Current Rheumatology Reports

, Volume 14, Issue 1, pp 87–94

Potential Use of Statins in the Treatment of Antiphospholipid Syndrome

  • Chary Lopez-Pedrera
  • Patricia Ruiz-Limon
  • M. Angeles Aguirre
  • Antonio Rodriguez-Ariza
  • Maria José Cuadrado
ANTIPHOSPHOLIPID SYNDROME (RAS ROUBEY, SECTION EDITOR)

Abstract

Antiphospholipid syndrome (APS) is a disorder characterized by the association of arterial or venous thrombosis and/or pregnancy morbidity with the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant antibodies, and/or anti–β2-glycoprotein I antibodies). Several studies have contributed to uncovering the basis of antiphospholipid antibody pathogenicity, including the targeted cellular components, affected systems, involved receptors, intracellular pathways used, and the effector molecules that are altered in the process. Therapy for thrombosis traditionally has been based on long-term oral anticoagulation; however, bleeding complications and recurrence despite high-intensity anticoagulation can occur. Based on all the data obtained, new potential therapeutic agents have been proposed. Statins have a variety of direct effects on gene expression and the function of cells of both the innate and adaptive immune systems, many of which are related to blockade of GTPase isoprenylation. In APS, statins have multiple profound effects on monocyte, lymphocyte, and endothelial cell activities, all of which may contribute to thrombosis prevention in APS patients. Nevertheless, larger randomized trials are needed to validate the role of statins in the treatment of this autoimmune disease.

