A novel approach to induce early remission in high-risk primary membranous nephropathy

A considerable proportion of primary membranous nephropathy (PMN) patients do not achieve early clinical remission with current immunosuppression regimens. Our objective was to develop a novel multitargeted approach for the induction of early remission to prevent life-threatening complications of nephrotic syndrome. We demonstrate a highly efficacy and safety of “never-used-before” treatment regimen including rituximab, cyclophosphamide, and corticosteroids at low cumulative doses (RCP) in high-risk PMN patients.

We present results of an ongoing prospective single-arm study (NCT05679336) with 30 high-risk PMN patients with persistent nephrotic syndrome (NS) and elevated antibodies to the phospholipase A2 receptor who underwent RCP treatment. The study was approved by the Institutional Ethics Committee (No.: 266), and all patients provided their written informed consent. The experimental protocol included: RTX infusion as a single intravenous (IV) dose of 375 mg/m2. Extra RTX infusion at the same dose was administered on weeks 8-12, 20-24, and 32-36 in the absence of complete remission and the occurrence of peripheral CD19+ cell reconstitution >5 cells/μl. Immediately before RTX infusion, a single IV infusion of methylprednisolone 500 mg was administered, followed by oral prednisolone 1 mg/kg daily but not exceeding 60 mg daily during week 1. Next, the dosage was decreased by 10 mg/weekly and stopped by week 49. Four IV infusions of CYC were administered at a dose of 7.5 mg/kg every other week (in weeks 1, 3, 5, and 7). We compared the effectiveness of RCP with that of historic controls who received rituximab-based therapy (RTX, n=15) or cyclosporine+corticosteroids (CSA, n=42). The primary outcomes were complete remission (CR) and overall remission (OR) by month 12 and the time to remission. The cumulative remission rate was estimated by Kaplan‒Meier plots using the log-rank test to assess the significance of intergroup differences, and propensity score analysis was used to reduce the risk of bias.

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In the RCP group, the OR and CR rates by 12 months (97% and 60%) were higher than those in the RTX group (60% and 7%, P≤0.009) and the CSA group (50% and 24%, P≤0.003). (Figure 1 A, B). The median time to OR (2.8 (1.6–3.9)months) was shorter compared to RTX (7.1 (3.4–17.5) months, P=0.008) and CSA (7.3 (6.0–13.6) months, P<0.001) (Figure 1A). In adjusted Cox regression, hazard ratios for OR and CR attainment for RCP versus other treatments were 5.2 (95% CI: 2.8–9.6) and 4.8 (95% CI: 2.2–10.3), respectively. Propensity score-matched group analyses confirmed these results. Only one SAE occurred in the RCP group in the follow-up of 56 patient-years.

RCP therapy is considered effective and safe for inducing early remission and preventing NS complications in high-risk PMN patients.