Statins for the Treatment of Antiphospholipid Syndrome?
Elizabeth Papalardo
Division of Rheumatology, Department of Internal Medicine, Antiphospholipid Standardization Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
Search for more papers by this authorZurina Romay-Penabad
Division of Rheumatology, Department of Internal Medicine, Antiphospholipid Standardization Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
Search for more papers by this authorCaroline Gleason
Rheumatology Associates of Louisville, Louisville, Kentucky, USA
Search for more papers by this authorSilvia S. Pierangeli
Division of Rheumatology, Department of Internal Medicine, Antiphospholipid Standardization Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
Search for more papers by this authorElizabeth Papalardo
Division of Rheumatology, Department of Internal Medicine, Antiphospholipid Standardization Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
Search for more papers by this authorZurina Romay-Penabad
Division of Rheumatology, Department of Internal Medicine, Antiphospholipid Standardization Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
Search for more papers by this authorCaroline Gleason
Rheumatology Associates of Louisville, Louisville, Kentucky, USA
Search for more papers by this authorSilvia S. Pierangeli
Division of Rheumatology, Department of Internal Medicine, Antiphospholipid Standardization Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
Search for more papers by this authorAbstract
Fluvastatin has been shown to revert proinflammatory/prothrombotic effects of antiphospholipid antibodies (aPL) in vitro and in mice. Here, we examined whether fluvastatin affects the levels of proinflammatory/prothrombotic markers in antiphospholipid syndrome (APS) patients. Vascular endothelial growth factor (VEGF), soluble tissue factor (sTF), tumor necrosis factor-α (TNF-α), soluble intercellular adhesion molecule-1 (sICAM-1), sE-selectin (E-sel), C-reactive protein (CRP), and soluble vascular cell adhesion molecule (sVCAM-1), were measured in the sera of 93 APS patients and 60 controls and in the sera of nine patients with APS before and after 30 days of treatment with fluvastatin. Elevated levels of VEGF, sTF, and TNF-α were found in APS patients. Fluvastatin significantly reduced those markers in the majority of treated subjects. The data from this study show that statins may be beneficial in aPL-positive patients and warrant larger clinical trials to confirm the efficacy of the drug for the treatment of APS clinical manifestations.
References
- 1 Harris, E.N. 1987. Syndrome of the black swan. Br. J. Rheumatol. 26: 324–326.
- 2 Miyakis, S., M.D. Lockshin, T. Atsumi, et al . 2006. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4: 295–306.
- 3 Boey, M.L., C.B. Colaco, A.E. Gharavi, et al . 1983. Thrombosis in SLE: striking associations with the presence of circulating “lupus anticoagulant”. Br. Med. J. 287: 1021–1023.
- 4 Ginsburg, K.S., M.H. Liang, L. Newcomer, et al . 1992. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann. Intern. Med. 117: 997–1002.
- 5 Levine, J.S., D.W. Branch & J. Rauch. 2002. The antiphospholipid syndrome. N. Engl. J. Med. 346: 752–763.
- 6 Kittner, S.J. & P.B. Gorelick. 1992. Antiphospholipid antibodies and stroke: an epidemiological perspective. Stroke 23(Suppl I): 19–22.
- 7 Love, P.E. & S.A. Santoro. 1990. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and non-SLE disorders. Prevalence and clinical significance. Ann. Intern. Med. 112: 682–698.
- 8 Coon, W.W., P.W. Willis & J.B. Keller. 1973. Venous thromboembolism and other venous disease in the Tecumseh Community Health Study. Circulation 48: 839–846.
- 9 Moroni, G., D. Ventura, P. Riva, et al . 2004. Antiphospholipid antibodies are associated with an increased risk for chronic renal insufficiency in patients with lupus nephritis. Am. J. Kidney Dis. 43: 28–36.
- 10 Moroni, G., F. Tantardini, B. Gallelli, et al . 2005. The long-term prognosis of renal transplantation in patients with lupus nephritis. Am. J. Kidney Dis. 45: 903–911.
