Premature atherosclerosis is a major cause of mortality and late morbidity in patients with systemic lupus erythematosus (SLE) (1–3). In several cohort studies, it was found that atherosclerotic cardiovascular and cerebrovascular diseases are more common causes of late deaths than active SLE itself (1, 4–6). More recent studies have demonstrated that subclinical coronary heart disease and carotid plaque were present in a significantly higher proportion of SLE patients than in age- and sex-matched control subjects with similar risk factors (7, 8). The etiology of accelerated atherosclerosis in SLE is multifactorial and cannot be fully explained by traditional risk factors (9).
Compared with individuals without SLE, the risk of myocardial infarction in SLE patients is 2–50 times higher, and the risk of stroke is 2–10 times higher (2, 9, 10). The prevalence of symptomatic coronary heart disease in SLE patients has been reported to be 6–20%, depending on the characteristics of the cohort, disease duration, study design, prevalence of antiphospholipid antibodies (aPL), and ethnic composition (11). The frequency of stroke is less well studied, but it has been reported that 3–15% of SLE patients have a nonfatal stroke (2, 12, 13).
A number of risk factors for symptomatic coronary heart disease and stroke in SLE have been identified in case–control studies. These risk factors include age at SLE diagnosis (10, 14, 15), disease duration (10, 14), hypertension (15–17), dyslipidemia (10, 15, 17, 18), hyperhomocysteinemia (18, 19), oxidized low-density lipoprotein (LDL) (18), smoking (14, 16), use of corticosteroids and their duration (10, 15, 18), aPL (14, 18, 20, 21), and valvular abnormalities of the heart (22). Other factors that may be relevant to arterial or venous thromboembolism in SLE are genetic mutations (23), pregnancy, and the use of exogenous estrogens (24) for contraception, climacteric symptoms, and control of cyclic SLE activity. The use of hydroxychloroquine in SLE, on the other hand, may be protective (25).
It is well established that aPL are associated with both arterial and venous thrombosis. Recent studies have also shown that the antiphospholipid syndrome with thrombotic complications in SLE is a major adverse factor for irreversible organ damage and survival (26). In large cohort studies, the lupus anticoagulant has been shown to be a significant risk factor for myocardial infarction (20) and stroke (27) in both Caucasian and non-Caucasian patients with SLE.
While most reported studies have involved Caucasian patients and have focused on arterial thromboembolism, data regarding the risk of venous thromboembolism, particularly in non-Caucasian SLE patients, are scant. The present prospective study was undertaken to determine the incidence and risk factors for arterial and venous thromboembolic events in Chinese and African American SLE patients as compared with those in Caucasian SLE patients.
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- PATIENTS AND METHODS
This was a prospective study on the incidence and risk factors of arterial and venous thromboembolism in a large number of patients with new-onset SLE. Toloza et al (14) reported that 7.1% of Caucasian SLE patients experienced arterial vascular events over a mean observation period of 73.8 months, whereas in the study by Manzi et al (10), 6.6% of Caucasian SLE patients developed MI or angina pectoris over a mean followup of ∼7 years. Esdaile et al (9) studied 263 Caucasian patients with SLE who were followed up for a mean of 8.6 years. The incidence of MI or death related to MI was 13%, and the incidence of stroke or death related to stroke was 6%. A study of 397 SLE patients by Rahman et al (29) showed that 9% of patients had coronary heart disease. The incidence of arterial events in the present study (cumulative risk at 5 years 5.1% in Caucasians) is similar to that in these previous studies.
However, few studies have reported the incidence of arterial thrombosis in African American patients with SLE. In the LUMINA (LUpus in MInorities, NAture versus nurture) study by Toloza et al (14), 7.5% of African American SLE patients developed arterial vascular events. This incidence is very similar to the 8.1% found in our study. In fact, in the previous study of the Hopkins Lupus Cohort (the participating institute of the current study) that was reported more than 10 years ago (15), the incidence of MI, angina pectoris, and cardiac death was 8.3%. At that time, data from Caucasian and African American patients were not separated, and the analyses did not include other arterial events, such as stroke and peripheral vascular disease. This precludes direct comparison with the current results.
