甲氨蝶呤或来氟米特联合环磷酰胺治疗类风湿关节炎的临床研究及对外周血白细胞介素-6核因子κB受体活化因子配体表达的影响

Effect of Methotrexate or Leflunomide combined with Cyclophosphamide on expression levels of IL-6 and RANKL in treatment of rheumatoid arthritis: a clinical study

目的探讨白细胞介素-6(IL-6)、核因子κB受体活化因子配体(RANKL)与类风湿关节炎(RA)疾病活动性及骨破坏的关系,阐明周期特异性药物甲氨蝶呤(MTX)或来氟米特(LEF)联合周期非特异性药物(环磷酰胺CTX)小剂量间歇给药治疗类风湿关节炎(RA)的优势及作用机制。方法选取活动期RA 37例及健康对照9名,随机分为甲氨蝶呤组(MTX 10 mg/周)及来氟米特组(LEF 10 mg/日),治疗12周。若12周后临床缓解,继续单用药。若未缓解,进入联合组:MTX+CTX组、LEF+CTX组及MTX+LEF组。MTX和LEF剂量不变,CTX剂量为400 mg 1次/3周,静脉滴注,观察至24周。于第0、12、24周留取各治疗组临床资料,进行DAS28评分及Sharp评分。检测IL-6及RANKL水平。结果与健康对照组相比,RA患者外周血中IL-6、RANKL水平明显增高(P<0.05)。5个治疗组治疗前后比较:(1)治疗24周后各组DAS28评分均低于基线值(P<0.05)。(2)治疗24周各治疗组Sharp评分均较基线值无明显增加(P>0.05)。(3)24周时,MTX+CTX组及LEF+CTX组的外周血IL-6及RANKL水平均较第0周降低(P<0.05);MTX+CTX组及LEF+CTX组的IL-6及RANKL水平低于MTX+LEF组,差异无统计学意义(P>0.05)。(4)外周血IL-6水平与ESR、DAS28评分呈正相关(P<0.01);(5)外周血RANKL水平与Sharp评分无明显正相关(P>0.05);(6)外周血IL-6水平与RANKL水平呈正相关(P<0.01)。结论外周血IL-6水平可作为判断RA疾病活动性指标之一;联合用药对单用药无效的RA患者仍有治疗作用。

Objective To investigate the relationship between interleukin-6(IL-6),receptor activator of nuclear factor-κB ligand(RANKL)and disease activity of rheumatoid arthritis(RA)and joint destruction,and to identify the advantage and mechanism of low-dose intermittent administration of cell cycle phase-specific drugs[Methotrexate(MTX)or Leflunomide(LEF)]combined with cell cycle phase-nonspecific drugs[Cyclophosphamide(CTX)]in the treatment of RA.Methods Thirty-seven with active RA and nine healthy controls were included in the study.The patients were randomly divided into the MTX group(10 mg/week)and the LEF group(10 mg/week)for 12-week treatment.For patients with clinical remission at 12 weeks,drug monotherapy was continued,otherwise combination therapy was given by groups:MTX+CTX group,LEF+CTX group and MTX+LEF group.The doses of MTX and LEF were unchanged,and the dose of CTX was 400 mg once/3 weeks with intravenous drip,and the effect was followed up until 24 weeks.The clinical data in each treatment group were obtained at 0,12,and 24 weeks,and the DAS28 score and Sharp score were assessed.The IL-6 and RANKL levels were measured.Results Compared with the healthy control group,the levels of IL-6 and RANKL in peripheral blood of RA patients significantly increased(P<0.05).Comparison between 5 treatment groups before and after the treatment:①The DAS28 score at 24 weeks after the treatment in each group was lower than that at the baseline(P<0.05).②There was no significant increase in the Sharp score of each treatment group at 24 weeks after the treatment compared with that at he baseline(P>0.05).③At 24 weeks,the levels of IL-6 and RANKL in peripheral blood of MTX+CTX group and LEF+CTX group decreased compared with those at 0week(P<0.05).The levels of IL-6 and RANKL in MTX+CTX group and LEF+CTX group were lower than those in MTX+LEF group,butwith no statistically significant differences(P>0.05).④The IL-6 level inperipheral blood was positively correlated with ESR and DAS28 scores(P<0.01).⑤There was no significant positive correlation between RANKL level in peripheral blood and Sharp score(P>0.05).⑥The IL-6 level was positively correlated with RANKL level inperipheral blood(P<0.01).Conclusion Peripheral blood IL-6 level may be used as one of the indicators to evaluate the activity of RA disease.The combination therapy is effective for RA patients who are resistant to single drug.