Immunological remission in PLA2R-antibody–associated membranous nephropathy: cyclophosphamide versus rituximab

Abstract

For the treatment of patients with idiopathic membranous nephropathy, rituximab is considered an alternative to alkylating agents. Still, the nonresponse rate to rituximab is approximately 35%,1Ruggenenti P. Debiec H. Ruggiero B. et al.Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy.J Am Soc Nephrol. 2015; 26: 2545-2558Crossref PubMed Scopus (214) Google Scholar, 2Dahan K. Debiec H. Plaisier E. et al.Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up.J Am Soc Nephrol. 2017; 28: 348-358Crossref PubMed Scopus (202) Google Scholar and partial remission rate is lower with rituximab compared with cyclophosphamide.3van den Brand J. Ruggenenti P. Chianca A. et al.Safety of rituximab compared with steroids and cyclophosphamide for idiopathic membranous nephropathy.J Am Soc Nephrol. 2017; 28: 2729-2737Crossref PubMed Scopus (83) Google Scholar The discovery of antibodies against PLA2R (aPLA2R) has positioned immunological remission as a major goal in the treatment of idiopathic membranous nephropathy. We questioned whether rituximab is less effective than cyclophosphamide in inducing an immunological remission in patients with idiopathic membranous nephropathy. We evaluated patients treated with cyclophosphamide (1.5 mg/kg/d, duration 8–24 weeks; Nijmegen cohort) or rituximab (cumulative dose 1.5–2.0 g; French cohort). There were no significant differences between the groups (Supplementary Table S1). In stored blood samples (baseline and after 6 months) aPLA2R was measured. We divided the Nijmegen patients according to tertiles of aPLA2R levels and used these classes to classify the French patients. Figure 1 illustrates that in the patients treated with cyclophosphamide, antibodies disappeared in almost all patients, independent of baseline level. In contrast, disappearance of aPLA2R was less likely in patients treated with rituximab with an aPLA2R titer higher than 152 relative units/ml. Statistical analysis, using a mixed model with aPLA2R level at 6 months as the dependent outcome variable, showed that both baseline titer and type of treatment were significantly independent predictors (P < 0.001; Supplementary Figure S1). Thus, rituximab, in cumulative dosages up to 2 g, is less effective than cyclophosphamide in inducing an immunological remission in patients with idiopathic membranous nephropathy and high antibody levels. Our study highlights the potential role of aPLA2R measurements to guide initial therapy. The work leading to these results received funding from European Union Seventh Framework Programme FP7/2007-2013 grant 305608: European Consortium for High-Throughput Research in Rare Kidney Diseases. We would like to thank the technicians of the laboratory of Medical Immunology in the Radboud University Medical Center (especially Carla Verweij-Ligthart) for their support in performing aPLA2R enzyme-linked immunosorbent assays. Download .docx (.01 MB) Help with docx files Table S1Baseline characteristics. The authors replyKidney InternationalVol. 94Issue 4PreviewDr. Ramachandran and colleagues provide support for our finding that the level of anti-PLA2R antibodies (aPLA2Rab) may explain observed differences in efficacy of immunosuppressive agents.1,2 They studied patients with membranous nephropathy who were resistant to previous immunosuppressive therapy or had developed a relapse. In contrast, our study mainly included treatment-naive patients. Full-Text PDF Open ArchiveAntibodies to M-type phospholipase receptor and immunological remission in treatment-resistant and relapsing membranous nephropathyKidney InternationalVol. 94Issue 4PreviewThe report by van de Logt and colleagues1 adds to the expanding literature on the utility of measurement of antibodies against M-type phospholipase A2 receptor (aPLA2R) in diverse clinical circumstances in management of patients with membranous nephropathy. They show that rituximab is less effective than cyclophosphamide in effecting reduction in aPLA2R levels (immunological response), and that baseline antibody titers predict response to treatment, whether with rituximab or cyclic cyclophosphamide-glucocorticoid (cCTX-GC). Full-Text PDF Open ArchivePersonalized phospholipase A2 receptor antibody–driven rituximab treatment strategy in membranous nephropathyKidney InternationalVol. 99Issue 4PreviewIn the Sequential Treatment with Tacrolimus and Rituximab versus Alternating Corticosteroids and Cyclophosphamide in Primary Membranous Nephropathy trial, Fernández-Juárez et al. have shown that a sequential tacrolimus/rituximab protocol is effective yet inferior to the standard cyclophosphamide/corticosteroid combination to treat membranous nephropathy. Adverse events were more frequent in the cyclophosphamide/corticosteroid group.1 Previous studies have shown that cyclophosphamide/corticosteroid combination allows earlier and higher immunological remission rate than does rituximab alone2 and that rituximab is efficient and not inferior to cyclosporine. Full-Text PDF Retreatment with rituximab for membranous nephropathy with persistently elevated titers of anti-phospholipase A2 receptor antibodyKidney InternationalVol. 95Issue 1PreviewRituximab is an effective, safe alternative to alkylating agents in patients with membranous nephropathy.1,2 In a previous study, we observed that, compared with cyclophosphamide, rituximab induced less complete immunological remissions at 6 months in patients with high titer of phospholipase A2 receptor (PLA2R)-Ab.3 Twenty-one of the 46 rituximab-treated patients included in this study3 were followed up in our department. Two patients developed end-stage renal disease; 9 achieved immunological and clinical remission at 3 and 6 months, respectively. Full-Text PDF Open Archive