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Multiple antiphospholipid antibodies positivity and antiphospholipid syndrome criteria re-evaluation R Forastiero Lupus 2014 23: 1252 DOI: 10.1177/0961203314531635 The online version of this article can be found at: http://lup.sagepub.com/content/23/12/1252
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Lupus (2014) 23, 1252–1254 http://lup.sagepub.com
SPECIAL ARTICLE
Multiple antiphospholipid antibodies positivity and antiphospholipid syndrome criteria re-evaluation R Forastiero Department of Physiology, Thrombosis and Hemostasis, FavaloroUniversity, Buenos Aires, Argentina
The antiphospholipid syndrome (APS) is characterized by the presence of aPL and thrombosis and/or pregnancy morbidity. The last APS laboratory classification criteria include the presence of at least one of the antiphospholipid antibodies (aPL) [lupus anticoagulant (LA), anticardiolipin (aCL) and/or anti-b2 glycoprotein I antibodies (ab2GPI)] and introduced the concept of subclassification of APS patients into two different categories of aPL assay positivity (combination or single aPL). Several studies have recently shown that the risk for thrombosis increases with each additional aPL detected. We found that the presence of IgG antibodies to b2GPI and/or prothrombin increased thrombotic risk in patients with LA and/ or aCLin a prospective study. Various studies have recently demonstrated that patients with triple positivity (LA, aCL and ab2GPI) are at the highest risk for venous and arterial thrombosis and for obstetric complications. In retrospective but also in prospective studies the rate of thrombotic recurrence was high in subjects with triple positivity even while on anticoagulant therapy. In addition, the occurrence of a first thrombotic event in asymptomatic carriers of triple positivity was higher than in those with single aPL positivity. The inclusion of the detection of antibodies against domain I of b2GPI and/or antibodies to prothrombin would probably help to further identify more clinically relevant aPL. Based on the last findings, there are some proposals to consider only patients with triple positivity as definite APS (thrombotic and obstetric). Lupus (2014) 23, 1252–1254. Key words: Antiphospholipid antibodies; antiphospholipid syndrome; thrombosis; pregnancy morbidity
The antiphospholipid syndrome (APS) is an autoimmune disease characterized clinically by the occurrence of objectively proven venous or arterial thrombosis in different vascular beds, and/or pregnancy morbidity.1 Cerebrovascular infarction is the most common clinical feature within the arterial circulation, whereas lower limb deep venous thrombosis and pulmonary embolism are the main clinical manifestations within the venous circulation. Antiphospholipid antibodies (aPL) are a heterogeneous family of antibodies detected by coagulation tests and immunological assays. The diagnosis of lupus anticoagulant (LA) relies on a set of successive phospholipid-dependent clotting tests, and anticardiolipin (aCL) and anti-b2 glycoprotein I antibodies (ab2GPI) are measured by different immunological assays.2 aPL may bind phospholipids directly, but most autoimmune aPL require Correspondence to: Ricardo R. Forastiero, Hematologı´ a, Universidad Favaloro, Solı´ s 453, (C1078AAI) Buenos Aires, Argentina. Email: [email protected]
b2GPI and prothrombin for antibody binding to phospholipids. Positivity on the aCL assay not directed against b2GPI is commonly found in the setting of several infectious disorders. There is evidence that the most important epitope of ab2GPI is situated on the Gly40-Arg43 region in the first domain of b2GPI. The detection of persistently elevated levels of aPL is a requisite laboratory feature for the diagnosis of APS. Positivity for at least one aPL test – LA and/or IgG/IgMaCL(at titres higher than 40 units or the normal 99th percentile) and/or ab2GPI (at titres higher than the normal 99th percentile) – must be detected. They must be found on two or more occasions at least 12 weeks apart. In the 2006 updated APS criteria it is advised to classify patients with APS into one of two different categories. Patients with more than one positive aPL test must be placed in category I, while those with single aPL positivity must be placed in category II.1 According to the 2006 criteria for the classification of APS, a single positivity of any of the three
