Safety of Rituximab Compared with Steroids and Cyclophosphamide for Idiopathic Membranous Nephropathy

Abstract

Guidelines recommend steroid plus cyclical cyclophosphamide (St-Cp) therapy for patients with idiopathic membranous nephropathy at high risk of progression to ESRD. Rituximab (Rtx) may be a safer alternative. In this retrospective, observational cohort study, we compared time to any adverse event (primary outcome); serious or nonserious events; partial and complete remission of the nephrotic syndrome; and a composite of doubling of serum creatinine, ESRD, or death between 100 Rtx-treated patients and 103 patients who received daily St-Cp We monitored patients with standardized protocols and adjusted for baseline characteristics by Cox regression. Over a median follow-up of 40 months, the Rtx group had significantly fewer adverse events than the St-Cp group (63 versus 173; P<0.001), both serious (11 versus 46; P<0.001) and nonserious (52 versus 127; P<0.001). Cumulative incidence of any first (35.5% versus 69.0%; P<0.001), serious (16.4% versus 30.2%; P=0.002), or nonserious (23.6% versus 60.8%; P<0.001) event was significantly lower with Rtx Adjusted hazard ratios (95% confidence intervals) between Rtx and St-Cp groups were 0.27 (0.16 to 0.44) for any first adverse event, 0.32 (0.15 to 0.68) for serious adverse events, and 0.23 (0.13 to 0.41) for nonserious adverse events. Although the cumulative incidence of partial remission was lower in the Rtx group, rates of complete remission and the composite renal end point did not differ significantly between groups. Because of its superior safety profile, we suggest that Rtx might replace St-Cp as first-line immunosuppressive therapy in patients with idiopathic membranous nephropathy and nephrotic syndrome.

Keywords: adverse events; clinical epidemiology; cyclophosphamide; drug safety; membranous nephropathy; rituximab.

Figure 1.

Cumulative incidence curves for safety outcomes in iMN patients treated with steroids and cyclophosphamde compared to rituximab. Cumulative incidence curves for (A) time until the first adverse event, either serious or nonserious; (B) time to the first serious adverse event; or (C) time to the first nonserious adverse event. The solid lines describe the events in St-Cp–treated patients; the dashed lines describe the events in Rtx-treated patients.

Figure 2.

Forest plot of the associations between Rtx therapy and St-Cp–based immunosuppression for the time to any first adverse event (primary outcome), nonserious adverse event, and first serious adverse event. Analyses were adjusted for the following covariates. First adverse event: sex, age, disease duration, urine protein-to-creatinine ratio (UPCR), eGFR (by Modification of Diet in Renal Disease four-variables equation), cholesterol, ACE inhibitor/ARB, diuretics, and prior immunosuppressive therapy. Serious adverse event: age, disease duration, and prior therapy. Nonserious adverse event: sex, age, disease duration, UPCR, eGFR, cholesterol, and prior immunosuppressive therapy.

Figure 3.

Forest plot of the associations between Rtx therapy and St-Cp–based immunosuppression for the time to partial remission, complete remission, or renal failure. Analyses were adjusted for the following covariates. Partial remission: sex, age, disease duration, urine protein-to-creatinine ratio (UPCR), eGFR, and prior therapy. Complete remission: sex, age, disease duration, UPCR, eGFR, and prior therapy. Renal failure: sex, age, disease duration, UPCR, and eGFR.