Tacrolimus, a Calcineurin Inhibitor, Overcomes Treatment Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

Abstract

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. (First Release Jan 15 2010;

Disease control by regulation of P-glycoprotein on lymphocytes in patients with rheumatoid arthritis

“…In our clinical trial, we experienced refractory patients with high disease activity who were treated with lowdose cyclosporine or tacrolimus and showed significant improvement of clinical features within two weeks, which was not accompanied by falls in Pgp expression levels on lymphocytes [30] . One representative case was a 56yearold woman with Pgpoverexpressing lymphocytes.…”

Long-term therapeutic effects and safety of tacrolimus added to methotrexate in patients with rheumatoid arthritis

“…*p \ 0.05, compared with 0 months Rheumatol Int including MTX and glucocorticoids. Previous studies have revealed that the high P-gp expression by the lymphocytes of RA patient is related to a high DAS score and that TAC and cyclosporine-A overcome the treatment unresponsiveness mediated by P-gp [20][21][22]. Therefore, we believe that, because patients with a high DAS score despite MTX treatment had the possibility of having high P-gp activity, the patients with higher DAS scores would experience a better treatment response to TAC, including improvement of intracellular accumulation of concurrent drugs, such as MTX.…”

Successful Treatment of Class IV+V Lupus Nephritis with Combination Therapy of High-dose Corticosteroids, Tacrolimus and Intravenous Cyclophosphamide

“…The other mechanism of tacrolimus depends on its inhibitory effects on Pglycoprotein, which accelerate to excrete concomitant drugs from the inside of cells. Therefore, tacrolimus can restore the intracellular therapeutic levels of corticosteroids, thereby leading to the improvement of LN (29). A previous study showed that treatment with angiotensin receptor blockers reduces proteinuria in conjunction with immunosuppressive therapy in patients with LN (30).…”