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Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis
  1. Shizuyo Tsujimura (s35-a721{at}med.uoeh-u.ac.jp)
  1. University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan
    1. Kazuyoshi Saito (kazu-s{at}med.uoeh-u.ac.jp)
    1. University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan
      1. Masao Nawata
      1. University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan
        1. Shingo Nakayamada
        1. University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan
          1. Yoshiya Tanaka (tanaka{at}med.uoeh-u.ac.jp)
          1. University of Occupational & Environmental Health, Japan

            Abstract

            Objective: P-glycoprotein (P-gp), a member of ATP-binding cassette transporters, causes drug-resistance by exclusion of intracellular drugs. Here we elucidated 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 disease activity score (DAS) 28-3 of > 5.1 despite taking at least two 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 corticosteroids and disease modifying antirheumatic drugs (DMARDs) of 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 suitable for selecting infliximab or DMARDs including tacrolimus for RA.

            • P-glycoprotein
            • Rheumatoid arthritis
            • disease activity
            • drug resistance
            • lymphocyte

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