High MDR1 expression in rheumatoid arthritis is associated with increased MMP-3 levels and use of bDMARDs: potential independence of JAK inhibitors from MDR1

Abstract Objectives To identify patient-related factors linked to high multidrug resistance gene 1 (MDR1) expression in rheumatoid arthritis (RA) and assess whether MDR1 expression affects Janus kinase (JAK) inhibitor effectiveness. Methods Synovial tissues were obtained from 53 RA patients undergoing total knee arthroplasty between October 2020 and June 2024, with 41 included in the primary analysis after exclusion. MDR1 expression was measured by reverse transcription polymerase chain reaction (RT-PCR). Correlations with clinical characteristics were evaluated using Pearson’s correlation and multiple regression analyses. For secondary analysis, patients with six highest and six lowest MDR1 expression levels were compared. Fibroblast-like synoviocytes from these patients were cultured after treatments with JAK inhibitors (tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib), bucillamine, or the P-glycoprotein inhibitor verapamil, and expression of matrix metalloproteinases, inflammatory cytokines, and angiogenic factors was quantified by RT-PCR. Results High MDR1 expression significantly correlated with elevated serum MMP-3 levels (β = –0.0010; 95% confidence interval (CI), –0.0019 to –0.0001; p= 0.030) and increased use of biologic disease-modifying antirheumatic drugs (bDMARDs) (β = –0.406; 95% CI, –0.727 to –0.086; p= 0.015). In vitro, bucillamine suppressed MMP1, MMP3, ICAM1, and MCP1 expression less effectively in the high-MDR1 group, an effect reversed by verapamil. In contrast, all JAK inhibitors consistently suppressed cytokine expression regardless of MDR1 status. Conclusion High MDR1 expression correlates with elevated MMP-3 levels and more frequent bDMARDs use. JAK inhibitors remain effective regardless of MDR1 status, potentially bypassing MDR1-mediated cellular drug resistance in RA.