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.
- Rheumatoid arthritis
- disease activity
- drug resistance