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类风湿关节炎患者外周血淋巴细胞P-糖蛋白的表达水平及逆转耐药作用的研究 被引量:6

Study of the expression of peripheral blood lymphocyte P-glycoprotein in rheumatoid arthritis patients and reversing P-glycoprotein-induced drug resistance
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摘要 目的检测耐药分子P-糖蛋白(P-dycoprotein)在类风湿关节炎(RA)患者外周血淋巴细胞的表达水平及相关影响因素,探讨周期联合甲氨蝶呤或来氟米特与环磷酰胺对P-糖蛋白介导耐药性的逆转作用。方法本研究为横断面研究,纳入RA患者42例,其中初发组15例,治疗组27例,根据治疗前后类风湿关节炎疾病活动性评分(DAS28)的变化,治疗组分为治疗缓解组12例和难治组15例。按治疗方案,分为单用药组(甲氨蝶呤或来氟米特)、甲氨蝶呤+来氟米特联合组,甲氨蝶呤或来氟米特+环磷酰胺联合组。用流式细胞术测定外周血淋巴细胞P-糖蛋白的表达水平。采用SPSS13.0进行统计分析,方法采用两独立样本t检验、单因素方差分析、Bonferroni法和LSD法、计数资料比较采用χ2检验,Pearson相关性分析。结果①健康对照组、初发组、缓解组、难治组相对荧光强度(RFI)平均值分别为2.0±0.7、2.9±1.0、3.5±1.4、5.0±2.0,4组间总体比较差异有统计学意义(F=7.955,P〈0.01)。两两比较:健康对照组与初发组差异无统计学意义(P=0.137),缓解组与难治组比较差异有统计学意义(P=0.013)。②RA患者P.糖蛋白与性别、发病年龄、病程、类风湿因子(RF)滴度均无相关性,与红细胞沉降率(ESR)及DAS28呈正相关(r=0.447,P=0.002;r=0.398,P=0.012);③单用药组(甲氨蝶呤或来氟米特)、甲氨蝶呤±来氟米特联合组,甲氨蝶呤或来氟米特+环磷酰胺联合组P—gP表达水平的RFI值分别为5.1±2.2、6.0±1.2、3.4±1.1,甲氨蝶呤或来氟米特+环磷酰胺联合组低于单用药组(P〈0.05),甲氨蝶呤+来氟米特联合组表达水平高于单用药组,但差异无统计学意义。结论RA患者外周血淋巴细胞P.糖蛋白的表达水平和疾病活动平行,改变病情抗风湿药(DMARDs)疗效下降与其表达水平增加有关。甲氨蝶呤或来氟米特+环磷酰胺联合治疗一定程度上逆转P-糖蛋白介导的耐药性。 Objective To study the expression of peripheral blood lymphocyte P-glycoprotein (P-gp) and related impact factors in rheumatoid arthritis (RA) patients, and explore whether the periodic combination of methotrexate (MTX) or leflunomide (LEF) with cyclophosphamide (CTX) could reverse P-gpinduced drug resistance. Methods This study was a cross-sectional study. Forty-two RA patients were enrolled ( 15 cases in the primary untreatment group, while 27 cases in the treatment group). In the treatment group, patients were divided into the improvement group (12 patients) and the refractory group (15 patients) respectively according to their disease activity scores (DAS 28). According to the medication used, 42 patients were divided into 3 groups:the monotherapy group (MTX or LEF), the MTX+LEF combination treatment group and MTX or LEF+CTX treatment group. The expression of peripheral blood lymphocyte P-gp in each group was detected by flow cytometry. T test, ANOVA, LSD test, Bonferroni test, χ2 test and Pearson correlation analysis were used for statistical analysis with software 13.0. Results ①) Mean relative fluorescence intensity (RFI) of P-gp was 2.0±0.7, 2.9±1.0, 3.5±1.4, 5.0±2.0 respectively in healthy control group, the primary untreatment group, the improvement group and the refractory group, the difference was signifi- cant (F=7.955, P〈0.01). In multiple comparisons, the fluorescence intensity was higher in the primary untrea-tment group as compared to the healthy group, but the difference was not statistically significant(P=0.137); however, it was significantly higher in the refractory group as compared to the improvement group (P=0.013). ② There was no correlation between the expression of P-gp in RA patients and sex, age of onset, disease duration or positive rate of RF. But the expression of P-gp was significantly correlated with ESR and DAS28 (r=0.447, P=0.002; r=0.398, P=0.012). ③ RFI of the P-gp group was 5.1±2.2, 6.0±1.2, 3.4±1.1 respectively in monotherapy group, MTX+LEF group and MTX/LEF+ CTX group (P〈0.05). The expression of P-gp was significantly lower in the MTX/LEF+CTX group as compared to the monotherapy group (P〈0.05), but higher in the MTX+LEF group (P〉0.05). Conclusion The expression of peripheral blood lymphocyte P-gp in RA is correlated with disease activity. The loss of efficacy in DMARDs is due to the enhanced expression of P-gp. Combination of methotrexate or leflunomide with cyclo-phosphamide reverses P-glycoproteininduced drug resistance.
出处 《中华风湿病学杂志》 CAS CSCD 北大核心 2013年第10期672-676,共5页 Chinese Journal of Rheumatology
基金 山西省科技攻关项目(20110313013-1) 山西省卫生厅科研课题计划(201201072)
关键词 关节炎 类风湿 P糖蛋白 甲氨蝶呤 环磷酰胺 抗药性 Arthritis rheumatoid P-glycoprotein Methotrexate Cyclophosphamide Drug resistance
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参考文献17

