Retreatment with rituximab for membranous nephropathy with persistently elevated titers of anti-phospholipase A2 receptor antibody

Rituximab is an effective, safe alternative to alkylating agents in patients with membranous nephropathy.1Dahan 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 (201) Google Scholar, 2Cravedi P. Ruggenenti P. Sghirlanzoni M.C. et al.Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy.Clin J Am Soc Nephrol. 2007; 2: 932-937Crossref PubMed Scopus (135) Google Scholar 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.3van de Logt A.-E. Dahan K. Rousseau A. et al.Immunological remission in PLA2R-antibody–associated membranous nephropathy: cyclophosphamide versus rituximab.Kidney Int. 2018; 93: 1016-1017Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Twenty-one of the 46 rituximab-treated patients included in this study3van de Logt A.-E. Dahan K. Rousseau A. et al.Immunological remission in PLA2R-antibody–associated membranous nephropathy: cyclophosphamide versus rituximab.Kidney Int. 2018; 93: 1016-1017Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar 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. The 10 remaining patients save 1 (including 5 patients with initial titer > 152 RU/ml) reached nadir levels of PLA2R-Ab at 3 months by enzyme-linked immunosorbent assay (median, 21 RU/ml [interquartile range 5–97]) and by immunofluorescence testing, without clinical remission (Figure 1). At 6 months, we observed no further decrease of PLA2R-Ab (22 RU/ml [interquartile range 15–125.5]). Although these patients might be considered “rituximab resistant,” they were given a second course of rituximab (Table S1), without any other immunosuppressive treatment. At last follow-up (median 19.5 months [interquartile range 17.4–30.3]), 8 of 10 patients achieved complete immunological remission, irrespective of the initial PLA2R-Ab titer (median, 157.5 RU/ml [interquartile range 94–566]), and all achieved clinical remission (Figure 1, Table S2). In membranous nephropathy, CD19 B-cell repletion is faster than in other diseases, correlating with a lower blood rituximab concentration.4Rosenzwajg M. Languille E. Debiec H. et al.B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab.Kidney Int. 2017; 92: 227-237Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Here, we show that rituximab efficacy can be improved by a second course in patients with persistent PLA2R-Ab. One course of rituximab may not suffice because of short duration of immunosuppression, which calls for repeated rituximab infusions. A major endpoint is complete immunological remission by both enzyme-linked immunosorbent assay and immunofluorescence testing, more sensitive than enzyme-linked immunosorbent assay. Prospective studies are needed to validate a serological-based approach of rituximab therapy. This research is supported by the European Research Council ERC-2012 ADG_20120314 grant 322947 and the Seventh Framework Programme of the European Community contract no. 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases) Download .docx (.01 MB) Help with docx files Table S1Evolution of biological parameters over time. Download .docx (.01 MB) Help with docx files Table S2Patients characteristics. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximabKidney InternationalVol. 92Issue 1PreviewPrimary membranous nephropathy (PMN) is characterized by antibodies to the podocyte, but little is known about B- and T-cell populations and their response to rituximab is controversial. To help resolve this we compared 33 lymphocyte subpopulations and 27 cytokines/chemokines in 25 patients with severe PMN and 27 age-matched healthy individuals. At baseline, patients had a significantly increased percentage of naive B-cells with significantly decreased switched and non-switched memory B-cells. There was a significantly decreased percentage of natural killer (NK) cells with an increase in the CD56brightCD16-/lo NK subset. Full-Text PDF Open ArchiveImmunological remission in PLA2R-antibody–associated membranous nephropathy: cyclophosphamide versus rituximabKidney InternationalVol. 93Issue 4PreviewFor 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%,1,2 and partial remission rate is lower with rituximab compared with cyclophosphamide.3 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. Full-Text PDF Open Archive