The personalized approach to rituximab treatment in membranous nephropathy: a multi-center randomized controlled trial

Background: Membranous nephropathy is a renal autoimmune disease associated with autoantibodies against phospholipase A2 receptor (PLA2R1) in 50-80% of cases. Patients develop immunity towards a single or multiple PLA2R1 domains, defining a cascade immunization or epitope spreading associated with worse prognosis and low rate of spontaneous remission. We aimed to compare the efficacy of standard versus personalized treatment (based on biomarker: epitope spreading) with the immunosuppressor rituximab on remission rate at month-12. Methods: rituximab infusions at month-6 in case of persistent nephrotic syndrome) or to the personalized protocol (patients without epitope spreading at month-0/month-6 followed the GEMRITUX protocol, while patients with epitope spreading at month-0/month-6 were treated immediately with two 1 g rituximab infusions). The primary outcome was the combined endpoint of partial or complete clinical remission at month-12. Findings: Thirty-one patients (48%) were randomized to the GEMRITUX arm and 33 (52%) to the personalized arm. In the GEMRITUX arm, four patients were treated with NIAT only since they entered into spontaneous remission at month-6, while 24 patients received low dose rituximab at month-6. In the personalized arm stratified according to their epitope spreading status, non-spreaders (n = 16) received NIAT for six months, while spreaders (n = 17) were immediately treated with high-dose rituximab. At month-12, the clinical remission rate was higher in the personalized group (67% versus 35%, p = 0.01), associated with improved kidney function (p = 0.0498 for estimated glomerular filtration rate). There was no difference in the rate of spontaneous remission nor in the number of adverse events between both groups suggesting that patients in the personalized arm were not over-treated. Interpretation: Personalized treatment protocol based on PLA2R1 epitope spreading status is superior to the standard GEMRITUX protocol in achieving clinical remission at month-12 by stratifying the patients according to the immunological severity of the disease and by immediately treating the patients at risk of treatment failure with rituximab. Funding: DGOS, PHRC National 2017.