- 11 McClain, M.T., M.R. Arbuckle, L.D. Heinlen, et al . 2004. The prevalence, onset and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus. Arthritis Rheum. 50: 1226–1232.
- 12 Weber, M., G. Hayem, M. De Band, et al . 2000. The family history of patients with primary or secondary antiphospholipid antibody syndrome (APS). Lupus 9: 258–263.
- 13 Branch, D.W., D.J. Dudley, M.D. Mitchell, et al . 1990. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss. Am. J. Obstet. Gynecol. 163: 210–216.
- 14 Pierangeli, S.S., X.W. Liu, G.H. Anderson, et al . 1995. Induction of thrombosis in a mouse model by IgG, IgM and IgA immunoglobulins from patients with the antiphospholipid syndrome. Thromb. Haemost. 74: 1361–1367.
- 15 Pierangeli, S.S., M. Colden-Stanfield, X. Liu, et al . 1999. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation 99: 1997–2000.
- 16 Jankowski, M., I. Vreys, C. Wittevrongel, et al . 2003. Thrombogenicity of β2glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster. Blood 101: 157–162.
- 17 Simantov, E., J. LaSala, S.K. Lo, et al . 1995. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J. Clin. Invest. 96: 2211–2219.
- 18 Del Papa, N., L. Guidali, A. Sala, et al . 1997. Endothelial cell target for antiphospholipid antibodies. Human polyclonal and monoclonal anti-β2glycoprotein I and induce endothelial cell activation. Arthritis Rheum. 40: 551–561.
- 19 Gharavi, A.E., S.S. Pierangeli, M. Colden-Stanfield, et al . 1999. GDKV-induced antiphospholipid antibodies enhance thrombosis and activate endothelial cells in vivo and in vitro. J. Immunol. 163: 2922–2927.
- 20 Pierangeli, S.S., X. Liu, R. Espinola, et al . 2000. Functional analyses of patient-derived IgG monoclonal anticardiolipin antibodies using in vivo thrombosis and in vivo microcirculation models. Thromb. Haemost. 84: 388–395.
- 21 Pierangeli, S.S., R.G. Espinola, X. Liu & E.N. Harris. 2001. Thrombogenic effects of antiphospholipid antibodies are mediated by intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. Circ. Res. 88: 245–250.
- 22 Espinola, R.G., X. Liu, M. Colden-Stanfield, et al . 2002. E-selectin mediated pathogenic effects of antiphospholipid antibodies. J. Thromb. Haemost. 1: 843–848.
- 23 Cuadrado, M.J., C. Lopez-Pedrera, M.A. Khamashta, et al . 1997. Thrombosis in primary antiphospholipid syndrome: a pivotal role for monocyte tissue factor expression. Arthritis Rheum. 40: 834–841.
- 24 Amengual, O., T. Atsumi, M.A. Khamashta & G.R.V. Hughes. 1998. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb. Haemost. 79: 276–281.
- 25 Dobado-Barrios, M., C. Lopez-Perrara, F. Velasco, et al . 1999. Increased levels of TF mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome. Thromb. Haemost. 82: 1578–1582.
- 26 Reverter, J.C., D. Tassies, J. Font, et al . 1998. Effects of human monoclonal anticardiolipin antibodies on platelet function and on tissue factor expression on monocytes. Arthritis Rheum. 41: 1420–1427.
- 27 Kornberg, A., M. Blank, S. Kaufman & Y. Shoenfeld. 1994. Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies. J. Immunol. 153: 1328–1332.
- 28 Zhou, H., A.S. Woldberg & R.A. Roubey. 2004. Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep. Blood 104: 2353–2358.
- 29 Vega-Ostertag, M., K. Casper, R. Swerlick, et al . 2005. Involvement of p38 MAPK in the up-regulation of tissue factor on endothelial cells by antiphospholipid antibodies. Arthritis Rheum. 52: 1545–1554.
- 30 Vega-Ostertag, M.E., X. Liu & S.S. Pierangeli. 2005. In Vivo effects of an inhibitor of p38 mitogen-activated protein kinase on the procoagulant and proinflammatory activities of antiphospholipid antibodies. Abstract. Arthritis Rheum. 52(Suppl.): S252.
