3 Epidemiology of Antiphospholipid Syndrome

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1 3 Epidemiology of Antiphospholipid Syndrome Michelle Petri This chapter will review classification criteria of the antiphospholipid syndrome (APS), the prevalence of antiphospholipid antibodies [apl; anticardiolipin (acl); lupus anticoagulant (LA)] in normals and in systemic lupus erythematosus (SLE), the prevalence of apl in venous thrombosis, arterial thrombosis, and pregnancy loss, and longitudinal studies. Classification Criteria for APS Classification criteria for APS (Table 3.1) were developed by consensus at the Sapporo antiphospholipid meeting [1]. These criteria, for the first time, emphasized that vasculopathy (and not just thrombosis) was part of APS and broadened the pregnancy criterion to include severe pre-eclampsia. The Sapporo criteria were validated in an exercise by Lockshin et al [2]. The sensitivity was The Sapporo criteria were not evidence based. As part of the Taormina antiphospholipid meeting, evidenced-based criteria were prepared. These criteria required that the criterion be valid in both primary (non-sle) and secondary (SLE) APS and be proven by more than one study (and more than one study design). The evidence-based criteria do not include pregnancy morbidity, but do include cardiac valve disease (valvular thickening and/or vegetations; Table 3.2) [3]. Table 3.1. Sapporo classification criteria for antiphospholipid syndrome. Clinical Vascular thrombosis Pregnancy morbidity 3 or more concurrent spontaneous abortions 1 or more unexplained deaths of a normal fetus at or beyond 10th week of gestation 1 or more premature births before 34 weeks because of severe preeclampsia or placental insufficiency Laboratory* IgG anticardiolipin moderate or high IgM anticardiolipin moderate or high Lupus anticoagulant *Present at least twice 6 weeks apart. 22

2 Epidemiology of Antiphospholipid Syndrome 23 Table 3.2. Taormina evidence-based classification criteria for antiphospholipid syndrome. Clinical Vascular thrombosis Pregnancy 3 or more early fetal losses 1 intrauterine fetal demise Laboratory IgG anticardiolipin moderate or high IgM anticardiolipin moderate or high Lupus anticoagulant Cardiac Valve thickening and/or vegetations Table 3.3. Prevalence of antiphospholipid antibodies in normals. Study, year Number of Controls Type of controls acl-igg acl-igm LA Anti- 2 GPI Harris et al, 1991 [4] 1449 Pregnant women Infante-Rivard et al, 1991 [5] 993 Pregnant women Perez et al, 1991 [6] 1200 Pregnant women 1.25 Rix et al, 1992 [7] 2856 Pregnant women 0.07 Pattison et al, 1993 [8] 933 Pregnant women Phadke et al, 1993 [9] 504 Healthy, age-matched Juby et al, 1998 [10] 250 Healthy, young 1.2 Bruce et al, 2000 [11] 129 Healthy 3% Prevalence of apl Antibodies in Normals The prevalence of acl in most large studies of normals has been 1% to 5%. The prevalence of the LA has been in the range of 0% to 4% (Table 3.3). Prevalence of apl in SLE Representative recent studies of the prevalence of acl, LA, and anti 2 -glycoprotein I (anti- 2 GPI) in SLE are compiled in Table 3.4. In general, acl is more fre- Table 3.4. Prevalence of antiphospholipid antibodies in systemic lupus erythematosus. Study, year Number of SLE Assay LA acl Anti- 2 GPI Padmakumar et al, 1990 [12] 55 KCT 13% Mayumi et al, 1991 [13] 106 aptt 16% McHugh et al, 1991 [14] 58 KCT, RVVT, TTI 22% 29% Wong et al, 1991 [15] 91 aptt, RVVT, PNP, TTI 11% 44% Cervera et al, 1993 [16] 1000 Multiple 15% 24% Jones et al, 1991 [17] % Kutteh et al, 1993 [18] % Axtens et al, 1994 [19] % Tsutsumi et al, 1996 [20] % 10.1% Bruce et al, 2000 [11] % 15.8% Tubach et al, 2000 [21] % 18.6%

3 24 Hughes Syndrome quent than LA. However, any cross-sectional study in SLE may underestimate the true frequency of apl because disease activity and treatment lead to fluctuations over time. In the Hopkins Lupus Cohort, a longitudinal study in which apl are measured quarterly, at 5 years of follow up the prevalence of acl was 26% and that of the LA (by drvvt) was 31%. Prevalence of apl in Venous Thrombosis Bick and colleagues [22] found, in 100 patients with venous thrombosis, that 24% had acl and 4% had LA. In a study of 122 consecutive venous thrombotic patients, close to 15% had LA, apl, or anti- 2 GPI phospholipid. The presence of the LA was strongly associated with the severity of thrombosis [23]. In 227 consecutive patients with acute deep venous thrombosis or pulmonary embolism, 31% had apl. Anti- 2 GPI, present in 8.4%, was associated with a higher rate of recurrent thromboembolism [24]. Prevalence of apl in Arterial Thrombosis The most informative studies have been the prevalence of apl in stroke patients less than 50 years (Table 3.5). These studies suggest that about 29% of young people with a stroke have acl. Prospective studies have found an association of apl with myocardial infarction in middle-aged men [31, 32]. No association of anti- 2 GPI and coronary atherosclerosis was found in a cross-sectional study of 97 subjects [33]. A study of 60 peripheral vascular disease patients found the LA in 43% versus 0% of controls [34]. Recurrent Fetal Loss Multiple cross-sectional studies have reported an association of acl and/or LA with recurrent fetal loss, in a general range of 10% to 19% (Table 3.6). Anti- 2 GPI was not associated with recurrent fetal loss in one study [45]. In terms of pregnancy morbidity, the LA was not associated with pregnancyinduced hypertension [46]. Table 3.5. Antiphospholipid antibody prevalence in young stroke patients. Study, year Number of patients Assays Frequency Brey et al, 1990 [25] 46 LA, acl 46% Czlonkowska et al, 1992 [26] 49 acl 32% Nencini et al, 1992 [27] 44 23% de Jong et al, 1993 [28] 44 LA, acl 2% Ferro et al, 1993 [29] 33 LA 18% Tietjen et al, 1993 [30] 68 LA, acl 43%

4 Epidemiology of Antiphospholipid Syndrome 25 Table 3.6. Antiphospholipid antibody in recurrent fetal loss. Study, year Number of women LA acl acl-igg acl-igm Anti- 2 GPI Taylor et al, 1990 [35] 189 3% 15% Parazzini et al, 1991 [36] 220 7% Parazzini et al, 1991 [36] 99 19% Parke et al, 1991 [37] % 7.4% 4.9% Aoki et al, 1993 [38] 334 8% Bagger et al, 1993 [39] 158 4% 26% Toyoshima et al, 1993 [40] 148 8% MacLean et al, 1994 [41] % 8.2% Rai et al, 1995 [42] % 3.3% 2.2% Ogasawara et al, 1996 [43] % 9.7% Kumar et al, 2002 [44] % 40.2% Thrombocytopenia In a study of 52 newly diagnosed patients with idiopathic thrombocytopenic purpura (ITP), 38% were apl positive at diagnosis. Patients with apl positivity were significantly more likely to have a thrombosis in the next 5 years. After 38 median months of follow up, 45% of the ITP patients with apl had developed APS [47]. Longitudinal Studies The Hopkins Lupus Cohort Study is a longitudinal study in which apl (LA by drvvt and acl by polyclonal ELISA) are measured quarterly. SLE patients with the LA have a 50% chance of a venous thrombotic event within 10 years of diagnosis [48]. In a second SLE cohort of 139 patients, IgM acl was negatively associated with survival. However, thromboembolic events were not a major cause of death in the cohort [49]. In a third study, 37 SLE patients with LA and 37 matched SLE patients without LA were followed for a median of 22 years. Deep venous thrombosis occurred in 54% of those with LA. Events tended to occur in the first 8 years [50]. In patients already diagnosed with APS, several studies have shown a high risk of recurrence. In a study of APS with either arterial or venous thrombotic events, the risk of thrombosis recurrence was high if anti-coagulation was not maintained [51]. In patients with APS and venous thrombosis, the risk of recurrent venous thrombosis was 50% within 2 years [52]. In patients with stroke, the odds ratio for recurrent stroke and for all events (stroke, myocardial infarction, and death) is significantly higher in those with acl [53]. References 1. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:

5 26 Hughes Syndrome 2. Lockshin MD, Sammaritano LR, Schwartzman S. Validation of the Sapporo criteria for antiphospholipid syndrome. Arthritis Rheum 2000;43: Petri M, Akhtar S, Branch DW, Brey RL, Lockshin MD, Roubey RA. Evidence-based classification criteria for antiphospholipid antibody syndrome (APS) [abstract]. Arthritis Rheum 2003;48:S Harris EN, Spinnato JA. Should anticardiolipin tests be performed in otherwise healthy pregnant women? Am J Obstet Gynecol 1991;165: Infante RC, David M, Gauthier R, Rivard GE. Lupus anticoagulants, anticardiolipin antibodies, and fetal loss. A case-control study. N Engl J Med 1991;325: Perez MC, Wilson WA, Brown HL, Scopelitis E. Anticardiolipin antibodies in unselected pregnant women in relationship to fetal outcome. J Perinatol 1991;11: Rix P, Stentoft J, Aunsholt NA, Dueholm M, Tilma KA, Hoier-Madsen M. Lupus anticoagulant and anticardiolipin antibodies in an obstetric population. Acta Obstet Gynecol Scand 1992;71: Pattison NS, Chamley LW, McKay EJ, Liggins GC, Butler WS. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations. Br J Obstet Gynaecol 1993;100: Phadke KV, Phillips RA, Clarke DT, Jones M, Naish P, Carson P. Anticardiolipin antibodies in ischaemic heart disease: marker or myth? Br Heart J 1993;69: Juby AG, Davis P. Prevalence and disease associations of certain autoantibodies in elderly patients. Clin Invest Med 1998:21: Bruce IN, Clark-Soloninka CA, Spitzer KA, Gladman DD, Urowitz MB, Laskin CA. Prevalence of antibodies to beta2-glycoprotein I in systemic lupus erythematosus and their association with antiphospholipid antibody syndrome criteria: a single center study and literature review. J Rheumatol 2000;27: Padmakumar K, Singh RR, Rai R, Malaviya AN, Saraya AK. Lupus anticoagulants in systemic lupus erythematosus: prevalence and clinical associations. Ann Rheum Dis 1990;49: Mayumi T, Nagasawa K, Inoguchi T, et al. Haemostatic factors associated with vascular thrombosis in patients with systemic lupus erythematosus and the lupus anticoagulant. Ann Rheum Dis 1991;50: McHugh NJ, Moye DAH, James IE, Sampson M, Maddison PJ. Lupus anticoagulant: clinical significance in anticardiolipin positive patients with systemic lupus erythematosus. Ann Rheum Dis 1991;50: Wong K-L, Liu H-W, Ho K, Chan K, Wong R. Anticardiolipin antibodies and lupus anticoagulant in Chinese patients with systemic lupus erythematosus. J Rheumatol 1991;18: Cervera R, Khamashta MA, Font J, et al., and the European Working Party on Systemic Lupus Erythematosus. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. Medicine (Baltimore) 1993;72: Jones HW, Ireland R, Senaldi G, et al. Anticardiolipin antibodies in patients from Malaysia with systemic lupus erythematosus. Ann Rheum Dis 1991;50: Kutteh WH, Lyda EC, Abraham SM, Wacholtz MC. Association of anticardiolipin antibodies and pregnancy loss in women with systemic lupus erythematosus. Fertil Steril 1993:60: Axtens RS, Miller MH, Littlejohn GO, Topliss DJ, Morand EF. Single anticardiolipin measurement in the routine management of patients with systemic lupus erythematosus. J Rheumatol 1994;21: Tsutsumi A, Matsuura E, Ichikawa K, et al. Antibodies to b 2 -glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus. Arthritis Rheum 1996;39: Tubach F, Hayem G, Marchand J-L, et al. IgG anti- 2 -glycoprotein I antibodies in adult patients with systemic lupus erythematosus: prevalence and diagnostic value for the antiphospholipid syndrome. J Rheumatol 2000;27: Bick RL, Jakway J, Baker WF Jr. Deep vein thrombosis: prevalence of etiologic factors and results of management in 100 consecutive patients. Semin Thromb Hemost 1992;18: Eschwege V, Peynaud-Debayle E, Wolf M. Prevalence of antiphospholipid-related antibodies in unselected patients with history of venous thrombosis. Blood Coagul Fibrinolysis 1998;9: Zanon E, Prandoni P, Vianello F, et al. Anti- 2 -glycoprotein I antibodies in patients with acute venous thromboembolism: prevalence and association with recurrent thromboembolism. Thromb Res 1999;96: Brey RL, Hart RG, Sherman DG, Tegeler CH. Antiphospholipid antibodies and cerebral ischemia in young people. Neurology 1990;40: Czlonkowska A, Meurer M, Palasik W, Baranska-Gieruszczak M, Mendel T, Wierzchowska E. Anticardiolipin antibodies, a disease marker for ischemic cerebrovascular events in a younger patient population? Acta Neurol Scand 1992;86: Nencini P, Baruffi MC, Abbate R, Massai G, Amaducci L, Inzitari D. Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischemia. Stroke 1992;23:

6 Epidemiology of Antiphospholipid Syndrome de Jong AW, Hart W, Terburg M, Molenaar JL, Herbrink P, Hop WC. Cardiolipin antibodies and lupus anticoagulant in young patients with a cerebrovascular accident in the past. Neth J Med 1993;42: Ferro D, Quintarelli C, Rasura M, Antonini G, Violi F. Lupus anticoagulant and the fibrinolytic system in young patients with stroke. Stroke 1993;24: Tietjen GE, Levine SR, Brown E, Mascha E, Welch KMA. Factors that predict antiphospholipid immunoreactivity in young people with transient focal neurological events. Arch Neurol 1993;50: Puurunen M, Manttari M, Manninen V, et al. Antibody against oxidized low-density lipoprotein predicting myocardial infarction. Arch Intern Med 1994;154: Vaarala O, Manttari M, Manninen V, et al. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 1995;91: Limaye V, Beltrame J, Cook R, Gillis D, Pile K. Evaluation of antibodies to beta2-glycoprotein 1 in the causation of coronary atherosclerosis as part of the antiphospholipid syndrome. Aust N Z J Med 1999;29: Fligelstone LJ, Cachia PG, Ralis H. Lupus anticoagulant in patients with peripheral vascular disease: a prospective study. Eur J Vasc Endovasc Surg 1995;9: Taylor M, Cauchi MN, Buchanan RRC. The lupus anticoagulant, anticardiolipin antibodies, and recurrent miscarriage. Am J Reprod Immunol 1990;23: Parazzini F, Acaia B, Faden D, et al. Antiphospholipid antibodies and recurrent abortion. Obstet Gynecol 1991;77: Parke AL, Wilson D, Maier D. The prevalence of antiphospholipid antibodies in women with recurrent spontaneous abortion, women with successful pregnancies, and women who have never been pregnant. Arthritis Rheum 1991;34: Aoki K, Hayashi Y, Hirao Y, Yagami Y. Specific antiphospholipid antibodies as a predictive variable in patients with recurrent pregnancy loss. Am J Reprod Immunol 1993;29: Bagger PV, Andersen V, Baslund B, et al. Anti-cardiolipin antibodies (IgG and IgA) in women with recurrent fetal loss correlate to clinical and serological characteristics of SLE. Acta Obstet Gynecol Scand 1993;72: Toyoshima K, Makino T, Ozawa N, Umeuchi M, Nozawa S. Effect of anticardiolipin antibody in patients with recurrent fetal loss on thrombomodulin-dependent protein C activation. J Clin Lab Anal 1993;7: MacLean MA, Cumming GP, McCall F, Walker ID, Walker JJ. The prevalence of lupus anticoagulant and anticardiolipin antibodies in women with a history of first trimester miscarriages. Br J Obstet Gynaecol 1994;101: Rai RS, Regan L, Clifford K, et al. Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod 1995;10: Ogasawara M, Aoki K, Matsuura E, Sasa H, Yagami Y. Anti beta 2glycoprotein I antibodies and lupus anticoagulant in patients with recurrent pregnancy loss: prevalence and clinical significance. Lupus 1996;5: Kumar KS, Jyothy A, Prakash MS, Rani HS, Reddy PP. Beta2-glycoprotein I dependent anticardiolipin antibodies and lupus anticoagulant in patients with recurrent pregnancy loss. J Postgrad Med 2002;48: Maejima M, Fujii T, Okai T, Kozuma S, Shibata Y, Taketani Y. Beta2-glycoprotein I-dependent anticardiolipin antibody in early recurrent spontaneous abortion. Hum Reprod 1997;12: Matsumoto T, Sagawa N, Ihara Y, Kobayashi F, Itoh H, Mori T. Relationship between lupus anticoagulant (LAC) and pregnancy-induced hypertension. Reprod Fertil Dev 1995;7: Diz-Kucukkaya R, Hacihanefioglu A, Yenerel M, et al. Antiphospholipid antibodies and antiphospholipid syndrome in patients presenting with immune thrombocytopenic purpura: a prospective cohort study. Blood 2001;98: Somers E, Magder LS, Petri M. Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with SLE. J Rheumatol 2002;29: Gulko PS, Reveille JD, Koopman WJ, Burgard SL, Bartolucci AA, Alarcon GS. Anticardiolipin antibodies in systemic lupus erythematosus: clinical correlates, HLA associations, and impact on survival. J Rheumatol 1993;20: Jouhikainen T, Stephansson E, Leirisalo-Repo M. Lupus anticoagulant as a prognostic marker in systemic lupus erythematosus. Br J Rheumatol 1993;32: Rosove MH, Brewer PMC. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992;117:

7 28 Hughes Syndrome 52. Derksen RHWM, de Groot PG, Kater L, Nieuwenhuis HK. Patients with antiphospholipid antibodies and venous thrombosis should receive long term anticoagulant treatment. Ann Rheum Dis 1993;52: The Antiphospholipid Antibodies in Stroke Study Group (APASS). Anticardiolipin antibodies and the risk of recurrent thrombo-occlusive events and death. Neurology 1997;48:91 94.