AB0253 BIOMARKERS OF CLINICAL RESPONSE TO IL6-R BLOCKADE IN DMARDS INCOMPLETE RESPONDERS (AR-BIOM TRIAL): IL23 AND BAFF AS BIOLOGICAL TARGETS, AND ALBUMIN AS BIOLOGICAL PREDICTOR. (June 2019) - Ferraccioli, Gianfranco
Abstract : Background: The therapeutic algorithm in persistently active Rheumatoid Arthritis, despite conventional synthetic DMARDs(csDMARDs), identifies TNFα blockers and other biologics as first line treatment, without clear indications of which biologic should be adopted first in persistently active patients. Objectives: In the AR-BIOM trial we analyzed several biomarkers to define which one could help to identify the best responder to IL6-R blockade. Methods: Sixty-nine RA persistently active despite csDMARDs treatment, were enrolled in this Interventional Phase IV, prospective, multicenter, non-randomized, no-profit study(Clinical Trial:n.2012-001760-30) and followed for 18 months after Tocilizumab(TCZ) treatment monotherapy or in combination with csDMARDs. The study was conducted in 10 outpatient clinics of "Gruppo Italiano di Studio sulle Early Arthritis" network(GISEA Study Group) in Italy. The primary end point was the clinical response to TCZ, as LDA(DAS<2.4) at 12 months follow-up(FU), correlated with Matrix 1 (pathway of Innate inflammation:IL-8, MCP1, Chemerin) vs Matrix 2(Pathway of IL1/IL6/TH17:IL1α, IL1β, IL17, IL23) along with the Pathway of regulatory T cells activity(IL-10, BAFF) and acute phase reactants (Albumin, Fibrinogen, CRP, ESR) as biomarkers of interest. DAS and SDAI remission were secondary end-points at 12 and 18 months FU. A ROC analysis of soluble biomarkers was performed to obtain thresholds allowing the prediction of DAS-remission or LDA at 12 months FU. A multivariate logistic analysis, in which "LDA or DAS/SDAI remission at 12 months FU" were the dependent variables, was performed. Results: During the 18 months of the study, 9/69 patients(13.0%) discontinued the study because of treatment failure, 2(2.9%) for an AE, 2 for a SAE, and 5(7.2%) for other reasons. At 12 months FU, LDA was achieved in 75.0% and DAS-R and SDAI-R in 63.3% and 41.7% respectively, of RA patients, without significant differences between mono and combination therapy. Considering baseline biomarkers predictive of LDA at 12 months FU, IL23 plasma levels ≥43.6pg/ml arose as potent predictor [OR(95%CIs):20.0(1.9-211.2)], whereas the best predictors of DAS-R were baseline BAFF plasma levels ≥563.3pg/ml [OR(95%CIs):3.9(1.1-14.3)] and IL23 plasma levels ≥43.6pg/ml [OR(95%CIs):4.1(1.1-15.2)]. In addition, Albumin levels ≥4.25g/dl at 3 months FU, arose as a biochemical parameter predicting DAS-R [OR(95%CIs):26.0(3.9-173.1)] and SDAI-R [OR(95%CIs):5.3(1.2-22.9)] at 12 months FU. Conclusion: IL23 and BAFF related inflammation are targets of IL6 blockade that significantly increases Albumin levels. High plasma levels of IL23 and BAFF at baseline represent biomarkers for LDA and DAS-R achievement in RA inflammation driven by IL6. Albumin after three months of therapy represents the strongest predictor of remission at 12 months. Disclosure of Interests: Gianfranco Ferraccioli Speakers bureau: BMS, Roche, Barbara Tolusso: None declared, Florenzo Iannone Consultant for: F Iannone has received consultancy fees and/or speaker honoraria from Pfizer, AbbVie, MSD, BMS, Novartis, Lilly, UCB outside this work, Speakers bureau: F Iannone has received consultancy fees and/or speaker honoraria from Pfizer, AbbVie, MSD, BMS, Novartis, Lilly, UCB outside this work, Maurizio Rossini: None declared, Piercarlo Sarzi-Puttini Speakers bureau: Novartis, Marcello Govoni Paid instructor for: Pfizer, Roche, Speakers bureau: Pfizer, Abbvie, MSD, Roche, Eli-Lilly, Celgene, Sanofi, Janssen, Rosario Foti: None declared, Andrea Doria: None declared, Francesco Paolo Cantatore Speakers bureau: PFIZER, ROCHE, Giovanni Francesco Miceli: None declared, oscar massimiliano epis: None declared, Anna Laura Fedele: None declared, Antonio Carletto: None declared, Nicola Maruotti: None declared, Elena De Stefani: None declared, Giorgio Amato: None declared, Elisa Gremese Consultant for: AbbVie, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Sanofi, UCB, Roche, and Pfizer, Speakers bureau: BMS, Speakers bureau: Roche, Speakers bureau: AbbVie, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Sanofi, UCB, Roche, and Pfizer, Giovanni Lapadula: None declared