Research Article
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
Jaime Calvo-Alén, Sergio M. A. Toloza, Mónica Fernández, Holly M. Bastian, Barri J. Fessler, Jeffrey M. Roseman, Gerald McGwin Jr., Luis M. Vilá,
John D. Reveille,
Graciela S. Alarcón,
LUMINA Study Group,
Luis M. Vilá
University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
Search for more papers by this authorJohn D. Reveille
University of Texas Health Science Center at Houston
Search for more papers by this authorCorresponding Author
Graciela S. Alarcón
University of Alabama at Birmingham
830 Faculty Office Tower, 510 20th Street South, Birmingham, Alabama 35294-3408Search for more papers by this authorLUMINA Study Group
Search for more papers by this authorJaime Calvo-Alén, Sergio M. A. Toloza, Mónica Fernández, Holly M. Bastian, Barri J. Fessler, Jeffrey M. Roseman, Gerald McGwin Jr., Luis M. Vilá,
John D. Reveille,
Graciela S. Alarcón,
LUMINA Study Group,
Luis M. Vilá
University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
Search for more papers by this authorJohn D. Reveille
University of Texas Health Science Center at Houston
Search for more papers by this authorCorresponding Author
Graciela S. Alarcón
University of Alabama at Birmingham
830 Faculty Office Tower, 510 20th Street South, Birmingham, Alabama 35294-3408Search for more papers by this authorLUMINA Study Group
Search for more papers by this authorAbstract
Objective
Venous thrombosis is a relatively frequent and serious complication in systemic lupus erythematosus (SLE) that has been associated with the presence of antiphospholipid antibodies (aPL). However, venous thrombotic events can also be seen in patients without aPL, and only a few patients with aPL develop venous thrombosis. This study was carried out to ascertain other factors contributing to the development of venous thrombosis in SLE.
Methods
Patients with SLE, ages ≥16 years with ≤5 years disease duration and of Hispanic, African American, or Caucasian ethnicity, from LUMINA (LUpus in MInorities, NAture versus nurture), a multiethnic, longitudinal study of outcome, were studied. Selected socioeconomic/demographic, clinical, laboratory, and treatment-exposure variables were compared between patients who developed and those who did not develop venous thrombotic events. Significant and clinically relevant variables were then entered into different multivariable models (Cox proportional hazards and unconditional stepwise logistic regression) to identify independent risk factors associated with the primary outcome. In another model, only patients who developed an event after enrollment (time 0) in the cohort were included.
Results
Of 570 LUMINA patients, 51 developed at least 1 venous thrombotic event after SLE diagnosis. In univariable analyses, smoking (P = 0.020), shorter disease duration at time 0 (P = 0.017), serum levels of total cholesterol, low-density lipoprotein, and triglycerides (all P < 0.0001), and presence of lupus anticoagulant (LAC) (P = 0.045) were associated with venous thrombotic events. Survival analyses showed a time-dependent significant association of the primary outcome with smoking (P = 0.008) and a borderline significant association with the presence of LAC (P = 0.070). Multivariable models showed an independent association with smoking, age at time 0, disease activity over time, LAC, mean dose of glucocorticoids, and shorter disease duration at time 0.
Conclusion
Venous thrombotic events occur early in the course of SLE. Our data confirm the association between LAC and venous thrombotic events. Smoking, shorter disease duration, older age, disease activity over time, and higher mean daily glucocorticoid dose were identified as additional risk factors for the development of this vascular complication. These findings may have implications for the management of patients with SLE.
REFERENCES
- 1 Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al, and the European Working Party on Systemic Lupus Erythematosus. Morbidity and mortality in systemic lupus erythematosus during a 5-year period: a multicenter prospective study of 1,000 patients. Medicine (Baltimore) 1999; 78: 167–75.
- 2 Somers E, Magder LS, Petri M. Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with systemic lupus erythematosus. J Rheumatol 2002; 29: 2531–6.
- 3 Wahl DG, Guillemin F, de Maistre E, Perret-Guillaume C, Lecompte T, Thibaut G. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7: 15–22.
- 4 Wahl DG, Guillemin F, de Maistre E, Perret C, Lecompte T, Thibaut G. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus: a meta-analysis. Lupus 1997; 6: 467–73.
- 5 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders: prevalence and clinical significance. Ann Intern Med 1990; 112: 682–98.
- 6 Petri M, Rheinschmidt M, Whiting-O'Keefe Q, Hellmann D, Corash L. The frequency of lupus anticoagulant in systemic lupus erythematosus: a study of sixty consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level. Ann Intern Med 1987; 106: 524–31.
