Epitope Spreading of Phospholipase A2 Receptor as a Predictor of Proteinuria Remission in Primary Membranous Nephropathy

Background: M-type phospholipase A2 receptor (PLA2R) is the predominant autoantigen in primary membranous nephropathy (PMN), accounting for approximately 70–80% of cases. Circulating anti-PLA2R IgG is a widely used biomarker for disease activity and treatment monitoring. In recent years, antibodies targeting specific PLA2R domains have been identified, and epitope spreading—the progression of immune reactivity from an initial dominant epitope to additional epitopes—has been suggested to correlate with disease severity and resistance to treatment. However, its clinical relevance remains controversial. This study aimed to evaluate whether epitope spreading offers superior prognostic value compared with total anti-PLA2R IgG levels in patients with PMN. Methods: This retrospective study enrolled 74 patients with biopsy-proven PMN and at least 6 months of follow-up. Clinical data and serum samples were collected at baseline (M0), month 6 (M6), and month 12 (M12). PLA2R-IgG, domain-specific antibodies (CysR-, CTLD1-, and CTLD7/8-IgG/IgG4), and anti-rituximab antibodies (ARA) were measured using time-resolved fluoroimmunoassay (TRFIA). Logistic regression and receiver operating characteristic (ROC) curve analysis were used to assess prognostic factors and model performance. Results: Patients were divided into cyclophosphamide (CTX) and rituximab (RTX) treatment groups. There was no significant difference in remission rates between groups at M6 (CTX: 37.9% vs. RTX: 60.0%, P = 0.875) or M12 (61.5% vs. 75.6%, P = 0.220). However, the RTX group showed faster antibody clearance by M6 and a significantly higher immunologic remission rate at M12 (96.2% vs. 65.6%, P = 0.017). In the RTX group, epitope spreading significantly decreased by M6 (P = 0.027), and four patients (22.2%) with no clinical remission were ARA-positive. Multivariable logistic regression identified epitope spreading as an independent risk factor for non-remission at M6 (P = 0.002; AUC = 0.771). All four ARA-positive patients achieved partial remission within 3–9 months after switching to obinutuzumab. Conclusion: Compared with CTX, RTX induced a higher rate of immunologic remission at 12 months. Epitope spreading was identified as an independent risk factor for treatment response at 6 months. Obinutuzumab may be a potential alternative in patients with poor response to rituximab and ARA positivity.