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北京大学学报（医学版） ›› 2022, Vol. 54 ›› Issue (6): 1112-1116. doi: 10.19723/j.issn.1671-167X.2022.06.009

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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

邵苗1,郭惠芳2,雷玲彦2,赵清3,丁艳杰3,林进4,吴锐5,于峰6,李玉翠7,苗华丽7,张莉芸7,杜燕8,焦瑞英9,庞丽霞9,龙丽10,栗占国1,*(),李茹1,*()   

  1. 1. 北京大学人民医院风湿免疫科，北京 100044
    2. 河北医科大学第二医院风湿免疫科，石家庄 050000
    3. 河南大学淮河医院风湿免疫科，河南开封 475000
    4. 浙江大学医学院附属第一医院风湿免疫科，杭州 310003
    5. 南昌大学第一附属医院风湿免疫科，南昌 330006
    6. 北京大学第一医院肾内科，北京 100034
    7. 山西白求恩医院风湿免疫科，太原 030032
    8. 浙江大学医学院附属第二医院风湿免疫科，杭州 310009
    9. 呼伦贝尔市人民医院风湿免疫科，内蒙古呼伦贝尔 021008
    10. 四川省人民医院风湿免疫科，成都 610071
  • 收稿日期:2022-08-15 出版日期:2022-12-18 发布日期:2022-12-19
  • 通讯作者: 栗占国,李茹 E-mail:Li99@bjmu.edu.cn;doctorliru123@163.com
  • 基金资助:
    国家自然科学基金(32000639);国家自然科学基金(82171772);国家自然科学基金(81871281);北京大学人民医院研究与发展基金(RS2020-01)

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

Miao SHAO1,Hui-fang GUO2,Ling-yan LEI2,Qing ZHAO3,Yan-jie DING3,Jin LIN4,Rui WU5,Feng YU6,Yu-cui LI7,Hua-li MIAO7,Li-yun ZHANG7,Yan DU8,Rui-ying JIAO9,Li-xia PANG9,Li LONG10,Zhan-guo LI1,*(),Ru LI1,*()   

  1. 1. Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing 100044, China
    2. Department of Rheumatology and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
    3. Department of Rheumatology and Immunology, Huaihe Hospital of Henan University, Kaifeng 475000, Henan, China
    4. Department of Rheumatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
    5. Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
    6. Renal Division, Department of Medicine, Peking University First Hospital, Beijing 100034, China
    7. Department of Rheumatology and Immunology, Shanxi Bethune Hospital, Taiyuan 030032, China
    8. Department of Rheumatology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
    9. Department of Rheumatology and Immunology, Hulunbuir People's Hospital, Hulunbuir 021008, Inner Mongolia, China
    10. Department of Rheumatology and Immunology, Sichuan Provincial People's Hospital, Chengdu 610071, China
  • Received:2022-08-15 Online:2022-12-18 Published:2022-12-19
  • Contact: Zhan-guo LI,Ru LI E-mail:Li99@bjmu.edu.cn;doctorliru123@163.com
  • Supported by:
    the National Natural Science Foundation of China(32000639);the National Natural Science Foundation of China(82171772);the National Natural Science Foundation of China(81871281);Peking University People's Hospital Research and Development Funds(RS2020-01)

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摘要：

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1 022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/m2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。

关键词: 系统性红斑狼疮, 环磷酰胺, 不良反应

Abstract:

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 1 022 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/m2 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.

Key words: Systemic lupus erythematosus, Cyclophosphamide, Adverse events

中图分类号: 

  • R593.2

图1

两组应用不同剂量环磷酰胺的SLE患者停药原因比较"

表1

两组应用不同剂量环磷酰胺的SLE患者临床特征比较"

Items SILD IV-CYC(n=506) HD IV-CYC(n=256) P value
Female/male, n 463/43 234/22 1.000
Age/years, M(P25，P75) 40 (31, 51) 39 (30, 50) 0.699
Age/years, M(P25，P75) 32 (24, 43) 31.5 (23.0, 42.0) 0.421
CYC course/months, M(P25，P75) 6.0 (3.0, 10.63) 6.0 (4.0, 8.75) 0.471
Accumulated dose of CYC/g, M(P25，P75) 4.8 (2.4, 8.4) 5.6 (3.2, 8.0) 0.139
Lupus nephritis, M(P25，P75) 269 (53.16) 149 (58.20) 0.187
NPSLE, M(P25，P75) 70 (13.83) 30 (11.72) 0.414
Respiratory system, M(P25，P75) 65 (12.85) 23 (8.98) 0.115
Hematologic system, M(P25，P75) 136 (26.88) 58 (22.66) 0.206
Diabetes mellitus, M(P25，P75) 19 (3.75) 10 (3.91) 0.918
Hypertension, M(P25，P75) 92 (18.18) 60 (23.43) 0.086
Coronary heart disease, M(P25，P75) 12 (2.37) 4 (1.56) 0.462
Hyperlipemia, M(P25，P75) 24 (4.74) 17 (6.64) 0.273
Glucocorticoid dose/ (mg/d)，M(P25，P75) 20.0 (10.0, 45.0) 18.75 (10.0, 35.0) 0.089
HCQ, n (%) 450 (88.93) 221 (86.33) 0.295
SLEDAI, M(P25，P75) 6.0 (2.0, 9.0) 6.0 (2.0, 9.0) 0.316

表2

不同剂量环磷酰胺不良反应发生率的比较"

Adverse events Patients(n=762) SILD IV-CYC (n=506) HD IV-CYC (n=256) P values
n % n % n %
Infection 123 16.14 66 13.04 57 22.27 0.001*
Gastrointestinal reaction 168 22.05 88 17.39 80 31.25 < 0.001*
Myelosuppression 100 13.12 49 9.68 51 19.92 < 0.001*
Abnormal menstruation 127a 30.02 71b 25.18 56c 39.72 0.001*
Drug-induced hepatic injury 46 6.04 27 5.34 19 7.42 0.253
Hemorrhagic cystitis 4 0.52 3 0.59 1 0.39 1.000
Fatigue 46 6.04 33 6.52 13 5.08 0.429
Alopecia 117 15.35 68 13.44 49 19.14 0.039*
Rash 12 1.57 10 1.98 2 0.78 0.355
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