Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy

Abstract

Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among treatment effect, circulating nephritogenic anti-phospholipase A 2 receptor (anti-PLA 2 R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m 2 ) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0-145.4) months, 84 of 132 rituximabtreated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA 2 R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA 2 R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio [HR], 7.90; 95% confidence interval [95% CI], 2.54 to 24.60; P,0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA 2 R antibody depletion. On average, 50% anti-PLA 2 R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P,0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA 2 R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.

Anti-phospholipase A2 receptor antibody in membranous nephropathy; an Indian experience

“…Anti-PLA 2 R was negative in five patients with secondary MN, majority with SLE as the secondary cause. This is consistent with the current data of anti-PLA 2 R antibody's specificity for idiopathic MN (8,(12)(13)(14)(15)(16)(17)26). Amongst subjects in clinical remission, PLA 2 R was detectable in just one of 29 patients (3%).…”

“…The circulating anti-PLA 2 R antibodies target a specific region of the PLA 2 R protein and are predominantly of the IgG4-type (8)(9)(10)(11). Similar results with prevalence of anti-PLA 2 R antibodies ranging from 60%-80% in idiopathic MN have been observed by different researchers worldwide (12)(13)(14)(15)(16)(17). The anti-PLA 2 R antibodies have been associated with high specificity and sensitivity of approximately 95% and 75% respectively for diagnosis of pMN.…”

“…shown that, the antibody titres disappear with remission and reappear with disease relapses (8,13,14,17,18,(27)(28)(29)(30)(31)(32). Moreover, anti-PLA 2 R levels were in direct proportion to proteinuria and serum albumin levels.…”

“…Few recent studies have also reported correlation of anti-PLA 2 R levels with the clinical severity, with higher spontaneous remission rates observed in patients and with lower antibody titres. They can therefore be considered as a non-invasive marker for both diagnosis and prognosis in iMN (14)(15)(16)(17)(18)(19). The US Food and Drug Administration (FDA) in 2014, accepted two commercially available tests for anti-PLA 2 R autoantibodies, including an enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay (IIFA).…”

Untitled

“…The non-proliferating LLMPCs are known to provide the basis for humoral memory and refractory autoimmune diseases. [5][6][7][8][9] Recent evidence has suggested the existence of 2 independent plasma cell (CD19+/CD20+ and CD38+/CD138+) compartments that contribute to autoantibody and alloantibody production. 5,6 As expected, LLMPCs that lack CD20 markers [5][6][7] would be refractory to a CD20+-targeting immunosuppressive therapy (Figure 1).…”