Presentation: Tacrolimus Overcomes Treatment-Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis (2007)

1781 Tacrolimus Overcomes Treatment-Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

PURPOSE: Tacrolimus inhibits calcineurin-mediated lymphocyte signal transduction and is used as effective drug for rheumatoid arthritis (RA). At the same instant, tacrolimus also inhibits P-glycoprotein (P-gp) by its competitive binding to P-gp, which is product of multidrug resistance-1 (MDR-1) gene. P-gp expels various drugs including glucocorticoids and anti-rheumatic drugs (DMARD) from cytoplasm and is thought to involve in drug-resistance of several diseases. The aim of this study is to investigate the mechanisms of drug-resistance in and effect of tacrolimus on the resolution of drug resistance in RA patients, shedding light upon P-gp.
METHODS. In 40 healthy subjects and 100 patients with active RA, P-gp expression levels on peripheral blood CD4+, CD8+ and CD19+ lymphocytes were measured by flow cytometric analysis. Intracellular dexamethasone levels were evaluated after in vitro incubation of peripheral lymphocytes with radiolabeled-dexamethasone to monitor the function of P-gp.
RESULTS. We initially examined the expression of P-gp using mAb against the MRK-16 epitope of P-gp on peripheral lymphocytes from RA patients and 40 normal volunteers. P-gp was significantly highly expressed on CD4+, CD8+ and CD19+ lymphocytes in patients with RA, although P-gp was not expressed on those of normal volunteers. Its expression was positively correlated disease activity score 28 (DAS28) of each patients. When radiolabeled-dexamethasone was added to lymphocytes in vitro, the intracellular dexamethasone levels were significantly decreased in lymphocytes in active RA, which were inversely correlated with disease activity, but they were improved by addition of tacroliums in a dose-dependent manner. Next, RA patients who were resistant to conventional DMARD were treated with additional use of tacrolimus (3mg/day). Add-on of tacrolimus resulted in a successful improvement of DAS28 scores and 16 among 80 patients were satisfied with a good response of EULAR criteria. Furthermore, P-gp expression was decreased after the treatment in accordance with an improvement of DAS28 scores and intracellular dexamethasone levels in vitro quickly recovered to the level of healthy individuals.
CONCLUSION: These findings indicate that expression of P-gp on lymphocytes was closely correlated with disease activity of RA and P-gp could be involved in the drug resistance of RA from in vitro and in vivo results. The levels of corticosteroid in lymphocytes from RA patients were significantly recovered by the addition of tacrolimus, an antagonist to P-gp, implying that P-gp could be involved in the induction of resistance to other substrate drugs such as sulfasalazine, chloroquine and many and that tacrolimus should overcome the drug resistance in refractory RA patients in a similar mechanisms.

 K. Suzuki, None; K. Saito, None; S. Tsujimura, None; S. Iwata, None; N. Sawamukai, None; Y. Tanaka, None.