P-糖蛋白与类风湿关节炎多药耐药的相关研究

The association analysis of P-gp with Mltidrug resistance in rheumatoid arthritis

目的检测P-糖蛋白（P—gP）在类风湿关节炎（RA）初发未治组、治疗有效组及难治组患者外周血淋巴细胞上的表达，分析RA患者的病程、用药时间与P—gP表达水平的关系，探讨P—gp与难治性RA多药耐药的相关性和难治性RA多药耐药形成的可能机制。方法按照入组标准收集健康人20名，RA初发未治组、治疗有效组及难治组各20例。采用流式细胞仪间接免疫荧光法检测外周血淋巴细胞P—gP。分析P—gP表达水平与RA治疗有效组及难治组患者的病程和用药时间的相关性。所有数据经t检验、单因素方差分析和直线相关分析进行统计学处理。结果RA初发未治组外周血淋巴细胞P—gP荧光值（4．26±0．74）表达与健康对照组（4．03±0．34）相比无明显增加，2组间差异无统计学意义（t=1．26，P〉0．05）；RA治疗有效组外周血淋巴细胞P—gP荧光值（6．74±0．23）表达与健康对照组及RA初发未治组相比有轻度增加，差异有统计学意义（t=21．20，P〈0．05）；RA难治组外周血淋巴细胞P—gp荧光值（13．10±0．33）表达与健康对照组、RA初发未治组及RA治疗有效组相比有明显增加，差异有统计学意义（t=85．60，P〈0．05）；P—gP表达水平与RA患者的病程、用药时间均无相关性（r=0．380，P〉0．05）。结论RA患者未接受改善病情抗风湿药（DMARDs）治疗前P—gP耐药蛋白表达无增高；甲氨蝶呤、来氟米特在治疗RA的同时，可诱导患者外周血淋巴细胞上的P—gp表达升高，导致RA患者耐药；P—gp参与难治性RA多药耐药，可能是难治性RA多药耐药形成机制之一；RA患者外周血淋巴细胞P—gp表达水平与病程和用药年限无明显关联。

Objective To detect the P-glycoprotein （P-gp） expression of peripheral blood lymphocytes in rheumatoid arthritis （RA） in early untreated group, treatment group and the refractory patients and analyze the association between the course of RA patients the P-gp expression levels and drug resistance as well as to explore the possible mechanisms of muhidrug resistance in refractory RA. Methods Patients were divided into RA in early untreated group, treatment group and 20 cases of refractory group based on the standard of sample enrollcment. Flow cytometry withindirect immunofluorescenee assay was used to measure the peripheral blood lymphocytes P-gp. The association between P-gp expression level and the effectiveness of the treatment group and the refractory RA group and the duration of treatment was carried out. All the data were analysis by t test, one-way ANOVA and linear correlation. Results The peripheral blood lymphocytes P-gp expression fluorescence value of the RA early untreatedgroup （4.26±0.74） was significantly increased when compared to the normal control group （4.03±0.34）（t=1.26, P〉0.05）. The peripheral blood lymphocyte P-gp expression fluorescence value of the RA treatment group （6.74±0.23） was mildly increased when compared with the normal control group and untreated early RA group, but the difference was significant （t= 21.20, P〈0.05）. The peripheral blood lymphocytes P-gp expression fluorescence value of the RA refractorygroup （13.10±0.33） were markedly increased when compared with that of the normal control group,the untreated early RA group and RA treatment group and the difference was significant （t=85.60, P〈0.05）. The P-gp expression levels and the course of disease in patients with RA was not correlated with the duration of treat-ment （r=0.380, P〉0.05）. Conclusion The expression level of the P-gp of the peripheral blood mononuclear cells of the early RA untreated patients is not significantly increased compared with the control group. For those patients who did not receive prompt treatment did not develop resistance. Methotrexate, leflunomide in the treatment of rheumatoid arthritis can induce the expression of P-glyeoprotein in the peripheral blood lymphocytes which in turn leading to drug-resistance. P-gp is involved in the multi-drug resistance of refractory RA and may be one of the possible mechanisms. The P-gp expression level of the peripheral blood lymphocytes in patients with RA is not associated with the duration of drug treatment.