Value of Isolated IgA Anti–β₂‐Glycoprotein I Positivity in the Diagnosis of the Antiphospholipid Syndrome

Abstract

Purpose To examine the prevalence of isolated IgA anti-β2Glycoprotein I (anti-β2GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of β2GPI, with clinical manifestations of the Antiphospholipid Syndrome (APS) in three patients groups. The pathogenicity of IgA anti-β2GPI was also evaluated in a mouse model of thrombosis. Methods Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n=558), patients with SLE from the Hopkins Lupus Cohort (n=215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n=5,098) were evaluated. IgA anti-β2GPI titers and binding to domain IV/V of β2GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti- β2GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity. Results A total of 198 patients were found to be positive for IgA anti-β2GPI isotype, and 57 patients were positive exclusively for IgA anti-β2GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-β2GPI positive serum samples reacted with domain IV/V of anti-β2GPI, and 77% of those had clinical features of APS. Isolated IgA anti-β2GPI positivity was associated with an increased risk for arterial thrombosis (p<0.001), venous thrombosis (p=0.015) and all thrombosis (p<0.001). The association between isolated IgA anti-β2GPI and arterial thrombosis (p=0.0003) and all thrombosis (p=0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-β2GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls. Conclusion Isolated IgA anti-β2GPI positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid (aPL) tests are negative and APS is suspected is recommended. IgA anti-β2GPI antibodies directed to domain IV/V of β2GPI represent an important subgroup of clinically relevant antiphospholipids.

Differential assay reactivity of immunglobulin A anti-ß2 glycoprotein I antibodies: implications for the clinical interpretation of antiphospholipid antibody testing

“…The diagnostic value of IgA aCL and anti-β 2 GPI antibodies has been largely ignored because this antibody isotype is commonly present with IgG and IgM antibodies. Murthy et al (8) recently reported the presence of isolated IgA anti-β 2 GPI antibodies and concluded that this isotype may identify additional patients with the clinical features of APS as well as recommended the testing for IgA antibodies when other antiphospholipid antibodies are absent and APS is suspected. discrepant results among laboratories and commonly used commercial IgA anti-β 2 GPI enzyme-linked immunoassay (ELISA) tests when testing SLE and/or APS serum samples.…”

Reactivity against the Five Domains of β2 Glycoprotein I: A Focus on Systemic Lupus Erythematosus

“…While anti-DI antibodies were related to thrombosis in the study by de Laat et al which did not differentiate between APS and lupus patients, the only study on the clinical meaning of anti-DI antibodies conducted specifically in a lupus popupulation did not evince a significant association with aPL-related clinical events [44]. On the other hand, in the same study a significant association emerged between anti-DIV/V IgA and stroke; consistently, Murthy et al observed that 77% of patients with positive for anti-DIV/V antibodies had clinical manifestations of SAPS [53].…”

“…IgA anti-β 2 GPI DIV/V titers well correlated with IgA anti-β 2 GPI titers (p<0.0001). Of the 62 patients whose samples were positive for binding of IgA to anti-β 2 GPI DIV/V, 77% had clinical manifestations of APS that included DVT, strokes, myocardial infarction, pulmonary arterial hypertension, seizures, pregnancy losses, skin ulcers, and livedo reticularis [53].…”

The Prevalence and Clinical Significance of Iga Anti-Phosphatidylserine/ Prothrombin Antibodies in Systemic Autoimmune Diseases

“…In-house aPS/PT ELISA was performed as previously described [19]. Medium binding plates (Costar, Cambridge, USA) were coated with phosphatidyserine in chloroform/methanol 1:4 and dried overnight at 4°C.…”

“…Although antiprothrombin antibodies have not yet been included in the classification criteria of APS, they are emerging as an increasingly important supportive marker [1,[19][20][21]. We have previously reported of IgG and/or IgM antibodies against complex phosphatidylserine/prothrombin (aPS/PT) exhibiting the highest percentage of LA activity, as compared to aCL or anti-β2GPI [19] and their strong association to thrombosis and adverse pregnancy outcome, irrespective of other antiphospholipid antibodies [20,22]. The latest systematic review concluded that routine measurement of aPS/PT antibodies of IgG and/or IgM isotype in serum or plasma might be useful in establishing the thrombotic risk of patients with previous thrombosis and/or (SLE) [21].…”