LAUSR

Background: Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). Antibodies to proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) decrease with therapy (1) and may therefore be used as biomarkers. Objectives: To investigate the relationship between rituximab concentration and ANCA levels in AAV patients. Methods: 92 AAV patients from the RAVE trial (rituximab for ANCA- associated vasculitis) were assessed. Both MPO-ANCA, and PR3-ANCA antibody levels were used as biomarkers. ANCA levels were measured at baseline, at months 1, 2, 4, 6, 9, 18, and every 6 months until the second rituximab cycle if any, using ELISA supplied by Euroimmun. A semi-mechanistic model including a deep compartment which was sensitive to rituximab and a feedback mechanism, and a blood compartment were tested to describe the concentration-ANCA autoantibodies relationship. A population modeling approach using sequential methods was used for model building. Influence of sex, body surface area (BSA), BVAS/WG score, newly diagnosed status, major renal involvement at baseline, and relapse were investigated as covariates on pharmacodynamics parameters. Results: A two compartment model including feedback mechanism from the circulating ANCA well described the concentration autoantibody relationship. The mean (interindividual standard deviation) estimated rituximab IC50, assessing potency, in patients with MPO-ANCA and PR3-ANCA were 21.9 mg/l (28%) and 11.2 mg/l (48.6%), respectively. Moreover, among patients with PR3-ANCA, rituximab IC50 was higher in patients with major renal involvement at baseline (p=2.47 x 10-2) and newly diagnosed status (p=6.42 x 10-5) than in others.Figure 1 Simulations of ANCA-time profile in patients with MPO-ANCA (red line) and PR3-ANCA (purple line), using typical pharmacodynamic parameters. The central curve are the median dynamics of ANCA and the shadow are 90% prediction intervals. Conclusion: A two compartments model including feedback mechanism from the circulating ANCA well described concentration-ANCA levels relationship. The potency of rituximab was higher in patients with PR3-ANCA than in patients with MPO-ANCA. Reference [1] Fussner LA, et al. Factors Determining the Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3. Arthritis Rheumatol. 2016;68:1700-10. Disclosure of Interests: Amina Bensalem: None declared, David Ternant Speakers bureau: Sanofi, Amgen, Nicolas Azzopardi: None declared, Gilles Paintaud Grant/research support from: Novartis, Roche Pharma, Sanofi-Genzyme, Chugai, Pfizer and Shire, Valérie Gouilleux-Gruart: None declared, Divi Cornec: None declared, Ulrich Specks: None declared, Denis Mulleman Speakers bureau: Pfizer, Novartis, Grifols