Background/Purpose: Rheumatoid arthritis (RA) is independently associated with a higher risk of cardiovascular disease (CVD) and premature atherosclerosis. Mechanisms of atherosclerosis include (1) Endothelial dysfunction/activation mediated by intercellular adhesion molecules (e.g., ICAM-1, VCAM-1, E-selectin) and oxidative stress (e.g., through MPO activity); (2) Inflammation mediated by cytokines (e.g., IL-6); (3) Plaque stability mediated by CD40-CD40L interactions; and (4) Proteolysis/Plaque rupture mediated by proteolytic enzymes (e.g. MMP-9). This study evaluates whether these serum biomarkers are higher in RA subjects, and/or associated with subclinical carotid atherosclerosis.

Methods: Carotid ultrasounds were performed with measurement of intima-media thickness (cIMT, using maximum of both sides) and plaque presence (of either side), and serum biomarkers (ICAM-1, VCAM-1, E-selectin, MPO, IL-6, CD40L, and MMP-9) were measured by ELISA in all subjects (46 RA cases and 70 controls). Each of the biomarkers, cIMT, plaque presence, and demographic data, were tested for differences between cases and controls, using the Wilcoxon rank-sum test (for continuous data) or chi-square test. The relationship between each serum biomarker and cIMT or plaque presence was tested by Spearman correlations or rank-sum test (for IL-6 only, which was categorized as above detection limit [for 21%] or not).

Results: Mean age, BMI, and gender frequency were similar (p≥0.19) between RA (59.3 years, 28.9, 72% female) and controls (54.7 years, 28.7, 67% female); race was significantly different (4.4% African-American or other in RA vs. 28.6% in controls; p=0.001). Mean cIMT and detectable IL-6 presence were higher in RA (0.88 and 31.8%) than controls (0.79 and 14.3%; p=0.02 and 0.03). Mean (+/-SD) MPO was lower in RA (594.9+/-670.9) than controls (727.4+/-464.6) (p=0.01). Plaque presence was found in 47.8% of RA cases vs. 37.7% of controls (p=0.28). None of the other serum biomarkers were significantly different between RA vs. controls.

ICAM-1 (r=0.36, p<0.001), VCAM-1 (r=0.28, p=0.002), and E-selectin (r=0.32, p<0.001) were positively associated with cIMT in the overall group. Mean cIMT was higher in those with IL-6 above detection limit (0.91 vs. 0.80; p=0.05). Mean CD40L and MPO were lower in those with plaque presence (8385 for CD40L and 554 for MPO) compared to plaque absence (9433 for CD40L and 754 for MPO). Results were similar when examined in the RA and control groups separately, though the magnitude of the correlations with cIMT was slightly higher in the control group for ICAM-1, VCAM-1, and E-selectin. In the RA group only, mean ICAM-1 was higher (292) in those with plaque than in those without plaque (234) (p=0.05).

Conclusion: This study confirms previous observations that cIMT is higher in RA than non-RA subjects. Markers of endothelial dysfunction (ICAM-1, VCAM-1, E-selectin) are significantly associated with higher cIMT in both RA and non-RA subjects. This suggests possible common pathways of atherosclerotic progression as evidenced by cIMT and biomarker elevation. Further studies are needed to determine the predictive ability of these and other serum biomarkers in CVD risk stratification algorithms in RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/can-modulators-of-inflammation-serve-as-biomarkers-for-subclinical-atherosclerosis-in-rheumatoid-arthritis/