Neutralizing Anti-Rituximab Antibodies and Relapse in Membranous Nephropathy Treated With Rituximab
Sonia Boyer‐Suavet, Marine Andreani, Maël Lateb, Benjamin Savenkoff, Vesna Brglez, Sylvia Benzaken, Ghislaine Bernard, Patrick H. Nachman, Vincent Esnault, Barbara Seitz‐Polski
Abstract
Membranous Nephropathy (MN) is an autoimmune disease associated with antibodies against podocyte proteins: M-type phospholipase A2 receptor (PLA2R1) or thrombospondin type-1 domain-containing 7A (THSD7A) in 70% and 3% of patients, respectively. Antibody titer is correlated with disease activity. Therefore, decreasing PLA2R1-Antibodies titer has become an important goal of therapy. Rituximab a chimeric monoclonal antibody induces remission in 60-80% of MN patients. All monoclonal antibodies such as rituximab can elicit antidrug antibodies, which may interfere with therapeutic response. We aim to analyze the relevance of anti-rituximab antibodies on the outcome of MN after a first course of rituximab. Forty-four MN patients were included and treated with two 1g infusions of rituximab at 2-week interval. Anti-rituximab antibodies, CD19 count, and clinical response were analyzed. Then, we (i) analyzed the association of anti-rituximab antibodies at month-6 with response to treatment: remission, relapse and the need for another rituximab course; (ii) confirmed if anti-rituximab antibodies could neutralize rituximab B-cells depletion and (iii) tested whether anti-rituximab antibodies could cross-inhibit new humanized anti-CD20 therapies. Anti-rituximab antibodies were detected in 10 patients (23%). Seventeen patients received a second rituximab course after a median time of 12 months [7-12], following nine cases of resistance and eight relapses. Anti-rituximab antibodies were significantly associated with faster B-cell reconstitution at month-6 (75 [57-89] vs 2 [0-41] cells/μl, p=0.006), higher proteinuria 12 months after rituximab infusion (1.7 [0.7; 5.8] vs 0.6 [0.2; 3.4], p=0.03) and before treatment modification (3.5 [1.6; 7.1] vs 1.7 [0.2; 1.7] p=0.0004). Remission rate 6 months after rituximab was not different according to anti-rituximab status (p>0.99) but the rate of relapse was significantly higher for patients with anti-rituximab antibodies (p<0.001). These patients required more frequently a second course of rituximab infusions (7/10 vs 10/34, p=0.03). Anti-rituximab antibodies neutralized rituximab activity in 8/10 patients and cross-reacted with other humanized monoclonal antibodies in only two patients. Three patients with anti-rituximab antibodies were successfully treated with ofatumumab. Anti-rituximab antibodies could neutralize rituximab B cells cytotoxicity and impact clinical outcome of MN patients. Humanized anti-CD20 seems to be a satisfying therapeutic alternative for patients with anti-rituximab antibodies and resistant or relapsing MN.