Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Accelerated atherosclerosis in patients with SLE—mechanisms and management

Abstract

Rapid-onset cardiovascular disease (CVD) is a major concern for many patients with systemic lupus erythematosus (SLE). Cardiovascular events occur more frequently and with earlier onset in patients with SLE compared with healthy individuals. Traditional risk factors, such as altered lipid levels, aging and smoking, do not fully explain this increased risk of CVD, strongly suggesting that autoimmunity contributes to accelerated atherosclerosis. Altered immune system function is recognized as the primary contributor to both the initiation and progression of atherosclerosis. Multiple manifestations of autoimmunity, including changes in cytokine levels and innate immune responses, autoantibodies, adipokines, dysfunctional lipids, and oxidative stress, could heighten atherosclerotic risk. In addition, multiple SLE therapeutics seem to affect the development and progression of atherosclerosis both positively and negatively. SLE-specific cardiovascular risk factors are beginning to be discovered by several groups, and development of a comprehensive, clinically feasible biomarker panel could be invaluable for identification and treatment of patients at risk of developing accelerated atherosclerosis. Here, we discuss the epidemiology of CVD in SLE and the implications of immune system dysfunction on the development and progression, monitoring and treatment of atherosclerosis in individuals with this disease.

Key Points

  • Cardiovascular disease (CVD) is a substantial contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE)

  • SLE-specific risk factors for accelerated atherosclerosis exist, but are poorly understood

  • Endothelial cell dysfunction plays a major part in accelerated atherosclerosis in patients with SLE

  • Identification of SLE-specific mechanisms of, and biomarkers, for accelerated atherosclerosis should lead to the development of novel screening protocols for early detection of CVD and discovery of new therapeutic targets

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Atherosclerosis in SLE.
Figure 2: Continuum of SLE-specific and traditional risk factors for CVD.

Similar content being viewed by others

References

  1. Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Urowitz, M. B. et al. The bimodal mortality pattern of systemic lupus erythematosus. Am. J. Med. 60, 221–225 (1976).

    Article  CAS  PubMed  Google Scholar 

  3. Nossent, J. et al. Current causes of death in systemic lupus erythematosus in Europe, 2000–2004: relation to disease activity and damage accrual. Lupus 16, 309–317 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Esdaile, J. M. et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 44, 2331–2337 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Manzi, S. 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. 145, 408–415 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Roman, M. J. et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N. Engl. J. Med. 349, 2399–2406 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Roman, M. J. et al. Rate and determinants of progression of atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 56, 3412–3419 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Manzi, S. et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum. 42, 51–60 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Asanuma, Y. et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N. Engl. J. Med. 349, 2407–2415 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Bruce, I. N., Burns, R. J., Gladman, D. D. & Urowitz, M. B. Single photon emission computed tomography dual isotope myocardial perfusion imaging in women with systemic lupus erythematosus. I. Prevalence and distribution of abnormalities. J. Rheumatol. 27, 2372–2377 (2000).

    CAS  PubMed  Google Scholar 

  11. El-Magadmi, M. et al. Systemic lupus erythematosus: an independent risk factor for endothelial dysfunction in women. Circulation 110, 399–404 (2004).

    Article  PubMed  Google Scholar 

  12. Recio-Mayoral, A. et al. Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease. Eur. Heart J. 30, 1837–1843 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Folsom, A. R. et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch. Intern. Med. 168, 1333–1339 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Salel, A. F. et al. Accuracy of numerical coronary profile. Correlation of risk factors with arteriographically documented severity of atherosclerosis. N. Engl. J. Med. 296, 1447–1450 (1977).

    Article  CAS  PubMed  Google Scholar 

  15. Moore, K. J. & Tabas, I. Macrophages in the pathogenesis of atherosclerosis. Cell 145, 341–355 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rho, Y. H. et al. Macrophage activation and coronary atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Care Res. (Hoboken) 63, 535–541 (2011).

    Article  CAS  Google Scholar 

  17. Shah, P. K. et al. High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein E-deficient mice. Potential implications for acute plaque stabilization. Circulation 103, 3047–3050 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Wright, S. A. et al. Microcirculatory hemodynamics and endothelial dysfunction in systemic lupus erythematosus. Arterioscler. Thromb. Vasc. Biol. 26, 2281–2287 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Kahlenberg, J. M. & Kaplan, M. J. The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus. Arthritis Res. Ther. 13, 203 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Rajagopalan, S. et al. Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. Blood 103, 3677–3683 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Denny, M. F. et al. Interferon-α promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis. Blood 110, 2907–2915 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Denny, M. F. et al. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J. Immunol. 184, 3284–3297 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Villanueva, E. et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187, 538–552 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Gualtierotti, R., Biggioggero, M. & Meroni, P. L. Cutting-edge issues in coronary disease and the primary antiphospholipid syndrome. Clin. Rev. Allergy Immunol. http://dx.doi.org/10.1007/s12016-011-8268–9.

  25. Ames, P. R., Margarita, A., Sokoll, K. B., Weston, M. & Brancaccio, V. Premature atherosclerosis in primary antiphospholipid syndrome: preliminary data. Ann. Rheum. Dis. 64, 315–317 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Wu, R. et al. Antibodies against cardiolipin and oxidatively modified LDL in 50-year-old men predict myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 17, 3159–3163 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Vaarala, O. et al. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 91, 23–27 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Petri, M. in Dubois' Lupus Erythematosus, 7th edn (eds Wallace, D. J. & Hahn, B. H.) 1262–1297 (Lippincott Williams & Wilkins, Philadelphia, 2007).

    Google Scholar 

  29. Toloza, S. M. et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXIII. Baseline predictors of vascular events. Arthritis Rheum. 50, 3947–57 (2004).

    Article  PubMed  Google Scholar 

  30. McMahon, M. et al. Dysfunctional proinflammatory high-density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheum. 60, 2428–2437 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pengo, V., Bison, E., Ruffatti, A. & Iliceto, S. Antibodies to oxidized LDL/β2-glycoprotein I in antiphospholipid syndrome patients with venous and arterial thromboembolism. Thromb. Res. 122, 556–559 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Meroni, P. L., Raschi, E., Testoni, C. & Borghi, M. O. Endothelial cell activation by antiphospholipid antibodies. Clin. Immunol. 112, 169–174 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Hansson, G. K. & Hermansson, A. The immune system in atherosclerosis. Nat. Immunol. 12, 204–212 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Fesmire, J., Wolfson-Reichlin, M. & Reichlin, M. Effects of autoimmune antibodies anti-lipoprotein lipase, anti-low density lipoprotein, and anti-oxidized low density lipoprotein on lipid metabolism and atherosclerosis in systemic lupus erythematosus. Rev. Bras. Reumatol. 50, 539–551 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Vuilleumier, N. et al. Presence of autoantibodies to apolipoprotein A-1 in patients with acute coronary syndrome further links autoimmunity to cardiovascular disease. J. Autoimmun. 23, 353–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Dinu, A. R. et al. Frequency of antibodies to the cholesterol transport protein apolipoprotein A1 in patients with SLE. Lupus 7, 355–360 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. O'Neill, S. G. et al. Antibodies to apolipoprotein A-I, high-density lipoprotein, and C-reactive protein are associated with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum. 62, 845–854 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Ait-Oufella, H., Taleb, S., Mallat, Z. & Tedgui, A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31, 969–979 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Hansson, G. K., Jonasson, L., Holm, J., Clowes, M. M. & Clowes, A. W. γ-interferon regulates vascular smooth muscle proliferation and Ia antigen expression in vivo and in vitro. Circ. Res. 63, 712–719 (1988).

    Article  CAS  PubMed  Google Scholar 

  40. McLaren, J. E. & Ramji, D. P. Interferon γ: a master regulator of atherosclerosis. Cytokine Growth Factor Rev. 20, 125–135 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Uyemura, K. et al. Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J. Clin. Invest. 97, 2130–2138 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hansson, G. K. Immune mechanisms in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 21, 1876–1890 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Svenungsson, E. et al. TNF-α: a link between hypertriglyceridaemia and inflammation in SLE patients with cardiovascular disease. Lupus 12, 454–461 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Rho, Y. H. et al. Novel cardiovascular risk factors in premature coronary atherosclerosis associated with systemic lupus erythematosus. J. Rheumatol. 35, 1789–1794 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Thacker, S. G. et al. The detrimental effects of IFN-α on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. J. Immunol. 185, 4457–4469 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Asanuma, Y. et al. Increased concentration of proatherogenic inflammatory cytokines in systemic lupus erythematosus: relationship to cardiovascular risk factors. J. Rheumatol. 33, 539–545 (2006).