  • 1Numohamed MT, Dijkmans BA. Efficacy, tolerability and cost effectiveness of disease-modifying antirheumatic drugs and bio- logic agents in rheumatoid arthritis. Drugs, 2005, 65: 661-694.
  • 2Van der Heijden JW, Dijkmans BA, Scheper RJ, et al. Drug insight: resistance to methotrexate and other disease-modifying antirheumatic drugs-from bench to bedside. Nat Clin Pract Rheumatol, 2007, 3: 26-34.
  • 3王彩虹,李小峰,罗静,张改连,张琳,赵向聪.类风湿关节炎改变病情抗风湿药耐药性生物学标志研究进展[J].中华风湿病学杂志,2009,13(10):708-711. 被引量:4
  • 4Mittal N, Mittal R, Sharma A, et al. Treatment failure withdisease-modifying antirheumatic drugs in rheumatoid arthritis patients. Singapore Med J, 2012, 53: 532-536.
  • 5李小峰,张莉芸,牛红青,茹晋丽,王彩虹,高晋芳.甲氨蝶呤联合环磷酰胺治疗类风湿关节炎随机单盲对照临床研究[J].中华风湿病学杂志,2010,14(2):110-114. 被引量:22
  • 6Loo TW, Bartlett MC, Clarke DM, et al. Disulfide cross-linking analysis shows that transmembrane segments 5 and 8 of hu- man P-glycoprotein are close together on the cytoplasmic side of the membrane. J Biol Chem, 2004, 279: 7692-7697.
  • 7Lindqvist E, Saxne T, Geborek P, et al. Ten year outcome in a cohort of patients with early rheumatoid arthritis: health status, disease process, and damage. Ann Rheum Dis, 2002, 61 : 1055- 1059.
  • 8Morgan C, Lunt M, Brightwell H, et al. Contribution of patient related differences to multidrug resistance in rheumatoid arthritis. Ann Rheum Dis, 2003, 62: 15-19.
  • 9Agarwal V, Mittal SK, Misra R. Expression of muhidrug re- sistance-1 protein correlates with disease activity rather than the refractoriness to methotrexate therapy in rheumatoid arthritis. Clin Rheumatol, 2009, 28: 427-433.
  • 10Tsujimura S, Saito K, Nawata M, et al. Overcoming drug re- sistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis. Ann Rheum Dis, 2008, 67: 380-388.

二级参考文献51

  • 1Trentham DE, Townes AS, Kang AH. Autoimmunity to type Ⅱ collagen an experimental model of arthritis. J Exp Med, 1977, 146: 857-868.
  • 2Schett G, Middleton S, Bolon B, et al . Additive bone-protective effects of anabolic treatment when used in conjunction with RANKL and tumor necrosis factor inhibition in two rat arthritis models .Arthritis Rheum, 2005,52: 1604-1611.
  • 3Rantalaiho V, Korpela M, Hannonen P, et al. The good initial response to therapy with a combination of traditional diseasemodifying antirheumatie drugs is sustained over time: the elevenyear results of the Finnish rheumatoid arthritis combination therapy trial. Arthritis Rheum ,2009,60:1222-1231.
  • 4Verschueren P, Esselens G, Westhovens R. Daily practice effectiveness of a step-down treatment in comparison with a tight step-up for early rheumatoid arthritis. Rheumatology (Oxford), 2008, 47: 59-64.
  • 5Sethi G, Ahn KS, Sandur SK, et al. Indirubin enhances TNF- induced apoptosis through modulation of nuclear factor-kappa B signaling pathway. J Biol Chem, 2006, 281: 23425-23435.
  • 6Fleischmann RM. Is there a need for new therapies for rheumatoid arthritis? J Rheumatol, 2005, 73 Suppl: S3-S7.
  • 7Galindo-Rodriguez G, Avina-Zubieta JA, Russell AS, et al. Disappointing hongterm results with disease modifying antirheumatic drugs: a practice based study. J Rheumatol, 1999, 26: 2337- 2343.
  • 8Choy EH, Smith C, Dore C J, et al. A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology (Oxford), 2005, 44: 1414-1421.
  • 9Nurmohamed MT, Dijkmans BA. Efficacy, tolerability and cost effectiveness of disease-modifying antirheumatic drugs and biologic agents in rheumatoid arthritis. Drugs, 2005, 65: 661-694.
  • 10Aletaha D, Smolen JS. Effectiveness profiles and dose dependent retention of traditional disease modifying antirheumatic drugs for rheumatoid arthritis: an observational study. J Rheumatol, 2002, 29: 1631-1638.

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