Lupus & Atherosclerosis: Should Recent Findings Alter Our Care of Lupus Patients?

Special Report


Jane E. Salmon, MD

Jane E. Salmon, MD

Attending Physician, Hospital for Special Surgery
Senior Scientist, Hospital for Special Surgery
Professor of Medicine, Weill Cornell Medical College

In recent years, many physicians have noted increased evidence of atherosclerotic cardiovascular disease (ASCVD) in systemic lupus erythematosus (SLE) patients[1]. Perhaps addressing conventional ASCVD risk factors - treating SLE patients like a diabetes patients in terms of risk factor modification - as well as treating chronic inflammation more aggressively could reduce ASCVD events. Although we do not yet have data that prove that reduction of known cardiac risk factors will be as effective in preventing atherosclerosis in lupus patients as it is in the general population, it seems reasonable to take an aggressive approach, based on data in other high-risk groups, such as diabetics.

This article will summarize the latest findings in ASCVD risk for systemic lupus erythematosus. Our findings suggest that there is a need for close surveillance of SLE patients and active efforts at primary prevention.

The Findings

With the increased life expectancy of SLE patients due to improved therapy (particularly for renal-related problems), cardiovascular disease has emerged as a significant threat. Because SLE predominantly affects young women, a group that typically has a vanishingly small incidence of coronary disease, the finding of myocardial infarction in autopsy, epidemiologic, and observational studies of lupus patients was unexpected.

Our group at Hospital for Special Surgery recently reported in the New England Journal of Medicine a case-control study of the prevalence, magnitude and determinants of underlying atherosclerosis in a population-based sample of SLE patients. We found that:

  • atherosclerosis is significantly increased in lupus (i.e. carotid plaque in 37.1% of SLE patients vs 15.2% of controls), most strikingly in younger individuals;
  • the increase is not attributable to traditional cardiovascular risk factors or corticosteroid therapy;
  • the association of atherosclerosis with longer disease duration, higher damage score, and less aggressive immunosuppressive therapy argues that chronic inflammation is atherogenic in SLE[1].

Two disease patterns emerged:

    1. An increased likelihood of atherosclerosis was observed with:
      • smoldering, prolonged disease;
      • higher damage scores;
      • limited production of antibodies (especially an absence of anti-Smith antibodies for presence of plaque);
      • less treatment with immunosuppressives (such as hydroxychloroquine, prednisone, or cyclophosphamide).
    2. A decreased likelihood of atherosclerosis was observed with:
      • a wider autoantibody spectrum;
      • more aggressive immunosuppressive therapy[1].

The mechanism of the premature atherosclerosis remains unknown. Although aggressive efforts should be made to control traditional cardiovascular disease risk factors, when present, the association of atherosclerosis with longer disease duration, higher damage score, and less aggressive immunosuppressive therapy argues that chronic inflammation is atherogenic in SLE.

Practical Implications

How can we begin to develop a standard of care for monitoring and reducing risk in our SLE patients? We propose that this should be a two-pronged effort, the first related to traditional ASCVD risk factor modification and the second related to immunomodulatory therapy.

Traditional Risk Factor Modification

As we suggested previously[2], we propose that the presence of SLE is a sufficiently potent risk factor for ASCVD that aggressive goals for risk factor modification, analogous to the American Heart Association and American Diabetes Association recommendations for risk reduction in diabetes, be considered. The targets for reducing hyperlipidemia and hypertension are lower for diabetics because their risk for ASCVD is higher. Applying these targets to the management of conventional risk factors in SLE patients is unconventional in rheumatologic practice, but may prove of significant value to our patients.

Strategies to Reduce ASCVD in SLE - Aggressive Risk Factor Reduction

  • Hypertension (goal: <130/85 mmHg) (ACE inhibitors)[3],[4],[5].
  • Hyperlipidemia (goal: LDL <130mg/dl; <100 mg/dl if preclinical ASCVD present) (statins, antimalarials)[4]
  • Hyperglycemia (maintain normal fasting glucose)[4]
  • Smoking cessation
  • Weight reduction (goal: BMI <25 kg/m2)
  • Physical activity (goal: 30 min/day 3-4 times/week)
  • Diagnosis of hyperhomocysteinemia (folic acid)

Immunomodulatory Therapy

Beyond addressing traditional ASCVD risk factors, the clinical profile of our patients with atherosclerosis clearly supports a role for lupus-related factors in atherogenesis, and our findings suggest that more focused and effective immunomodulatory therapy will help prevent or attenuate this significant cause of morbidity and mortality in lupus.

The presence of lupus itself was the most important independent risk factor for atherosclerosis, other than age, in our study[1]. Of the two clinical patterns of lupus suggested in our results, the one characterized by smoldering disease with higher damage-index scores, and limited production of autoantibodies was also associated with atherosclerosis. This stood in contrast to the other clinical pattern of a wider autoantibody spectrum, associated with more aggressive immunosuppressive therapy, and a lower likelihood of plaque.

"The negative correlation between atherosclerosis and aggressive therapy suggests that more vigorous therapy might decrease the likelihood and burden of atherosclerosis in patients with lupus and, perhaps, in those with other chronic inflammatory diseases. Our results also suggest that the use of immunosuppressive therapy primarily for clinical flares may not adequately control the chronic atherogenic inflammatory milieu"[1].

It is hoped that the future identification of biologic markers of disease activity associated with atherosclerosis may help improve the management of risk and prevention of CVD for patients with lupus.

The association of lupus with atherosclerosis in our work and that of others leads us to think about how more aggressive therapy might help to reduce this burden of disease for SLE patients. Although we do not yet have evidence that reduction of conventional cardiac risk factors will be as beneficial in SLE patients as in other patients at increased risk for ASCVD, it seems prudent at this time to maximize primary prevention in these patients. Our data suggest that inflammation in lupus is associated with increased atherosclerotic risk, and leads to the hypothesis that aggressive control of lupus activity can reduce the risk of atherosclerosis.

 

[1] Roman MJ, Shanker B, Davis A, Lockshin MD, Sammaritano L, Simantov R, Crow MK, Schwartz JE, Paget SA, Devereaux RB, Salmon JE. Prevalence and Correlates of Accelerated Atherosclerosis in Systemic Lupus Erythematosus. N Engl J Med 2003 Dec 18;349(25):2399-406.

[2] Salmon JE, Roman MJ. Accelerated atherosclerosis in systemic lupus erythematosus: implications for patient management. Curr Opin Rheumatol. 2001 Sep;13(5):341-4.

[3] Scott M. Grundy, MD; Alan Garber, MD; Ronald Goldberg, MD; Stephen Havas, MD; Rory Holman, MD; Cynthia Lamendola, PhD; William James Howard, MD; Peter Savage, MD; James Sowers, MD; Gloria Lena Vega, PhD. AHA Conference Proceedings. Prevention Conference VI: Diabetes and Cardiovascular Disease. Circulation. 2002;105:e153. (Accessed February 19, 2004.)

[4] American Diabetes Association. Position Statement: Standards of Medical Care in Diabetes. Diab Care 2004;27:S15-S35. (Accessed February 19, 2004.

[5] American Diabetes Association. Position Statement: Hypertension Management in Adults With Diabetes. Diab Care 2004:27:S65-S67. (Accessed February 19, 2004)

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