Clinical Information

Antiphospholipid syndrome (APS) has traditionally been described as a systemic autoimmune disease characterized by thrombosis and/or specific pregnancy-related morbidities associated with persistent documentation of "criterial" antiphospholipid antibody (aPL) tests.(1,2) Based on the 2006 revised Sapporo consensus classification, the "criterial" aPL antibody tests include lupus anticoagulant (LAC) and IgG/IgM antibodies to the cardiolipin and beta2-glyocoprotein I (anti-B2 GPI) with all tests carrying equal diagnostic significance for disease.(1) In 2023, the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) published new classification criteria for APS that includes an entry criterion of at least one positive aPL antibody test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (LAC functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM aCL and/or IgG/IgM anti-B2 GPI).(3) Of note, aPL antibodies also occur in patients with autoimmune diseases with significant prevalence in systemic lupus erythematosus (SLE) as well as other clinical manifestations (eg, heart valve disease, livedo reticularis, thrombocytopenia, nephropathy and neurological) often associated with APS.(1-3) Thus, in addition to the 2023 APS classification criteria, the 2012 derivation and validation of the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE recommends testing for the criteria aPL antibody tests as well as aCL IgA and anti-B2GPI IgA.(4)

Unlike LAC, which is evaluated using functional assays, diverse solid-phase immunoassays, such as enzyme-linked immunosorbent assay, multiplex bead assay, chemiluminescent immunoassay, and fluorescence enzyme immunoassay are used in the clinical laboratories for the detection and measurement of aCL and anti-B2GPI IgA, IgG, and IgM antibodies.(5,6) For aCL IgG and IgM determinations, the APS classification guidance recommends antibody cutoff values greater than 40 IgG phospholipid (GPL) or IgM phospholipid (MPL) units (units traceable to the Harris standards for aCL antibody assays) or more than the 99th percentile for the testing laboratory's population for positivity. It also advocates for the use of values greater than the 99th percentile for the laboratory's population in the establishment of reference intervals for anti-B2GPI IgG and IgM antibody tests.(1) The use of cutoff values greater than 40 GPL or MPL units to define positivity is not be applicable to all aCL antibody immunoassays, as the threshold used to distinguish moderate-to-high positive from low positive results are test dependent.(6-8) In addition, the cutoff used at the 99th percentile of a laboratory's testing population may not be consistent with kits from the same manufacturer or 40 GPL units, in the case of aCL antibodies.(2,6-8)

The 2023 ACR/EULAR classification criteria for APS are meant for clinical studies and may not be appropriate for routine patient evaluation and management. Therefore, in clinical practice, if suspicion for disease is high but criteria aPL antibody tests are inconclusive or negative, deviation from the APS classification criteria may be justified. This may include testing for noncriteria aPL antibody tests such the aCL IgA and anti-B2GPI IgA recommended in 2012 SLICC guidance for SLE or evaluation of other noncriteria aPL antibody tests.(4-6,9,10) However, there is no formal guidance for the measurement and interpretation of aCL and anti-B2GPI IgA antibodies in patients with APS or SLE. Some clinical relevance between APS-related clinical symptoms and the presence of aCL/anti-B2GPI IgA have been reported, however, the added value is minimal.(10,11) Isolated aPL IgA is rare, and these antibodies are usually found in association with IgG and/or IgM.