Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up

Abstract

Randomized trials of rituximab in primary membranous nephropathy (PMN) have not been conducted. We undertook a multicenter, randomized, controlled trial at 31 French hospitals (NCT01508468). Patients with biopsy-proven PMN and nephrotic syndrome after 6 months of nonimmunosuppressive antiproteinuric treatment (NIAT) were randomly assigned to 6-month therapy with NIAT and 375 mg/m² intravenous rituximab on days 1 and 8 (n=37) or NIAT alone (n=38). Median times to last follow-up were 17.0 (interquartile range, 12.5-24.0) months and 17.0 (interquartile range, 13.0-23.0) months in NIAT-rituximab and NIAT groups, respectively. Primary outcome was a combined end point of complete or partial remission of proteinuria at 6 months. At month 6, 13 (35.1%; 95% confidence interval [95% CI], 19.7 to 50.5) patients in the NIAT-rituximab group and eight (21.1%; 95% CI, 8.1 to 34.0) patients in the NIAT group achieved remission (P=0.21). Rates of antiphospholipase A2 receptor antibody (anti-PLA2R-Ab) depletion in NIAT-rituximab and NIAT groups were 14 of 25 (56%) and one of 23 (4.3%) patients at month 3 (P<0.001) and 13 of 26 (50%) and three of 25 (12%) patients at month 6 (P=0.004), respectively. Eight serious adverse events occurred in each group. During the observational phase, remission rates before change of assigned treatment were 24 of 37 (64.9%) and 13 of 38 (34.2%) patients in NIAT-rituximab and NIAT groups, respectively (P<0.01). Positive effect of rituximab on proteinuria remission occurred after 6 months. These data suggest that PLA2R-Ab levels are early markers of rituximab effect and that addition of rituximab to NIAT does not affect safety.

Keywords: anti-PLA2R antibody; anti-THSD7A antibody; idiopathic membranous nephropathy; randomized controlled trial; rituximab; severe adverse event.

Figure 1.

Flow chart of the trial. The flow chart shows that premature discontinuation occurred in five patients within 3 months after inclusion: (1) two remissions at day 1 or inclusion; (2) one in NIAT for <6 months; (3) one lost to follow-up and one diagnosed with a pulmonary neoplasia; and (4) three treatment shifts between 3 and 6 months: two received rituximab or steroids because of deterioration of clinical condition and one was referred to another center.

Figure 2.

The secondary end points are expressed as percentage changes in proteinuria, serum albumin, and PLA2R-Ab with time. Mean±SEM percentage changes from baseline in (A) proteinuria, (B) serum albumin, and (C) anti–PLA2R-Ab levels. Please note that C shows percentage changes of PLA2R antibodies in the subset of patients who had PLA2R-Ab at baseline. Bonferroni correction was applied; P value <0.02 indicates statistical significance. NIAT is shown by blue lines, and NIAT-rituximab is shown by red lines. *P<0.02; **P<0.001; ***P<0.001.

Figure 3.

Study design. After a pre-inclusion period of 6 months during which NIAT was optimized, patients were assigned either to NIAT plus Rituximab (375 mg/m², two infusions at days 1 and 8) or to NIAT alone. Serum for anti-PLA2R-Ab determination was sampled at days 0 and 8, months 3 and 6, CD19 counts were determined at months 3 and 6; end points were assessed at month 6. The RCT was followed by an observational study during which follow-up was extended up to 24 months. IV, intravenous; R, rituximab.