Pharmacogenetics of rituximab in anca-associated vasculitis

Abstract

Background: Rituximab is effective for induction and maintenance of remission in ANCA-associated vasculitis; however, response to treatment is highly variable and relapse is common after its discontinuation. Biomarkers predicting response to rituximab do not exist and are needed to improve patients’ stratification. Objective: This study assesses potential genetic determinants of response to rituximab in ANCA-associated vasculitis. Methods: Genotyping of 18 candidate single nucleotide polymorphisms, chosen on the basis of a biological rationale or previous reports, was performed using TaqMan and Sequenom platforms. End-points were rituximab-failure rate at 6 months and time to rituximab-failure within a year of the first rituximab administration. Rituximab failure was defined as any form of active vasculitis requiring escalation of immunosuppressive treatment. Results: Two hundred and thirteen patients were enrolled in the primary and 109 in the replication cohorts. One single nucleotide polymorphism in the TNFSF13B regulatory gene region (BAFF) was associated with rituximab failure risk at 6 months and time to rituximab-failure in the two cohorts (respectively after meta-analysis, OR 8.8, p=0.0065; HR 7.3, p=8.5x10-06). Carriers of the risk genotype had a higher rate of detectable B-cells 6 months after rituximab (50% vs 14%, p=0.0146). This association was restricted to the PR3-ANCA patient subgroup. Conclusion: We have identified a single nucleotide polymorphism of the regulatory region of the gene BAFF that may be able to predict response to rituximab in ANCA-associated vasculitis.