Abstract
Background: Membranous Nephropathy (MN) is a rare autoimmune disease related to PLA2R1 antibodies in 70% of cases. One third of patients enter in spontaneous remission. PLA2R1 epitopes in MN have been characterized in four different domains of PLA2R1 and a mechanism of epitope spreading from the immunodominant CysR domain to CTLD1 and/or CTLD7 and/or CTLD8 domains has been associated with poor prognosis. Epitope spreading could predict spontaneous remission (45% in non-spreader patients vs. 0.05% in spreader patients). The comparison of different regimens of rituximab dosing showed that: (i) early remission rate depends on rituximab dosing, (ii) low dose could be enough for patients with anti-PLA2R1 activity restricted to CysR, (iii) high dose may be required for spreader patients. This study aims to evaluate the efficacy of personalized treatment in PLA2R1-related MN depending on the epitope spreading status, in comparison to the established GEMRITUX protocol.Methods: A multicenter, randomized, controlled, prospective clinical trial will be conducted in 22 French hospitals. Sixty-four consecutive patients with PLA2R1-related MN will be randomly assigned to either the control group following the GEMRITUX protocol (symptomatic treatment for 6 months, if the nephrotic syndrome (NS) persists at month-6, two 375 mg/m2 rituximab infusions at 1 week interval) or the personalized treatment group (patients with no epitope spreading at month-0 will be treated with symptomatic treatment for 6 months, if NS persists at month-6, two 375 mg/m2 rituximab infusions at 1 week interval; patients with epitope spreading at month-0 or month-6 with persistent NS will be treated immediately with two 1 g rituximab infusions at 2 week interval). The primary study outcome is the rate of clinical remission at month-12. The secondary outcomes include complete and partial remissions, immunological remissions, relapses, proteinuria, albuminuria, serum creatinine, eGFR, PLA2R1 antibody titers, severe infections, lymphocyte counts and lymphocyte phenotype, residual rituximab levels at month-3 and neutralizing anti-rituximab antibodies at month-6 and month-12 after rituximab treatment.Discussion: The results of this trial will confirm whether personalized treatment of PLA2R1-driven nephrotic MN is more efficient to induce clinical remission than the established GEMRITUX protocol, and may thus contribute to improved remission rates and reduced relapse rates.Trial registration: NCT 03804359 trial number. Registered on 15th January 2019.
Highlights
Membranous nephropathy (MN) is a rare, but severe autoimmune disease with an incidence of 1.3 cases/100,000 people/year in France [1] and a major cause of nephrotic syndrome in adults [2]
A recent clinical trial GEMRITUX compared low dose rituximab treatment and non-immunosuppressive antiproteinuric treatment (NIAT) alone, but failed to demonstrate the efficacy of rituximab in inducing remission at 6 months [20], while our data showed that a higher dose rituximab may be more effective, especially for patients with epitope spreading [33]
Our previous work based on a non-controlled open cohort [69 patients [18]], a controlled well-defined cohort [58 patients [20]] and a comparison of two well-defined cohorts [57 patients [33]] demonstrating better prognosis for patients with antibodies raised against the cysteine-rich domain (CysR) domain only in comparison to patients with multiple antibodies against CTLD1 and/or CTLD7 domains, and that epitope spreading is an independent prognosis factor of MN remission [20]
Summary
Membranous nephropathy (MN) is a rare, but severe autoimmune disease with an incidence of 1.3 cases/100,000 people/year in France [1] and a major cause of nephrotic syndrome in adults [2]. High titers of PLA2R1-Ab at presentation and their persistence predict poor clinical outcome [13, 14]. Membranous Nephropathy (MN) is a rare autoimmune disease related to PLA2R1 antibodies in 70% of cases. Epitope spreading could predict spontaneous remission (45% in non-spreader patients vs 0.05% in spreader patients). The comparison of different regimens of rituximab dosing showed that: (i) early remission rate depends on rituximab dosing, (ii) low dose could be enough for patients with anti-PLA2R1 activity restricted to CysR, (iii) high dose may be required for spreader patients. This study aims to evaluate the efficacy of personalized treatment in PLA2R1-related MN depending on the epitope spreading status, in comparison to the established GEMRITUX protocol
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