Background Rheumatoid arthritis (RA) is associated with increased cardiovascular (CV) risk  secondary to endothelial dysfunction (ED) . There is accumulating evidence that methotrexate (MTX), first intention DMARD, reduces CV risk in RA , but the mechanisms involved are still unknown.
Objectives The aim of this study was to determine the effect of MTX on endothelial function in arthritis and to investigate its effect on endothelial pathways.
Methods Experiments were conducted in the adjuvant-induced arthritis (AIA) model in Lewis rat. At onset of arthritis, rats were treated by a sub-cutaneous injection of MTX (1 mg/kg/week) or phosphate buffer saline (vehicle) for 3 weeks. Arthritis score was daily monitored. At the end of treatment, thoracic aorta was harvested to measure the relaxation to acetylcholine on pre-constricted aortic rings in the presence or not of inhibitor of nitric oxide (NO) synthase (L-NAME), arginase (nor-NOHA), EDHF (Apamin/Charybdotoxin), or a superoxide dismutase analog (Tempol). The effect of norepinephrine (NE) and sodium nitroprusside (SNP) was studied on endothelium-denuded aortic rings. The effect of MTX on hind paw radiographic score, serum lipids and plasma pro-inflammatory cytokines (TNFα and IL-1β) levels was measured.
Results As compared to Vehicle rats, MTX significantly reduced arthritis score (p<0.01) but did not change radiographic score. It reduced plasma cytokines levels (p=0.02) but not total cholesterol and triglycerides levels. MTX did not change Ach-induced relaxation as compared to Vehicle. As regards endothelial pathways, MTX increased vascular NOS activity (p<0.0001) and decreased superoxide anions production but did change neither COX-2 and arginase activities nor EDHF production. Vascular smooth muscle reactivity to NE and SNP was unchanged by the treatment.
Conclusions Despite a reduction of clinical and biological inflammation, MTX did not improve endothelial function in AIA rats. The study of endothelial mechanisms highlights the role of COX and arginase as seminal targets for reducing ED in RA. This study suggests that other mechanisms than improvement of endothelial function are involved in the CV benefits of MTX in RA that remain to be elucidated. Our data also suggest that the adjunction of drugs targeting endothelial function to MTX in RA patients might improve their CV prognostic.
Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2016:annrheumdis-2016–209775. doi:10.1136/annrheumdis-2016–209775.
Prati C, Demougeot C, Guillot X, et al. Endothelial dysfunction in joint disease. Joint Bone Spine Rev Rheum 2014;81:386–91. doi: 10.1016/j.jbspin.2014.01.014.
Roubille C, Richer V, Starnino T, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2015;74:480–9. doi: 10.1136/annrheumdis-2014–206624.
Disclosure of Interest None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.