Keywords

Antiphospholipid syndrome Statins Thrombosis Treatment Proteomic approaches 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Espinosa G, Cervera R, Font J, Shoenfeld Y. Antiphospholipid syndrome: pathogenic mechanisms. Autoimmun Rev. 2003;2:86–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Koike T, Bohgaki M, Amengual O, Atsumi T. Antiphospholipid antibodies, Lessons from the bench. J Autoimmun. 2007;28:129–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Cuadrado MJ, Lopez-Pedrera C, Khamashta MA, et al. Thrombosis in primary antiphospholipid syndrome: a pivotal role for monocyte tissue factor expression. Arthritis Rheum. 1997;40:834–41.PubMedCrossRefGoogle Scholar
  4. 4.
    Dobado-Berrios PM, Lopez-Pedrera Ch, Velasco F, et al. Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome. Thromb Haemost. 1999;82:1578–82.PubMedGoogle Scholar
  5. 5.
    Dobado-Berrios PM, Lopez-Pedrera Ch, Velasco F, Cuadrado MJ. The role of TF in the antiphospholipid syndrome. Arthritis Rheum. 2001;44:2467–76.PubMedCrossRefGoogle Scholar
  6. 6.
    López-Pedrera Ch, Buendía P, Cuadrado MJ, et al. Antiphospholipid antibodies from antiphospholipid syndrome patients induce monocyte expression through the simultaneous activation of both NFkB/Rel proteins via p38 MAPK pathway, and the MEK1/ERK pathway. Arthritis Rheum. 2006;54:301–11.PubMedCrossRefGoogle Scholar
  7. 7.
    Vega-Ostertag M, Harris EN, Pierangeli SS. Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin. Arthritis Rheum. 2004;50:2911–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Bohgaki M, Atsumi T, Yamashita Y, et al. The p38 mitogen-activated protein kinase (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti-beta2glycoprotein I antibodies. Int Immunol. 2004;16:1633–41.PubMedCrossRefGoogle Scholar
  9. 9.
    Montiel-Manzano G, Romay-Penabad Z. Papalardo de Martinez E, et al.: In vivo effects of an inhibitor of nuclear factor-kappa B on thrombogenic properties of antiphospholipid antibodies. Ann N Y Acad Sci. 2007;1108:540–53.PubMedCrossRefGoogle Scholar
  10. 10.
    Dunoyer-Geindre S, de Moerloose P. Galve-de Rochemonteix B, et al.: NFkappa B is an essential intermediate in the activation of endothelial cells by anti-beta(2)- glycoprotein 1 antibodies. Thromb Haemost. 2002;88:851–7.PubMedGoogle Scholar
  11. 11.
    Vega-Ostertag M, Casper K, Swerlick R, et al. Involvement of p38 MAPK in the upregulation of tissue factor on endothelial cells by antiphospholipid antibodies. Arthritis Rheum. 2005;52:1545–54.PubMedCrossRefGoogle Scholar
  12. 12.
    Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002;20:4368–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Williams FMK, Parmar K, Hughes GRV, Hunt BJ. Systemic endothelial cell markers in primary antiphospholipid syndrome. Thromb Haemost. 2000;84:742–6.PubMedGoogle Scholar
  14. 14.
    Cuadrado MJ, Buendía P, Velasco F, et al. Vascular endothelial growth factor expression in monocytes from patients with primary antiphospholipid syndrome. J Thromb Haemost. 2006;4:2461–9.PubMedCrossRefGoogle Scholar
  15. 15.
    George J, Harats D, Gilburd B, et al. Immunolocalization of beta2-glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression. Circulation. 1999;99:2227–30.PubMedGoogle Scholar
  16. 16.
    Shoenfeld Y, Sherer Y, George J, Harats D. Autoantibodies associated with atherosclerosis. Ann Med. 2000;32:37–40.PubMedGoogle Scholar
  17. 17.
    Veres K, Lakos G, Kerenyi A, et al. Antiphospholipid antibodies in acute coronary syndrome. Lupus. 2004;13:423–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Jara LJ, Medina G, Vera-Lastra O. Systemic antiphospholipid síndrome and atherosclerosis. Clin Rev Allergy Immunol. 2007;32:172–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Pierangeli SS, Girardi G, Vega-Ostertag M, et al. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum. 2005;52:2120–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med. 2004;10:1222–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Pierangeli SS, Chen PP, Raschi E, et al. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost. 2008;34:236–50.PubMedCrossRefGoogle Scholar
  22. 22.
    Stone S, Khamashta MA, Poston L. Placentation, antiphospholipid syndrome and pregnancy outcome. Lupus. 2001;10:67–74.PubMedCrossRefGoogle Scholar
  23. 23.
    Di Simone N, Luigi MP, Marco D, et al. Pregnancies complicated with antiphospholipid syndrome: the pathogenic mechanism of antiphospholipid antibodies: a review of the literature. Ann N Y Acad Sci. 2007;1108:505–14.PubMedCrossRefGoogle Scholar
  24. 24.