- 7 Alarcon GS, Friedman AW, Straaton KV, Moulds JM, Lisse J, Bastian HM, et al. Systemic lupus erythematosus in three ethnic groups. III. A comparison of characteristics early in the natural history of the LUMINA cohort. Lupus 1999; 8: 197–209.
- 8 Alarcon GS, Roseman J, Bartolucci AA, Friedman AW, Moulds JM, Goel N, et al. Systemic lupus erythematosus in three ethnic groups. II. Features predictive of disease activity early in its course. Arthritis Rheum 1998; 41: 1173–80.
- 9 Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–7.
- 10 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 1997; 40: 1725.
- 11 Reveille JD, Moulds JM, Ahn C, Friedman AW, Baethge B, Roseman J, et al, for the LUMINA Study Group. Systemic lupus erythematosus in three ethnic groups. I. The effects of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset. Arthritis Rheum 1998; 41: 1161–72.
- 12 Liang MH, Socher SA, Larson MG, Schur PH. Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 1989; 32: 1107–18.
- 13 Gladman DD, Urowitz MB, Goldsmith CH, Fortin P, Ginzler E, Gordon C, et al. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum 1997; 40: 809–13.
- 14 Harris EN. The second international anti-cardiolipin standardization workshop/the Kingston Anti-Phospholipid Antibody Study (KAPS) Group. Am J Clin Pathol 1990; 94: 476–84.
- 15 Roisin JP, Contant G, Martinoli JL. Detection of lupus-like anticoagulants (LA): use of hexagonal phosphatidylethanolamine and of an APTT reagent sensitive to LA. Thromb Haemost 1991; 65: 2023.
- 16 Triplett DA, Barna LK, Unger GA. A hexagonal (II) phase phospholipid neutralization assay for lupus anticoagulant identification. Thromb Haemost 1993; 70: 787–93.
- 17 Wu R, Lefvert AK. Autoantibodies against oxidized low density lipoproteins (oxLDL): characterization of antibody isotype, subclass, affinity and effect on the macrophage uptake of oxLDL. Clin Exp Immunol 1995; 102: 174–80.
- 18 Costenbader KH, Kim DJ, Peerzada J, Lockman S, Nobles-Knight D, Petri M, et al. Cigarette smoking and the risk of systemic lupus erythematosus: a meta-analysis. Arthritis Rheum 2004; 50: 849–57.
- 19 Formica MK, Palmer JR, Rosenberg L, McAlindon TE. Smoking, alcohol consumption, and risk of systemic lupus erythematosus in the Black Women's Health Study. J Rheumatol 2003; 30: 1222–6.
- 20 Ghaussy NO, Sibbitt WJ, Qualls CR. Cigarette smoking, alcohol consumption, and the risk of systemic lupus erythematosus: a case-control study. J Rheumatol 2001; 28: 2449–53.
- 21 Hardy CJ, Palmer BP, Muir KR, Sutton AJ, Powell RJ. Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study. Ann Rheum Dis 1998; 57: 451–5.
- 22 Ghaussy NO, Sibbitt WJ, Bankhurst AD, Qualls CR. Cigarette smoking and disease activity in systemic lupus erythematosus. J Rheumatol 2003; 30: 1215–21.
- 23 Ward MM, Studenski S. Clinical prognostic factors in lupus nephritis. Arch Intern Med 1992; 152: 2082–8.
- 24 Petri M. Smoking is a risk factor for musculoskeletal, pulmonary and cardiac disease in systemic lupus erythematosus [abstract]. Arthritis Rheum 1997; 40 Suppl 9: S118.
- 25 Brown K, Petri M, Goldman D. Cutaneous manifestations of SLE: associations with other manifestations of SLE and with smoking [abstract]. Arthritis Rheum 1995; 38 Suppl 6: R27.
- 26 Rahman P, Gladman DD, Urowitz MB. Smoking interferes with efficacy of antimalarial therapy in cutaneous lupus. J Rheumatol 1998; 25: 1716–9.
- 27 Jay SJ. Cigarette smoking: risk factor for venous thromboembolic disease? Arch Intern Med 1998; 158: 2315–23.
- 28 Kahn SR. The clinical diagnosis of deep venous thrombosis: integrating incidence, risk factors, and symptoms and signs. Arch Intern Med 1998; 158: 2315–23.
- 29 Pollock AV, Evans M. Cigarette smoking and postoperative deep-vein thrombosis. Br Med J 1978; 2: 637.
