Consistent with previous reports, we found that, after controlling for traditional risk factors, individuals with SLE are at increased risk for CVEs (1
). Our estimate of the overall rate ratio of 2.66 is lower than some earlier estimates (3
) but consistent with more recent estimates (1
). Also consistent with all previous reports, the excess risk was most pronounced among individuals under 40 years of age (3
If the higher rates of CVEs among SLE patients are due, in part, to the cumulative effect of immunologic processes associated with SLE disease activity, one would expect that those who have had SLE longer would be at higher risk of a CVE. However, after adjusting for age, we did not observe a positive association between duration of SLE and rates of CVEs. This is consistent with most of the previous studies of this relation (3
) with one exception (2
). Several studies reported a positive association between subclinical markers of CVE and SLE duration (16
), but the investigators did not adjust for age.
We observed a dose-dependent increase in CVE rates in patients currently taking corticosteroids. Those on 20 mg/day or more had a 5-fold increased rate after adjustment for age, and current use had a stronger association with CVE than did cumulative past use. Three previous studies of other large non-SLE cohorts similarly found that current (but not past) use of corticosteroids was associated with higher CVE rates (18
). All 3 studies found that the increased risk was highest among those with higher current doses. Our findings, along with these previous consistent findings, suggest that there is an acute impact of corticosteroids on CVE risk.
One alternative explanation for the observed association between current use of corticosteroids and CVE risk, raised by Huiart et al. (19
), is that current use of corticosteroids is merely a marker for a flare of disease activity that is the real cause of the increased CVE risk. However, in our multivariable analysis, the association between corticosteroids and CVEs persisted after we controlled for the disease activity level measured at the time of the corticosteroid prescription decision (Table ).
Another possibility is that association between current use of corticosteroids and CVE risk is due to their impact on traditional risk factors, such as blood pressure or serum lipids. In our analysis, the effect of corticosteroid use on CVE risk persisted after we controlled for blood pressure and serum cholesterol, which suggests that the association is independent of the effect of corticosteroids on these risk factors. However, the blood pressure and serum cholesterol measurements used in our analyses were those taken at the most recent visit, which might have been several months earlier, so we cannot totally rule out the possibility that corticosteroids resulted in an increase in those risk factors in the intervening time that affected the risk of a CVE.
Although the univariate results suggested that those on hydroxychloroquine had a reduced rate of CVE, we did not obtain strong evidence of a protective effect (P
= 0.13) in a multivariable model in which we controlled for other variables. In contrast, several other studies observed a protective effect of hydroxychloroquine on thrombosis, thrombovascular events (21
), vascular events (23
), and survival (24
) among SLE patients. Hydroxychloroquine has been shown to reduce serum cholesterol (26
), reduce glucose (26
), and be negatively associated with the presence of carotid plaque (17
) and vascular damage (28
For each measure of disease activity in Table (SLEDAI, musculoskeletal, skin, low complement, anti-dsDNA), the impact of recent activity appeared greater than the impact of a history of that type of disease activity. These findings and the fact that we did not observe an association between disease duration and CVE suggest that the impact of disease activity is more acute. Alternatively, these results are consistent with the possibility that levels of current disease activity are indicators of other clinical problems or higher doses of medications, which lead to the CVE. There was only a moderate association between SELENA-SLEDAI and CVE rates after adjusting for medication use.
To our knowledge, the present study is the largest cohort study of CVE rates in terms of number of SLE patients, duration of follow-up, and frequency of follow-up visits. However, there are some limitations to using this observational clinical cohort to address our study questions. First, this is a single-center cohort, so the CVE experience reflects the type of patient that comes to our center and the treatment strategies used there over the last 23 years. Second, clinical variables were only assessed quarterly, so the blood pressure, SLE disease activity, and other variables attributed to a person-month in the analysis might not represent the actual values of those variables in that month. This would have less affect on variables such as treatments (which tend to be stable between visits) and means across prior visits. Third, although sometimes patients attended more frequently than quarterly, sometimes patients missed visits, and in each month of follow-up, the most recent measurement of a variable in our analysis was more than 3 months earlier for 20% of the visits. Fourth, as noted above, some auto-antibodies (anti-Ro, anti-La, anti-ribonucleoprotein, and anti-Smith) were only measured once during cohort participation, so our information about them is limited. Many of these limitations tend to result in misclassification of predictors during person-months, which could attenuate estimates of associations.
In summary, the rate of CVEs in our SLE cohort was observed to be 2.66 times higher than would be expected in the general population with similar levels of traditional risk factors. After adjustment for age, the excess risk was not associated with SLE duration but was associated with current disease activity and anti-dsDNA. Most interestingly, consistent with several other recent studies, the excess risk was more strongly associated with the current dose of corticosteroid than with cumulative past dose of corticosteroids, which suggests a short-term impact of corticosteroid use on CVE risk.