The clinical significance of IgA antiphospholipid antibodies.

694 Antiphospholipid antibodies (aPL) are a heterogeneous group of circulating autoantibodies that are found in the sera of patients with autoimmune and infectious diseases, the antiphospholipid syndrome (APS), and in healthy subjects1,2. The “antiphospholipid syndrome” is characterized by the association of raised levels of circulating aPL with a spectrum of clinical manifestations such as arterial and venous thrombosis, recurrent fetal loss, and thrombocytopenia3. Interest in aPL was renewed by the recognition of the role played by plasma proteins such as ß2-glycoprotein I (ß2GPI) and prothrombin in the binding of aPL to their respective phospholipid antigens. Initially, aPL were thought to be directed against negatively charged phospholipids, but this view has now changed. The prevailing view is that in patients with autoimmune disease, serum aPL do not bind directly to phospholipid antigens alone, but to epitopes on plasma proteins, such as ß2-GPI or prothrombin, or to a complex of phospholipid and one of these proteins4. As a consequence of these findings, new ELISA have been developed for the estimation of anti-ß2-GPI and antiprothrombin antibodies. These new aPL assays are now proving very useful in research, especially in patients with APS, where anti-ß2-GPI antibodies have now been shown to be strongly associated with some of the clinical complications found in the APS5. Most studies on aPL have focused mainly on the estimation of the IgG and IgM isotypes, with only a few studies reporting the prevalence of IgA aPL as well. In studies where IgA aCL and/or anti-ß2-GPI were measured, conflicting findings of their prevalence and clinical significance have been reported; as a consequence, raised levels of the IgA isotype of aPL were not included in the classification criteria for the APS6. The reasons for these discrepancies could be due to the use of assays that are not yet fully standardized; for anti-ß2-GPI ELISA, the lack or limited availability of appropriate standards, the use of different cutoff values, and differences in the ethnic composition of the populations studied could account for these discrepancies7,8. These were highlighted in a recent study by Bizzaro, et al, who reported that patients with IgA monoclonal gammopathy gave false positive reactions for IgA aCL and anti-ß2-GPI 9. Although limited data are currently available, it appears that in patients with systemic lupus erythematosus (SLE), IgA aCL antibodies are similar to IgG aCL regarding their thrombogenicity and ß2-GPI requirements for their binding to the cardiolipin antigen10. In a mouse model designed to study thrombus formation, injected IgA immunoglobulins from patients with APS were shown to cause thrombosis; the mean times taken for thrombus formation using 2 different IgA immunoglobulin preparations were found to be significantly prolonged compared to the IgG and IgM preparations11. In patients with SLE, some studies reported a significant correlation between IgA aCL and anti-ß2-GPI levels 12,13, while others did not find such a correlation, suggesting that IgA aCL and anti-ß2-GPI antibodies represent 2 distinct autoantibody populations14. Faghiri, et al studied the origins of IgA aPL (mucosal vs nonmucosal) in a group of patients with SLE or human T cell leukemia virus (HTLV-1) related myelopathy, and concluded that IgA anti-ß2-GPI were more often of mucosal origin than IgA aCL15. Prevalence of IgA aCL and anti-ß2-GPI antibodies. The consensus from the literature is that elevated IgA aCL in patients with SLE and APS are usually present in patient sera in conjunction with raised IgG and/or IgM aCL, and that IgA aCL are very rarely present as the sole aCL isotype16,17. In unselected patients with SLE, the prevalence of increased titers of IgA aCL has been reported to vary from 1% to 44%. The lowest reported frequency was that found by Selva-O’Callaghan, et al, who detected IgA aCL in only 2 of their 200 patients with SLE18. Higher prevalences were reported in the 2 largest SLE patient cohort studies to date; in a recent European study, where the IgG, IgM, and IgA aCL isotypes were estimated in 577 SLE patients, IgA aCL was positive in only 13.9% of patients19. AlarconSegovia, et al, in an earlier study that included 500 patients with SLE, found increased titers of IgA aCL in 16.6% of their patients, using a cutoff point 2 SD above the mean of their healthy control group; positivity dropped to 4.3% when the cutoff was set at the mean plus 6 SD20. In a recent study, Spadaro, et al found IgA aCL to be positive in 13 (20%) of their 65 SLE patients21. In contrast, Weidmann, et al found IgA aCL to be positive in 44% of 92 SLE patients, and also Editorial