Systemic Lupus Erythematosus and Accelerated Atherosclerosis

Abstracts & Commentary

Synopsis: SLE now joins the list of conditions that are associated with an increased risk of the development of vascular disease, particularly CAD.

Sources: Roman MJ, et al. N Engl J Med. 2003;349: 2399-2406; Asanuma Y, et al. N Engl J Med. 2003; 349:2407-2415; Hahn BH, et al. N Engl J Med. 2003; 349:2379-2380.

Systemic lupus erythematosus (SLE) should now be established as an additional major risk factor for the development of coronary atherosclerosis. Thus, along with chronic kidney disease and metabolic syndrome, physicians must be alert and aggressive with respect to identification of all coronary artery disease (CAD) risk factors, as well as preventive measures for SLE individuals. Two reports published simultaneously, one from Medical College of Cornell University (Roman and associates), and the other from Vanderbilt University School of Medicine (Asanuma and associates), unequivocally confirm that SLE is associated with premature vascular disease, often asymptomatic, and this is a particularly important problem in younger individuals with SLE. The studies included SLE patients and matched controls. The Cornell group used carotid ultrasonography for assessment of vascular disease; 197 SLE patients and matched controls were included. The Vanderbilt group studied 65 patients with SLE and matched controls and used electron beam computed tomography (EBCT) for coronary calcification as the primary screening method to identify CAD. Both studies included a variety of serum markers and evaluated the risk of SLE for vascular disease using conventional risk factors, including gender, age, and lipids. In addition, the Cornell group assessed SLE-specific therapy as a potential factor in increasing or decreasing CAD risk. They used sophisticated laboratory analyses, including tests for double-stranded DNA antibodies, Smith antibodies, ribonuclear protein, and antiphospholipid antibodies. Interleukin-6, TNF55, and 75 receptors were assayed; in addition, VCAM-1, ICAM-1, and homocysteine levels following a methionine load were part of the evaluation process. The Vanderbilt group relied on imaging with EBCT and measured only standard lab tests, including LP(a) lipoprotein and homocysteine.

The results from the 2 studies are concordant and unequivocally indicate that SLE is a potent risk factor for early CAD and vascular disease, no matter the age and gender. The risk ratios were considerable, and in younger SLE women, were estimated to be up to 50 times the risk of having CAD when compared to matched controls. Assessment of plaque by carotid ultrasound was 2-3-fold more likely in the SLE patients and 5-6 times greater in SLE individuals younger than 40.

Intimal-medial thickness, however, was less and luminal diameter greater in SLE patients than controls. Serologic markers of lupus were less common in those individuals with plaque than those without. Antidouble-stranded DNA and antiphospholipid antibodies were no different between those with and without plaque; anticardiolipid antibodies were less common in SLE patients with carotid plaque. Current or prior prednisone therapy was less likely to be associated with plaque, and cyclophosphamide and hydroxychloroquine use was lower in individuals with plaque. Inflammatory markers were not different, including CRP, IL-6, TNF receptors, CD40 ligand, ICAM-1, and VCAM-1. Major predictors of atherosclerosis in SLE patients in the Cornell study included age, disease duration, and a damage-index score. Negative predictors included cyclophosphamide use, anti-SM antibody, and hydroxychloroquine use. In the Vanderbilt patients (EBCT expertise was provided by Dr. P. Raggi of Tulane University School of Medicine), coronary artery calcifications was more frequent in SLE patients (20 of 65) than in controls (6 of 69; P = .002). The mean Agatston calcification score in the lupus patients was 69 vs 9 in the controls; lipid profiles were not abnormal in the SLE patients, although levels of triglycerides and homocysteine were elevated. Coronary calcifications were common in older males, but measurement of disease activity in the lupus individuals were similar in those with and without coronary calcification. Coronary calcification was more common in younger patients with SLE than controls, increasingly with age. The Vanderbilt authors concluded that "asymptomatic atherosclerosis is frequently present in patients with lupus and cannot be predicted by the presence or absence of other cardiovascular risk factors." This is essentially similar to the Cornell conclusions. Overall, SLE patients had little differences in their lipid profiles from controls. The Vanderbilt, but not the Cornell, cohort tended to be hypertensive when compared to controls.

The Cornell investigators suggest that chronic inflammation may be a major player in atherogenesis in the SLE population. An increased prevalence of atherosclerosis was seen in individuals with longer duration of SLE, a higher damage-index, and in general, less aggressive immunosuppressant therapy. However, markers of inflammation were not increased in those individuals with carotid plaque vs without. The Cornell investigators believe "the presence of plaque is a more potent predictor of clinical events, particularly myocardial infarction, and is a better index than the intimal-medial thickness." They postulate that there are essentially 2 patterns of SLE: one with a protracted course and "less virulent disease that fosters atherosclerosis," and the other dominated by autoimmunity and a more aggressive clinical course, resulting in a greater likelihood of receiving immunosuppressive therapy. They emphasize the "significant negative ratio between the use of hydroxychloroquine and the presence of atherosclerosis," and conclude, "SLE is associated with an increased prevalence of atherosclerosis, which was most striking in young patients." They point out that traditional CAD risk factors cannot explain the accelerated course; the data from the EBCT cohort are congruous.

Comment by Jonathan Abrams, MD

These 2 publications unequivocally resolve the longstanding controversy as to whether having SLE and/or being treated with steroids over a long period of time are related to the development of atherosclerosis. The data in these case controlled reports are very convincing. Cerebrovascular atherosclerosis was assessed by carotid ultrasound and coronary atherosclerosis by coronary calcium score. The more sophisticated Vanderbilt report provides a great deal of laboratory analysis, which turned out not to be particularly helpful in differentiating high- vs low-risk individuals. Nevertheless, there were certain differences in the prevalence of a number of markers in patients with and without carotid plaque that do support the Cornell authors’ hypothesis that SLE may be associated with 2 divergent clinical courses. It is unlikely that the carotid or the coronary imaging techniques are sensitive enough to allow for much greater distinctions among SLE patients regarding the subsequent risk of CAD. The total number of patients studied with SLE in the 2 trials is approximately 250, a clinical base that makes these observations valid. However, differentiation of plaque in the carotid vessels, or EBCT calcium scores, particularly when not very high, do not have sufficient specificity and sensitivity to rule in or out the presence of vascular disease in a given patient with SLE.

The implication for primary care physicians and rheumatologists, as well as cardiologists, is quite simple: very aggressive CAD risk factor strategies should be employed in SLE subjects. While there are no data confirming that aggressive lipid or blood pressure control will make a difference, it is likely to be the case; given the virulence of chronic SLE, it makes sense to reduce the CAD risk factor burden as much as possible. Furthermore, SLE patients, particularly the younger ones, probably should be tested for LP(a) and homocysteine. If homocysteine is elevated in SLE patients, therapy with folate and B vitamins would appear to be appropriate.

In conclusion, SLE now joins the list of conditions that are associated with an increased risk of the development of vascular disease, particularly CAD. These include chronic kidney disease, the metabolic syndrome, rheumatoid arthritis, and even uncomplicated type II diabetes. Many physicians do not recognize that all such individuals are at substantially increased risk and demand aggressive risk factor assessment, as well as therapeutic approaches. Although SLE is a very potent inducer of atherosclerosis, lupus is relatively uncommon when compared to these other conditions. Nevertheless, the recognition that a diagnosis of SLE, whether freshly made or chronic, should trigger a search for vascular disease markers and risk factors, is news for the general medical community and deserves our attention.

Dr. Abrams, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, is on the Editorial Board of Clinical Cardiology Alert.