Rituximab therapy in idiopathic membranous nephropathy: a 2-year study

Abstract

Background and objectives: It was postulated that in patients with membranous nephropathy (MN), four weekly doses of Rituximab (RTX) would result in more effective B cell depletion, a higher remission rate, and maintaining the same safety profile compared with patients treated with RTX dosed at 1 g every 2 weeks. This hypothesis was supported by previous pharmacokinetic (PK) analysis showing that RTX levels in the two-dose regimen were 50% lower compared with nonproteinuric patients, which could potentially result in undertreatment.

Design, setting, participants, & measurements: Twenty patients with MN and proteinuria >5 g/24 h received RTX (375 mg/m(2) × 4), with re-treatment at 6 months regardless of proteinuria response. PK analysis was conducted simultaneously with immunological analyses of T and B cells to ascertain the effect of RTX on lymphocyte subpopulations.

Results: Baseline proteinuria of 11.9 g/24 h decreased to 4.2 and 2.0 g/24 h at 12 and 24 months, respectively, whereas creatinine clearance increased from 72.4 ml/min per 1.73 m(2) at baseline to 88.4 ml/min per 1.73 m(2) at 24 months. Of 18 patients who completed 24-month follow-up, 4 are in complete remission, 12 are in partial remission, 1 has a limited response, and 1 patient relapsed. Serum RTX levels were similar to those obtained with two doses of RTX.

Conclusions: Four doses of RTX resulted in more effective B cell depletion, but proteinuria reduction was similar to RTX at 1 g every 2 weeks. Baseline quantification of lymphocyte subpopulations did not predict response to RTX therapy.

Figure 1.

(A) Box plots of urine protein by months since start of RTX therapy. The top and bottom of the box are the estimated 75th and 25th percentiles, respectively. The intermediate horizontal line and “+” sign represent the median and mean urine protein, respectively. The vertical lines extend to the largest (smallest) data point that is within 1.5 times the interquartile range (75th to 25th percentile) above the 75th percentile (or below the 25th). The square symbol identifies points outside of this range. The number of patients with follow-up at 0, 1, 3, 6, 9 12, 18, and 24 months are 20, 20, 20, 19, 18, and 18, respectively. *P < 0.05, **P < 0.001. (B) Longitudinal effect of RTX on proteinuria (log-transformed).

Figure 2.

Observed serum RTX concentrations from patients with MN versus PK profile simulated using model derived from the estimated PK parameters and inter- and intraindividual variability for RA patients treated with RTX (375 mg/m² × 4). Gray symbols represent the original observations. Solid black line represents the median of the simulated data in RA patients, whereas black dashed lines represent the lines 5th and 95th percentiles, respectively. By day 56, most patients with MN have RTX levels that are below the 5th percentile for patients with RA.

Figure 3.

Dynamics of CD19⁺ B cells in patients with idiopathic MN versus RA versus AAV. Patients with MN were treated with RTX (1 g intravenously) on days 1 and 15 in our previous study (1) and with 375 mg/m² × 4 on days 1, 8, 15, and 22 in this study. Patients with RA were treated with RTX (1 g intravenously) on days 1 and 15, and patients with AAV received RTX (375 mg/m² × 4) on days 1, 8, 15, and 22 (1).