Cardiac Events May Occur Before Lupus Starts

It is well known that systemic lupus erythematosus patients are at high risk for cardiovascular problems. New research, however, suggests that patients may have heart and vessel problems much earlier in the lupus disease course than previously suspected. In some cases, heart attacks even precede the diagnosis of lupus.

A new study published in Lupus Science & Medicine using systemic lupus international collaborating clinics (SLICC) data, highlights the potential link between autoimmunity and atherosclerosis - a link that requires more research, said study author Murray B Urowitz, M.D., a rheumatologist at the University of Toronto University Health Network. For clinicians, the findings expand the group of people who may be at risk for developing systemic lupus erythematosus, Urowitz told Rheumatology Network.

"Just as lupus physicians and rheumatoid arthritis physicians are looking for artherosclerotic disease in their patients, general internists who are seeing young women with premature cardiac events should at least be thinking of a possible underlying connective tissue disease like lupus," Urowitz said.

Urowitz and his colleagues were the first to report, in 1976, that lupus is associated with accelerated artherosclerosis and death from heart attack. In their original study, the five patients who died because of or shortly after myocardial infarctions did so an average of 8.6 years after diagnosis.  [[{"type":"media","view_mode":"media_crop","fid":"48340","attributes":{"alt":"©SebastianKaulitzki/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_4355724009026","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5762","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"©SebastianKaulitzki/Shutterstock.com","typeof":"foaf:Image"}}]]

That research led to the recognition of cardiovascular disease as a major problem of systemic lupus. A 2001 paper using the Framingham study found a litany of increased relative risks for lupus patients: 10.1 (95% CI, 4.0-13.6) for a nonfatal myocardial infarction, 7.5 (95% CI 5.1-10.4) for coronary heart disease, 7.9 for stroke (95% CI, 4.0-13.6) and 17 for death by coronary heart disease (95% CI, 8.1-29.7).

That study, notably, excluded patients who had a vascular event before their lupus diagnosis. Such an exclusion may obscure the shared processes that lead to both cardiovascular disease and lupus, Urowitz's new findings suggest.

The study focused on 1,848 patients who entered the SLICC cohort between 2000 and 2014. The mean follow-up was 8.9, plus or minus 3.3 years.

A mere 31 patients out of this cohort had a myocardial infarction, highlighting the importance of research driven by large databases. What struck Urowitz and his colleagues was that 23 of these 31 had their cardiac event either before their systemic lupus erythematosus diagnosis or within the first two years after the diagnosis.

The discovery of heart attacks early in the lupus disease course or prior to diagnosis was surprising, even with the knowledge that lupus puts patients at risk, Urowitz said. The 1,640 females in the sample had a mean age at diagnosis of only 34.7, plus or minus 13 years.

"Women should not be having heart attacks when they're under the age of 70 or 75," he said. "And we're talking about people who are in their 40s or, at most, their early 50s."

The findings point to an underlying process that unites cardiovascular disease and lupus, Urowitz said. People with systemic lupus erythematosus have been found to develop autoantibodies well before disease diagnosis; a 2003 study in the New England Journal of Medicine found pre-diagnosis autoantibodies in 88 percent of 130 SLE patients who had samples in the Department of Defense Serum Repository. The mean for detection was 3.3 years prior to diagnosis, but some patients had developed autoantibodies nearly a decade before they were diagnosed.

Similarly, cardiovascular disease doesn't happen overnight. The question, Urowitz said, is whether the immune abnormalities in lupus are causing cardiovascular inflammation, putting patients at risk. Alternatively, there might be a genetic profile that causes both cardiovascular disease and lupus, he said.

"The same genes that are predisposing you to lupus may be the same genes that are predisposing you to atherosclerosis," Urowitz said.

Uncovering the linkage between lupus autoimmunity and atherosclerosis "opens up a whole new field" of research, he said. He and his team are interested in running studies using DNA chips for cardiovascular disease to see if patients with lupus have genes that give them a predisposition for cardiac disease.

In the meantime, though, the research suggests that clinicians need to flip the script when thinking about atherosclerosis and lupus. Currently, everyone knows to consider lupus patients at high risk for cardiovascular disease, Urowitz said. What's missing is thinking about the opposite: Are cardiovascular patients (particularly young, female patients) at risk for lupus?

"If a younger woman comes in with a heart attack, you may need to at least think about it," Urowitz said. Currently, however, no one has done the research to find out how many people with early myocardial infarction or cardiovascular disease end up developing lupus or other connective tissue diseases.

The new study isn't the first to hint at the connection, though. A 2014 retrospective cohort study published in The Journal of Rheumatology examined incidents of systemic lupus erythematosus diagnosed between 1991 and 2008 in an epidemiological study area in Wisconsin. Patients with SLE were 3.8 times more likely (95% CI, 1.4, 1.9) to have received a cardiovascular disease diagnosis in the two years prior to their lupus diagnosis than comparison patients without the autoimmune disorder. SLE patients were 5.1 times more likely to have had a stroke before their lupus diagnoses than comparison cases. 

Both of these studies highlight the importance of large databases for teasing out such relationships.

"You can't make these observations in a single practice," Urowitz said. "It's not possible. It has to be in a database, you have to have large numbers of patients and you have to be documenting their past histories."

References:

Urowitz MB, Gladman DD, Anderson NM, et al. Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort. Lupus Science & Medicine Lupus Sci Med 2016;3(1). doi:10.1136/lupus-2015-000143.

The bimodal mortality pattern of systemic lupus erythematosus. The American Journal of Medicine 1976;60(2). doi:10.1016/0002-9343(76)90449-6.

Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis & Rheumatism 2001;44(10):2331–2337. doi:10.1002/1529-0131(200110)44:10<2331::aid-art395>3.0.co;2-i.

Autoantibodies before the Clinical Onset of Systemic Lupus Erythematosus. New England Journal of Medicine N Engl J Med 2004;350(3):305–305. doi:10.1056/nejm200401153500320.

Bartels CM, Buhr KA, Goldberg JW, et al. Mortality and Cardiovascular Burden of Systemic Lupus Erythematosus in a US Population-based Cohort. The Journal of Rheumatology 2014;41(4):680–687. doi:10.3899/jrheum.130874.