Dataset Information

Rituximab in Membranous Nephropathy: Not All Studies Are Created Equal.

ABSTRACT: Many prospective studies and a recent randomized controlled trial have shown that the B-cell-depleting monoclonal antibody, rituximab, safely promotes the remission of nephrotic syndrome in approximately 65% of patients with membranous nephropathy (MN). Mechanistic studies have indicated that rituximab-induced proteinuria reduction is associated with clearance of anti-podocyte antigens phospholipase 2 receptor autoantibodies and subepithelial immune complexes, the hallmarks of the disease. A recently published study reported results which, at first sight, looked less favorable and implied that, due to a publication bias against negative results, the efficacy of rituximab in MN might be overestimated. Since patients received only one or 2 rituximab administrations, the authors suggest that when rituximab is used, higher doses and longer treatments should be considered. In this study, we highlight limitations of the study and warn against an oversimplified interpretation of the data. Though information on the optimal dose of rituximab to use in MN is still limited, available data from studies with predefined rituximab administration protocols collectively support the concept of titrating rituximab to the number of circulating B-cells that are invariably depleted after the first or second administration. Additional doses may increase the risk of adverse effects and related costs without augmenting efficacy. Importantly, underpowered studies with inconclusive results should not be confused with negative studies formally proving a neutral effect of a treatment. Until data from ad hoc designed clinical trials are available, the B-cell-driven protocol should be the preferred regimen, since it is similarly effective, but safer and more cost effective than other protocols employing multiple rituximab administrations.

SUBMITTER: Cravedi P

PROVIDER: S-EPMC5214174 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rituximab in Membranous Nephropathy: Not All Studies Are Created Equal.

Cravedi Paolo P

Nephron 20160928 1

Many prospective studies and a recent randomized controlled trial have shown that the B-cell-depleting monoclonal antibody, rituximab, safely promotes the remission of nephrotic syndrome in approximately 65% of patients with membranous nephropathy (MN). Mechanistic studies have indicated that rituximab-induced proteinuria reduction is associated with clearance of anti-podocyte antigens phospholipase 2 receptor autoantibodies and subepithelial immune complexes, the hallmarks of the disease. A rec ...[more]

PMID: 27676651

Similar Datasets

Project description:Membranous Nephropathy (MN) is an autoimmune disease associated with antibodies against podocyte proteins: M-type phospholipase A2 receptor (PLA2R1) or thrombospondin type-1 domain-containing 7A (THSD7A) in 70 and 3% of patients, respectively. Antibody titer is correlated with disease activity: rising during active disease and decreasing before remission. Therefore, decreasing PLA2R1-Antibodies titer has become an important goal of therapy. Rituximab a chimeric monoclonal antibody induces remission in 60-80% of primary MN patients. All monoclonal antibodies such as rituximab can elicit antidrug antibodies, which may interfere with therapeutic response. We aim to analyze the relevance of anti-rituximab antibodies on the outcome of MN after a first course of rituximab. Forty-four MN patients were included and treated with two 1 g infusions of rituximab at 2-weeks interval. Anti-rituximab antibodies, CD19 count, and clinical response were analyzed. Then, we (i) analyzed the association of anti-rituximab antibodies at month-6 with response to treatment: remission, relapse and the need for another rituximab course; (ii) confirmed if anti-rituximab antibodies could neutralize rituximab B-cells depletion; and (iii) tested whether anti-rituximab antibodies could cross-inhibit new humanized anti-CD20 therapies. Anti-rituximab antibodies were detected in 10 patients (23%). Seventeen patients received a second rituximab course after a median time of 12 months (7-12), following nine cases of resistance and eight relapses. Anti-rituximab antibodies were significantly associated with faster B-cell reconstitution at month-6 (75 [57-89] vs. 2 [0-41] cells/μl, p = 0.006), higher proteinuria 12 months after rituximab infusion (1.7 [0.7; 5.8] vs. 0.6 [0.2; 3.4], p = 0.03) and before treatment modification (3.5 [1.6; 7.1] vs. 1.7 [0.2; 1.7] p = 0.0004). Remission rate 6 months after rituximab was not different according to anti-rituximab status (p > 0.99) but the rate of relapse was significantly higher for patients with anti-rituximab antibodies (p < 0.001). These patients required more frequently a second course of rituximab infusions (7/10 vs. 10/34, p = 0.03). Anti-rituximab antibodies neutralized rituximab activity in 8/10 patients and cross-reacted with other humanized monoclonal antibodies in only two patients. Three patients with anti-rituximab antibodies were successfully treated with ofatumumab. Anti-rituximab antibodies could neutralize rituximab B cells cytotoxicity and impact clinical outcome of MN patients. Humanized anti-CD20 seems to be a satisfying therapeutic alternative for patients with anti-rituximab antibodies and resistant or relapsing MN.

Project description:Background and objectivesDifferent rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy.Design, setting, participants, & measurementsTwenty-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.ResultsRemissions 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.ConclusionsOur 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.

Dataset Information

Rituximab in Membranous Nephropathy: Not All Studies Are Created Equal.

Publications

Rituximab in Membranous Nephropathy: Not All Studies Are Created Equal.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets