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NEJM
Bevra Hannahs Hahn, M.D. An association between accelerated atherosclerosis and systemic lupus erythematosus (SLE), typified by the occurrence of a myocardial infarction in a 30-year-old woman who had had the disease for more than 10 years, was suggested in 1976.1 The two studies by Roman et al. (pages 2399�2406) and Asanuma et al. (pages 2407�2415) in this issue of the Journal confirm this association and provide important information regarding risk factors. The reported prevalence of myocardial infarcts in patients with SLE ranges from 4 percent to 45 percent, with studies of surrogate markers providing support for the higher figure. For example, in one study 40 percent of patients with SLE had atherosclerotic plaques on carotid ultrasonography2; women with SLE had a relative risk of atherosclerosis of 5, as compared with the general population, and in those younger than 45 years, the risk was a staggering 50. Factors that increase the risk in the general population also increase the risk among patients with SLE, but SLE itself is an independent risk factor.3 Both studies reported in this issue enrolled consecutive patients and controls from the general population who were matched for age, race, and sex. Asanuma et al. used electron-beam computed tomography to detect coronary-artery calcification; Roman et al. used carotid-artery ultrasonography to identify plaque. Although the patient populations differed, the majority of patients were white women who had had SLE for 10 to 15 years. Both studies found a higher prevalence of atherosclerosis among the patients at all ages, a prevalence of approximately 33 percent among patients younger than 50 years, and independent associations between atherosclerosis and age, hypertension, and SLE itself. Overall, surrogate markers for atherosclerosis were positive in 31 to 37 percent of patients, as compared with 9 to 15 percent of controls, and in 70 to 80 percent of patients 50 years of age or older, as compared with 21 to 45 percent of controls. The odds ratios for atherosclerosis in the SLE populations were 4.8 in the study by Roman et al. and 9.8 in the study by Asanuma et al. Neither study found significant correlations with markers of systemic inflammation, such as clinical or serologic measures of disease activity, or serum levels of C-reactive protein. However, most measurements were obtained once; an analysis of markers of inflammation over time would be more informative. Expected associations with hyperlipidemia or elevated levels of homocysteine were found in one study but not both. Interestingly, both groups found that long-term treatment with corticosteroids was not associated with a significantly increased risk; this challenges the widely held opinion that prolonged administration of corticosteroids accelerates atherosclerosis. Furthermore, Roman et al. found that patients without plaque had a significantly higher mean daily dose of prednisone and more frequent use of hydroxychloroquine and cyclophosphamide than did those with plaque, suggesting that more aggressive control of disease activity might help prevent atherosclerosis. Why does accelerated atherosclerosis develop in patients with SLE? Several mechanisms are suggested in the Figure, including factors related to SLE and unrelated factors. What can be done to prevent accelerated atherosclerosis? Physicians should consider aggressive suppression of disease activity and other modifiable risk factors for atherosclerosis. Only salicylates, hydroxychloroquine, and corticosteroids have been approved by the Food and Drug Administration as treatments for SLE. Hydroxychloroquine is useful in the management of non�life-threatening SLE, has a relatively low level of toxicity, and has weak but measurable antiplatelet and lipid-lowering effects. Aggressive therapy for life-threatening SLE is limited by the toxicity of available treatments. But corticosteroids are not all bad; they are the only current option for rapidly improving (within days) severe SLE.
Cyclophosphamide, which is widely used to decrease the activity of severe SLE and sometimes to maintain the subsequent improvement, is often disliked by patients because of its side effects, including potential infertility. There is currently great interest in the use of mycophenolate mofetil both to decrease disease activity and as maintenance therapy, since it probably has fewer adverse effects than cyclophosphamide (as does azathioprine when it is used as maintenance therapy), but long-term comparisons with cyclophosphamide are not yet available.4 What is the role of statin therapy in SLE? Since some of these agents have antiinflammatory as well as lipid-lowering activity, should most patients with SLE receive them? I have found that the elevated lipid levels identified during periods of disease activity often revert to values that do not require treatment according to current guidelines when disease activity is suppressed. It may be wise to consider therapy with statins or other antiatherosclerosis interventions if hyperlipidemia or hypertension occurs during a period of stable disease. All of us eagerly await the results of current prospective trials, including those evaluating statins in SLE, mycophenolate mofetil and cyclophosphamide in lupus nephritis, the safety of sex-hormone replacement in women with SLE, and the effects of several new biologic agents on disease activity, renal function, and other outcomes. In summary, in patients with SLE, physicians should manage both disease-related activity and traditional risk factors for atherosclerosis. In my experience, hypertension, hyperglycemia, obesity, and hyperlipidemia are frequently treated inadequately in patients with SLE, probably because of the risk and expense of additional medications, as well as the time involved and potential constraints placed by third-party payers on medical visits. The current standard of care should include efforts to suppress SLE and prevent atherosclerosis.
I am indebted to Daniel E. Furst, M.D., for reviewing and
giving advice about this article.
From the David Geffen School of Medicine at the University of California Los Angeles, Los Angeles. References
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