    Chamley LW, Allen JL, Johnson PM. Synthesis of beta2 glycoprotein 1 by the human placenta. Placenta. 1997;18:403–10.PubMedCrossRefGoogle Scholar
  25. 25.
    Di Simone N, Raschi E, Testoni C, et al. Pathogenic role of anti-beta 2-glycoprotein I antibodies in antiphospholipid associated fetal loss: characterisation of beta 2-glycoprotein I binding to trophoblast cells and functional effects of anti-beta 2-glycoprotein I antibodies in vitro. Ann Rheum Dis. 2005;64:462–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Mulla MJ, Brosens JJ, Chamley LW, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol. 2009;62:96–111.PubMedCrossRefGoogle Scholar
  27. 27.
    • Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA: Antiphospholipid syndrome. Lancet 2010;376:1498-1509. This is an elegant revision centered on the recent suggestions for therapy of thrombosis as well as obstetric care in APS patients, including a perspective on the future use of therapies such as hydroxychloroquine, statins, rituximab, and new anticoagulant drugs. PubMedCrossRefGoogle Scholar
  28. 28.
    Cortellaro M, Cofrancesco E, Arbustini E, et al. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost. 2002;88:41–7.PubMedGoogle Scholar
  29. 29.
    Ridker PM, Danielson E, Fonseca FA, et al. JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175–82.PubMedCrossRefGoogle Scholar
  30. 30.
    Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360:1851–61.PubMedCrossRefGoogle Scholar
  31. 31.
    Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006;6:358–70.PubMedCrossRefGoogle Scholar
  32. 32.
    Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89–118.PubMedCrossRefGoogle Scholar
  33. 33.
    Undas A, Brummel-Ziedins E, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol. 2005;25:1–8.CrossRefGoogle Scholar
  34. 34.
    Kuipers HF, Biesta PJ, Groothuis TA, et al. Statins affect T cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing microdomains. Hum Immunol. 2005;66:653–65.PubMedCrossRefGoogle Scholar
  35. 35.
    Ghittoni R, Patrussi L, Pirozzi K, et al. Simvastatin inhibits T-cell activation by selectively impairing the function of Ras superfamily GTPases. FASEB J. 2005;19:605–7.PubMedGoogle Scholar
  36. 36.
    Dunn SE, Youssef S, Goldstein MJ, et al. Isoprenoids determine Th1/Th2 fate in pathogenic T cells providing a mechanism of modulation of autoimmunity by atorvastatin. J Exp Med. 2006;203:401–12.PubMedCrossRefGoogle Scholar
  37. 37.
    Greenwood J, Walters CE, Pryce G, et al. Lovastatin inhibits brain endothelial Rho-dependent lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 2003;17:905–7.PubMedGoogle Scholar
  38. 38.
    Yoshida M, Sawada T, Ishii H, et al. HMG-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol. 2001;21:1165–71.PubMedCrossRefGoogle Scholar
  39. 39.
    Rezaie-Majd A, Prager GW, Bucek RA, et al. Simvastatin reduces the expression of adhesion molecules in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2003;23:397–403.PubMedCrossRefGoogle Scholar
  40. 40.
    Turner NA, O’Regan DJ, Ball SG, Porter KE. Simvastatin inhibits MMP-9 secretion from human saphenous vein smooth muscle cells by inhibiting the RhoA/ROCK pathway and reducing MMP-9 mRNA levels. FASEB J. 2005;19:804–6.PubMedGoogle Scholar
  41. 41.
    Youssef SO, Stuve JC, Patarroyo PJ, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420:78–84.PubMedCrossRefGoogle Scholar
  42. 42.
    Zhang X, Jin J, Peng X, Ramgolam VS, Markovic-Plese S. Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol. 2008;180:6988–96.PubMedGoogle Scholar
  43. 43.
    Chasman DI, Posada D, Subrahmanyan L, et al. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA. 2004;291:2821–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Siest G, Marteau JB, Maumus S, et al. Pharmacogenomics and cardiovascular drugs: need for integrated biological system with phenotypes and proteomic markers. Eur J Pharmacol. 2005;527:1–22.PubMedCrossRefGoogle Scholar
  45. 45.
    Duran MC, Martin-Ventura JL, Mohammed S, et al. Atorvastatin modulates the profile of proteins released by human atherosclerotic plaques. Eur J Pharmacol. 2007;562:119–29.PubMedCrossRefGoogle Scholar
  46. 46.
    Grobbee DE, Bots ML. Atherosclerotic disease regression with statins: studies using vascular markers. Int J Cardiol. 2004;96:447–59.PubMedCrossRefGoogle Scholar
  47. 47.
    Anderson NG, Anderson NL. Twenty years of two-dimensional electrophoresis: past, present and future. Electrophoresis. 1996;17:443–53.PubMedCrossRefGoogle Scholar
  48. 48.