    CAS  PubMed  Google Scholar 

  47. Sabio, J. M. et al. Metabolic syndrome is associated with increased arterial stiffness and biomarkers of subclinical atherosclerosis in patients with systemic lupus erythematosus. J. Rheumatol. 36, 2204–2211 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Rua-Figueroa, I. et al. Factors involved in the progress of preclinical atherosclerosis associated with systemic lupus erythematosus: a 2-year longitudinal study. Ann. Rheum. Dis. 69, 1136–1139 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Shin, M. S., Lee, N. & Kang, I. Effector T-cell subsets in systemic lupus erythematosus: update focusing on TH17 cells. Curr. Opin. Rheumatol. 23, 444–448 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. von Vietinghoff, S. et al. Mycophenolate mofetil decreases atherosclerotic lesion size by depression of aortic T-lymphocyte and interleukin-17-mediated macrophage accumulation. J. Am. Coll. Cardiol. 57, 2194–2204 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Marder, W. et al. Interleukin 17 as a novel predictor of vascular function in rheumatoid arthritis. Ann. Rheum. Dis. 70, 1550–1555 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Foks, A. C. et al. Differential effects of regulatory T cells on the initiation and regression of atherosclerosis. Atherosclerosis 218, 53–60 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Toma, I. & McCaffrey, T. A. Transforming growth factor-β and atherosclerosis: interwoven atherogenic and atheroprotective aspects. Cell Tissue Res. 347, 155–175 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Jackson, M., Ahmad, Y., Bruce, I. N., Coupes, B. & Brenchley, P. E. Activation of transforming growth factor-β1 and early atherosclerosis in systemic lupus erythematosus. Arthritis Res. Ther. 8, R81 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. van Leuven, S. I. et al. Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone Ldlr−/− mice. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2011-200071.

  56. Campbell, L. A. et al. The acute phase reactant response to respiratory infection with Chlamydia pneumoniae: implications for the pathogenesis of atherosclerosis. Microbes Infect. 12, 598–606 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Miller, Y. I. et al. Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. J. Biol. Chem. 278, 1561–1568 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Huang, Q. & Pope, R. M. Toll-like receptor signaling: a potential link among rheumatoid arthritis, systemic lupus, and atherosclerosis. J. Leukoc. Biol. 88, 253–262 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Symmons, D. P. & Gabriel, S. E. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat. Rev. Rheumatol. 7, 399–408 (2011).

    Article  PubMed  Google Scholar 

  60. Von Feldt, J. M. et al. Homocysteine levels and disease duration independently correlate with coronary artery calcification in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 2220–2227 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. McMahon, M. et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 54, 2541–2549 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Charles-Schoeman, C. et al. Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis. Arthritis Rheum. 60, 2870–2879 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Charakida, M. et al. Vascular abnormalities, paraoxonase activity, and dysfunctional HDL in primary antiphospholipid syndrome. JAMA 302, 1210–1217 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Avalos, I. et al. Oxidative stress in systemic lupus erythematosus: relationship to disease activity and symptoms. Lupus 16, 195–200 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Malinow, M. R., Nieto, F. J., Szklo, M., Chambless, L. E. & Bond, G. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study. Circulation 87, 1107–1113 (1993).

    Article  CAS  PubMed  Google Scholar 

  66. Wall, R. T., Harlan, J. M., Harker, L. A. & Striker, G. E. Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb. Res. 18, 113–121 (1980).

    Article  CAS  PubMed  Google Scholar 

  67. Hajjar, K. A. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J. Clin. Invest. 91, 2873–2879 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Woo, K. S. et al. Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation 96, 2542–2544 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Upchurch, G. R. Jr. et al. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J. Biol. Chem. 272, 17012–17017 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. McCully, K. S. Homocysteine and vascular disease. Nat. Med. 2, 386–389 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Petri, M. Detection of coronary artery disease and the role of traditional risk factors in the Hopkins Lupus Cohort. Lupus 9, 170–175 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Svenungsson, E. et al. Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation 104, 1887–1893 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Refai, T. M., Al-Salem, I. H., Nkansa-Dwamena, D. & Al-Salem, M. H. Hyperhomocysteinaemia and risk of thrombosis in systemic lupus erythematosus patients. Clin. Rheumatol. 21, 457–461 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Bruce, I. N., Urowitz, M. B., Gladman, D. D., Ibanˇez, D. & Steiner, G. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum. 48, 3159–3167 (2003).

    Article  PubMed  Google Scholar 

  75. Manger, K. et al. Factors associated with coronary artery calcification in young female patients with SLE. Ann. Rheum. Dis. 62, 846–850 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Potter, K., Hankey, G. J., Green, D. J., Eikelboom, J. W. & Arnolda, L. F. Homocysteine or renal impairment: which is the real cardiovascular risk factor? Arterioscler. Thromb. Vasc. Biol. 28, 1158–1164 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Taleb, S. et al. Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 27, 2691–2698 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Garcia-Gonzalez, A. et al. Serum leptin levels in women with systemic lupus erythematosus. Rheumatol. Int. 22, 138–141 (2002).

