Advanced glycation endproducts are increased in rheumatoid arthritis patients with controlled disease.

INTRODUCTION: Advanced glycation end products (AGEs) are produced and can accumulate during chronic inflammation, as might be present in patients with rheumatoid arthritis (RA). AGEs are involved in the development of cardiovascular disease. The aim of this study is to evaluate whether AGEs are increased in patients with long-standing RA and whether AGE accumulation is related to disease activity, disease severity and measures of (premature) atherosclerosis, such as endothelial activation, endothelial dysfunction and intima media thickness (IMT). METHODS: In a cross-sectional study, 49 consecutive RA patients with longstanding disease (median disease duration of 12.3 years (range 9.3 to 15.1)), receiving standard of care, were included and compared with 49 age- and sex-matched healthy controls (HC). AGEs were determined by skin autofluorescence. Disease activity was evaluated by the Disease Activity Score of 28 joints (DAS-28) score and joint damage by modified Sharp-v.d. Heijde score. Endothelial activation (soluble vascular cellular adhesion molecule-1) sVCAM-1, von Willebrand factor (vWF), thrombomodulin), endothelial dysfunction (determined by small artery elasticity (SAE)) and IMT were measured and related to AGE accumulation. RESULTS: AGEs were increased in RA patients (median 2.4 arbitrary units (a.u.), range 1.6 to 4.2) compared to HC (2.2, 1.3 to 3.8). RA patients had a DAS-28 score of 2.9 (0.8 to 6.9) and a modified Sharp-v.d. Heijde score of 19 (0 to 103). sVCAM-1 and vWF levels were higher in RA patients. SAE was significantly decreased in RA (3.9 ml/mmHg (1.4 to 12.2) vs. 6.1 in HC (1.7 to 12.9). IMT did not differ between the two groups. Combining both groups' AGEs correlated with vWF, sVCAM-1 and IMT, and was inversely related to SAE. In RA, AGEs had an inverse relation with SAE, but did not relate to disease activity or radiological damage. In multivariate analysis for both groups, smoking, glucose levels, vWF, SAE and male gender were significantly related to the formation of AGEs. CONCLUSIONS: AGEs were increased in RA patients with long-standing disease and without signs of premature atherosclerosis. AGEs were related to endothelial activation and endothelial dysfunction. This supports the hypothesis that in RA AGEs may be an early marker of cardiovascular disease.

Is small artery elasticity decreased prior to intima-media thickening in patients with longstanding rheumatoid arthritis?

OBJECTIVE: To determine small artery elasticity (SAE) in patients with longstanding rheumatoid arthritis (RA) in comparison to healthy controls, and to investigate its relation to markers of endothelial cell activation, disease activity, joint damage, and the presence of atherosclerosis. METHODS: Forty-nine patients with RA and 50 age- and sex-matched healthy controls were studied. Traditional cardiovascular risk factors and disease-related factors were recorded. SAE was measured noninvasively by pulse-wave analysis (PWA). Endothelial activation was assessed by measuring levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and von Willebrand factor (vWF). Carotid intima-media thickness (IMT), as an indicator of subclinical atherosclerosis, was assessed using ultrasonography. RESULTS: Patients with RA had higher body mass index, blood pressure, and triglyceride levels and were more often cigarette smokers compared to controls. SAE was decreased in RA patients compared to controls and was inversely related with age, smoking, blood pressure, vWF, sVCAM-1, high sensitivity C-reactive protein, and IMT. Presence of RA was independently related to SAE in multivariate linear regression analysis. SAE was inversely related with the Health Assessment Questionnaire score. No correlation was found between SAE and other disease activity markers and damage. IMT in patients and controls was not different. CONCLUSION: Small artery elasticity was decreased in patients with longstanding RA. The presence of RA was independently associated with SAE. Whereas IMT in patients with RA was not increased, we hypothesize that endothelial dysfunction, reflected by decreased SAE, is present prior to IMT thickening in these patients.

Angiopoietin-2 is highly correlated with inflammation and disease activity in recent-onset rheumatoid arthritis and could be predictive for cardiovascular disease.

OBJECTIVE: To investigate whether serum levels of endothelial cell activation markers in early RA patients can serve as biomarkers for inflammation and disease activity, and are associated with radiological progression and development of cardiovascular disease (CVD). METHODS: Serum levels of VEGF, soluble vascular cell adhesion molecule (sVCAM)-1 and angiopoietin-2 (Angpt-2) were measured by ELISA in 176 patients with recent-onset RA, at the time of diagnosis and after 2 years. Markers of inflammation and disease activity were assessed, as well as radiological damage of hands and feet, at diagnosis and after 2 years. Prevalence of CVD of all patients after 12.5 years disease duration was retrieved from medical records. RESULTS: Patients with RA had higher levels of VEGF and Angpt-2 at disease onset compared with healthy controls, which correlated with markers of inflammation, but were not predictive of radiological progression after 2 years. Angpt-2 levels, moreover, significantly correlated with measures of disease activity. Nearly 18% of RA patients developed CVD after an average of 12.5 years of disease, and these patients had a significantly higher level of Angpt-2 at the onset of RA compared with patients who did not develop CVD. CONCLUSIONS: In early RA, markers of endothelial activation are highly correlated with inflammation and disease activity, but not with radiological progression. Angpt-2 could be predictive for the development of CVD since Angpt-2 levels were significantly higher in CVD patients than in non-CVD patients.

Risk factors and early detection of atherosclerosis in rheumatoid arthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased morbidity and mortality due to cardiovascular disease (CVD). This cannot be explained alone by the increased prevalence of traditional cardiovascular risk factors like smoking and hypertension. Other factors therefore seem to be involved in the pathogenesis of atherosclerosis in RA. METHODS: Literature was searched for epidemiology and pathophysiology of atherosclerosis in RA, with special focus on the role of advanced glycation end products (AGE's), endothelial activation, endothelial dysfunction and premature atherosclerosis as measured by intima media thickness (IMT). Finally, a literature search was performed on therapeutic strategies to prevent atherosclerosis in RA. RESULTS: In RA increased AGE accumulation, endothelial activation, endothelial dysfunction and premature atherosclerosis can be identified. Treatment of RA activity by multiple disease modifying anti rheumatic drugs (DMARD's) has shown to be effective in reducing premature atherosclerosis in RA. CONCLUSION: Cardiovascular disease is increased in RA. Tight disease control and treatment of other risk factors is recommended to prevent morbidity and mortality due to CVD in RA.