The objective of this study is to identify the effects of statins and risk factors for thrombosis in patients with new onset of systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL). Consecutive patients with SLE without history of thrombotic events were retrospectively enrolled from April 1997 to February 2014. The development of first thrombosis and death caused by thrombosis were defined as the study endpoint. Risk and protective factors for developing thrombosis were analyzed. A total of 152 patients, 80 positive and 72 negative for aPL, were included. In aPL-positive patients, 15 developed arterial (n = 6) and venous (n = 9) thrombosis (median follow-up period 69 months). Cox’s proportional hazards model showed that older age at SLE onset and IgG-anticardiolipin antibodies (aCL) were statistically significant risks for thrombosis. Statin therapy was identified as a statistically significant protective factor against thrombosis (hazard ratio 0.12, 95% confidence interval 0.01–0.98). In aPL-negative patients (median follow-up period 46 months), seven patients developed thrombosis (five arterial and two venous). No risk factors for thrombosis were found in this group. In aPL-positive patients with SLE, the late disease onset and the presence of IgG-aCL represented additional risk factors for thrombosis. Statin treatment appeared as a protective factor for thrombosis.
FeldmanCHHirakiLTWinkelmayerWCet al.Serious infections among adult Medicaid beneficiaries with systemic lupus erythematosus and lupus nephritis. Arthritis Rheumatol2015; 67: 1577–1585.
2.
CerveraRKhamashtaMAFontJet al.Morbidity and mortality in systemic lupus erythematosus during a 10-year period: A comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore)2003; 82: 299–308.
3.
BernatskySBoivinJFJosephLet al.Mortality in systemic lupus erythematosus. Arthritis Rheum2006; 54: 2550–2557.
4.
MokCCTangSSToCHPetriM. Incidence and risk factors of thromboembolism in systemic lupus erythematosus: A comparison of three ethnic groups. Arthritis Rheum2005; 52: 2774–2782.
5.
LovePESantoroSA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med1990; 112: 682–698.
6.
HarrisENGharaviAEAshersonRABoeyMLHughesGR. Cerebral infarction in systemic lupus: Association with anticardiolipin antibodies. Clin Exp Rheumatol1984; 2: 47–51.
7.
AtsumiTIekoMBertolacciniMLet al.Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum2000; 43: 1982–1993.
8.
MiyakisSLockshinMDAtsumiTet al.International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost2006; 4: 295–306.
9.
Calvo-AlénJTolozaSMFernándezMet al.Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum2005; 52: 2060–2068.
10.
TektonidouMGLaskariKPanagiotakosDBMoutsopoulosHM. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum2009; 61: 29–36.
11.
CrowtherMAGinsbergJSJulianJet al.A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med2003; 349: 1133–1138.
12.
FinazziGMarchioliRBrancaccioVet al.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 Haemost2005; 3: 848–853.
13.
GarciaDAKhamashtaMACrowtherMA. How we diagnose and treat thrombotic manifestations of the antiphospholipid syndrome: A case-based review. Blood2007; 110: 3122–3127.
14.
LimWCrowtherMAEikelboomJW. Management of antiphospholipid antibody syndrome: A systematic review. JAMA2006; 295: 1050–1057.
15.
Ruiz-IrastorzaGHuntBJKhamashtaMA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum2007; 57: 1487–1495.
16.
RidkerPM. JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: Rationale and design of the JUPITER trial. Circulation2003; 108: 2292–2297.
17.
Biere-RafiSHuttenBASquizzatoAet al.Statin treatment and the risk of recurrent pulmonary embolism. Eur Heart J2013; 34: 1800–1806.
18.
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med1998; 339: 1349–1357.
19.
GlynnRJDanielsonEFonsecaFAet al.A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med2009; 360: 1851–1861.
20.
MeroniPLRaschiETestoniCet al.Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: Effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum2001; 44: 2870–2878.
21.
FerraraDESwerlickRCasperKet al.Fluvastatin inhibits up-regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J Thromb Haemost2004; 2: 1558–1563.
22.
López-PedreraCRuiz-LimónPAguirreMÁet al.Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome. Ann Rheum Dis2011; 70: 675–682.
