短间期小剂量环磷酰胺治疗系统性红斑狼疮耐受性的多中心对照研究

A multicenter study on the tolerance of intravenous low-dose cyclophosphamide in systemic lupus erythematosus

目的:比较大剂量环磷酰胺及短间期小剂量环磷酰胺两种方案治疗系统性红斑狼疮(systemic lupus erythematosus,SLE)患者的耐受性。方法:收集2017年3月至2018年7月期间在全国17个省份24家医院就诊的1022例SLE患者的基本信息、临床表现、实验室检查结果、不良反应及伴随疾病等。根据静脉输注环磷酰胺的治疗方案分为短间期小剂量环磷酰胺组(short-interval low-dose intravenous cyclophosphamide therapy,SILD IV-CYC,每次400 mg,每2周1次)和大剂量环磷酰胺组(high-dose intravenous cyclophosphamide therapy,HD IV-CYC,每次500 mg/m 2体表面积,每月1次),有256例接受大剂量环磷酰胺治疗,506例接受短间期小剂量环磷酰胺治疗,比较两组患者停药原因及治疗过程中的不良反应发生率,另有260例患者因没有规律应用环磷酰胺未纳入两组治疗方案不良反应的比较。此外,377例接受短间期小剂量环磷酰胺治疗和214例接受大剂量环磷酰胺治疗的SLE患者随访到停用环磷酰胺,对其停药原因进行分析。结果:在所有591例停环磷酰胺的患者中,有199例(33.67%)SLE患者因发生药物相关不良反应停药,238例(40.27%)SLE患者因为病情改善而停用环磷酰胺。大剂量环磷酰胺治疗组的SLE患者中因不良反应停用环磷酰胺的比例为38.79%(83/214),明显高于短间期小剂量环磷酰胺治疗组的30.77%(116/377,P=0.048)。进一步比较506例接受短间期小剂量环磷酰胺治疗和256例接受大剂量环磷酰胺治疗患者的不良反应提示,短间期小剂量环磷酰胺治疗组感染(13.04%vs.22.27%,P=0.001)、胃肠道反应(17.39%vs.31.25%,P<0.001)、骨髓抑制(9.68%vs.19.92%,P<0.001)、月经异常(25.18%vs.39.72%,P=0.001)、脱发(13.44%vs.19.14%,P=0.039)等不良反应发生率明显低于大剂量环磷酰胺治疗组。结论:短间期小剂量环磷酰胺方案(SILD方案)治疗SLE的耐受性明显优于大剂量环磷酰胺治疗,患者不良反应的发生率较低。

Objective:To compare the safety of low-dose cyclophosphamide and high-dose cyclophosphamide in the treatment of systemic lupus erythematosus(SLE).Methods:A total of 1022 patients with systemic lupus erythematosus from 24 hospitals in China between March 2017 to July 2018 were enrolled.Their clinical manifestations,laboratory tests,adverse events,reasons for stopping receiving intravenous cyclophosphamide and comorbidities were collected.Among them,506 SLE patients received short-interval low-dose intravenous cyclophosphamide therapy(SILD IV-CYC,400 mg every two weeks),and 256 patients underwent high-dose cyclophosphamide therapy(HD IV-CYC,500 mg/m 2 of body surface area every month),the side effects between the two groups were compared,the remaining 260 SLE patients were treated with IV-CYC irregularly.Moreover,a total of 377 patients in SILD IV-CYC group and 214 patients in HD IV-CYC group had medical records of the reasons for stopping recei-ving IV-CYC.The reasons for stopping receiving IV-CYC in these two groups were analyzed.Results:In this study,only 40.27%(238/591)of the SLE patients stopped receiving intravenous cyclophosphamide for the causes of disease improvement,however,up to 33.67%(199/591)of the patients for the reason of drug-related side effects.There were 83 patients out of 214(38.79%)with high-dose intravenous cyclophosphamide treatment who stopped receiving IV-CYC for the drug-related side effects,which was significantly higher than that in the low-dose cyclophosphamide group(30.77%,116/337,P=0.048).Of theses 506 patients in SILD IV-CYC group,88(17.39%)patients experienced gastrointestinal reactions,66(13.04%)suffered from infections,49(9.68%)had myelosuppression and 68(13.44%)had alopecia,respectively.Among the 256 patients in the HD IV-CYC group,80(31.25%)experienced gastrointestinal reactions,57(22.27%)suffered from infections,51(19.92%)had myelosuppression and 49(19.14%)had alopecia.Moreover,71(25.18%)of 282 female patients with age between 16 to 45 years in SILD IV-CYC group had abnormal menstruation,while menstrual disorder occurred in 39.72%(56/141)patients of HD IV-CYC group.There was no difference of drug-induced hepatic injury,hemorrhagic cystitis and fatigue between the two groups.Conclusion:Low-dose cyclophosphamide showed a lower prevalence of adverse events than high-dose cyclophosphamide in systemic lupus erythematosus patients.