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Dyslipoproteinemia and premature atherosclerosis in pediatric systemic lupus erythematosus

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Abstract

While modern treatments for systemic lupus erythematosus (SLE) have resulted in greatly improved long term outcome in children and adults, complications of atherosclerosis have become a major cause of morbidity and mortality. Although children and adolescents with SLE rarely experience adverse cardiovascular events before adulthood, dyslipoproteinemia and early evidence of premature atherosclerosis is present much earlier. Accelerated atherogenesis in SLE is multifactorial, most likely reflecting vascular, immune, and inflammatory changes along with medication effects. The long term complications of cardiovascular disease in childhood lupus present a particularly important target for intervention because of the potential return on investment by significantly lengthening life and improving quality of life over many decades. An ongoing multi-center, randomized, controlled trial, Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE), testing the efficacy of statins in preventing premature atherosclerosis in children and adolescents with SLE will guide future therapeutic intervention.

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References and Recommended Reading

  1. Trager J, Ward MM: Mortality and causes of death in systemic lupus erythematosus. Curr Opin Rheumatol 2001, 13:345–351.

    Article  PubMed  CAS  Google Scholar 

  2. 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.

    PubMed  CAS  Google Scholar 

  3. Manzi S, Selzer F, Sutton-Tyrrell K, et al.: Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999, 42:51–60.

    Article  PubMed  CAS  Google Scholar 

  4. Svenungsson E, Jensen-Urstad K, Heimburger M, et al.: Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation 2001, 104:1887–1893.

    PubMed  CAS  Google Scholar 

  5. Ilowite NT, Samuel P, Ginzler E, Jacobson MS: Dyslipoproteinemia in pediatric systemic lupus erythematosus. Arthritis Rheum 1988, 31:859–863. This publication represents the first identification of DLP in SLE.

    Article  PubMed  CAS  Google Scholar 

  6. Falaschi F, Ravelli A, Martignoni A, et al.: Nephrotic-range proteinuria, the major risk factor for early atherosclerosis in juvenile-onset systemic lupus erythematosus. Arthritis Rheum 2000, 43:1405–1409.

    Article  PubMed  CAS  Google Scholar 

  7. Gazarian M, Feldman BM, Benson LN, et al.: Assessment of myocardial perfusion and function in childhood systemic lupus erythematosus. J Pediatr 1998, 132:109–116.

    Article  PubMed  CAS  Google Scholar 

  8. Libby P: The vascular biology of atherosclerosis. In Heart Disease: A Textbook of Cardiovascular Medicine. Edited by Braunwald E, Zipes DP, Libby P. Philadelphia: W.B. Saunders; 2001:995–1006.

    Google Scholar 

  9. Salmon JE, Roman MJ: Accelerated atherosclerosis in systemic lupus erythematosus: implications for patient management. Curr Opin Rheumatol 2001, 13:341–344.

    Article  PubMed  CAS  Google Scholar 

  10. Trager J, Ward MM: Mortality and causes of death in systemic lupus erythematosus. Curr Opin Rheumatol 2001, 13:345–351.

    Article  PubMed  CAS  Google Scholar 

  11. Esdaile JM, Abrahamowicz M, Grodzicky T, et al.: Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 2001, 44:2331–2337.

    Article  PubMed  CAS  Google Scholar 

  12. Bruce IN, Urowitz MB, Gladman DD, et al.: Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum 2003, 48:3159–3167.

    Article  PubMed  Google Scholar 

  13. Asanuma Y, Oeser A, Shintani AK, et al.: Premature coronaryartery atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003, 349:2407–2415.

    Article  PubMed  CAS  Google Scholar 

  14. Roman MJ, Shanker BA, Davis A, et al.: Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003, 349:2399–2406. A comprehensive evaluation of the risk factors associated with development of atherosclerosis in SLE with a matched control group.

    Article  PubMed  CAS  Google Scholar 

  15. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  17. Guerci AD, Arad Y: Potential use of Ca++ scanning to determine the need for and intensity of lipid-lowering therapy in asymptomatic adults. Curr Cardiol Rep 2001, 3:408–415.

    PubMed  CAS  Google Scholar 

  18. Mukherjee D, Yadav JS: Carotid artery intimal-medial thickness: indicator of atherosclerotic burden and response to risk factor modification. Am Heart J 2002, 144:753–759.

    Article  PubMed  Google Scholar 

  19. Espeland MA, Craven TE, Riley WA, et al.: Reliability of longitudinal ultrasonographic measurements of carotid intimalmedial thicknesses. Asymptomatic Carotid Artery Progression Study Research Group. Stroke 1996, 27:480–485.

    PubMed  CAS  Google Scholar 

  20. Levesque M, Weinberg JB: The dichotomous role of nitric oxide in the pathogenesis of accelerated atherosclerosis associated with systemic lupus erythematosus. Curr Mol Med 2004, 4:777–786.

    Article  PubMed  CAS  Google Scholar 

  21. Lee T, von Scheven E, Sandborg C: Systemic lupus erythematosus and antiphospholipid syndrome in children and adolescents. Curr Opin Rheumatol 2001, 13:415–421.

    Article  PubMed  CAS  Google Scholar 

  22. Lima DS, Sato EI, Lima VC, et al.: Brachial endothelial function is impaired in patients with systemic lupus erythematosus. J Rheumatol 2002, 29:292–297.

    PubMed  Google Scholar 

  23. Soep JB, Mietus-Snyder M, Malloy MJ, et al.: Assessment of atherosclerotic risk factors and endothelial function in children and young adults with pediatric-onset systemic lupus erythematosus. Arthritis Rheum 2004, 51:451–457.

    Article  PubMed  Google Scholar 

  24. 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. A comprehensive evaluation of the risks of premature atherosclerosis in SLE.

    Article  PubMed  Google Scholar 

  25. Willerson JT, Ridker PM: Inflammation as a cardiovascular risk factor. Circulation 2004, 109(Suppl 1):II2–10. A comprehensive review of the role of inflammation in atherosclerosis.

    PubMed  Google Scholar 

  26. Schonbeck U, Libby P: Inflammation, immunity, and HMGCoA reductase inhibitors: statins as antiinflammatory agents? Circulation 2004, 109(Suppl 1):II18–26. A comprehensive review of the anti-inflammatory effects of statins.

    PubMed  Google Scholar 

  27. Prasad A, Zhu J, Halcox JP, Waclawiw MA, et al.: Predisposition to atherosclerosis by infections: role of endothelial dysfunction. Circulation 2002, 106:184–190.

    Article  PubMed  Google Scholar 

  28. Stemme S, Faber B, Holm J, et al.: T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A 1995, 92:3893–3897.

    Article  PubMed  CAS  Google Scholar 

  29. Zhu J, Katz RJ, Quyyumi AA, et al.: Association of serum antibodies to heat-shock protein 65 with coronary calcification levels: suggestion of pathogen-triggered autoimmunity in early atherosclerosis. Circulation 2004, 109:36–41.

    Article  PubMed  CAS  Google Scholar 

  30. Frostegard J: Autoimmunity, oxidized LDL and cardiovascular disease. Autoimmun Rev 2002, 1:233–237.

    Article  PubMed  CAS  Google Scholar 

  31. Wu R, Svenungsson E, Gunnarsson I, et al.: Antibodies to adult human endothelial cells cross-react with oxidized low-density lipoprotein and beta 2-glycoprotein I (beta 2-GPI) in systemic lupus erythematosus. Clin Exp Immunol 1999, 115:561–566.

    Article  PubMed  CAS  Google Scholar 

  32. Dinu AR, Merrill JT, Shen C, et al.: Frequency of antibodies to the cholesterol transport protein apolipoprotein A1 in patients with SLE. Lupus 1998, 7:355–360.

    Article  PubMed  CAS  Google Scholar 

  33. Hayem G, Nicaise-Roland P, Palazzo E, et al.: Anti-oxidized low-density-lipoprotein (OxLDL) antibodies in systemic lupus erythematosus with and without antiphospholipid syndrome. Lupus 2001, 10:346–351.

    Article  PubMed  CAS  Google Scholar 

  34. Romero FI, Khamashta MA, Hughes GR: Lipoprotein(a) oxidation and autoantibodies: a new path in atherothrombosis. Lupus 2000, 9:206–209.

    Article  PubMed  CAS  Google Scholar 

  35. Nuttall SL, Heaton S, Piper MK, et al.: Cardiovascular risk in systemic lupus erythematosus-evidence of increased oxidative stress and dyslipidaemia. Rheumatology (Oxford) 2003, 42:758–762.

    Article  CAS  Google Scholar 

  36. Posadas-Romero C, Torres-Tamayo M, Zamora-Gonzalez J, et al.: High insulin levels and increased low-density lipoprotein oxidizability in pediatric patients with systemic lupus erythematosus. Arthritis Rheum 2004, 50:160–165.

    Article  PubMed  CAS  Google Scholar 

  37. Ohlenschlaeger T, Garred P, Madsen HO, Jacobsen S: Mannosebinding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus. N Engl J Med 2004, 351:260–267.

    Article  PubMed  CAS  Google Scholar 

  38. Molloy KJ, Thompson MM, Jones JL, et al.: Unstable carotid plaques exhibit raised matrix metalloproteinase-8 activity. Circulation 2004, 110:337–343.

    Article  PubMed  CAS  Google Scholar 

  39. Wierzbicki AS: Lipids, cardiovascular disease and atherosclerosis in systemic lupus erythematosus. Lupus 2000, 9:194–201. An excellent review.

    Article  PubMed  CAS  Google Scholar 

  40. Sari RA, Polat MF, Taysi S, et al.: Serum lipoprotein(a) level and its clinical significance in patients with systemic lupus erythematosus. Clin Rheumatol 2002, 21:520–524.

    Article  PubMed  CAS  Google Scholar 

  41. Formiga F, Meco JF, Pinto X, et al.: Lipid and lipoprotein levels in premenopausal systemic lupus erythematosus patients. Lupus 2001, 10:359–363.

    Article  PubMed  CAS  Google Scholar 

  42. Ilowite NT, Copperman N, Leicht T, et al.: Effects of dietary modification and fish oil supplementation on dyslipoproteinemia in pediatric systemic lupus erythematosus. J Rheumatol 1995, 22:1347–1351. Only clinical trial of lipid lowering therapy in children with lupus.

    PubMed  CAS  Google Scholar 

  43. Borba EF, Bonfa E: Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies. Lupus 1997, 6:533–539. Showed that DPL related to disease activity.

    PubMed  CAS  Google Scholar 

  44. Svenungsson E, Gunnarsson I, Fei GZ, et al.: Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. Arthritis Rheum 2003, 48:2533–2540. Describes role of TNF-α in atherosclerosis of lupus.

    Article  PubMed  CAS  Google Scholar 

  45. Aderka D, Wysenbeek A, Engelmann H, et al.: Correlation between serum levels of soluble tumor necrosis factor receptor and disease activity in systemic lupus erythematosus. Arthritis Rheum 1993, 36:1111–1120.

    Article  PubMed  CAS  Google Scholar 

  46. Studnicka-Benke A, Steiner G, Petera P, Smolen JS: Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus. Br J Rheumatol 1996, 35:1067–1074.

    Article  PubMed  CAS  Google Scholar 

  47. Svenungsson E, Fei GZ, Jensen-Urstad K, et al.: TNF-alpha: a link between hypertriglyceridaemia and inflammation in SLE patients with cardiovascular disease. Lupus 2003, 12:454–461.

    Article  PubMed  CAS  Google Scholar 

  48. Borba EF, Bonfa E, Vinagre CG, et al.: Chylomicron metabolism is markedly altered in systemic lupus erythematosus. Arthritis Rheum 2000, 43:1033–1040.

    Article  PubMed  CAS  Google Scholar 

  49. Reichlin M, Fesmire J, Quintero-Del-Rio AI, Wolfson-Reichlin M: Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus erythematosus. Arthritis Rheum 2002, 46:2957–2963.

    Article  PubMed  CAS  Google Scholar 

  50. Shah M, Adams-Huet B, Kavanaugh A, et al.: Nutrient intake and diet quality in patients with systemic lupus erythematosus on a culturally sensitive cholesterol lowering dietary program. J Rheumatol 2004, 31:71–75.

    PubMed  Google Scholar 

  51. Rahman P, Gladman DD, Urowitz MB, et al.: The cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs. J Rheumatol 1999, 26:325–330.

    PubMed  CAS  Google Scholar 

  52. Eriksson C, Engstrand S, Sundqvist KG, Rantapaa-Dahlqvist S: Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF-alpha therapy. Ann Rheum Dis 2004, In press.

  53. Ballantyne CM: Current and future aims of lipid-lowering therapy: changing paradigms and lessons from the Heart Protection Study on standards of efficacy and safety. Am J Cardiol 2003, 92:3K-9K.

    Article  PubMed  CAS  Google Scholar 

  54. Crisby M, Nordin-Fredriksson G, Shah PK, et al.: Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001, 103:926–933.

    PubMed  CAS  Google Scholar 

  55. Molloy KJ, Thompson MM, Schwalbe EC, et al.: Comparison of levels of matrix metalloproteinases, tissue inhibitor of metalloproteinases, interleukins, and tissue necrosis factor in carotid endarterectomy specimens from patients on versus not on statins preoperatively. Am J Cardiol 2004, 94:144–146.

    Article  PubMed  CAS  Google Scholar 

  56. McCarey DW, McInnes IB, Madhok R, et al.: Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 2004, 363:2015–2021.

    Article  PubMed  CAS  Google Scholar 

  57. Stuve O, Youssef S, Steinman L, Zamvil SS: Statins as potential therapeutic agents in neuroinflammatory disorders. Curr Opin Neurol 2003, 16:393–401.

    Article  PubMed  Google Scholar 

  58. Penson MG, Fricker FJ, Thompson JR, et al.: Safety and efficacy of pravastatin therapy for the prevention of hyperlipidemia in pediatric and adolescent cardiac transplant recipients. J Heart Lung Transplant 2001, 20:611–618.

    Article  PubMed  CAS  Google Scholar 

  59. Wiegman A, Hutten BA, de Groot E, et al.: Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004, 292:331–337.

    Article  PubMed  CAS  Google Scholar 

  60. Pasternak RC, Smith SC, Jr., Bairey-Merz CN, et al.: ACC/AHA/ NHLBI Clinical Advisory on the Use and Safety of Statins. Circulation 2002, 106:1024–1028. The official statements of the American College of Cardiology, American Heart Association, and the National Institute of Heart, Lung, and Blood regarding the use and safety of statins.

    Article  PubMed  Google Scholar 

  61. Pavlov OV, Bobryshev YuV, Balabanov YuV, Ashwell K: An in vitro study of the effects of lovastatin on human fetal brain cells. Neurotoxicol Teratol 1995, 17:31–39.

    Article  PubMed  CAS  Google Scholar 

  62. Muldoon MF, Barger SD, Ryan CM, et al.: Effects of lovastatin on cognitive function and psychological well-being. Am J Med 2000, 108:538–546.

    Article  PubMed  CAS  Google Scholar 

  63. Cucchiara B, Kasner SE: Use of statins in CNS disorders. J Neurol Sci 2001, 187:81–89.

    Article  PubMed  CAS  Google Scholar 

  64. Schanberg L, Sandborg C, Allen A, et al.: Atherosclerosis prevention in pediatric lupus erythematosus: APPLE Trial Design [abstract]. Arthritis Rheum 2004, 50:S532.

    Google Scholar 

  65. Kiana A, Petri M: Statin toxicity in the lupus atherosclerosis prevention study. Arthritis Rheum 2003, 48:S370.

    Article  CAS  Google Scholar 

  66. Banchereau J, Pascual V, Palucka AK: Autoimmunity through cytokine-induced dendritic cell activation. Immunity 2004, 20:539–550.

    Article  PubMed  CAS  Google Scholar 

  67. Freedman DS, Srinivasan SR, Shear CL, et al.: The relation of apolipoproteins A-I and B in children to parental myocardial infarction. N Engl J Med 1986, 315:721–726.

    Article  PubMed  CAS  Google Scholar 

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Schanberg, L.E., Sandborg, C. Dyslipoproteinemia and premature atherosclerosis in pediatric systemic lupus erythematosus. Curr Rheumatol Rep 6, 425–433 (2004). https://doi.org/10.1007/s11926-004-0021-4

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