Relevance of P-glycoprotein on CXCR4⁺ B cells to organ manifestation in highly active rheumatoid arthritis

Abstract

Introduction: In rheumatoid arthritis (RA), P-glycoprotein (P-gp) expression on activated B cells is associated with active efflux of intracellular drugs, resulting in drug resistance. CXCR4 is associated with migration of B cells. This study was designed to elucidate the relevance of P-gp expression on CXCR4⁺ B cells to clinical manifestations in refractory RA.

Methods: CD19⁺ B cells were analyzed using flow cytometry and immunohistochemistry.

Results: P-gp was highly expressed especially on CXCR4⁺CD19⁺ B cells in RA. The proportion of P-gp-expressing CXCR4⁺ B cells correlated with disease activity, estimated by Simplified Disease Activity Index (SDAI), and showed marked expansion in RA patients with high SDAI and extra-articular involvement. In highly active RA, massive infiltration of P-gp⁺CXCR4⁺CD19⁺ B cells was noted in CXCL12-expressing inflammatory lesions of RA synovitis and RA-associated interstitial pneumonitis. In RA patient with active extra-articular involvement, intracellular dexamethasone level (IDL) in lymphocytes diminished with expansion of P-gp⁺CXCR4⁺ CD19⁺ B cells. Adalimumab reduced P-gp⁺CXCR4⁺ CD19⁺ B cells, increased IDL in lymphocytes, and improved the clinical manifestation and allowed tapering of concomitant medications.

Conclusions: Expansion of P-gp⁺CXCR4⁺ B cells seems to be associated with drug resistance, disease activity and progressive destructive arthritis with extra-articular involvement in RA.

Keywords:

• P-glycoprotein
• CXCR4
• B cell
• rheumatoid arthritis

Acknowledgements

The authors thank Yasuyuki Sasaguri for the instructions on immunohistochemical analysis.

Conflict of interest

Y. Tanaka has received consulting fees, speaking fees, and/or honoraria from Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB, GlaxoSmithKline, Bristol-Myers and has received research grants from Mitsubishi-Tanabe, Chugai, MSD, Astellas, and Novartis. All other authors declare no conflict of interest.

Additional information

Funding

This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, Japan Agency for Medical Research and Development, and the University of Occupational and Environmental Health, Japan, through UOEH Grant for Advanced Research. Y. Tanaka has received speaking fees, and/or honoraria from Daiichi-Sankyo, Astellas, Pfizer, Mitsubishi-Tanabe, Bristol-Myers, Chugai, YL Biologics, Eli Lilly, Sanofi, Janssen, UCB and has received research grants from Mitsubishi-Tanabe, Takeda, Bristol-Myers, Chugai, Astellas, Abbvie, MSD, Daiichi-Sankyo, Pfizer, Kyowa- Kirin, Eisai, Ono.