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at UNIV OF CONNECTICUT on October 5, 2014
10.1177/0961203314531635
Multiple antiphospholipid antibodies positivity and APS criteria re-evaluation R Forastiero
1253
abovementioned aPL tests fulfil the serological criteria. However, in recent years numerous studies have shown that the risk of thrombosis increases with the number of positive tests in APS patients and also in asymptomatic carriers of persistent aPL. The concept of triple positivity (LA/aCL/ ab2GPI) conferring a higher risk for thromboembolic events and pregnancy losses has been proposed, taking into account several retrospective and prospective studies in patients with or without systemic lupus erythematosus (SLE).3–5A large, prospective multicentre study on triple aPL-positive APS patients reported a cumulative incidence of thrombosis of 12.2%, 26.1%, and 44.2% after 1, 5 and 10 years of follow-up, respectively.4 In addition, it was reported that the annual incidence of the first thrombotic event was 5.3% per year among 104 triple aPL-positive patients with no history of thrombosis (aPL carriers) followed-up for a mean of 4.5 years.5 These findings reinforce the concept that patients with LA and the triple positive population have a more severe course of the disease. It is likely that the presence of triple positivity is due to antibodies directed against the Gly40-Arg43 epitope in the first domain (D1) of b2GPI. The detection of ab2GPI-D1 seems to be a promising biomarker in diagnosis / risk assessment of APS. The family of aPL is continuously expanding, and testing for other aPL such as antibodies to prothrombin and the complex of prothrombin with phosphatidylserine (aPS/PT) has been proposed to be relevant to APS. In our prospective study in 20056 we showed that the triple positivity for LA, IgGab2GPI, and IgG antiprothrombin antibodies gave the highest annual rate of thrombosis (8.4%), which was statistically significant in multivariate analysis (OR, 2.6; 95% CI, 1.35–5.01). The results of a 15-year longitudinal study showed the IgG antiprothrombin antibodies to be the most useful predictor of thrombosis in patients with SLE.7 A recent retrospective study analysed a large series of patients with SLE, and assessed the potential clinical usefulness of combining routinely tested aPL with new aPL specificities in an attempt to find a profile that will identify patients at higher risk of APS. Among the 23 possible combinations of the six aPL tested, LA þ ab2GPI þ aPS/PT had the best diagnostic accuracy for APS as a whole, and for both thrombosis and pregnancy loss. When comparing it with the combination suggested by the current criteria and all the other tested combinations, positivity for LA/ab2GPI/aPS/PT had the best diagnostic performance in terms of specificity and predictive value in this SLE cohort.8
Table 1 Proposal of risk categories for the antiphospholipid syndrome Definite APS Probable APS Possible or non-APS
Patients with at least triple aPL positivity (high-risk group) Patients with double aPL positivity (medium-risk group) Patients with single aPL positivity (low-risk group)
Pengo et al. proposed to consider only patients with triple positivity (LA/aCL/ab2GPI) as definite APS (thrombotic and obstetric).9,10 However, taking into account the increasing knowledge and the occurrence of different combinations of aPL, it is now proposed that the definition of APS should include a different clinical risk to develop APSrelated events (Table 1). Likely this risk stratification would improve the clinical management of patients with aPL.
Funding We acknowledged the support of a grant from the National Fund of Science and Technology (PICT 2010-1173), Ministry of Culture and Education, Argentina. No writing assistance was utilized in the preparation of this manuscript.
Conflict of interest statement The author has no conflicts of interest to declare.
