This study underscores the importance of examining potential race-specific risk factor interactions on CVD measures in SLE patients. Examining for specific race-related interactions revealed novel findings. Smoking significantly increased mIMT values in Blacks with SLE, but not in Whites. If race-specific interactions had not been sought in our cohort as potential covariables, smoking would not have been detected as having any impact on the outcome of mIMT. Since race was not significant in the bivariate analysis for mIMT, it would not ordinarily have been included in a regression analysis, and the interaction may not have been investigated. Many studies suggest that there is a SLE specific factor that is contributing to early CVD. Not investigating race and race interactions on CVD outcomes could potentially ignore important covariables that may be specific to the SLE population.
There is great variability in the prevalence of CVD in populations with rheumatic diseases depending on the study and the type of outcome measure used. Both IMT measurements, with or without identification of carotid plaque (8
) and CAC (9
) have been used as measures of CAD in SLE as predictors of cardiovascular events, as well as in rheumatoid arthritis. (23
) In the general population, mean IMT has predictive ability for both myocardial infarction and stroke. (24
Recent data from the Multi-Ethnic Study of Atherosclerosis (MESA) demonstrates that there are significant differences in IMT and CAC measures depending on age, race, and gender. MESA is a multiethnic study that examined 6814 participants free of any clinical heart disease between the ages of 45–84. (25
) Prior to this study, expected CAC scores for race-matched populations were not available. Results from MESA have also shown that there are racial differences between relationships of certain IMT measurements (e.g., common versus internal carotid locations) and CAC. To date, there has never been any examination of inter-racial comparisons of IMT or CAC, and whether there is any relationship between these two measures in SLE patients.
Similar to our findings, previous studies examining CVD and SLE demonstrated that advancing age (8
) and elevated fasting glucose levels (10
) are associated with increased IMT measurements. Elevated triglycerides have been found to be linked with increasing IMTs in the general population as well as in other groups with inflammatory diseases known to have accelerated atherosclerosis, such as rheumatoid arthritis (26
) and psoriatic arthritis (27
), but not in SLE. In addition to age, the age-race interaction significantly affected IMT. Mean IMT did not significantly increase in the bivariate analysis in Black subjects in our cohort, but did in White subjects. This racial difference may be a reflection of our cohort. In the MESA study, incremental increases in IMT measures were not as great in Black women as in White women, but did increase with age (28
). In addition to age, other studies have reported variables including duration of corticosteroid use (8
), higher CRP levels, elevated cholesterol, and increased pulse pressure as being associated with higher IMT measurements. (10
) Differing results for covariables between studies are likely mutifactorial, including methodological differences, population differences between cohorts, and whether studies are appropriately powered.
Smoking is recognized as a risk factor for development of SLE and for the presence of vascular disease in patients with SLE. A meta-analysis examining the effect of smoking on SLE demonstrated that current smoking increased the odds of developing SLE by 50%.(29
) Active cigarette smoking has also been associated with higher disease activity (30
) and a 4-fold increased risk of having seropositivity for anti-double stranded DNA antibodies. (31
) Smoking contributes independently to vascular events in SLE (7
) with current smokers having an OR of 3.7 (95% CI 1.4, 10.0) compared to non-smokers. Ethnicity has not been shown to be independently associated with vascular events in SLE. (7
) The total numbers of SLE subjects with a cardiovascular event in any one report have been low and the total numbers of Black SLE subjects even lower; 10/19 in the Hopkins cohort (33
), 6 “non-Caucasians”/33 in the Pittsburgh cohort (34
), and 15/34 in the LUMINA cohort. (7
) It does not appear that the race-smoking interaction was investigated as a potential variable in the regression models in these three studies. Since race was not a significant factor in the bivariate analyses, the interaction of race and smoking was probably not investigated further, even if smoking was found to be a significant univariate variable, as it was in the LUMINA study.
