High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy

Abstract

Background and objectives: Different rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy.

Design, setting, participants, & measurements: Twenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m2 at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses.

Results: Remissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (P=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (P=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3-9] and 9 [IQR, 6-12] months for NICE and GEMRITUX cohorts respectively (P=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.3 µg/L [IQR, 0.0-10.8] versus 0.0 [IQR, 0.0-0.0] P<0.001 and 0.0 [IQR, 0.0-2.0] versus 16.5 [IQR, 2.5-31.0] P<0.001) at month 3, lower level of anti-PLA2R1 antibodies at month 6 (0.0 [IQR, 0.0-8.0] versus 8.3 [IQR, 0.0-73.5] P=0.03). In the combined study population, lower epitope spreading at diagnosis and higher rituximab levels at month 3 were associated with remissions at month 6 (13/26 (50%) versus 22/29 (76%) P=0.05 and 2.2 µg/ml [IQR, 0.0-10.9] versus 0.0 µg/ml [IQR, 0.0-0.0] P<0.001 respectively). All non-spreaders entered into remission whatever the protocol. Eight of the 41 participants who reached remission had relapses. Epitope spreading at diagnosis (8/8 (100%) versus 16/33 (48%) P=0.01) and incomplete depletion of anti-PLA2R1 antibodies at month 6 (4/8 (50%) versus 5/33 (9%) P=0.05) were associated with relapses.

Conclusions: Our work suggests that higher dose rituximab protocol is more effective on depletion of B-cells and lack of epitope spreading is associated with remission of membranous nephropathy.

Trial registration: ClinicalTrials.gov NCT01508468 NCT02199145 NCT01897961.

Keywords: B-lymphocytes; Cohort Studies; Epitopes; Humans; Recurrence; Rituximab; clinical immunology; lomerulonephritis, Membranous; membranous nephropathy.

Copyright © 2019 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Temporal changes of circulating intermediate markers of rituximab effect in the NICE and GEMRITUX cohorts. (A) Comparison of serum residual rituximab level at month 3 between the NICE (n=28, two infusions of 1 g at 2-week intervals) and GEMRITUX (n=27, two infusions of 375 mg/m2 at 1-week intervals) cohorts. Note variability of residual rituximab concentrations and lower concentrations in the GEMRITUX participants (P<0.001). Threshold of detection was 2 μg/ml. (B) Evolution of CD19 count at month 3 and month 6 according to the regimens received. *CD19 count was lower in NICE cohort at month 3 (P>0.001). **CD19 count was lower at month 6 in NICE cohort (P=0.03). (C) Evolution of anti-PLA2R1 titer at baseline, month 3, and month 6 according to the regimens received. **Anti-PLA2R1 titer was lower at month 6 in NICE cohort (P>0.001).

Figure 2.

Time from initiation of rituximab to remission of membranous nephropathy in the NICE and GEMRITUX cohorts. Note that NICE the log-rank P value for remission was P<0.001. Numbers in the table are number at risk.

Figure 3.

Intermediate outcomes according to serum rituximab concentration at 3 months. (A) Comparison of serum rituximab concentrations according to remission (n=26) or absence of remission (n=29) at month 6 in the pooled NICE and GEMRITUX cohorts. Note higher concentration of residual rituximab concentrations at month 3 in participants who achieved remission (P<0.001). (B) Correlation of serum rituximab concentrations at month 3 and proteinuria at month 6 in the pooled NICE and GEMRITUX cohorts (r=−0.41; P=0.003). (C) Correlation of serum rituximab concentrations at month 3 and proteinuria at baseline in the pooled NICE and GEMRITUX cohorts (r=0.26; P=0.06).

Figure 4.

Remission of membranous nephropathy in the NICE and GEMRITUX cohorts according to epitope spreading at baseline. (A) Remission at month 6 according to epitope spreading at baseline and rituximab protocol received. A categorical variable combining treatment and spreading was built to investigate the impact of the interaction between treatment and spreading on the response (P=0.003; comparing the null hypothesis that there are no differences among groups). Note that the lowest remission rate is observed in participants with epitope spreading treated by GEMRITUX protocol. (B) Remission at last follow-up according to epitope spreading at baseline and rituximab protocol received. A categorical variable combining treatment and spreading was built to investigate the effect of the interaction between treatment and spreading on the response (P=0.01; comparing the null hypothesis that there are no differences among groups). Note that all participants without epitope spreading are in remission at last follow-up whatever the protocol received and participants with epitope spreading benefit from the NICE protocol (remission rate 79% versus 55%).