THU0084 TOFACITINIB REVERSED ENDOTHELIAL DYSFUNCTION IN RHEUMATOID ARTHRITIS: MECHANISTIC INSIGHTS FROM THE RAT ADJUVANT-INDUCED ARTHRITIS MODEL.

Background: Tofacitinib, an inhibitor of JAK3 and JAK1, is approved for the treatment of rheumatoid arthritis (RA)1. Cardiovascular (CV) risk2 and events3 in RA patients treated with Tofacitinib is a matter of debate, but the vascular mechanisms involved are unknown. Objectives: The aim of this study was to investigate whether Tofacitinib improves endothelial dysfunction (ED) and if so to explore the underlying mechanisms in the model of adjuvant-induced arthritis (AIA) in rats. Methods: AIA was induced by injection of Mycobacterium butyricum in the tail of male Lewis rats. A group of rats without arthritis served as controls. At the first signs of arthritis, AIA received Tofacitinib (10 mg/kg twice daily, s.c.) or 33%DMSO/PEG300 (Vehicle). Arthritis score was daily evaluated. After 21 days, preconstricted isolated aortic rings were relaxed with acetylcholine (Ach, 10-11-10-4 moles/liter) in the presence or not of inhibitor of nitric oxide (NO) synthase (L-NAME), cyclooxygenase-2 (NS398), arginase (nor-NOHA), endothelium-derived hyperpolarizing factor (EDHF) (apamin/charybdotoxin) and superoxide anions production (Tempol). Endothelium-denuded rings were used to determine the vasorelaxant response to the NO-donor sodium nitroprussiate (SNP, 10-11-10-4 moles/liter). Blood pressure and heart rate were measured by invasive method. A radiographic score was attributed to hind paws. Results: Compared to AIA-Vehicle, Tofacitinib dramatically reduced arthritis (-76%) and radiographic (-73%) scores (p Conclusion: The present results demonstrated that Tofacitinib reversed arthritis-induced ED, through the correction of all the acknowledged impaired endothelial pathways in the AIA model. As ED is the primum movens of atherogenesis, these data provide a mechanistic explanation to the potential benefits of Tofacitinib on the cardiovascular comorbidities associated to RA. References: [1]Lee EB. et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. (2014);370:2377-86. [2]Nurmohamed et al. The Impact of Biologics and Tofacitinib on Cardiovascular Risk Factors and Outcomes in Patients with Rheumatic Disease: A Systematic Literature Review. Drug Saf. (2018);41(5):473-488. [3]Charles-Schoeman et al. Risk Factors for Major Adverse Cardiovascular Events in Phase III and Long-Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. (2019);71(9):1450-1459. Disclosure of Interests: Perle Totoson: None declared, Clement Prati: None declared, Daniel Wendling: None declared, Aurore Quirie: None declared, Christine Marie: None declared, Celine Demougeot Grant/research support from: With an institutional support from Pfizer.