Heart Disease Can Strike Early in Women
With Autoimmune Rheumatic Diseases

Autoimmune rheumatic diseases (AIRDs), such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), disproportionately affect women.1,2 AIRDs are associated with increased cardiovascular morbidity and mortality, caused primarily by accelerated atherosclerosis.3 Additionally, women with RA or SLE often have an increased extent of subclinical atherosclerosis,3 so thorough cardiac risk assessment may be warranted in such patients. This issue of Know Her Heart examines AIRDs and the cardiac threat they pose to women.

AIRDs Disproportionately Affect Women
While RA and SLE affect both men and women, the large majority of patients are women.
  • RA affects approximately 3 million people in the US, and 70% of them are women1
  • The prevalence of SLE among US adults (based on self-reported physician diagnosis) is estimated to be 241 per 100,000 (>730,000 people),2 with a rate of 345/100,000 for women, compared with 127/100,000 for men2

Younger Women at Unusually High Risk
In general, cardiac risk increases with age, and younger patients are usually not at high risk for myocardial infarction (MI) or cardiac death. Also, women generally present with coronary heart disease (CHD) approximately 10 years later in life than men.4 However, in women with AIRDs, cardiac risk may be significantly increased at a much younger age:
  • RA has been associated with a 3.64-fold increased risk for CHD mortality in women aged 15-49 years5
  • 35- to 44-year-old women with SLE were 52 times more likely to have an MI compared with non-SLE controls6



RA: Coronary Disease and Events
  • RA is a significant risk factor for multivessel coronary artery disease (CAD)7
  • RA patients have a greater extent of subclinical atherosclerosis3
  • Atherosclerotic plaques may be more unstable in RA patients8
  • CHD risk in RA often precedes diagnosis of RA9,10
  • CHD is responsible for 40%-50% of deaths in RA patients9
  • RA patients are at increased risk of unrecognized MI and sudden cardiac death10
  • A large meta-analysis (N=111,758) found that RA increased risk for ischemic heart disease mortality by 59%11



SLE: Coronary Disease and Events
  • SLE patients are at ≥5 times increased risk for CAD12
  • SLE patients often have subclinical or asymptomatic atherosclerosis12-15
    • 35%-40% of women with SLE and no history of CAD were found to have myocardial perfusion imaging (MPI) abnormalities12,15
  • CHD is the leading cause of death among women with SLE16
  • Overall, SLE patients have a 5-fold increased incidence of MI14



Why Do These Conditions Increase Cardiac Risk?
The precise mechanisms of increased risk in AIRDs are not fully understood, but a number of important factors have been recognized:
  • Chronic inflammatory mechanisms and mediators appear to play an important role in accelerating atherosclerosis in AIRDs3,17,18
  • Other contributors that may play a role in atherosclerosis in AIRDs include:
    • Traditional risk factors3,18
      • Traditional risk factors may operate in a synergistic manner with inflammatory mechanisms19
      • In a study of 265 SLE patients from the Hopkins Lupus Cohort, the prevalence of CAD risk factors far exceeded those in an age-, sex-, and race-matched normal population20
    • Prolonged corticosteroid use (but the evidence is unclear)3,17,18
    • Endothelial dysfunction21-24
    • In SLE, presence of antiphospholipid antibodies or renal disease and its resulting hypertension17
    • Reduced physical activity associated with RA25
  • SLE patients also have been shown to have significant levels of certain antibodies that may accelerate the development of atherosclerosis26



High Suspicion for CHD May Be Prudent
RA patients are less likely to report angina,10 which may delay presentation and diagnosis of CHD. Additionally, younger age at presentation of women with SLE may reduce recognition of MI and delay treatment.6,27

Because women with RA or SLE should be treated as a high cardiovascular risk group,3 family practitioners should be aware of the increased cardiac risk among their patients with AIRDs. Cardiac screening may be an important part of overall care for these patients to help avoid having coronary disease develop unrecognized.

Targeting Subclinical Coronary Disease in AIRDs
In patients with AIRDs, established CHD risk factors should be evaluated and managed aggressively,22,25 and subclinical disease should be targeted for early identification and prevention therapy (SOR: A).3
  • Diagnostic testing can help identify patients with coronary disease
  • MPI may detect ischemic heart disease in RA patients8
    • In one study, pharmacologic stress MPI found a 2-fold prevalence of stable ischemic heart disease in RA patients versus closely matched osteoarthritic controls (50% vs 27%, respectively)8
  • MPI may detect subclinical or early CAD in SLE patients15,28,29 and identify candidates for more aggressive secondary risk-factor prevention22
  • Persistent joint inflammation in RA can lead to chronic pain, loss of function, and disability30 ; joint and muscle pain is also common in SLE31
    • Such symptoms may reduce exercise capacity and interfere with exercise stress testing or imaging

