New study findings represent a step forward in the use of rituximab as first-line therapy for severe membranous nephropathy (MN), researchers concluded.
The study, which was the first randomized controlled trial (RCT) of rituximab in primary MN, demonstrated a positive treatment effect after 6 months and identified early markers of rituximab effect. The study also demonstrated that adding this drug to non-immunosuppressive antiproteinuric treatment (NIAT) does not affect safety.
Karine Dahan, MD, of Tenon Hospital in Paris, and colleagues randomly assigned patients with biopsy-proven primary MN and nephrotic syndrome after 6 months of NIAT to receive 6 months of therapy with either NIAT and 375 mg/m2 intravenous rituximab on days 1 and 8 (37 patients) or NIAT alone (38 patients). The median time to last follow-up was 17 months in both groups. The primary outcome was a combined endpoint of complete or partial remission of proteinuria at 6 months. The researchers defined complete and partial remission using 2012 Kidney Disease: Improving Global Outcomes (KDIGO) criteria on the basis of proteinuria.
At month 6, 13 patients in the NIAT-rituximab arm (35.1%) and 8 (21.1%) in the NIAT-only arm achieved the primary endpoint, a non-significant difference between the groups, Dr Dahan’s team reported online ahead of print in the Journal of the American Society of Nephrology.
During a post-RCT observational phase, however, remission rates based on the last follow-up differed significantly between the combination-therapy and NIAT-only arms (64.9% vs. 34.2%). The median time to remission was 7 months in both groups.
Rates of full antiphospholipase A2 receptor antibody (PLA2R-Ab) depletion—indicating complete immunologic remission—at months 3 and 6 were 56% and 50%, respectively, in the NIAT-rituximab arm compared with 4.3% and 12%, respectively, in the NIAT-only arm, a significant difference between the groups. Eight serious adverse events occurred in each treatment arm.
The researchers said their study demonstrated that, compared with NAIT alone, adding 2 infusions of rituximab to NIAT decreased PLA2R-Ab as early as month 3 and was associated with a higher percentage increase of serum albumin at months 3 and 6.
“These data suggest that PSA2R-Ab levels are early markers of rituximab effect and that addition of rituximab to NIAT does not affect safety,” the researchers concluded.
In addition, the investigators concluded that trial data suggest that criteria for defining remission should include serum albumin and PLA2R-Ab levels.
Dr Dahan’s group offered some explanations for lack of effect of the NIAT-rituximab regimen on the rate of proteinuria remission at 6 months, including a high rate of remission in the NIAT-only group. Another explanation could be the lower rate of remission than expected in the combination arm. The researchers calculated sample size from initial studies of rituximab, which they said probably overestimated the rate of remission in the NIAT-rituximab group and led to a lack of statistical power. Other possibilities include the short duration of the RCT phase and the fact that proteinuria is a delayed marker of treatment effect, according to the researchers.