The risk of thromboembolism in Chinese SLE patients is virtually unknown. In a recent survival analysis of Chinese SLE patients followed up at Tuen Mun Hospital, a participating institute of the present study, cardiovascular and cerebrovascular events accounted for 31% of the deaths in a 10-year period (30). It is intriguing to note that Chinese patients had a higher incidence of arterial vascular events and that Chinese race (as compared with non-Chinese) emerged as an independent predictor of these events in the multivariate model. From the comparative analysis of risk factors, it appeared that the only unfavorable factor for arterial events in the Chinese patients was the lower frequency of the use of HCQ, which might have a beneficial effect on the lipid profile (25, 31). However, HCQ was not a significant protective factor in the current study. The greater interethnic variation in the incidence of arterial events in aPL-negative versus aPL-positive patients suggests that risk factors other than aPL might make a greater contribution to the observed difference. While differences in the health care delivery systems of the two centers, as well as the health-seeking and compliance behaviors of the patients, might contribute to the observed interethnic difference in the risk of arterial thrombosis in the current study, factors that were not addressed, such as serum homocysteine levels, genetic factors, including mannose-binding lectin polymorphisms (23), and overall SLE activity throughout the entire observation period, warrant further evaluation.
A number of factors have been reported to increase the risk of clinical and subclinical atherosclerotic vascular disease in patients with SLE. These include increasing age (7, 8, 10, 14, 15, 32–35), male sex (7), smoking (14, 16), longer disease duration (8, 10, 14, 15), dyslipidemia (8, 10, 15, 16, 18, 32–34, 36), hyperhomocysteinemia (18, 19, 36), presence of aPL (14, 18, 20), higher damage scores (8), duration and cumulative doses of corticosteroids (10, 15, 16, 18, 33), systolic hypertension (15, 17, 32–34), and obesity (15, 36).
In the current study, traditional risk factors, such as age, smoking, diabetes mellitus, and hypertension, were not found to be significant predictors of arterial thrombosis. Two possible explanations can be offered. First, atherosclerosis is a slow and longstanding process. The relatively short exposure of our patients to these risk factors (<5 years) may not be adequate for the development of arterial events, especially when risk factors that were present at any time since the diagnosis of SLE were used in the analyses. Second, the sample size of the cohorts may not be large enough to allow a demonstration of the significant contribution of these risk factors to arterial thrombosis.
Dyslipidemia, as manifested by high levels of serum total and LDL cholesterol, high levels of triglycerides, and low levels of HDL cholesterol, is a well-recognized conventional risk factor for arterial thrombosis in SLE patients (10, 15, 16, 18, 36). Although hypertriglyceridemia and LDL hypercholesterolemia were not found to predict arterial events in the present study, a low serum level of HDL cholesterol was found to be a significant risk factor in both univariate and multivariate analyses. This is consistent with the findings of other studies (16, 18). Intriguingly, a low serum level of HDL cholesterol was also found to be an independent risk factor for venous thrombosis. The importance of a low HDL cholesterol level in vascular thrombosis is illustrated by a recent study that showed a high prevalence of antibodies to apolipoprotein A-I in SLE patients, which was associated with the presence of aPL (37). Sera with antibodies to apolipoprotein A-I showed a high affinity for mature HDL cholesterol molecules, which might account for the low serum HDL levels observed in SLE patients at risk of vascular thrombosis.
Most studies of venous thromboembolism in SLE have been cross-sectional or retrospective. The incidence of venous thromboembolism in SLE patients with disease duration of >10 years ranges from 3% to 16% (38–40). The cumulative risk of venous thromboembolism in Caucasian SLE patients in the current study (10.3% at 5 years of diagnosis) fell into the expected range. However, Chinese patients had a significantly lower risk of venous thrombosis as compared with Caucasian patients, even after adjustment for other factors in the full multivariate model. This is consistent with the clinical observation that Chinese and Asian patients generally have a lower incidence of deep vein thrombosis and pulmonary embolism compared with Caucasian patients (41, 42). While the lower prevalence of aPL and the less frequent use of exogenous hormones might contribute to the lower incidence of venous thrombosis observed in our Chinese patients, other factors not addressed in this study may be responsible for this ethnic difference. These include differences in the prevalence of acquired activated protein C resistance, factor V Leiden mutation, β2-glycoprotein I genetic mutation, and antiprothrombin antibodies, which have been reported in association with venous thromboembolism in SLE patients (43–47).
The procoagulant activity of aPL is related to their effects on coagulation factors, platelets, and endothelial cells. These antibodies are associated with both arterial and venous thrombosis in patients with SLE. The demonstration of aPL as one of the independent predictors of venous thrombosis in the current study is consistent with this.
In summary, interethnic differences in the incidence of arterial and venous thromboembolism in patients with SLE are important and may have therapeutic implications. These differences cannot be fully explained by differences in the prevalence of the risk factors we studied. Further study of other genetic and immunologic factors will be necessary to account for these racial differences.