23.
ErkanDAguiarCLAndradeDet al.14th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends. Autoimmun Rev2014; 13: 685–696.
24.
HochbergMC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725–1725.
25.
TanEMCohenASFriesJFet al.The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1982; 25: 1271–1277.
BrandtJTTriplettDAAlvingBScharrerI. Criteria for the diagnosis of lupus anticoagulants: An update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost1995; 74: 1185–1190.
28.
PengoVTripodiAReberGet al.Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost2009; 7: 1737–1740.
29.
HarrisENGharaviAEPatelSPHughesGR. Evaluation of the anti-cardiolipin antibody test: Report of an international workshop held 4 April 1986. Clin Exp Immunol1987; 68: 215–222.
30.
AmengualOAtsumiTKhamashtaMAKoikeTHughesGR. Specificity of ELISA for antibody to beta 2-glycoprotein I in patients with antiphospholipid syndrome. Br J Rheumatol1996; 35: 1239–1243.
31.
TolozaSMUribeAGMcGwinGJret al.Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXIII. Baseline predictors of vascular events. Arthritis Rheum2004; 50: 3947–3957.
32.
KaiserRClevelandCMCriswellLA. Risk and protective factors for thrombosis in systemic lupus erythematosus: Results from a large, multi-ethnic cohort. Ann Rheum Dis2009; 68: 238–241.
33.
CerveraRKhamashtaMAFontJet al.Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore)1999; 78: 167–175.
34.
WahlDGGuilleminFde MaistreEPerretCLecompteTThibautG. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus—a meta-analysis. Lupus1997; 6: 467–473.
35.
FinazziGBrancaccioVMoiaMet al.Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: A four-year prospective study from the Italian Registry. Am J Med1996; 100: 530–536.
36.
SarabiZSChangEBobbaRet al.Incidence rates of arterial and venous thrombosis after diagnosis of systemic lupus erythematosus. Arthritis Rheum2005; 53: 609–612.
37.
Romero-DíazJGarcía-SosaISánchez-GuerreroJ. Thrombosis in systemic lupus erythematosus and other autoimmune diseases of recent onset. J Rheumatol2009; 36: 68–75.
38.
JohannesdottirSAHorváth-PuhóEDekkersOMet al.Use of glucocorticoids and risk of venous thromboembolism: A nationwide population-based case-control study. JAMA Intern Med2013; 173: 743–752.
39.
WahlDGBounameauxHde MoerloosePSarasinFP. Prophylactic antithrombotic therapy for patients with systemic lupus erythematosus with or without antiphospholipid antibodies: Do the benefits outweigh the risks? A decision analysis. Arch Intern Med2000; 160: 2042–2048.
40.
ErkanDHarrisonMJLevyRet al.Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: A randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum2007; 56: 2382–2391.
41.
HoKTAhnCWAlarcónGSet al.Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of thrombotic events. Rheumatology (Oxford)2005; 44: 1303–1307.
42.
KwakBMulhauptFMyitSMachF. Statins as a newly recognized type of immunomodulator. Nat Med2000; 6: 1399–1402.
43.
TsaiAWCushmanMRosamondWDet al.Coagulation factors, inflammation markers, and venous thromboembolism: The longitudinal investigation of thromboembolism etiology (LITE). Am J Med2002; 113: 636–642.
Sen-BanerjeeSMirSLinZet al.Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation2005; 112: 720–726.
46.
KabaNKFrancisCWMossAJet al.Effects of lipids and lipid-lowering therapy on hemostatic factors in patients with myocardial infarction. J Thromb Haemost2004; 2: 718–725.
47.
YeYZhaoXXieHTianZZhangS. Efficacy and safety of statins in the prevention of atherosclerosis in patients with systemic lupus erythematosus—a meta-analysis of randomized controlled trials. Int J Cardiol2013; 167: 301–303.
48.
FerraraDELiuXEspinolaRGet al.Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum2003; 48: 3272–3279.
49.
ErkanDWillisRMurthyVLet al.A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients. Ann Rheum Dis2014; 73: 1176–1180.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
