4. Discussion
Recently, the clinical application of RTX in treating IMN has been gradually improved. In KDIGO 2012 guideline, RTX is not recommended for the primary treatment of IMN. The guidelines suggest that glucocorticoids combined with alkylating agents are the first choice, and the Italian protocol is recommended. Calcineurin inhibitors are recommended for those unsuitable for Italian protocol [9, 10]. While in the KDIGO 2020 guideline, RTX is recommended for patients with a high risk of progression to ERSD after 6 months of CNIs treatment, except the patients with loss of PLA2R antibodies after CNIs treatment [24]. It is a symbol that the position of RTX in the treatment of MN has improved, and RTX may be a more efficient and safe option.
Although some meta-analysis papers on RTX for IMN have been published resently[43-45], They provide no evidence of the superiority of RTX over other conventional treatments. This article compared RTX with conventional therapy in IMN treatment and inclusion studies were stratified according to patients’ pre-treatment proteinuria level. In a subgroup analysis, RTX showed a greater advantage in patients with moderate risk IMN. That’s probably because, for patients with proteinuria > 8 g/d, more severe glomerular injury causes some drug-protein molecules to be lost from the glomerular filtration membrane, so RTX cannot form effective drug concentration and play a therapeutic role, which leads the high-risk patients had a lower TR after RTX treatment. RTX is expected to become the first-line drug in MN treatment. In a study from Dahan et al. [46], patients were randomly assigned to 6-month therapy with nonimmunosuppressive antiproteinuric treatment (NIAT) and 375 mg/m2 intravenous RTX on days 1 and 8 or NIAT alone. The results show that at 6 months, 13 patients in the NIAT-RTX group and 8 patients in the NIAT group achieved remission. During the observational phase, TR rates before the change of assigned treatment were 24 of 37 (64.9%) and 13 of 38 (34.2%) patients in NIAT-RTX and NIAT groups, respectively. Data from Fervenza et al. [47] also confirmed that RTX was more effective than conventional therapy in improving the remission of IMN. However, van den Brand et al. [28] have published a study claiming that the cumulative incidence of PR was lower in the RTX group, rates of CR and the composite renal endpoint did not differ significantly between groups (RTX vs. steroid plus cyclical cyclophosphamide).
Different dosages of RTX have been successfully used in IMN treatment [20, 25], but the ideal dosage regimen and long-term adverse effects of a high dosage of RTX remain controversial. Traditional RTX is 375 mg/m2 once weekly for 4 weeks, or 1000 mg RTX on day 1 and day 15 (short protocols) [23]. Some clinicians also use B cell-driven treatment which gives a second course routinely according to the B cell counts (when B cell ≥ 5/mm3) [31, 48]. Remuzzi et al. [49] demonstrated that low-dose therapy is also effective as standard protocol and has the characteristics of no serious adverse reactions [32]. However, in 2017, Moroni et al. [34] published a study showing that low-dose RTX obtains remission in < 50% of IMN patients, which means low-dose RTX is poorly effective in IMN treatment. Some studies have also found that a higher dose RTX protocol is more effective on the depletion of B-cells and lacking epitope spreading is associated with the remission of IMN [50]. In this article, six low-dose therapy and six standard treatment researches about RTX were included, and subgroup analysis was divided into two groups according to the RTX dosage. mMeta-analysis results showed that not only the low dose RTX but the standard dose can reduce the level of proteinuria (Low dose regimen MD = -3.99, standard dose regimen MD = -5.22) in patients. However, the standard dose RTX regimen was better than the low dose RTX regimen in reducing proteinuria. We also reported the effect of different doses of RTX on the recovery of Scr and ALB levels. The results showed that the standard dose of RTX could significantly improve the ALB levels after treatment. Different doses of RTX do not affect the remission of Scr. Despite the high cost of RTX treatment, to better improve the remission of IMN and repress recurrence, a standard dose regimen will be a better choice for IMN patients.
There are also some defects in this paper. In the study of the comparison of RTX and traditional therapies for remission, most of the included studies are from western countries, and the sample size is small. Due to the lack of specific information about adverse events, CR, PR and PLA2R provided in the included studies, we were unable to made the evidence of the paper adequate.
In conclusion, this is the first paper comparing the efficacy of rituximab versus conventional therapy and different dosage of rituximab in IMN. Based on the results from the above meta-analysis study, the efficiency of RTX is superior to that of other immunosuppressants in IMN. In terms of reducing proteinuria and restoring ALB, standard dose regimens were more advantageous than low-dose regimens. Although this paper demonstrates the superiority of RTX and the advantage of standard dose RTX in IMN treatment, more clinical studies are needed for further confirmation.