Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis.
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.
Tsujimura
S
S
The First Department of Internal Medicine, University of Occupational & Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu 807-8555 Japan.
Saito
K
K
Nawata
M
M
Nakayamada
S
S
Tanaka
Y
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood* / Q000187:drug effects; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D000069285:Infliximab; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D015415:Biomarkers; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D008727:Methotrexate