Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide.

Abstract

OBJECTIVE:

To determine whether multidrug-resistance efflux transporters are expressed on immune effector cells in synovial tissue from patients with rheumatoid arthritis (RA) and compromise the efficacy of methotrexate (MTX) and leflunomide (LEF).

METHODS:

Synovial tissue biopsy samples obtained from RA patients before treatment and 4 months after starting treatment with MTX (n = 17) or LEF (n = 13) were examined by immunohistochemical staining and digital image analysis for the expression of the drug efflux transporters P-glycoprotein, multidrug resistance-associated protein 1 (MRP-1) through MRP-5, MRP-8, MRP-9, and breast cancer resistance protein (BCRP), and the relationship to clinical efficacy of MTX and LEF was assessed.

RESULTS:

BCRP expression was observed in all RA synovial biopsy samples, both pretreatment and posttreatment, but not in control noninflammatory synovial tissue samples from orthopedic patients. BCRP expression was found both in the intimal lining layer and on macrophages and endothelial cells in the synovial sublining. Total numbers of macrophages in RA patients decreased upon treatment; in biopsy samples with persistently high macrophage counts, 2-fold higher BCRP expression was observed. Furthermore, median BCRP expression was significantly increased (3-fold) in nonresponders to disease-modifying antirheumatic drugs (DMARDs) compared with responders to DMARDs (P = 0.048). Low expression of MRP-1 was found on synovial macrophages, along with moderate expression in T cell areas of synovial biopsy specimens from one-third of the RA patients.

CONCLUSION:

These findings show that the drug resistance-related proteins BCRP and MRP-1 are expressed on inflammatory cells in RA synovial tissue. Since MTX is a substrate for both BCRP and MRP-1, and LEF is a high-affinity substrate for BCRP, these transporters may contribute to reduced therapeutic efficacy of these DMARDs.

• Authors: Joost W van der Heijden, Ruud Oerlemans, Paul P Tak, Yehuda G Assaraf, Maarten C Kraan, George L Scheffer, Conny J van der Laken, Willem F Lems, Rik J Scheper, Ben A C Dijkmans, Gerrit Jansen
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 60 Issue 3 Pg. 669-77 (Mar 2009) ISSN: 0004-3591 [Print] United States
• PMID: 19248091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antirheumatic Agents
• Isoxazoles
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Leflunomide
• multidrug resistance-associated protein 1
• Methotrexate

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Antirheumatic Agents (pharmacology)
• Arthritis, Rheumatoid (drug therapy, metabolism)
• Biopsy
• Case-Control Studies
• Drug Resistance, Multiple (physiology)
• Endothelial Cells (metabolism, pathology)
• Humans
• Isoxazoles (pharmacology)
• Leflunomide
• Macrophages (metabolism, pathology)
• Methotrexate (pharmacology)
• Multidrug Resistance-Associated Proteins (metabolism)
• Neoplasm Proteins (metabolism)
• Synovial Membrane (metabolism, pathology)