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A new study, led by physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and the Hospital for Special Surgery, finds that atherosclerosis (arterial plaque) occurs prematurely and more commonly in patients with systemic lupus erythematosus (lupus). The first-of-its-kind clinical study, which appears in the December 18 issue of the New England Journal of Medicine, also finds that atherosclerosis occurs as a result of lupus, independently of traditional cardiovascular disease risk factors, contradicting earlier hypotheses. According to the study's authors, the findings will likely impact the treatment of the estimated 1.5 million Americans with lupus.

The study is authored by principal investigator Dr. Mary J. Roman, a cardiologist and Professor of Medicine at Weill Cornell Medical College and Attending Physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, and by co-investigator Dr. Jane E. Salmon, a rheumatologist and Professor of Medicine at Weill Cornell Medical College and Director of the Mary Kirkland Center for Lupus Research at the Hospital for Special Surgery.

Of the enrolled patients with lupus, 37.1 percent (73 of 197) were found to have atherosclerosis, compared to 15.2 percent (30 of 197) of lupus-free patients with matched cardiovascular disease risk factors and demographic variables, indicating that lupus increased the likelihood of having atherosclerosis by 140 percent. The difference was even more pronounced in lupus patients 40 years and younger for whom the risk was increased by 480 percent. Not only is atherosclerosis more prevalent in patients with lupus, but the study also provides evidence that lupus disease-related factors cause atherosclerosis. This contradicts the prevailing hypothesis that atherosclerosis in lupus patients is attributable to an increased frequency of conventional risk factors such as hypertension, high cholesterol, smoking, and diabetes. As evidence, the authors note that while immunosuppressive (anti-inflammatory) drugs have the potential to exacerbate these risk factors, in fact, lupus patients who received the treatments showed a lower prevalence of atherosclerosis.

"Lupus is best known for leading to kidney, neurologic, skin and brain disease. Now we know that lupus is also directly responsible for plaque build-up that may result in heart attack, stroke, and other negative cardiovascular outcomes," says Dr. Roman.

"The current study's results underscore the need for more focused and effective treatments that address more than just the disease's symptoms," add Drs. Roman and Salmon. "Further clinical studies are needed to determine the best biomarker for the propensity to develop plaque, as well as the best treatment—whether it is immunosuppressant drugs, statins, or other types of medications. However, the negative correlation between atherosclerosis and immunosuppressive treatments suggests that more vigorous therapy might decrease the likelihood and burden of atherosclerosis in lupus and, perhaps, in other chronic inflammatory diseases as well."

An ongoing longitudinal study by Dr. Roman and colleagues is examining the progression of atherosclerosis over time. This study will seek to 1) examine whether any clinical or laboratory markers predict atherosclerosis progression and thus serve as treatment targets, and 2) determine how many patients might need to be included in a possible intervention trial.

Patients treated with the immunosuppressive therapies such as prednisone, cyclophosphamide, and hydroxychloroquine, which are indicated to treat painful flares of lupus, were shown in the study to have a lower prevalence of atherosclerosis.

"The current study supports the hypothesis that lupus itself, perhaps due to chronic systemic inflammation, causes atherosclerosis," says Dr. Roman.

Dr. Roman and her colleagues first hypothesized a causal link between lupus and atherosclerosis after noticing that an unusual number of heart attacks occurred in relatively young lupus patients. Conventional wisdom held that these heart attacks were caused by cardiovascular risk factors such as a family history of premature myocardial infarction, smoking history, hypertension, diabetes mellitus, and high cholesterol. But the evidence contradicted this theory as many of the heart attacks occurred in patients who were young and without traditional cardiovascular risk factors. One study showed that women age 35 to 54 years with lupus were 50 times more likely to have a heart attack than women without lupus (S. Manzi, Am J Epidemiol, 1997). The data in this study were limited, and so Dr. Roman cast the net wider by focusing on the pre-clinical disease (small plaques seen in the carotid arteries), which would have a significantly greater prevalence. "The presence of carotid plaque is a potent predictor of future heart attack," says Dr. Roman.

Although the traditional, well-established cardiovascular disease risk factors are not primarily responsible for accelerated atherosclerosis in lupus, their importance in the population as a whole is well established. Thus it is prudent to identify and aggressively treat traditional risk factors in all lupus patients, say the study's authors.

Atherosclerosis is the process in which deposits of fatty substances, cholesterol, cellular waste products, calcium, and other substances collect in the inner lining of an artery. This build-up is called plaque.

Lupus is a chronic inflammatory disease that can affect various parts of the body, especially the skin, joints, blood, and kidneys. In lupus, the immune system loses its ability to differentiate between foreign substances (antigens) and its own cells and tissues. The immune system then makes antibodies directed against "self." These antibodies, called "auto-antibodies," react with the "self" antigens to form immune complexes. The immune complexes build up in the tissues and can cause inflammation, injury to tissues, and pain. For most people, lupus is a mild disease affecting only a few organs. For others, it may cause serious and even life-threatening problems. Lupus most commonly appears in women of childbearing age, for reasons unknown; about nine times more females than males have lupus. And it is three times more common in African-American women than in Caucasian women. More than 16,000 Americans develop lupus each year.

The study's co-authors include Dr. Richard B. Devereux, Professor of Medicine at Weill Cornell Medical College and Attending Physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center; Dr. Ronit Simantov, formerly of NewYork-Presbyterian/Weill Cornell; Dr. Michael D. Lockshin, Dr. Lisa Sammaritano, Dr. Mary K. Crow, Dr. Stephen A. Paget, Beth-Ann Shanker, and Adrienne Davis of the Hospital for Special Surgery; and Dr. Joseph E. Schwartz of the State University of New York at Stony Brook.

The study is supported by grants from the National Institute of Arthritis, Musculoskeletal, and Skin Disease; the National Heart, Lung, and Blood Institute; the Public Health Service; the Mary Kirkland Center for Lupus Research at the Hospital for Special Surgery; and the Bugher Foundation.