RESEARCH - Involvement of BCRP on RA synovial tissue macrophages in resistance to MTX and LEF

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Arthritis Rheum. 2009 Feb 26;60(3):669-677.

Involvement of breast cancer resistance protein expression on

rheumatoid arthritis synovial tissue macrophages in resistance to

methotrexate and leflunomide.

van der Heijden JW, Oerlemans R, Tak PP, Assaraf YG, Kraan MC,

Scheffer GL, van der Laken CJ, Lems WF, Scheper RJ, Dijkmans BA,

Jansen G.

VU University Medical Center, Amsterdam, The Netherlands.

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.

PMID: 19248091

http://www.ncbi.nlm.nih.gov/pubmed/19248091

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