Identifying Vulnerable Plaque in Rheumatoid Arthritis: A Pilot Study Using Novel Microbubble-Contrast Enhanced Carotid Ultrasonography

Kimberly P. Liang1, Douglas P. Landsittel2, Suresh R. Mulukutla3, Steven E. Reis3, Marc C. Levesque1, Flordeliza S. Villanueva3, Hunter C. Champion4, Larry W. Moreland1.
1Division of Rheumatology; University of Pittsburgh. 2Center for Health Care Research Data Center; University of Pittsburgh. 3Division of Cardiology; University of Pittsburgh. 4Division of Pulmonary, Allergy and Critical Care Medicine; University of Pittsburgh.

BACKGROUND: Rheumatoid arthritis (RA) is independently associated with a higher risk of cardiovascular disease (CVD). Markers of inflammation, as seen in RA, are associated with plaque vulnerability. Increased vasa vasorum neovascularization has been identified as a common feature of inflammation and plaque vulnerability, and independently predicts future CV events in the non-RA general population. Excess CVD risk in RA may be caused by disease-related factors leading to vulnerable plaque characterized by increased vasa vasorum neovascularization, which is not assessed by traditional imaging modalities. Microbubble contrast-enhanced carotid ultrasound (CU) is a novel imaging technique that has been validated in detecting measures of vulnerable plaque, namely increased adventitial vasa vasorum density (aVVD), in non-RA subjects.
Our objective was to establish feasibility of measuring aVVD in RA patients; to determine whether RA patients have higher aVVD compared to non-RA controls, and whether disease-related RA measures correlate with increased aVVD, using CU.
METHODS: We performed a preliminary cross-sectional study of 23 RA cases and 28 non-RA controls; this project is ongoing. All 51 subjects underwent CU with measurement of intima-media thickness (IMT, using maximum of both sides) and the mean common carotid artery adventitial to lumen videointensity ratio (using maximum of both sides) to quantify aVVD. Demographic and CV risk factor data were collected on all subjects, and tested for differences between cases and controls, using the Wilcoxon rank-sum test for continuous data and Fisher’s exact test for categorical data. RA disease activity measures (CDAI and DAS28), erythrocyte sedimentation rate, high sensitivity C-reactive protein (CRP), rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP), were collected systematically on RA subjects. Spearman correlations were assessed between disease activity measures and aVVD and IMT within cases.
RESULTS: Demographic and CV risk factors between RA and controls were similar, except for mean age (58.0 years in RA, 66.1 years in controls; p<0.01); systolic blood pressure (138 in RA, 120 in controls; p<0.01); race (91.3% white in RA, 64.3% white in controls; p=0.02); and personal history of CVD (17.4% in RA, 42% in controls; p=0.08). The aVVD in RA was 0.633, whereas in controls it was 0.595; this difference was not statistically significant (p=0.31). The difference in IMT between RA and controls was even less significant (0.85 in RA, 0.80 in controls; p=0.65). After adjusting for age and personal history of CVD, results did not qualitatively change. CRP, RF and CCP were all significantly higher in RA than controls (p<0.001). No correlation between disease activity measures with aVVD and IMT were significant.
CONCLUSIONS: Measurement of aVVD to quantify plaque vulnerability in RA patients is feasible utilizing the novel CU technique. In this pilot study, the aVVD was slightly higher in RA than control subjects, though this difference was not statistically significant. Our study is ongoing, with plans for targeted enrollment of larger numbers and adjustment for differences in demographic and CV risk factors.