Elsevier

Autoimmunity Reviews

Volume 9, Issue 5, March 2010, Pages A299-A304
Autoimmunity Reviews

The geoepidemiology of the antiphospholipid antibody syndrome

https://doi.org/10.1016/j.autrev.2009.11.013Get rights and content

Abstract

Antiphospholipid antibodies (aPL) can be detected by functional (lupus anticoagulant) and/or by solid phase assays (anti-cardiolipin and anti-beta2 glycoprotein I). Although detectable in 1–5% of asymptomatic apparently healthy subjects, persistent aPL are significantly associated with recurrent arterial/venous thrombosis and with pregnancy morbidity. Such an association is the formal classification tool for the antiphospholipid syndrome (APS).

The prevalence of the syndrome with no associated systemic connective tissue diseases (primary APS) in the general population is still a matter of debate since there are no sound epidemiological studies in the literature so far. aPL display higher prevalence in systemic lupus erythematosus and rheumatoid arthritis than in other systemic autoimmune diseases. However not all the aPL positive lupus patients display the clinical manifestations. Comparable findings may be found in the paediatric population, although anti-beta2 glycoprotein I antibodies are detected in healthy children more frequently than in adults.

High prevalence of aPL has been also reported in clinical manifestations that are not formal APS classification criteria: heart valve disease, livedo reticular, nephropathy, neurological manifestations, and thrombocytopenia.

Antiphospholipid antibodies can be associated with infectious processes, active vaccination, drug administration and malignancies. Their prevalence and titres are lower and the relationship with the APS clinical manifestations are less strong than in the previously mentioned conditions.

Ethnicity was also reported to influence the prevalence of aPL.

Introduction

The antiphospholipid syndrome (APS) is a systemic autoimmune disease defined by the occurrence of recurrent thromboembolic events and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Antiphospholipid antibodies are formally detected by functional coagulation assay (the so called lupus anticoagulant – LAC) and/or by solid phase assays: anti-cardiolipin (aCL), or anti-β2 glycoprotein I (anti-β2GPI) antibody tests.

Classification criteria for APS have been developed at the Sapporo antiphospholipid meeting and then recently updated [1]. APS is defined by the presence of at least one of the clinical criteria and one of the laboratory criteria. The criteria define patients with “primary” APS (PAPS) as those with the diagnosis in the absence of any underlying autoimmune disease, and patients with “secondary” APS (SAPS) as those with autoimmune disorders, aPL and the clinical manifestations of the syndrome [1].

A variant of APS characterized by acute thrombotic microangiopathy with subsequent multiorgan failure and high mortality rate has been also identified: the so called catastrophic APS (CAPS) [2]. Probable and microangiopathic APS are additional disease subsets that have been suggested but not yet formally accepted [2].

The present chapter will address the aPL prevalence in the formal clinical manifestations of the syndrome both in adults and in the paediatric populations as well as their occurrence in association with other systemic autoimmune conditions. The occurrence (and prevalence) of aPL in asymptomatic subjects or in association with other non-autoimmune conditions will also be evaluated.

Section snippets

aPL and arterial thrombosis

The cumulative retrospective literature analysis indicates that approximately 30% to 40% of patients with aPL have a history of thrombosis and that 30% of the events are arterial [3].

Cerebral circulation is the most commonly affected arterial district while coronary arteries and additional arterial anatomical localizations are less frequently reported [4].

The Euro-Phospholipid Group analyzed the prevalence of the most relevant clinical and immunological features in a cohort of 1000 APS patients

aPL and venous thrombosis

Venous thrombosis (VT) is the most common APS clinical manifestation, usually deep vein thrombosis (DVT), and occurs in more than 30% of patients [5].

Frequencies of aPL in venous thrombosis have been reported to range from 5.2% to 30% for any aPL, 0.6–16% for LA, and 4–24% for aCL [7].

Galli et al. performed a meta-analysis of case–control, cross-sectional, and ambispective studies to calculate the OR with 95% confidence interval (CI) of LAC and IgG/IgM aCL for venous thrombosis. All the studies

aPL and pregnancy morbidity

Multiple cross-sectional studies reported an association between aCL and/or LAC and recurrent foetal loss, with a frequency ranging from 10% to 19%; however some studies failed to confirm such a finding [7]. Foetal losses can occur in any trimester of pregnancy, although their frequency was higher before the 10th week of gestation than after (35.4% vs. 16.9% respectively) in the Euro-phospholipid series. The specificity of recurrent early abortion is still discussed because of the difficulty in

aPL and non-classification criterial clinical manifestations

According to the 2006 International consensus statement for classification of definite APS, the following manifestations are not included in the updated criteria: heart valve disease (vegetations, valve thickening and dysfunction), livedo reticularis (LR), nephropathy, neurological manifestations (cognitive dysfunction, migraine, multiple sclerosis, transverse myelopathy, and epilepsy), and thrombocytopenia. Although undoubtedly frequent the above mentioned features are not thought to be

aPL and systemic autoimmune diseases

The antiphospholipid syndrome can occur in association with other systemic autoimmune diseases and in particular with SLE: 37% of the patients of the Europhospholipid series was suffering from full blown SLE, while 4% was associated with lupus-like disease [5].

The prevalence of aPL among patients with SLE ranges from 12% to 44% for aCL, from 15% to 34% for LAC, and from 10% to 19% for anti-β2GPI [7]. It has been suggested that fluctuations of the antibody titers because of disease activity

aPL in the general population and in other pathological conditions

Antiphospholipid antibodies can be found in apparently healthy control subjects with a prevalence ranging from 1 to 5% for both aCL and LAC. In most of the cases the antibodies displayed low titres [7]. An increased prevalence of the antibodies detectable with all the assays has been reported with ageing. The highest values were reported in healthy centenarians but without a clear association with the APS clinical manifestations [30].

Since the association of aPL and syphilis was first

aPL in the paediatric antiphospholipid syndrome

Antiphospholipid antibodies can be found in a high percentage of children without any underlying disorder, with an estimated frequency that ranges from 3 to 28% for aCL and from 3 to 7% for anti-β2GPI. The reason of such frequent occurrence in comparison with the adults has been related to the frequent infectious processes taking place during childhood [36]. Increased prevalence of anti-β2GPI antibodies (up to 42%) was also detected in children suffering from atopic dermatitis with no APS

aPL and the ethnicity

Environmental and genetic factors contribute to ethnic variation and susceptibility to APS and thus interethnic differences in disease patterns may be due to environmental or genetic factors, or both [38].

Genetic factors are important in the development of APS. This is demonstrated by animal models, by the familial occurrence of this syndrome, and by its association with various HLA alleles. Some HLA alleles carry the risk to produce aPL, and this is independent on the clinical context. In

Take-home messages

  • aPL can be detected in asymptomatic healthy controls (prevalence 1–5%). aPL can be induced by infections, malignancies, vaccinations and drugs. In these cases the autoantibodies are usually transient, at low titre, and with a weak association with the APS clinical manifestations.

  • Arterial thrombosis displays a strong association with LAC and anti-β2GPI. Cerebral circulation is the most commonly affected arterial district in APS patients.

  • Venous thrombosis is the most frequent APS clinical

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