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  • Title: Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis.
    Author: Suzuki K, Saito K, Tsujimura S, Nakayamada S, Yamaoka K, Sawamukai N, Iwata S, Nawata M, Nakano K, Tanaka Y.
    Journal: J Rheumatol; 2010 Mar; 37(3):512-20. PubMed ID: 20080907.
    Abstract:
    OBJECTIVE: Tacrolimus, a calcineurin inhibitor, is used for treatment of rheumatoid arthritis (RA). It also inhibits functions of P-glycoprotein, which is involved in drug resistance. We examined the mechanisms of early response to 2-week tacrolimus treatment in patients with RA. METHODS: One hundred thirteen patients with refractory RA despite at least 3 antirheumatic agents, including methotrexate, were treated with tacrolimus (1.5-3 mg/day) and the response was assessed at 2 weeks. Expression of the multidrug resistance (MDR-1) gene and P-glycoprotein was assessed in peripheral blood mononuclear cells (PBMC) collected from 113 patients and 40 healthy subjects. The drug exclusion function by the P-glycoprotein was measured by the residual amount of intracellular tritium-labeled dexamethasone cell/medium ratio (C/M ratio). RESULTS: The disease activity of enrolled patients was 5.8 +/- 1.2 (mean +/- SD) by DAS28 erythrocyte sedimentation rate. A good response to tacrolimus was noted at 2 weeks in 22 of 113 patients. At baseline, PBMC of patients with RA showed upregulated expression of MDR-1 gene and P-glycoprotein and low C/M ratio. The response to tacrolimus correlated with P-glycoprotein expression and C/M ratio. A significant improvement in C/M ratio was noted after 2 weeks of treatment. The C/M ratio correlated significantly with P-glycoprotein expression on CD4+ lymphocytes. CONCLUSION: Early efficacy of tacrolimus treatment depended on its inhibitory effect on the drug exclusion function of P-glycoprotein, leading to restoration of intracellular therapeutic levels of corticosteroids and clinical improvement. Evaluation of P-glycoprotein expression on lymphocytes is potentially useful for predicting the response to RA treatment.
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