欢迎访问《中国循证儿科杂志》官方网站，今天是
English Version
中国循证儿科杂志

中国循证儿科杂志 ›› 2023, Vol. 18 ›› Issue (1): 13-20.DOI: 10.3969/j.issn.1673-5501.2023.01.002

• 论著 • 上一篇    下一篇

频复发/激素依赖肾病综合征儿童利妥昔单抗治疗1年以上随访情况的系统评价/Meta分析

刘佳璐1a，陈秋霞2，邵蕾霖1a，张崇凡1b，王慧珊1b，王颖雯1c，张爱华2，夏正坤3，沈茜1a，徐虹1a   

  1. 1复旦大学附属儿科医院肾脏科上海，201102，a 肾脏科，上海市肾脏发育和儿童肾脏病研究中心，b 复旦大学GRADE中心，c 护理部；2 南京医科大学附属南京儿童医院肾脏科南京，210093；3 中国人民解放军东部战区总医院南京，2100022
  • 收稿日期:2023-04-04 修回日期:2023-04-04 出版日期:2023-02-25 发布日期:2023-02-25
  • 通讯作者: 徐虹，沈茜

Over 1-year follow-up for children with frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome after receiving treatment of rituximab: A systematic review and meta-analysis

LIU Jialu1a, CHEN Qiuxia2, SHAO Leilin1a,  ZHANG Chongfan1b, WANG Huishan1b, WANG Yingwen1c, ZHANG Aihua2, XIA Zhengkun3, SHEN Qian1a, XU Hong1a   

  1. 1 Children's Hospital of Fudan University, Shanghai 201102, China, a Department of Nephrology, Shanghai Kidney Development and Pediatric Kidney Disease Research Center, b Fudan University GRADE Center, c Department of Nursing; 2 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210093, China; 3 General Hospital of the Eastern Theater of the Chinese People's Liberation Army, Nanjing 210002, China
  • Received:2023-04-04 Revised:2023-04-04 Online:2023-02-25 Published:2023-02-25
  • Contact: XU Hong,email:hxu@shmu.edu.cn；SHEN Qian,email:shenqian@shmu.edu.cn

PDF

376

补充材料

1

摘要： 背景：权威指南和共识均推荐将利妥昔单抗（RTX）应用于儿童激素敏感型肾病综合征（SSNS）中频复发/激素依赖肾病综合征（FRNS/SDNS）的治疗，但仍存在临床适应证不统一、治疗和随访方案多样等问题。 目的：了解RTX首疗程治疗缓解期FRNS/SDNS随访1年以上复发和激素使用情况结局。 设计：系统评价/Meta分析。 方法：检索PubMed、Embase、Cochrane、Scopus和中国生物医学文献服务系统数据库，从建库至2022年6月26日，以SSNS、FRNS、SDNS和 RTX构建中英文数据库检索式。同一篇文献初筛、全文筛选和证据提取均由2人完成，有争议和不确定的文献由第3人复核审查。纳入至少1组干预措施使用RTX治疗1~22岁SSNS患儿的研究。 主要结局指标:RTX干预后随访≥1年的复发率、首次复发时间，激素累积剂量和停用比例。 结果:符合本文临床结局的文献26篇（RCT 8篇、非随机对照试验 1篇、队列研究8篇、病例系列报告9篇），中文文献1篇，英文文献25篇。基于FRNS/SDNS病例的随访≥1年复发率的9项研究的Meta分析显示，RTX较对照组复发率下降了78%(OR=0.22，95%CI:0.09~0.53)，在FRNS/SDNS+（RTX干预前已使用其他免疫抑制剂）亚组病例中，RTX较对照组复发率下降了67%(OR=0.33，95%CI:0.12~0.94)，在FRNS/SDNS-（RTX干预前未使用其他免疫抑制剂）亚组病例中，RTX-（不联用其他并免疫抑制剂）较对照组复发率下降了85%(OR=0.15，95%CI:0.03~0.68)。基于20项研究的Meta分析显示，RTX复发率42% (95%CI:32%~53%)。基于FRNS/SDNS+随访≥1年首次复发时间的9项研究的Meta分析显示，首次复发时间9.89（95%CI: 7.14~12.65)月。基于FRNS/SDNS-开始干预至随访≥1年中位首次复发时间的3项研究的 Meta分析显示，RTX（1~2剂）较对照组中位首次复发时间长20 d，中位生存比（MSR）为0.69(95%CI:0.52~0.87）。基于FRNS/SDNS的12个月激素累积剂量减少结局的4项研究的Meta分析显示，RTX较对照组年激素累积剂量减少明显，差异有统计学意义(SMD=-1.12，95%CI:-1.49~-0.74)。基于FRNS/SDNS的随访3个月激素停用率的2项研究的Meta分析显示，RTX是对照组（CNI或CTX）随访3个月激素停用率的14.6倍 (OR=14.62，95%CI:5.43~39.39)。基于FRNS/SDNS+的RTX治疗6个月停用激素率的3项研究的Meta分析显示，停用激素率68%（95%CI:56%~79%）。 结论:与对照组相比，RTX从随访1年的首次复发时间中获益有限，可从激素减量中获益但不能从停用激素率中获益。RTX治疗FRNS/SDNS随访12个月较安慰剂治疗或空白对照至少可降低88%的复发率，FRNS/SDNS接受RTX治疗随访1年复发率43%。RTX治疗FRNS/SDNS+可获得10个月的无复发生存时间。