- 31 Kaplanski, G., P. Cacoub, C. Farnarier, et al . 2000. Increased soluble vascular cell adhesion molecule 1 concentrations in patients with primary or systemic lupus erythematosus-related antiphospholipid syndrome: correlations with the severity of thrombosis. Arthritis Rheum. 43: 55–64.
- 32 Forastiero, R.R., M.E. Martinuzzo & G. De Larranaga. 2005. Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprous related antiphospholipid antibodies. Lupus 14: 129–136.
- 33 Williams, F.M.K., K. Parmar, G.R.V. Hughes & B.J. Hunt. 2000. Systemic endothelial cell markers in primary antiphospholipid syndrome. J. Thromb. Haemost. 84: 742–746.
- 34 Meroni, P.L., M.O. Borghi, E. Raschi, et al . 2004. Inflammatory response and the endothelium. Thromb. Res. 114: 329–334.
- 35 Cuadrado, M.J., P. Buendia, F. Velasco, et al . 2006. Vascular endothelial growth factor expression in monocytes from patients with primary antiphospholipid syndrome. J. Thromb. Haemost. 4: 2461–2469.
- 36 Meroni, P.L., E. Raschi, C. Testoni, et al . 2001. Statins prevent endothelial cell activation induced by antiphospholipid (anti-β2glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum. 44: 2870–2878.
- 37 Ferrara, D.E., X. Liu & R.G. Espinola, et al . 2003. Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum. 48: 3272–3279.
- 38 Ferrara, D.E., R. Swerlick, K. Casper, et al . 2004. Fluvastatin inhibits upregulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J. Thromb. Haemost. 2: 1558–1563.
- 39 Pierangeli, S.S. & E.N. Harris. 2008. A protocol for determination of anticardiolipin antibodies by ELISA. Nat. Protoc. 3: 840–848.
- 40 Budd, R., E. Harley, A. Quarshie, et al . 2006. A re-appraisal of the normal cut-off assignment for anticardiolipin IgM tests. J. Thromb. Haemost. 4: 2210–2214.
- 41 The Scandinavian Simvastatin Survival Study. 1994. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet 344: 1383–1389.
- 42 Kwak, B., F. Mulhaupt, S. Myit & F. Mach. 2000. Statins as a newly recognized type of immunomodulator. Nat. Med. 6: 1399–1402.
- 43 Takemoto, M. & J.K. Liao. 2001. Pleiotropic effects of 3-hydroxy-3mehtylglutaryl conezume A reductase inhibitors. Arterioscler. Thromb. Vasc. Biol. 21: 1712–1719.
- 44 Niwa, S., T. Totsuka & S. Hayashi. 1996. Inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor on the expression of adhesion molecules on human monocyte cell line. Int. J. Immunopharmacol. 18: 669–675.
- 45 Eto, M., T. Kozai, F. Cosentino, et al . 2002. Statin prevents tissue factor expression in human endothelial cells. Role of Rho/Rho kinase and Akt pathways. Circulation 105: 1756–1759.
- 46 Ortego, M., A. Gomez-Hernandez, C. Vidal, et al . 2005. HMG-CoA reductase inhibitors reduce IkB kinase activity by oxidative stress in monocytes and vascular smooth muscle cells. J. Cardiovasc. Pharmacol. 45: 468–475.
- 47 Halcox, J.P.J. & J.E. Deanfield. 2004. Beyond the laboratory. Clinical implications for statin pleitropy. Circulation 109(Suppl II): II-42–II-48.
- 48 Colli, S., S. Eligini, M. Lalli, et al . 1997. Statins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb. Vasc. Biol. 17: 265–272.
- 49 Sukhova, G.K., J.K. Williams & P. Libby. 2002. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler. Thromb. Vasc. Biol. 22: 1452–1458.
- 50 Aikawa, M., E. Rabkin, S. Sugiyama, et al . 2001. An HMG-CoA inhbitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 103: 276–283.