- 30 Clayton JK, Anderson JA, McNicol GP. Effect of cigarette smoking on subsequent postoperative thromboembolic disease in gynaecological patients. Br Med J 1978; 2: 402.
- 31 Baglin T. Is smoking a risk factor for venous thromboembolism? Thromb Haemost 2002; 88: 881–2.
- 32 Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, et al. A prospective study of risk factors for venous thromboembolism among middle-aged men: the study of men born in 1913. J Am Med Assoc 1997; 277: 642–5.
- 33 Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: the study of men born in 1913. Arch Intern Med 1999; 159: 1886–90.
- 34 Miller GJ, Bauer KA, Cooper JA, Rosenberg RD. Activation of the coagulant pathway in cigarette smokers. Thromb Haemost 1998; 79: 549–53.
- 35 Doria A, Shoenfeld Y, Wu R, Gambari PF, Puato M, Ghirardello A, et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2003; 62: 1071–7.
- 36 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: 2399–406.
- 37 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: 513–9.
- 38 Petri M, Roubenoff R, Dallal G, Nadeau MR, Selhub J, Rosenbert IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996; 348: 1120–4.
- 39 Maxwell SR, Moots RJ, Kendall MJ. Corticosteroids: do they damage the cardiovascular system? Postgrad Med J 1994; 70: 863–70.
- 40 Wadman B, Werner I. Thromboembolic complications during corticosteroid treatment of temporal arteritis. Lancet 1972; 1: 907.
- 41 Fatti LM, Bottasso B, Invitti C, Coppola R, Cavagnini F, Mannucci PM. Markers of activation of coagulation and fibrinolysis in patients with Cushing's syndrome. J Endocrinol Invest 2000; 23: 145–50.
- 42 Boscaro M, Nicoletta S, Scarda A, Barzon L, Fallo F, Sartori M, et al. Anticoagulant prophylaxis markedly reduces thromboembolic complications in Cushing's syndrome. J Clin Endocrinol Metab 2002; 87: 3662–6.
- 43 Dal Bo Zanon R, Fornasiero L, Boscaro M, Ruffato G, Luzzato G, Fabris F, et al. Clotting changes in Cushing's syndrome: elevated factor VIII activity. Folia Haemotal Int Mag Klin Morphol Blutforsch 1983; 110: 268–77.
- 44 Ueda N. Effect of corticosteroids on some hemostatic parameters in children with minimal change nephrotic syndrome. Nephron 1990; 56: 374–8.
- 45 Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46: 1019–27.
- 46 Amigo MC, Khamashta MA, Hughes GR. Antiphospholipid syndrome in SLE. Baillieres Clin Rheumatol 1998; 12: 477–93.
- 47 Khamashta MA, Hughes GR. Antiphospholipid antibodies and antiphospholipid syndrome. Curr Opin Rheumatol 1995; 7: 389–94.
- 48 Toloza SM, Uribe AG, McGwin G Jr, Alarcon GS, Fessler BJ, Bastian HM, et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXIII. Baseline predictors of vascular events. Arthritis Rheum 2004; 50: 3947–57.
- 49 Ho KT, Ahn CW, Alarcon GS, Baethge BA, Tan FK, Roseman J, et al. Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of thrombotic events. J Rheumatol. In press.
- 50 Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH, et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992; 117: 997–1002.
- 51 Sairam S, Baethge BA, McNearney T. Analysis of risk factors and comorbid diseases in the development of thrombosis in patients with anticardiolipin antibodies. Clin Rheumatol 2003; 22: 24–9.
- 52 Fernandez M, Calvo-Alen J, Bertoli AM, Vila LM, Fessler B, Bastian H, et al. Hormone replacement therapy is not a risk factor for vascular arterial events in systemic lupus erythematosus and it does not negatively impact on disease activity: data from a large multi-ethnic cohort [abstract]. Lupus 2005; 14: 220.
- 53 Fernandez M, Calvo-Alen J, Alarcon GS, Roseman JM, Bastian HM, Fessler BJ, et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXI. Disease activity, damage accrual, and vascular events in pre- and postmenopausal women. Arthritis Rheum 2005; 52: 1655–64.
- 54 Hudson M, Herr AL, Rauch J, Neville C, Chang E, Ibrahim R, et al. The presence of multiple prothrombotic risk factors is associated with a higher risk of thrombosis in individuals with anticardiolipin antibodies. J Rheumatol 2003; 30: 2385–91.
