In the present study – the largest study to date investigating CAC in RA – we observed a higher prevalence and extent of CAC in RA patients compared with a geographically compatible population of non-RA controls after CV risk and sociodemographic adjustments. These associations were attenuated to varying degrees in models including IL-6, a marker of system inflammation – suggesting that IL-6 is a potential mediating variable. Increasing overall RA severity was also associated with a higher prevalence and extent of CAC, further suggesting that the RA disease process contributes to atherogenesis independently of traditional CV risk factors. We also observed age and gender heterogeneities with potential implications for RA patients. In particular, differences in CAC between men with RA and male controls were greater than those for women. In addition, the largest percentage difference in CAC between RA patients and their non-RA counterparts was observed in the youngest age category.
Two previous studies explored CAC in RA [5
]. Chung and colleagues investigated whether RA duration was associated with a higher CAC prevalence by enrolling only patients with either early RA (RA duration <5 years) or established RA (RA duration > 10 years), and compared these groups with a small group of non-RA controls [5
]. A greater prevalence of CAC was observed in the established RA group compared with both the control and early RA groups after adjusting for demographic and current CV risk factors. Their study did not, however, include a sufficient sample of men to analyze this group separately. In the study by Kao and colleagues, an association between the RA duration and the extent of CAC was observed, independently of demographic and CV risk factors [6
]. Their study did not incorporate a non-RA comparison group, however, and only women were enrolled. The present report differs from these prior studies in several important ways. The current study's larger size and comparison with MESA allowed subgroup comparisons by gender and age category that revealed potentially important heterogeneities. In addition, our exclusion of prior CV events allowed a focus on subclinical disease, thus limiting potential skewing of CAC in groups with prior CV events and procedures.
The mechanism underlying the observed increase in CAC in RA is likely complex and multifactorial. In multiple population-based studies [31
], individuals with the highest concentrations of circulating inflammatory markers were at greatest risk for CV events and mortality, and tended to demonstrate an increased burden of subclinical atherosclerosis, including CT-measured CAC [34
]. A direct effect of inflammatory cytokines on the vasculature in promoting atherogenesis and destabilizing coronary plaques has been proposed as a potential mechanism [13
]. RA patients have considerably higher circulating levels of inflammatory cytokines than non-RA controls, and adjustment for IL-6 in the statistical models partially attenuated the observed association between RA status and CAC, suggesting that systemic inflammation accounted for at least part of the association. We did not, however, see the same magnitude of attenuation upon adjustment for serum CRP concentration, which has been associated with CV events and subclinical atherosclerosis [31
]. While this apparent disconnection might suggest pathogenic specificity of individual inflammatory cytokines, these speculations are limited by the cross-sectional nature of the analysis, and the discrepancy may be the result of random variability. Importantly, a single measurement of inflammatory cytokines is not representative of the total inflammatory burden of RA patients. While follow-up will help to assess the associations of cumulative inflammation with progression of CAC in RA patients, the cross-sectional association of RA propensity scores (a clinical reflection of current and past burden of disease) with CAC nonetheless supports an association between inflammation and CAC. On the other hand, finding that the association of RA status and CAC is only partially attenuated by IL-6 suggests the presence of additional RA-related mediators. These might include a phenotypically unusual T-cell clone (CD4+
], shared risk factors (such as genetic predisposition), RA treatments (such as glucocorticoids and nonsteroidal anti-inflammatory drugs), and the debilitating effect of joint pain and stiffness on physical activity and fitness.
In most studies of CVD in RA, differences in the prevalence of traditional CV risk factors compared with controls have not been detected [11
]. We detected small but significant differences in blood pressure in RA patients compared with controls that could affect CV risk unfavorably. We also detected higher mean high-density lipoprotein-cholesterol, lower mean fasting glucose and diagnosed diabetes, and lower prevalence of the metabolic syndrome in the RA groups, however – all of which could decrease CV risk. Although heterogeneity in the associations with traditional CV risk factors, other than age and gender, on CAC by RA status was not explored, our findings suggest that conventional means of risk-stratifying RA patients probably underestimate their risk. In particular, the largest difference in CAC, by a several-fold increase, between RA patients and controls was observed in the youngest age category, an age group in which CAC is typically low in both men and women [16
]. This same heterogeneity by age has also been observed for carotid plaque in a study primarily of women with RA [4
], in which the largest percentage difference in the prevalence of carotid plaque was observed in the RA patients younger than age 50 years.
There are some notable limitations to our study. As MESA is a population-based study without exclusion of patients with rheumatic disease, it is possible that RA patients could have been included in the non-RA control group. As such potential misclassification would tend to lessen the observed differences between the RA and control groups, the true effect of complete accuracy in the classification of exposure status would actually strengthen the association of RA status with CAC. To reduce misclassification by RA status, we excluded patients from the control group who reported using medications commonly used to treat active RA. While this method of identification of RA is more reliable than patient self-report of the diagnosis [36
] and is commonly used in epidemiological studies for the diagnosis of RA, there are limitations – RA patients not taking DMARDs would be included, and those with other diseases in which these medications are used, such as Crohn's disease or psoriasis, would be excluded. Another limitation is that calcification of coronary plaque may not be equally representative of the same atherosclerotic burden in RA patients as controls, since noncalcified soft plaque is not detected by Agatston scoring [37
]. This limitation is supported by a recent autopsy study in which RA patients demonstrated scattered vulnerable plaques that were highly inflammatory on histologic examination despite having less extensive atherosclerotic burden overall compared with controls [7
]. Finally, differences in referral patterns into the study (community based for the MESA vs. clinic based for the ESCAPE RA study) could have introduced selection bias or confounding on factors not related to exposure status. However, as the two cohorts were geographically compatible, as all of the ESCAPE RA patients were community dwelling, and as many ESCAPE RA patients were recruited from community rheumatologists, it is likely that any bias related to selection would be limited. Another potential problem is that the analyses were cross-sectional, and thus temporality cannot be established.