This retrospective study evaluated the outcome of 28 patients with childhood-onset FR/SDNS, and every patient was followed for at least 12 months after RTX treatment. We have shown that RTX, when administered in association with other immunosuppressive agents (CNI or MMF), is efficacious in maintaining a longer proteinuria-free duration and is safe in these patients. We also found that the relapse-free period was prolonged with more frequent doses of RTX infusions. Patients given a 2-dose regimen and those given 3 or 4 doses experienced the same benefits in terms of recurrence rate of the nephrotic range proteinuria. Adverse effects were observed only in 16% of our cases; all of them were mild and transient.
The overall relapse-free rates at 6-, 10-, and 12-months post-rituximab therapy in our study are in concordance with several previous observations. In the largest randomized clinical trials, which enrolled 120 children, Basu et al. reported that a single course of 2 infusions of rituximab treatment for SDNS was associated with a relapse-free survival of 100% and 90% at 6-months and 12 months, respectively.18 Likewise, Kemper et al. analyzed the data of 37 patients and found that 70.3% of them remained in remission after 12 months of initial RTX infusion.19 Somewhat lower remission rates were observed in some studies. For instance, Ravani et al. reported that 48% of his study cohort (N = 46) who received one- to five doses of RTX were in remission without oral immunosuppressant agents at 6 months, and only 20% were still in remission after 1 year from any RTX treatment.17 Hogan et al. also found that the one-year relapse-free survival of the entire cohort (n = 61) was 60%. This lower remission rate in previously mentioned studies may be attributed to the definition criteria used to categorize the efficacy or to the fact that RTX was usually administered as a last therapeutic option in included patients who had high disease activity and not responded well to other steroid-sparing therapies.20
We found that the efficacy of two-dose RTX treatment in FR/SDNS was comparable to the efficacy of multiple doses (≥ 3 doses). Although 10- and 12-month relapse-free survival rates among those receiving multiple doses were higher than the 2-dosing group, the difference did not reach statistical significance. A recent German study demonstrated that there is no association between the number of RTX infusions and the duration of remission.20 By comparing four doses versus a single dose of RTX, Maxted et al. showed that a single dose of RTX had similar effects on inducing remission at 6-month follow-up. However, it was less effective at 12- and 24-month follow-up periods.21 Similar to this finding, Ravani et al. showed that there was no significant difference between patients who received two, three, or four RTX infusions.18 In contrast, Kemper et al. reported that the time to first relapse was significantly shorter in patients receiving one or two compared to three or four doses of RTX infusion.19 Hogan et al. also reported that one-year relapse-free survival was 59% and 72% in those received a single injection and those received two injections of 375 mg/m2 respectively, therefore, they concluded that there was a trend towards a higher risk of relapse with single dose of RTX in compared to multiple doses (risk rate of 1.67).20 Although a single dosage of RTX might help patients with refractory FR/SDNS, its ability to prevent relapses was short-lived. Even though some protocols for the administration of RTX have evolved in this direction in recent years, there has been a decrease from four to only two infusions for the first course of RTX therapy.
In literature, the median relapse-free intervals is 9 to 40 months, with variations attributed to study designs, patient demographics, and RTX and immunosuppressive treatments. In our study, the overall median relapse-free duration was 97.5 weeks (IQR: 70–180), with the mean time to first relapse at 70.8 weeks, and Group A experienced a notably shorter relapse-free survival compared to Group B (76 vs. 169 weeks). Likewise, Kemper et al. reported a shorter time to first relapse with lower RTX doses, with significant differences between one or two doses (10.3 ± 3.5 months) and three or four doses (23.3 ± 18.7 months).19 Iijima et al. found a 267-day relapse-free interval with four doses, corroborating the findings of two meta-analyses on improved outcomes with higher doses. 22–24
In concurring with several published reports, we found that RTX is safe in these children. None of our patients developed life-threatening adverse events, and no one had acute infusion reactions. However, a recent systematic review of six RCTs indicated fewer serious adverse reactions to RTX, yet serious complications, including infusion-related reactions, have occurred.25
The main limitations of our study include the retrospective design, single-center study, small sample size, loss of follow-up of some patients, and the fact that the fact that we didn’t concentrate on maintenance therapy after RTX therapy. Our study included children with FR/SDNS, as this is the group of children most in need of an effective and safe therapeutic option. We also excluded patients with initial steroid resistance due to a higher relapse risk. This patient selection is likely to influence treatment outcomes.