References 1 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306. 2 Forastiero R, Papalardo E, Watkins M, et al. Evaluation of different immunoassays for the detection of antiphospholipidantibodies: Report of a wet workshop during the 13th International Congress on Antiphospholipid Antibodies. Clin Chim Acta 2014; 428: 99–105. 3 Herna´ndez-Molina G, Espericueta-Arriola G, Cabral AR. The role of lupus anticoagulant and triple marker positivity as risk factors for rethrombosis in patients with primary antiphospholipid syndrome. Clin Exp Rheumatol 2013; 31: 382–388. 4 Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010; 8: 237–242. 5 Pengo V, Ruffatti A, Legnani C, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: A multicenter prospective study. Blood 2011; 118: 4714–4718. 6 Forastiero R, Martinuzzo M, Pombo G, et al. A prospective study of antibodies to b2 glycoprotein I and prothrombin and risk of thrombosis. J Thromb Haemost 2005; 3: 1231–1238. Lupus
Downloaded from lup.sagepub.com at UNIV OF CONNECTICUT on October 5, 2014
Multiple antiphospholipid antibodies positivity and APS criteria re-evaluation R Forastiero
1254 7 Bizzaro N, Ghirardello A, Zampieri S, et al. Anti-prothrombin antibodies predict thrombosis in patients with systemic lupus erythematosus: A 15-year longitudinal study. J Thromb Haemost 2007; 5: 1158–1164. 8 Sciascia S, Murru V, Sanna G, et al. Clinical accuracy for diagnosis of antiphospholipid syndrome in systemic lupus erythematosus: Evaluation of 23 possible combinations of
antiphospholipid antibody specificities. J Thromb Haemost 2012; 10: 2512–2518. 9 Pengo V, Banzato A, Denas G, et al. Correct laboratory approach to APS diagnosis and monitoring. Autoimmun Rev 2013; 12: 832–834. 10 Pengo V, Banzato A, Bison E, et al. Antiphospholipid syndrome: Critical analysis of the diagnostic path. Lupus 2010; 19: 428–431.
Lupus Downloaded from lup.sagepub.com at UNIV OF CONNECTICUT on October 5, 2014
http://lup.sagepub.com/
Multiple antiphospholipid antibodies positivity and antiphospholipid syndrome criteria re-evaluation R Forastiero Lupus 2014 23: 1252 DOI: 10.1177/0961203314531635 The online version of this article can be found at: http://lup.sagepub.com/content/23/12/1252
Published by: http://www.sagepublications.com
Additional services and information for Lupus can be found at: Email Alerts: http://lup.sagepub.com/cgi/alerts Subscriptions: http://lup.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Sep 16, 2014 What is This?
Downloaded from lup.sagepub.com at UNIV OF CONNECTICUT on October 5, 2014
Lupus (2014) 23, 1252–1254 http://lup.sagepub.com
SPECIAL ARTICLE
Multiple antiphospholipid antibodies positivity and antiphospholipid syndrome criteria re-evaluation R Forastiero Department of Physiology, Thrombosis and Hemostasis, FavaloroUniversity, Buenos Aires, Argentina
The antiphospholipid syndrome (APS) is characterized by the presence of aPL and thrombosis and/or pregnancy morbidity. The last APS laboratory classification criteria include the presence of at least one of the antiphospholipid antibodies (aPL) [lupus anticoagulant (LA), anticardiolipin (aCL) and/or anti-b2 glycoprotein I antibodies (ab2GPI)] and introduced the concept of subclassification of APS patients into two different categories of aPL assay positivity (combination or single aPL). Several studies have recently shown that the risk for thrombosis increases with each additional aPL detected. We found that the presence of IgG antibodies to b2GPI and/or prothrombin increased thrombotic risk in patients with LA and/ or aCLin a prospective study. Various studies have recently demonstrated that patients with triple positivity (LA, aCL and ab2GPI) are at the highest risk for venous and arterial thrombosis and for obstetric complications. In retrospective but also in prospective studies the rate of thrombotic recurrence was high in subjects with triple positivity even while on anticoagulant therapy. In addition, the occurrence of a first thrombotic event in asymptomatic carriers of triple positivity was higher than in those with single aPL positivity. The inclusion of the detection of antibodies against domain I of b2GPI and/or antibodies to prothrombin would probably help to further identify more clinically relevant aPL. Based on the last findings, there are some proposals to consider only patients with triple positivity as definite APS (thrombotic and obstetric). Lupus (2014) 23, 1252–1254. Key words: Antiphospholipid antibodies; antiphospholipid syndrome; thrombosis; pregnancy morbidity
The antiphospholipid syndrome (APS) is an autoimmune disease characterized clinically by the occurrence of objectively proven venous or arterial thrombosis in different vascular beds, and/or pregnancy morbidity.1 Cerebrovascular infarction is the most common clinical feature within the arterial circulation, whereas lower limb deep venous thrombosis and pulmonary embolism are the main clinical manifestations within the venous circulation. Antiphospholipid antibodies (aPL) are a heterogeneous family of antibodies detected by coagulation tests and immunological assays. The diagnosis of lupus anticoagulant (LA) relies on a set of successive phospholipid-dependent clotting tests, and anticardiolipin (aCL) and anti-b2 glycoprotein I antibodies (ab2GPI) are measured by different immunological assays.2 aPL may bind phospholipids directly, but most autoimmune aPL require Correspondence to: Ricardo R. Forastiero, Hematologı´ a, Universidad Favaloro, Solı´ s 453, (C1078AAI) Buenos Aires, Argentina. Email: [email protected]
b2GPI and prothrombin for antibody binding to phospholipids. Positivity on the aCL assay not directed against b2GPI is commonly found in the setting of several infectious disorders. There is evidence that the most important epitope of ab2GPI is situated on the Gly40-Arg43 region in the first domain of b2GPI. The detection of persistently elevated levels of aPL is a requisite laboratory feature for the diagnosis of APS. Positivity for at least one aPL test – LA and/or IgG/IgMaCL(at titres higher than 40 units or the normal 99th percentile) and/or ab2GPI (at titres higher than the normal 99th percentile) – must be detected. They must be found on two or more occasions at least 12 weeks apart. In the 2006 updated APS criteria it is advised to classify patients with APS into one of two different categories. Patients with more than one positive aPL test must be placed in category I, while those with single aPL positivity must be placed in category II.1 According to the 2006 criteria for the classification of APS, a single positivity of any of the three
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at UNIV OF CONNECTICUT on October 5, 2014
10.1177/0961203314531635
Multiple antiphospholipid antibodies positivity and APS criteria re-evaluation R Forastiero
1253
abovementioned aPL tests fulfil the serological criteria. However, in recent years numerous studies have shown that the risk of thrombosis increases with the number of positive tests in APS patients and also in asymptomatic carriers of persistent aPL. The concept of triple positivity (LA/aCL/ ab2GPI) conferring a higher risk for thromboembolic events and pregnancy losses has been proposed, taking into account several retrospective and prospective studies in patients with or without systemic lupus erythematosus (SLE).3–5A large, prospective multicentre study on triple aPL-positive APS patients reported a cumulative incidence of thrombosis of 12.2%, 26.1%, and 44.2% after 1, 5 and 10 years of follow-up, respectively.4 In addition, it was reported that the annual incidence of the first thrombotic event was 5.3% per year among 104 triple aPL-positive patients with no history of thrombosis (aPL carriers) followed-up for a mean of 4.5 years.5 These findings reinforce the concept that patients with LA and the triple positive population have a more severe course of the disease. It is likely that the presence of triple positivity is due to antibodies directed against the Gly40-Arg43 epitope in the first domain (D1) of b2GPI. The detection of ab2GPI-D1 seems to be a promising biomarker in diagnosis / risk assessment of APS. The family of aPL is continuously expanding, and testing for other aPL such as antibodies to prothrombin and the complex of prothrombin with phosphatidylserine (aPS/PT) has been proposed to be relevant to APS. In our prospective study in 20056 we showed that the triple positivity for LA, IgGab2GPI, and IgG antiprothrombin antibodies gave the highest annual rate of thrombosis (8.4%), which was statistically significant in multivariate analysis (OR, 2.6; 95% CI, 1.35–5.01). The results of a 15-year longitudinal study showed the IgG antiprothrombin antibodies to be the most useful predictor of thrombosis in patients with SLE.7 A recent retrospective study analysed a large series of patients with SLE, and assessed the potential clinical usefulness of combining routinely tested aPL with new aPL specificities in an attempt to find a profile that will identify patients at higher risk of APS. Among the 23 possible combinations of the six aPL tested, LA þ ab2GPI þ aPS/PT had the best diagnostic accuracy for APS as a whole, and for both thrombosis and pregnancy loss. When comparing it with the combination suggested by the current criteria and all the other tested combinations, positivity for LA/ab2GPI/aPS/PT had the best diagnostic performance in terms of specificity and predictive value in this SLE cohort.8
Table 1 Proposal of risk categories for the antiphospholipid syndrome Definite APS Probable APS Possible or non-APS
Patients with at least triple aPL positivity (high-risk group) Patients with double aPL positivity (medium-risk group) Patients with single aPL positivity (low-risk group)
Pengo et al. proposed to consider only patients with triple positivity (LA/aCL/ab2GPI) as definite APS (thrombotic and obstetric).9,10 However, taking into account the increasing knowledge and the occurrence of different combinations of aPL, it is now proposed that the definition of APS should include a different clinical risk to develop APSrelated events (Table 1). Likely this risk stratification would improve the clinical management of patients with aPL.
Funding We acknowledged the support of a grant from the National Fund of Science and Technology (PICT 2010-1173), Ministry of Culture and Education, Argentina. No writing assistance was utilized in the preparation of this manuscript.
Conflict of interest statement The author has no conflicts of interest to declare.
References 1 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306. 2 Forastiero R, Papalardo E, Watkins M, et al. Evaluation of different immunoassays for the detection of antiphospholipidantibodies: Report of a wet workshop during the 13th International Congress on Antiphospholipid Antibodies. Clin Chim Acta 2014; 428: 99–105. 3 Herna´ndez-Molina G, Espericueta-Arriola G, Cabral AR. The role of lupus anticoagulant and triple marker positivity as risk factors for rethrombosis in patients with primary antiphospholipid syndrome. Clin Exp Rheumatol 2013; 31: 382–388. 4 Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010; 8: 237–242. 5 Pengo V, Ruffatti A, Legnani C, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: A multicenter prospective study. Blood 2011; 118: 4714–4718. 6 Forastiero R, Martinuzzo M, Pombo G, et al. A prospective study of antibodies to b2 glycoprotein I and prothrombin and risk of thrombosis. J Thromb Haemost 2005; 3: 1231–1238. Lupus
Downloaded from lup.sagepub.com at UNIV OF CONNECTICUT on October 5, 2014
Multiple antiphospholipid antibodies positivity and APS criteria re-evaluation R Forastiero
1254 7 Bizzaro N, Ghirardello A, Zampieri S, et al. Anti-prothrombin antibodies predict thrombosis in patients with systemic lupus erythematosus: A 15-year longitudinal study. J Thromb Haemost 2007; 5: 1158–1164. 8 Sciascia S, Murru V, Sanna G, et al. Clinical accuracy for diagnosis of antiphospholipid syndrome in systemic lupus erythematosus: Evaluation of 23 possible combinations of
antiphospholipid antibody specificities. J Thromb Haemost 2012; 10: 2512–2518. 9 Pengo V, Banzato A, Denas G, et al. Correct laboratory approach to APS diagnosis and monitoring. Autoimmun Rev 2013; 12: 832–834. 10 Pengo V, Banzato A, Bison E, et al. Antiphospholipid syndrome: Critical analysis of the diagnostic path. Lupus 2010; 19: 428–431.
Lupus Downloaded from lup.sagepub.com at UNIV OF CONNECTICUT on October 5, 2014
