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