Endothelial function improves within 6 weeks of treatment with methotrexate or methotrexate in combination with a TNF-α inhibitor in rheumatoid arthritis patients

Cardiovascular disease (CVD), mainly caused by premature atherosclerosis, is the main cause of reduced life expectancy in rheumatoid arthritis (RA) patients (1). Endothelial dysfunction (ED) is regarded as the initial step in the atherosclerotic process, and independently predicts cardiovascular events (2). Non-invasive methods for detecting andmonitoring endothelial function (EF) are preferred (3). Inflammation appears to play an important role in causing ED and may contribute to the premature pathogenesis of atherosclerosis in RA (4). Thus, in theory, anti-inflammatory drugs may both reduce cardiovascular risk and improve the EF. The aim of the present study was to examine the effect of methotrexate (MTX) and MTX combined with antitumour necrosis factor (anti-TNF)-α treatment on the EF in RA patients as measured by the reactive hyperaemic index (RHI), using the non-invasive technique EndoPAT 2000 (5). This uses a finger plethysmograph, is easy to handle in a standardized manner, and the calculation of the RHI is made independently of the operator. RHI values below 1.7 indicate ED. We also explored associations between EF, the presence of autoantibodies, including anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin M (RF IgM), and inflammatory biomarkers during treatment. Fifty-two consecutive patients with RA according to the American College of Rheumatology (ACR; formerly the American Rheumatism Association) 1987 criteria (6) were enrolled and completed the ongoing PSARA study at Lillehammer Hospital for Rheumatic Diseases in the period October 2008–May 2010 (5). The decision about treatment modality was based on conventional clinical judgement by rheumatologists not involved in the study. None of the 52 patients were treated with any other disease-modifying anti-rheumatic drugs (DMARDs) at baseline or during the follow-up at 6 weeks and 6 months. RA patients starting with MTX plus TNF-α inhibitor had a marginally higher body mass index (BMI), longer RA duration, and had a lower proportion of smokers than those starting with MTX as monotherapy (Table 1). Otherwise, the demographic data, inflammatory clinical scores and biomarker levels, adjunct medication, any form of CVD or family history of CVD, hypertension and hyperlipidaemia were similar in the RA treatment groups at baseline. Of the 52 RA patients, 38% (n 1⁄4 20) had abnormal EF at baseline (RHI < 1.7), with a mean RHI of 1.50 (sd 1⁄4 0.13) in the ED group, whereas the mean RHI was 2.14 (sd 1⁄4 0.35) in the RA patients with normal EF. The improvement in RHI at 6 weeks and 6 months was similar in the two treatment arms (p6weeks 1⁄4 0.890, p6months 1⁄4 0.569). Furthermore, changes in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), RF IgM level, anti-CCP antibody level, triglycerides, cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), lipoprotein a [Lp(a)], apoprotein (apo) A1, white blood cell (WBC) count, glycosylated haemoglobin (HbA1c), Health Assessment Questionnaire (HAQ) score, and pain and fatigue on a visual analogue scale (VAS) did not differ between the two treatment arms at any points of the follow-up. Compared to baseline values, reduction in the disease activity score in 28 joints (DAS28) based on ESR (DAS28-ESR) was significantly greater at 6 weeks in the MTXþTNF-α inhibitor group (DAS28-ESR p 1⁄4 0.007) compared to the MTX group, whereas the reduction was similar in the groups after 6 months of treatment. When we analysed all 52 RA patients as one group, a significant improvement in RHI after 6 weeks of treatment was found (RHIbaseline 1⁄4 1.90, RHI6weeks 1⁄4 2.21; p 1⁄4 0.004). This improvement remained steady at 6 monthsfollow-up (RHI6months 1⁄4 2.16; p 1⁄4 0.014). The RHI in women increased significantly more than in men both at 6 weeks (p 1⁄4 0.029) and at 6 months (p 1⁄4 0.020). A total of 69% of the RA patients were positive for RF IgM. At baseline, the RF IgM-positive patients had a 240 Scand J Rheumatol 2012;41:240–248