First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.
J Rheumatol. 2010 Mar;37(3):512-20. doi: 10.3899/jrheum.090048. Epub 2010 Jan 15.
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.
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).
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.
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.
他克莫司（一种钙调磷酸酶抑制剂）被用于治疗类风湿关节炎（RA）。它还可以抑制 P 糖蛋白的功能，而后者与药物耐药性有关。我们研究了他克莫司治疗 2 周内对 RA 患者早期应答的机制。
113 例对至少 3 种抗风湿药物（包括甲氨蝶呤）治疗无效的难治性 RA 患者接受他克莫司（1.5-3mg/d）治疗，并在治疗 2 周时评估应答情况。从 113 例患者和 40 例健康对照者采集外周血单个核细胞（PBMC），检测多药耐药（MDR-1）基因和 P 糖蛋白的表达。通过细胞/培养基中氚标记地塞米松的残留量（C/M 比值）来测量 P 糖蛋白的药物外排功能。
纳入患者的疾病活动度（DAS28 红细胞沉降率）为 5.8±1.2（均数±标准差）。113 例患者中有 22 例在治疗 2 周时对他克莫司有良好的应答。基线时，RA 患者的 PBMC 表现出 MDR-1 基因和 P 糖蛋白的上调表达以及低 C/M 比值。对他克莫司的应答与 P 糖蛋白表达和 C/M 比值相关。治疗 2 周后 C/M 比值显著改善。C/M 比值与 CD4+淋巴细胞上 P 糖蛋白表达显著相关。
他克莫司治疗的早期疗效取决于其对 P 糖蛋白药物外排功能的抑制作用，从而恢复细胞内皮质激素的治疗水平并改善临床症状。对淋巴细胞上 P 糖蛋白表达的评估可能有助于预测 RA 治疗的反应。
