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

Abstract

Background:Tofacitinib, an inhibitor of JAK3 and JAK1, is approved for the treatment of rheumatoid arthritis (RA)1. Cardiovascular (CV) risk2and events3in 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 ofMycobacterium butyricumin 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, 10-11-10-4moles/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, 10-11-10-4moles/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<0.001), and improved Ach-induced vasorelaxation (p<0.05). Of note, Ach-induced vasorelaxation was not different between Tofacitinib-AIA and control rats. The response to SNP was not different between groups. The effect of Tofacitinib on ED was mediated by decreased cyclooxygenase-2 and arginase activities, decreased superoxide anions production, increased NO synthase activity and EDHF synthesis. As compared to AIA-Vehicle, Tofacitinib changed neither blood pressure nor heart rate.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 theprimum movensof atherogenesis, these data provide a mechanistic explanation to the potential benefits of Tofacitinib on the cardiovascular comorbidities associated to RA.