Hong Kong Journal of Nephrology
Volume 8, Issue 2 , Pages 48-54, October 2006

Premature Atherosclerosis in Systemic Lupus Erythematosus: Pathogenesis and Therapeutic Considerations

  • Lai-Shan Tam

      Affiliations

    • Corresponding Author InformationAddress correspondence and reprint requests to: Dr. Lai-Shan Tam, Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. Fax: (+852) 2637-3852
    • ,
  • Edmund K. Li
    • ,
  • Brian Tomlinson

Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China

Article Outline

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause that can affect any organ, and is characterized by a wide range of autoantibodies. Several studies of large cohorts of SLE patients have reported an increased prevalence of symptomatic subclinical cardiovascular disease (CVD). It is currently believed that accelerated atherosclerosis in SLE results from a combination of numerous risk factors. In addition to a high prevalence of traditional risk factors, inflammatory processes in SLE are considered to be important in atherogenesis. Chronic activation or damage to the endothelium in SLE may trigger the inflammatory cascade and thereby promote atherogenesis. Several forms of endothelial insult are being recognized in SLE, including hypercholesterolemia, hyperhomocysteinemia, mechanical stress from hypertension, increased oxidative stress and immunologic injury as a result of immune complex deposition. This review updates the modifiable risk factors in SLE. The main focus is on the potential utility of these risk factors. The putative mechanisms of accentuated risk as a result of underlying inflammation, and evidence for association with premature atherosclerosis are discussed. Strategies that may be useful in preventing the progression of atheroma in this population include close monitoring and aggressive treatment of the traditional risk factors as in patients with high risk of CVD. The role of antioxidants and immunomodulators are also explored.

Key words:  atherosclerosis , homocysteine , hyperlipidemia , oxidative stress , risk factors , systemic lupus erythematosus

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References 

  1. Cervera R , Khamashta MA , Font J , et al.   Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus . Medicine . 1993;72:113–124
  2. Urowitz MB , Bookman AA , Koehler BE , Gordon DA , Smythe HA , Ogryzlo MA . The bimodal mortality pattern of systemic lupus erythematosus . Am J Med . 1976;60:221–225
  3. Petri M , Perez-Gutthann S , Spence D , Hochberg MC . Risk factors for coronary artery disease in patients with systemic lupus erythematosus . Am J Med . 1992;93:513–519
  4. Abu-Shakra M , Urowitz MB , Gladman DD , Gough J . Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death . J Rheumatol . 1995;22:1259–1264
  5. 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
  6. Ward MM . Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus . Arthritis Rheum . 1999;42:338–346
  7. Doria A , Shoenfeld Y , Wu R , et al.   Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus . Ann Rheum Dis . 2003;62:1071–1077
  8. Selzer F , Sutton-Tyrrell K , Fitzgerald SG , et al.   Comparison of risk factors for vascular disease in the carotid artery and aorta in women with systemic lupus erythematosus . Arthritis Rheum . 2004;50:151–159
  9. 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
  10. Sella EM , Sato EI , Barbieri A . Coronary artery angiography in systemic lupus erythematosus patients with abnormal myocardial perfusion scintigraphy . Arthritis Rheum . 2003;48:3168–3175
  11. Arad Y , Spadaro LA , Goodman K , Newstein D , Guerci AD . Prediction of coronary events with electron beam computed tomography . J Am Coll Cardiol . 2000;36:1253–1260
  12. Asanuma Y , Oeser A , Shintani AK , et al.   Premature coronary artery atherosclerosis in systemic lupus erythematosus . N Engl J Med . 2003;349:2407–2415
  13. Ross R . Atherosclerosis-an inflammatory disease . N Engl J Med . 1999;340:115–126
  14. Fulton D , Gratton JP , McCabe TJ , et al.   Regulation of endothelium-derived nitric oxide production by the protein kinase Akt . Nature . 1999;399:597–601
  15. Iwai N , Katsuya T , Ishikawa K , et al.   Human prostacyclin synthase gene and hypertension: the Suita Study . Circulation . 1999;100:2231–2236
  16. Haynes WG , Webb DJ . Endothelin as a regulator of cardiovascular function in health and disease . J Hypertens . 1998;16:1081–1098
  17. Matsuura E , Koike T . Accelerated atheroma and anti-beta2-glycoprotein I antibodies . Lupus . 2000;9:210–216
  18. Petri M , Roubenoff R , Dallal GE , Nadeau MR , Selhub J , Rosenberg IH . Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus . Lancet . 1996;348:1120–1124
  19. Wallace DJ . Antimalarial agents and lupus . Rheum Dis Clin North Am . 1994;20:243–263
  20. Wallace DJ , Metzger AL , Stecher VJ , Turnbull BA , Kern PA . Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids . Am J Med . 1990;89:322–326
  21. Petri M , Lakatta C , Magder L , Goldman D . Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis . Am J Med . 1994;96:254–259
  22. Selzer F , Sutton-Tyrrell K , Fitzgerald S , Tracy R , Kuller L , Manzi S . Vascular stiffness in women with systemic lupus erythematosus . Hypertension . 2001;37:1075–1082
  23. Tam LS , Gladman DD , Hallett DC , Rahman P , Urowitz MB . Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus . J Rheumatol . 2000;27:2142–2145
  24. Nossen JO , Rustan AC , Barnard T , Drevon CA . Inhibition by chloroquine of the secretion of very low density lipoproteins by cultured rat hepatocytes . Biochim Biophys Acta . 1984;803:11–20
  25. Borba EF , Bonfa E . Long-term beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy . J Rheumatol . 2001;28:780–785
  26. Tam LS , Li EK , Lam CW , Tomlinson B . Hydroxychloroquine has no significant effect on lipids and apolipoproteins in Chinese systemic lupus erythematosus patients with mild or inactive disease . Lupus . 2000;9:413–416
  27. Petri M . Thrombosis and systemic lupus erythematosus: the Hopkins Lupus Cohort perspective . Scand J Rheumatol . 1996;25:191–193
  28. Wallace DJ , Linker-Israeli M , Metzger AL , Stecher VJ . The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE . Lupus . 1993;(2 Suppl 1):S13–S15
  29. Mok MY , Chan EY , Fong DY , Leung KF , Wong WS , Lau CS . Antiphospholipid antibody profiles and their clinical associations in Chinese patients with systemic lupus erythematosus . J Rheumatol . 2005;32:622–628
  30. Petri M . Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis . Lupus . 1996;(5 Suppl 1):S16–S22
  31. Cholesterol Treatment Trialists' (CTT) Collaborators  . Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins . Lancet . 2005;366:1267–1278
  32. Rosenson RS , Tangney CC . Antiatherothrombotic properties of statins: implications for cardiovascular event reduction . JAMA . 1998;279:1643–1650
  33. Rossen RD . HMG-CoA reductase inhibitors: a new class of antiinflammatory drugs? . J Am Coll Cardiol . 1997;30:1218–1219
  34. Van Doornum S , McColl G , Wicks IP . Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis . Ann Rheum Dis . 2004;63:1571–1575
  35. Graziadei IW , Obermoser GE , Sepp NT , Erhart KH , Vogel W . Drug-induced lupus-like syndrome associated with severe autoimmune hepatitis . Lupus . 2003;12:409–412
  36. Antonov D , Kazandjieva J , Etugov D , Gospodinov D , Tsankov N . Drug-induced lupus erythematosus . Clin Dermatol . 2004;22:157–166
  37. Noel B , Panizzon RG . Lupus-like syndrome associated with statin therapy . Dermatology . 2004;208:276–277
  38. Lantuejoul S , Brambilla E , Brambilla C , Devouassoux G . Statin-induced fibrotic nonspecific interstitial pneumonia . Eur Respir J . 2002;19:577–580
