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Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis
  1. S Tsujimura,
  2. K Saito,
  3. M Nawata,
  4. S Nakayamada,
  5. Y Tanaka
  1. The First Department of Internal Medicine, University of Occupational & Environmental Health, School of Medicine, Kitakyushu, Japan
  1. Professor Y Tanaka, The First Department of Internal Medicine, University of Occupational & Environmental Health, School of Medicine, 1–1 Iseigaoka, Yahata-nishi, Kitakyushu 807–8555 Japan; tanaka{at}med.uoeh-u.ac.jp

Abstract

Objective: P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, causes drug resistance by exclusion of intracellular drugs. Here, we elucidate the clinical relevance of P-gp expression on lymphocytes to drug resistance in patients with rheumatoid arthritis (RA).

Methods: P-gp expression on lymphocytes from 20 normal volunteers and 100 RA patients was analysed by flow cytometry. Drug exclusion analysis of lymphocytes was conducted by radioisotope-labelled dexamethasone.

Results: P-gp was overexpressed on RA lymphocytes compared with normal lymphocytes. P-gp expression levels were higher in partial responders with a Disease Activity Score (DAS) 28-3 of >5.1 despite taking at least two disease-modifying antirheumatic drugs (DMARDs) or one DMARD and corticosteroids for at least 2 years. P-gp expression levels correlated with DAS28-3. Intracellular dexamethasone levels (IDLs) in RA lymphocytes decreased according to P-gp expression. Tacrolimus, a P-gp inhibitor, restored IDLs in RA lymphocytes. P-gp overexpression in patients with highly active RA was suppressed by methotrexate but enhanced by corticosteroids. Furthermore, infliximab (3 mg/kg) resulted in improvement of RA disease activity, reduction of P-gp and recovery of IDLs.

Conclusions: P-gp overexpression on lymphocytes might cause efflux of corticosteroids and DMARDs, P-gp substrates, from lymphocytes, resulting in drug resistance in patients with highly active RA. P-gp inhibition/reduction could overcome such drug resistance. Measurement of P-gp expression on lymphocytes could be a potentially useful marker for assessing drug resistance in RA, and may be suitable for selecting infliximab or DMARDs including tacrolimus for RA treatment.

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Footnotes

  • Funding: This work was supported in part by a Research Grant-In-Aid for Scientific Research by the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan and University of Occupational and Environmental Health, Japan.

  • Competing interests: None declared.

  • Tacrolimus was kindly donated by Fujisawa. Co., Osaka, Japan.

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