    Article  PubMed  Google Scholar 

  79. Al, M. et al. Adipokines as novel biomarkers in paediatric systemic lupus erythematosus. Rheumatology (Oxford) 48, 497–501 (2009).

    Article  CAS  Google Scholar 

  80. McMahon, M. et al. Plasma leptin levels are associated with carotid artery plaque and intima-media thickness (IMT) in women with SLE and a matched population of healthy women [abstract 2091]. Arthritis Rheum. 56 (Suppl.), S796 (2007).

    Google Scholar 

  81. Reynolds, H. R. et al. Association of plasma soluble E-selectin and adiponectin with carotid plaque in patients with systemic lupus erythematosus. Atherosclerosis 210, 569–574 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Chung, C. et al. Adipocytokines in systemic lupus erythematosus: relationship to inflammation, insulin resistance and coronary atherosclerosis. Lupus 18, 799–806 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yazdany, J. et al. Provision of preventive health care in systemic lupus erythematosus: data from a large observational cohort study. Arthritis Res. Ther. 12, R84 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Mosca, M. et al. Development of quality indicators to evaluate the monitoring of SLE patients in routine clinical practice. Autoimmun. Rev. 10, 383–388 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Stone, N. J., Bilek, S. & Rosenbaum, S. Recent National Cholesterol Education Program Adult Treatment Panel III update: adjustments and options. Am. J. Cardiol. 96, 53–59 (2005).

    Article  Google Scholar 

  86. Chobanian, A. V. et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289, 2560–2572 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Graham, I. et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Atherosclerosis 194, 1–45 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Costenbader, K. H. et al. Barriers to a trial of atherosclerosis prevention in systemic lupus erythematosus. Arthritis Rheum. 53, 718–723 (2005).

    Article  PubMed  Google Scholar 

  89. Duran-Barragan, S., McGwin, G. Jr, Vilá, L. M., Reveille, J. D. & Alarcón, G. S. Angiotensin-converting enzyme inhibitors delay the occurrence of renal involvement and are associated with a decreased risk of disease activity in patients with systemic lupus erythematosus—results from LUMINA (LIX): a multiethnic US cohort. Rheumatology (Oxford) 47, 1093–1096 (2008).

    Article  CAS  Google Scholar 

  90. Peters, M. J. et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann. Rheum. Dis. 69, 325–331 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. Coffman, J. D. Raynaud's phenomenon. An update. Hypertension 17, 593–602 (1991).

    Article  CAS  PubMed  Google Scholar 

  92. Forrester, J. S. & Libby, P. The inflammation hypothesis and its potential relevance to statin therapy. Am. J. Cardiol. 99, 732–738 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Ferreira, G. A., Navarro, T. P., Telles, R. W., Andrade, L. E. & Sato, E. I. Atorvastatin therapy improves endothelial-dependent vasodilation in patients with systemic lupus erythematosus: an 8 weeks controlled trial. Rheumatology (Oxford) 46, 1560–1565 (2007).

    Article  CAS  Google Scholar 

  94. Petri, M. A., Kiani, A. N., Post, W., Christopher-Stine, L. & Magder, L. S. Lupus Atherosclerosis Prevention Study (LAPS). Ann. Rheum. Dis. 70, 760–765 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Kang, S., Wu, Y. & Li, X. Effects of statin therapy on the progression of carotid atherosclerosis: a systematic review and meta-analysis. Atherosclerosis 177, 433–442 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Aprahamian, T. et al. Simvastatin treatment ameliorates autoimmune disease associated with accelerated atherosclerosis in a murine lupus model. J. Immunol. 177, 3028–3034 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Nord, J. E., Shah, P. K., Rinaldi, R. Z. & Weisman, M. H. Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature. Semin. Arthritis Rheum. 33, 336–351 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Selzer, F. et al. Vascular stiffness in women with systemic lupus erythematosus. Hypertension 37, 1075–1082 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Rahman, P. et al. The cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs. J. Rheumatol. 26, 325–330 (1999).

    CAS  PubMed  Google Scholar 

  100. Jung, H. et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum. 62, 863–868 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Sun, S., Rao, N. L., Venable, J., Thurmond, R. & Karlsson, L. TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm. Allergy Drug Targets 6, 223–235 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Doria, A. et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann. Rheum. Dis. 62, 1071–1077 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Petri, M., Perez-Gutthann, S., Spence, D. & Hochberg, M. C. Risk factors for coronary artery disease in patients with systemic lupus erythematosus. Am. J. Med. 93, 513–519 (1992).