References
1. Arthritis Foundation. Rheumatoid arthritis: who is at risk? 2009. http://www.arthritis.org/disease-center.php?disease_id=31&df=whos_at_risk. Accessed May 13, 2009. 2. Ward MM. Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: results from the Third National Health and Nutrition Examination Survey. J Womens Health. 2004;13:713-718. 3. Shoenfeld Y, Gerli R, Doria A, et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation. 2005;112:3337-3347. 4. Wenger NK. Coronary heart disease in women: evolving knowledge is dramatically changing clinical care. In: Julian DG, Wenger NK, eds. Women and Heart Disease. London: Martin Dunitz; 1997:21-38. 5. Myllykangas-Luosujärvi R, Aho K, Kautiainen H, Isomäki H. Cardiovascular mortality in women with rheumatoid arthritis. J Rheumatol. 1995;22:1065-1067. 6. Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997;145:408-415. 7. Warrington KJ, Kent PD, Frye RL, et al. Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study. Arthritis Res Ther. 2005;7:R984-R991. 8. Kitas GD, Erb N. Tackling ischaemic heart disease in rheumatoid arthritis. Rheumatology (Oxford). 2003;42:607-613. 9. Turiel M, Peretti R, Sarzi-Puttini P, Atzeni F, Doria A. Cardiac imaging techniques in systemic autoimmune diseases. Lupus. 2005;14:727-731. 10. Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2005;52:402-411. 11. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, LaCaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008;59:1690-1697. 12. Bruce IN, Gladman DD, Urowitz MB. Premature atherosclerosis in systemic lupus erythematosus. Rheum Dis Clin North Am. 2000;26:257-278. 13. Bruce IN, Burns RJ, Gladman DD, Urowitz MB. Single photon emission computed tomography dual isotope myocardial perfusion imaging in women with systemic lupus erythematosus. I. Prevalence and distribution of abnormalities. J Rheumatol. 2000;27:2372-2377. 14. Asanuma Y, Oeser A, Shintani AK, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003;349:2407-2415. 15. Bruce IN, Gladman DD, Ibañez D, Urowitz MB. Single photon emission computed tomography dual isotope myocardial perfusion imaging in women with systemic lupus erythematosus: II. Predictive factors for perfusion abnormalities. J Rheumatol. 2003;30:288-291. 16. Manger K, Kusus M, Forster C, et al. Factors associated with coronary artery calcification in young female patients with SLE. Ann Rheum Dis. 2003;62:846-850. 17. Manzi S, Wasko MCM. Inflammation-mediated rheumatic diseases and atherosclerosis. Ann Rheum Dis. 2000;59:321-325. 18. Van Doornum S, Jennings GLR, Wicks IP. Reducing the cardiovascular disease burden in rheumatoid arthritis. Med J Aust. 2006;184:287-290. 19. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2005;52:722-732. 20. Petri M, Spence D, Bone LR, Hochberg MC. Coronary artery disease risk factors in the Johns Hopkins lupus cohort: prevalence, recognition by patients, and preventive practices. Medicine. 1992;71:291-302. 21. El-Magadmi M, Bodill H, Ahmad Y, et al. Systemic lupus erythematosus: an independent risk factor for endothelial dysfunction in women. Circulation. 2004;110:399-404. 22. Nikpour M, Urowitz MB, Gladman DD. Premature atherosclerosis in systemic lupus erythematosus. Rheum Dis Clin North Am. 2005;31:329-354. 23. Dessein PH, Joffe BI, Singh S. Biomarkers of endothelial dysfunction, cardiovascular risk factors and atherosclerosis in rheumatoid arthritis. Arthritis Rheum Ther. 2005;7:R634-R643. 24. Dessein PH, Joffe BI. When is a patient with rheumatoid arthritis at risk for cardiovascular disease? J Rheumatol. 2006;33:201-203. 25. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107:1303-1307. 26. Matsuura E, Kobayashi K, Lopez LR. Atherosclerosis in autoimmune diseases. Curr Rheum Rep. 2009;11:61-69. 27. Mattu A, Petrini J, Swencki S, Chaudhari C, Brady WJ. Premature atherosclerosis and acute coronary syndrome in systemic lupus erythematosus. Am J Emerg Med. 2005;23:696-703. 28. Sun S-S, Shiau Y-C, Tsai S-C, Lin C-C, Kao A, Lee C-C. The role of technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography (SPECT) in the detection of cardiovascular involvement in systemic lupus erythematosus patients with non-specific chest complaints. Rheumatology. 2001;40:1106-1111. 29. Sella EMC, Sato EI, Leite WA, Filho JAO, Barbieri A. Myocardial perfusion scintigraphy and coronary disease risk factors in systemic lupus erythematosus. Ann Rheum Dis. 2003;62:1066-1070. 30. Arthritis Foundation. Rheumatoid arthritis fact sheet. 2008. http://www.arthritis.org/media/newsroom/media-kits/Rheumatoid_Arthritis_Fact_Sheet.pdf. Accessed May 13, 2009. 31. Lupus Foundation of America. Joint and muscle pain. 2009. http://www.lupus.org/education/brochures/jointpain.html. Accessed May 13, 2009.

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