- 51 Bea, F., E. Blessing, M.I. Shelley, et al . 2003. Simvastatin inhibits expression of tissue factor in advanced atherosclerotic lesion of apolipoprotein E deficient mice independently of lipid lowering. Atherosclerosis 167: 187–194.
- 52 Baetta, R., M. Camera, C. Comparato, et al . 2002. Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in absence of lipid lowering. Arterioscler. Thromb. Vasc. Biol. 22: 692–698.
- 53 Cortellaro, M., E. Cofrancesco, E. Arbustini, et al . 2002. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb. Haemost. 88: 41–47.
- 54 Correale, J. & A. Villa. 2007. The blood-brain barriers in multiple sclerosis: functional roles and therapeutic targeting. Autoimmun. 40: 148–160.
- 55 Stuve, O., S. Youseef, M.S. Weber, et al . 2006. Immunomodulatory synergy by combination of atorvastatin and glatimer acetate in treatment of CNS autoimmunity. J. Clin. Invest. 116: 1037–1044.
- 56 Dunn, S.E., S. Youssef, M.J. Goldstein, et al . 2006. Isoprenoids determine TH1/TH2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J. Exp. Med. 203: 401–412.
- 57 López, P., C. Gutiérrez & A. Suárez. 2008. IFN-α treatment generates antigen-presenting cells insensitive to atorvastatin inhibition of MHC-II expression. Clin. Immunol. 129: 350–359.
- 58 Lawman, S., C. Mauri, E.C. Jury, et al . 2004. Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black.white F1 mice. J. Immunol. 173: 7641–7646.
- 59 Jury, E.C. & M.R. Ehrenstein. 2005. Statins: immunomodulators for autoimmune rheumatic disease? Lupus 14: 192–196.
- 60 Ames, P.R., A. Margarita & J.D. Alves. 2008. Antiphospholipid antibodies and atherosclerosis: insights from Systemic Lupus Erythematosus and Primary Antiphospholipid Syndrome. Clin. Rev. Allergy. Immunol. Nov 6 epub ahead of print.
- 61 Belizna, C.C., V. Richard, C. Thuillez, et al . 2007. Insights into atherosclerosis therapy in antiphospholipid syndrome. Autoimmun. Rev. 7: 46–51.
- 62 Aprahamian, T., R. Bonegio, J. Rizzo, et al . 2006. Simvastatin treatment ameliorates autoimmune disease associated with accelerated atherosclerosis in a murine lupus model. J. Immunol. 177: 3028–3034.
- 63 Spah, F. 2008. Inflammation in atherosclerosis and psoriasis: common pathogenic mechanims and the potential for an integrated treatment approach. Br. J. Dermatol. 159(Suppl 2): 10–17. Review.
- 64 Redecha, P., R. Tilley, M. Tencati, et al . 2007. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood 110: 2423–2431.
- 65 Redecha, P., C.W. Franczke, W. Ruf, et al . 2008. Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome. J. Clin. Invest. 118: 3453–3461.
- 66 Khamashta, M.A., M.J. Cuadrado, T. Mujic, et al . 1995. The management of thrombosis in the antiphospholipid antibody syndrome. N. Engl. J. Med. 332: 993–997.
- 67 Krnic-Barrie, S., C.R. O'Connor, S.W. Looney, et al . 1997. A retrospective review of 61 patients with antiphospholipid syndrome. Arch. Intern. Med. 157: 2101–2108.
- 68 Crowther, M.A., J.S. Ginsberg, J. Julian, et al . 2003. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N. Engl. J. Med. 349: 1133–1138.
- 69 Finazzi, G., R. Marchioli, V. Brancaccio, et al . 2005. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J. Thromb. Haemost. 3: 848–853.
- 70 Fischetti, F., P. Durigutto, V. Pellis, et al . 2005. Thrombus formation induced by antibodies to β2glycoprotein I is complement-dependent and requires a priming factor. Blood 106: 2340–2346.
- 71 De Groot, P.G. & R.H.W. Derksen. 2005. Pathophysiology of the antiphospholipid syndrome. J. Thromb. Haemost. 3: 1854–1860.