    Article  CAS  PubMed  Google Scholar 

  104. Bravo, Y., Quiroz, Y., Ferrebuz, A., Vaziri, N. D. & Rodríguez-Iturbe, B. Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension. Am. J. Physiol. Renal Physiol. 293, F616–F623 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. van Leuven, S. I. et al. Mycophenolate mofetil attenuates plaque inflammation in patients with symptomatic carotid artery stenosis. Atherosclerosis 211, 231–236 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. David, K. M. et al. Mycophenolate mofetil vs. azathioprine is associated with decreased acute rejection, late acute rejection, and risk for cardiovascular death in renal transplant recipients with pre-transplant diabetes. Clin. Transplant. 19, 279–285 (2005).

    Article  PubMed  Google Scholar 

  107. Kiani, A. N., Magder, L. S. & Petri, M. Mycophenolate mofetil (MMF) does not slow the progression of subclinical atherosclerosis in SLE over 2 years. Rheumatol. Int. http://dx.doi.org/10.1007/s00296-011-2048-y.

  108. Haque, S. et al. Risk factors for clinical coronary heart disease in systemic lupus erythematosus: the lupus and atherosclerosis evaluation of risk (LASER) study. J. Rheumatol. 37, 322–329 (2010).

    Article  PubMed  Google Scholar 

  109. Schanberg, L. E. et al. Premature atherosclerosis in pediatric systemic lupus erythematosus: risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort. Arthritis Rheum. 60, 1496–1507 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Caligiuri, G., Nicoletti, A., Poirier, B. & Hansson, G. K. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J. Clin. Invest. 109, 745–753 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Major, A. S., Fazio, S. & Linton, M. F. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler. Thromb. Vasc. Biol. 22, 1892–1898 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Kyaw, T., Tipping, P., Toh, B. H. & Bobik, A. Current understanding of the role of B cell subsets and intimal and adventitial B cells in atherosclerosis. Curr. Opin. Lipidol. 22, 373–379 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Kyaw, T. et al. Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis. J. Immunol. 185, 4410–4419 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Ait-Oufella, H. et al. B cell depletion reduces the development of atherosclerosis in mice. J. Exp. Med. 207, 1579–1587 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pego-Reigosa, J. M. et al. Long-term improvement of lipid profile in patients with refractory systemic lupus erythematosus treated with B-cell depletion therapy: a retrospective observational study. Rheumatology (Oxford) 49, 691–696 (2010).

    Article  CAS  Google Scholar 

  116. Van Lenten, B. J. et al. Apolipoprotein A-I mimetic peptides. Curr. Atheroscler. Rep. 11, 52–57 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Navab, M. et al. An oral apoJ peptide renders HDL antiinflammatory in mice and monkeys and dramatically reduces atherosclerosis in apolipoprotein E-null mice. Arterioscler. Thromb. Vasc. Biol. 25, 1932–1937 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Woo, J. M. et al. Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis. Arthritis Res. Ther. 12, R93 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kaplan, M. J. & Salmon, J. E. How does interferon-α insult the vasculature? Let me count the ways. Arthritis Rheum. 63, 334–336 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Li, J. et al. Interferon- α priming promotes lipid uptake and macrophage-derived foam cell formation: a novel link between interferon-α and atherosclerosis in lupus. Arthritis Rheum. 63, 492–502 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Mosca, M. et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann. Rheum. Dis. 69, 1269–1274 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to the many researchers whose relevant studies were not cited here owing to space constraints. Research pursuits of the authors were supported by funding from NIH/NIAMS (K01 AR-059,095-01 to B. J. Skaggs; K23 AR-053,864-01A1 to M. McMahon), the Arthritis National Research Foundation (B. J. Skaggs), the Arthritis Foundation, Pacific Region (B. J. Skaggs and M. McMahon), Rheuminations, Inc. (B. H. Hahn), Alliance for Lupus Research (B. H. Hahn and M. McMahon), and Lupus Research Institute (B. H. Hahn and M. McMahon). B. H. Hahn is also the recipient of a Kirkland Scholar award.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all stages of the preparation of this manuscript.

Corresponding author

Correspondence to Brian J. Skaggs.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Skaggs, B., Hahn, B. & McMahon, M. Accelerated atherosclerosis in patients with SLE—mechanisms and management. Nat Rev Rheumatol 8, 214–223 (2012). https://doi.org/10.1038/nrrheum.2012.14

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2012.14

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing