Effect of spironolactone on endothelial dysfunction in rheumatoid arthritis A Syngle 1 , K Vohra 2 , L Kaur 3 , S Sharma 2 1 Healing Touch City Clinic, Fortis Heart Institute and Multispeciality Hospital, Chandigarh, 2 Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, and 3 Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India Objective: Chronic inflammation in rheumatoid arthritis (RA) is associated with vascular endothelial dysfunction. The aim of this study was to determine the effect of spironolactone on endothelial function in anti-tumour necrosis factor (TNF)-naive RA patients. Methods: Twenty-four anti-TNF-naive RA patients (mean age 49¡1.8 years; disease duration 8.5¡5.8 years) with high disease activity [Disease Activity Score including a 28-joint count (DAS28w5.1)] despite treatment with stable doses of conventional disease-modifying anti-rheumatic drugs (DMARDs) were investigated. Inflammatory disease activity [DAS28 and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)], serum markers of endothelial dysfunction, serum nitrite concentration, and endothelium-dependent and -independent vasodilation of the brachial artery were measured before and after 12 weeks of therapy with oral spironolactone 2 mg/kg/day. Results: After treatment with spironolactone, flow-mediated vasodilation (FMD) improved from 3.18¡0.46% to 3.95¡0.49% (pv0.001) whereas there was no significant change in endothelium-independent vasodilation with nitroglycerin and baseline diameter (18.4¡1.15% vs. 18.3¡1.13%, p50.046, and 3.5¡0.1 vs. 3.52¡0.1 mm, p50.952, respectively); serum nitrite concentration was reduced significantly from 6.9¡0.34 to 6.8¡0.33 mmol/ L (pv0.001), ESR from 59.90¡4.86 to 51.22¡4.26 mm in the first hour (pv0.001), and CRP level from 15.2¡3.8 to 9.4¡2.6 mg/dL (p50.019). DAS28 and HAQ-DI scores were significantly reduced, from 6.9¡0.25 to 4.1¡0.31 (pv0.05) and from 1.47¡0.09 to 0.69¡0.1 (pv0.05), respectively. Conclusions: The study suggests that, in RA, endothelial dysfunction is part of the disease process and treatment with spironolactone improves both endothelial dysfunction and inflammatory disease activity in RA. Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease of unknown aetiology that attacks the synovial tissue, leading to irreversible joint damage (1). RA affects 1% of the adult population (1) and patients are two to five times more prone to cardiovascular (CV) morbidity and mortality compared to the general population (2). The increased CV risk in RA patients results in accelerated atherosclerosis (3). The chronic systemic inflammatory process in RA initiates atherosclerosis in these patients through its actions on the vascular endothelium (4). Evidence also suggests that RA and atherosclerosis may share an immunopathogenic mechanism (5). Apart from chronic inflammation, genetic factors, particularly the presence of certain human leucocyte antigen (HLA)-DRB1 genotypes in RA, may also predispose these patients to endothelial dysfunction (6). Endothelial dysfunction is an essential marker and a good predictor of atherosclerosis, thereby acting as a ‘barometer’ of cardiovascular health (7). Acute inflammation may interfere with endothelial function through the action of proinflammatory cytokines, which can modify the vascular release of both nitric oxide and endothelium-derived hyperpolarizing fac- tor (8). Chronic cytokine release from inflamed joints is implicated in the increased production of adhesion molecules by endothelial cells in RA and could impair endothelial function directly or through their effects on insulin sensitivity and on C-reactive protein (CRP) and fibrinogen production by the liver (9). It was reported recently in an animal arthritis model that adhesion molecule P-selectin mediates rapid accumulation of platelets at the inflamed endothelium and provides a basic matrix for increased endothelium–cell interactions (10). Ashit Syngle, Healing Touch City Clinic, Fortis Heart Insitute and Multispeciality Hospital; #547, Sector 16D, Chandigarh-160015, India. E-mail: ashitsyngle@yahoo.com Accepted 17 June 2008 Scand J Rheumatol 2009;38:15–22 15 # 2009 Taylor & Francis on license from Scandinavian Rheumatology Research Foundation DOI: 10.1080/03009740802279709 www.scandjrheumatol.dk