    Undas A, Celiska-Lowenhoff M, Kaczor M, Musial J. New nonlipid effects of statins and their clinical relevance in cardiovascular disease. Thromb Haemost. 2004;91:1065–77.PubMedGoogle Scholar
  49. 49.
    Krysiak R, Okopien B, Herman ZS. Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes. Drugs. 2003;63:1821–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Meroni PL, Raschi E, Testoni C, et al. Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum. 2001;44:2870–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Ferrara DE, Liu X, Espinola RG, et al. Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum. 2003;48:3272–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Ferrara DE, Swerlick R, Casper K, et al. Fluvastatin inhibits up-regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J Thromb Haemost. 2004;2:1558–63.PubMedCrossRefGoogle Scholar
  53. 53.
    Martínez LA, Amigo MC, Orozco A, et al. Effect of rosuvastatin on VCAM-1 expression by HUVEC exposed to APS serum in an in vitro model. Clin Exp Rheumatol. 2007;25:18–9.Google Scholar
  54. 54.
    • López-Pedrera C, Ruiz-Limón P, Aguirre MA, et al.: Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome. Ann Rheum Dis 2011;70:675-682. This study delineates the cellular and molecular mechanisms of action of fluvastatin on monocytes from APS patients through both an in vivo study and a confirmatory in vitro study. PubMedCrossRefGoogle Scholar
  55. 55.
    Redecha P, Franzke CW, Ruf W, et al. Neutrophil activation by the tissue factor/factor VIIa/PAR2 axis mediates foetal death in a mouse model of antiphospholipid syndrome. J Clin Invest. 2008;118:3453–61.PubMedGoogle Scholar
  56. 56.
    Redecha P, van Rooijen N, Torry D, Girardi G. Pravastatin prevents miscarriages in mice: role of tissue factor in placental and foetal injury. Blood. 2009;113:4101–9.PubMedCrossRefGoogle Scholar
  57. 57.
    • Jajoria P, Murthy V, Papalardo E, et al.: Statins for the treatment of antiphospholipid syndrome? Ann NY Acad Sci 2009;1173:736–745. This study examined whether fluvastatin affects the plasma levels of various proinflammatory/prothrombotic markers in APS patients. The authors found that fluvastatin significantly reduced those markers in the majority of treated patients. The data from this study show that statins may be beneficial in aPL-positive patients. PubMedCrossRefGoogle Scholar
  58. 58.
    Ridker PM, Danielson E, Fonseca FA. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;20:2195–207.CrossRefGoogle Scholar
  59. 59.
    Kenis I, Tartakover-Matalon S, Cherepnin N, et al. Simvastatin has deleterious effects on human first trimester placental explants. Hum Reprod. 2005;20:2866–72.PubMedCrossRefGoogle Scholar
  60. 60.
    Forbes K, Hurst LM, Aplin JD, Westwood M, Gibson JM. Statins are detrimental to human placental development and function; use of statins during early pregnancy is inadvisable. J Cell Mol Med. 2008;12:2295–6.PubMedCrossRefGoogle Scholar
  61. 61.
    Ponce J, de La Ossa NP, Hurtado O, et al. Simvastatin reduces the association of NMDA receptors to lipid rafts: a cholesterol mediated effect in neuroprotection. Stroke. 2008;39:1269–75.PubMedCrossRefGoogle Scholar
  62. 62.
    Ding J, Jiang D, Kurczy M, et al. Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse. BMC Dev Biol. 2008;8:120.PubMedCrossRefGoogle Scholar
  63. 63.
    Ferreira GA, Navarro TP, Telles RW, et al. Atorvastatin therapy improves endothelial-dependent vasodilation in patients with systemic lupus erythematosus: an 8 weeks controlled trial. Rheumatology. 2007;46:1560–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Kotyla PJ, Sliwinska-Kotyla B, Kucharz EJ. TNF-alpha as a potential target in the treatment of systemic lupus erythematosus: a role for the HMG-CoA reductase inhibitor simvastatin. J Rheumatol. 2006;33:2361–3.PubMedGoogle Scholar
  65. 65.
    Graham KL, Lee LY, Higgins JP, Steinman L, Utz PJ, Ho PP. Failure of oral atorvastatin to modulate a murine model of systemic lupus erythematosus. Arthritis and Rheumatism. 2008;58:2098–104.PubMedCrossRefGoogle Scholar
  66. 66.
    Norby GE, Holme I, Fellström B, et al. Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus a randomized placebo controlled study. Arthritis Rheumatism. 2009;60:1060–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Chary Lopez-Pedrera
    • 1
  • Patricia Ruiz-Limon
    • 1
  • M. Angeles Aguirre
    • 1
  • Antonio Rodriguez-Ariza
    • 1
  • Maria José Cuadrado
    • 1
  1. 1.Unidad de Investigación–Hospital Universitario Reina Sofía-e Instituto Manimónides de Investigación Biomédica de Córdoba (IMIBIC)CórdobaSpain

Personalised recommendations