Genetic variability between racial groups may contribute to group differences in measures of cardiovascular disease. It has been demonstrated that different haplotypes for specific genes have an impact on the risk for ischemic stroke and cardiovascular disease that differs between races. (36
) Potential race-specific interactions impacting accelerated atherosclerosis in patients with chronic inflammatory conditions is an area of great interest. Conditions in the general population associated with inflammation demonstrate gene-environment interactions, such that inflammatory exposures including smoking, obesity/abnormal glucose tolerance, and chronic infections are associated with significantly higher IMTs when patients have inflammatory gene polymorphisms, in particular IL-6 and NADPH oxidase. (38
) Race differences were not examined in these studies. It is easy for one to imagine that similar gene-environment variations may exist in SLE patients resulting in accelerated atherosclerosis depending on exposures and polymorphisms that may depend on race. Genetic associations with cardiovascular disease have been linked to other rheumatological conditions, including rheumatoid arthritis (RA). RA patients with HLA-DRB1*04 shared epitopes have poorer endothelial dependent vasodilation (41
) and an increased risk of CVD mortality. (42
) In addition, an interaction of smoking, shared epitopes from the HLA-DRB1 locus, and presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies has been associated with a substantially higher risk of CVD death in RA patients (Hazard Ratio=7.81). (43
We are unaware of any studies that have examined race interactions with smoking and IMT in the general population. The effects of smoking in different racial groups have been examined using alternative measures of CVD. Arterial stiffness has been shown to be greater in Black subjects that smoke, as compared to White subjects. (44
) In a recent study, smoking was found to be independently associated with premature coronary atherosclerosis, via angiogram, in Whites and Blacks without SLE. While smoking was the only factor impacting CVD in Whites, diabetes and dyslipidemia were also independently associated in Blacks. (45
) There are also investigations that identify racial differences with regard to the metabolism of nicotine. Blacks are known to have a 30% higher intake of nicotine per cigarette than Whites and have a slower clearance of nicotine metabolites. (46
) Perhaps the additive effect of inflammatory exposures (including smoking and/or rheumatic disease), race, along with specific gene polymorphisms all contribute to accelerated CVD. Whether our findings are specific to Black SLE patients or whether they reflect a race effect in the general population warrants further investigation.
Limitations of this study include the overall number of SLE subjects, including African-American subjects. The outcome measure of CAC was further limited in that only 22% of African-American subjects had a CAC measurement greater than zero. One further limitation may have included misclassification. We relied on self-report by patients on whether they had ever smoked or not. It appears that in the general population, self-reporting of active smoking is generally accurate. (48
) We were unable to determine if the interaction of race and smoking is seen in a similar group of control subjects. This study is the first to examine these racial interactions, and thus future studies are warranted to see if this is indeed a SLE specific finding. We also recognize, as discussed, that carotid IMT may or not be the best measure of subclinical vascular disease. There have not been large studies comparing measures of subclinical disease and CVD outcomes in SLE. Carotid IMT has been shown to be a strong predictor for myocardial infarction and stroke in the general population. (24
) Because no Black subjects reported ever having been on a lipid lowering agent, we were unable to assess whether these agents may have impacted any difference in the CVD measures. Of interest is that we did examine whether there were any significant differences between racial groups on fasting cholesterol levels >200 mg/dL, LDL >130 mg/dL, HDL <35 mg/dL, or TG >205 mg/dL. There were no significant differences (data not shown). Despite similar proportions of dyslipidemia in the two populations, 22% of Whites had been on a lipid lowering agent, while none of the Black subjects had. This difference may reflect reporting error or may be consistent with similar trends in the general population. A recent study was done to examine the trends in statin use after the publication of the National Cholesterol Education Program Third Adult Treatment Panel (ATP-III) guidelines in 2001. Results from this report demonstrate that non-Hispanic Blacks are 39% less likely than non-Hispanic Whites to be taking a statin. (49
In summary, we determined that in a model examining race-specific interactions for measures of subclinical CVD, that there are racial interactions with age and with smoking that impact carotid IMT. In addition, when controlling for age, increasing triglycerides and fasting glucose levels also were associated with higher IMT measurements. We did not detect any racial interactions with other risk factors for CAC. When controlling for age, SLE duration was the only other significant covariable impacting CAC score. Larger studies involving appropriately powered racial groups are warranted to examine racial interactions and their impact on measures of CVD and on CVD events in SLE patients.