关键词: 肾病综合征, 利妥昔单抗, 免疫抑制剂, 复发, 激素

Abstract: Background：Authoritative clinical practice guidelines and expert consensus have recommended the use of rituximab (RTX) in the treatment of children with frequent relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) of steroid-sensitive nephrotic syndrome(SSNS). However, there is a discrepancy in terms of clinical indications, treatment, and follow-up protocols. Objective：To comprehensively examine relapse and steroid therapy during over one year follow-up in patients diagnosed with FRNS/SDNS who were administered the initial course of RTX while being in remission. Design：Systematic review and meta-analysis. Methods：Keywords of SSNS, FRNS, SDNS, and RTX were used to search China Biology Medicine Database, PubMed, Embase, Scopus, and Cochrane from the inception to June 26, 2022. The preliminary and full-text screening were conducted by two independent reviewers, who also extracted the relevant data. Unsure or controversial literature underwent a third-party review. At least one RTX intervention for children aged between 1 and 22 years with SSNS was included. Main outcome measures：The frequency of relapse, time to the first relapse, cumulative steroid dosage, and percentage of patients who withdrew from steroids in those who were followed-up for more than 1 year after receiving RTX intervention. Results：A total of 26 studies (1 in Chinese and 25 in English) were eligible including 8 randomized controlled trials (RCT), 1 non-randomized study of interventions (NRSI), 8 cohort studies, and 9 case series reports. Two subgroups were defined as FRNS/SDNS+ group in which immunosuppressants were used before RTX intervention and FRNS/SDNS- group in which no other immunosuppressants were used before RTX intervention. Meta-analysis of 9 studies on the relapse rate of FRNS/SDNS during at least 1-year follow-up showed a 78% reduction in the relapse rate of RTX compared to the control group (OR=0.22, 95%CI: 0.09 to 0.53). In FRNS/SDNS+ group， RTX reduced the relapse rate by 67 % compared to the control group (OR=0.33, 95%CI: 0.12 to 0.94). In FRNS/SDNS- group, RTX reduced the relapse rate by 85 % compared to the control group (OR=0.15, 95%CI: 0.03 to 0.68) in the absence of other immunosuppressants. Additionally, the meta-analysis of 20 studies indicated that the relapse rate after RTX was 42% (95% CI: 32 to 53). The meta-analysis of 9 studies on the time to the first relapse of FRNS/SDNS+ during at least 1-year follow-up indicated that the median time to the first relapse was 9.89 months (95%CI: 7.14 to 12.65). According to the meta-analysis of 3 studies on the median relapse free survival (RFS) from the initiation of FRNS/SDNS- to at least 1-year follow-up, RTX (1-2 doses) had a longer median RFS of 20 days compared to the control, with a median survival ratio (MSR) of 0.69 (95%CI: 0.52 to 0.87). The meta-analysis of four studies on the reduction of FRNS/SDNS cumulative steroid dose over a 1-year period found that RTX produced a significant decrease compared to the control group with a statistically significant difference (SMD=-1.12, 95%CI: -1.49 to -0.74). According to the meta-analysis of two studies on FRNS/SDNS steroid withdrawal rate within a three-month follow-up, the rate of RTX was 14.6 times higher compared to the control group (CNI or CTX) (OR=14.62, 95% CI: 5.43 to 39.39). The meta-analysis of three studies on the steroid withdrawal rate of FRNS/SDNS+ during a six-month follow-up after RTX showed a withdrawal rate of 68% (95% CI: 56 to 79). Conclusions：Compared with controls, RTX showed limited benefits in terms of relapse rate and first relapse time from the initiation of treatment to 1-year follow-up, and it could provide benefits in steroid reduction rather than steroid withdrawal. Addition of RTX in FRNS/SDNS patients, as compared with placebo or blank control, can reduce the 1-year follow-up relapse rate by at least 88%. The overall relapse rate for FRNS/SDNS patients who received RTX treatment at the 1-year follow-up was 43%. The addition of RTX treatment for FRNS/SDNS can provide 10 months of relapse-free survival time.

Key words: Nephrotic syndrome, Rituximab, Immunosuppressants, Relapse, Steroid