  39. Schanberg LE , Sandborg C . Dyslipoproteinemia and premature atherosclerosis in pediatric systemic lupus erythematosus . Curr Rheumatol Rep . 2004;6:425–433
  40. Chabova V , Schirger A , Stanson AW , McKusick MA , Textor SC . Outcomes of atherosclerotic renal artery stenosis managed without revascularization . Mayo Clin Proc . 2000;75:437–444
  41. Mogensen CE , Vestbo E , Poulsen PL , et al.   Microalbuminuria and potential confounders. A review and some observations on variability of urinary albumin excretion . Diabetes Care . 1995;18:572–581
  42. Heart Outcomes Prevention Evaluation Study Investigators  . Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy . Lancet . 2000;355:253–259
  43. Homocysteine Studies C . Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis . JAMA . 2002;288:2015–2022
  44. Woo KS , Chook P , Lolin YI , Sanderson JE , Metreweli C , Celermajer DS . Folic acid improves arterial endothelial function in adults with hyperhomocystinemia . J Am Coll Cardiol . 1999;34:2002–2006
  45. Verhaar MC , Wever RM , Kastelein JJ , van-Dam T , Koomans HA , Rabelink TJ . 5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia . Circulation . 1998;97:237–241
  46. Verhaar MC , Stroes E , Rabelink TJ . Folates and cardiovascular disease . Arterioscler Thromb Vasc Biol . 2002;22:6–13
  47. Bonaa KH , Njolstad I , Ueland PM , Schirmer H , Tverdal A , Steigen T , et al.   Homocysteine lowering and cardiovascular events after acute myocardial infarction . N Engl J Med . 2006;354:1578–1588
  48. Lonn E , Yusuf S , Arnold MJ , Sheridan P , Pogue J , Micks M , et al.   Homocysteine lowering with folic acid and B vitamins in vascular disease . N Engl J Med . 2006;354:1567–1577
  49. Duvall WL . Endothelial dysfunction and antioxidants . Mt Sinai J Med . 2005;72:71–80
  50. Hornig B , Arakawa N , Kohler C , Drexler H . Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure . Circulation . 1998;97:363–368
  51. Ellis GR , Anderson RA , Lang D , Blackman DJ , Morris RH , Morris-Thurgood J , et al.   Neutrophil superoxide anion-generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy . J Am Coll Cardiol . 2000;36:1474–1482
  52. Gokce N , Keaney JF , Frei B , Holbrook M , Olesiak M , Zachariah BJ , et al.   Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease . Circulation . 1999;99:3234–3240
  53. Raitakari OT , Adams MR , McCredie RJ , Griffiths KA , Stocker R , Celermajer DS . Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect . J Am Coll Cardiol . 2000;35:1616–1621
  54. Darko D , Dornhorst A , Kelly FJ , Ritter JM , Chowienczyk PJ . Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in type II diabetes . Clin Sci (Lond) . 2002;103:339–344
  55. Simons LA , von-Konigsmark M , Simons J , Stocker R , Celermajer DS . Vitamin E ingestion does not improve arterial endothelial dysfunction in older adults . Atherosclerosis . 1999;143:193–199
  56. Elliott TG , Barth JD , Mancini GB . Effects of vitamin E on endothelial function in men after myocardial infarction . Am J Cardiol . 1995;76:1188–1190
  57. Tam LS , Li EK , Leung VY , Griffith JF , Benzie IF , Lim PL , et al.   Effects of vitamins C and E on oxidative stress markers and endothelial function in patients with systemic lupus erythematosus: a double blind, placebo controlled pilot study . J Rheumatol . 2005;32:275–282
  58. Makheja AN , Bloom S , Muesing R , Simon T , Bailey JM . Anti-inflammatory drugs in experimental atherosclerosis. 7. Spontaneous atherosclerosis in WHHL rabbits and inhibition by cortisone acetate . Atherosclerosis . 1989;76:155–161
  59. Bulkley BH , Roberts WC . The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. A study of 36 necropsy patients . Am J Med . 1975;58:243–264
  60. Svenungsson E , Jensen-Urstad K , Heimburger M , Silveira A , Hamsten A , de Faire U , et al.   Risk factors for cardiovascular disease in systemic lupus erythematosus . Circulation . 2001;104:1887–1893
  61. Ridker PM , Hennekens CH , Buring JE , Rifai N . C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women . N Engl J Med . 2000;342:836–843
  62. Roman MJ , Shanker BA , Davis A , Lockshin MD , Sammaritano L , Simantov R , et al.   Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus . N Engl J Med . 2003;349:2399–2406
  63. Folsom A . Fibrinogen and cardiovascular risk in the Atherosclerosis Risk in Communities (ARIC) study. . In:  Ernst E editors. Fibrinogen: A New Cardiovascular Risk Factor. . Oxford, UK: Blackwell; 1992;
  64. Manolio TA, Furberg CD, Shemanski L, Psaty BM, O'Leary DH, Tracy RP, et al. Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. The CHS Collaborative Research Group . Circulation . 1993;88:2163–2171
  65. Ernst E . Lowering the plasma fibrinogen concentration with drugs . Clin Pharm . 1992;11:968–971
  66. Sacks FM , McPherson R , Walsh BW . Effect of postmenopausal estrogen replacement on plasma Lp(a) lipoprotein concentrations . Arch Intern Med . 1994;154:1106–1110
  67. Jones PH , Pownall HJ , Patsch W , Herd JA , Farmer JA , Payton-Ross C , et al.   Effect of gemfibrozil on levels of lipoprotein[a] in type II hyperlipoproteinemic subjects . J Lipid Res . 1996;37:1298–1308
  68. Morgan JM , Capuzzi DM , Guyton JR . A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients . Am J Cardiol . 1998;82:29U–34U
  69. Beil FU , Terres W , Orgass M , Greten H . Dietary fish oil lowers lipoprotein(a) in primary hypertriglyceridemia . Atherosclerosis . 1991;90:95–97

PII: S1561-5413(09)60232-5

doi:10.1016/S1561-5413(09)60232-5

Hong Kong Journal of Nephrology
Volume 8, Issue 2 , Pages 48-54, October 2006

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