C (a) (negative control), 37°C (b) and 37°C (c) in the presence of verapamil. The non DNR-effluxing (fluorescent cluster at the right) and the DNR-effluxing (fluorescent cluster at the left) lymphocytes are clearly evident in either cytograms or histograms. (b): active RA patient with 46.5% lymphocytes able to extrude DNR; (c) Inhibitory effect of verapamil with only 22% of effluxing cells. Panel B. Representative flow cytometric analyses of mitoxantrone-extruding lymphocytes. The figure displays representative cytograms and their corresponding histograms obtained by cells incubated at 4°C (a) (negative control), 37°C (b) and 37°C (c) in the presence of KO143. The non-mitoxantrone effluxing-(fluorescence cluster at the right) and the mitoxantrone-effluxing (fluorescence cluster at the left) lymphocytes are clearly evident in either cytograms or histograms. b): active RA patient with 33.3% lymphocytes able to extrude mitoxantrone; (c) Inhibitory effect of KO143 with only 21.5% effluxing lymphocytes.

Fig 2. ABCB1 and ABCG2 transporters activity in active RA patients, in remission, and in those with recent diagnosis.

Shown are the percent effluxing lymphocytes from all patients studied in each group.