Value of isolated IgA anti-β2-glycoprotein i positivity in the diagnosis of the antiphospholipid syndrome

Vijaya Murthy, Rohan Willis, Zurina Romay-Penabad, Patricia Ruiz-Limõn, Laura A. Martínez-Martínez, Shraddha Jatwani, Praveen Jajoria, Alan Seif, Graciela S. Alarcõn, Elizabeth Papalardo, Jigna Liu, Luis M. Vilá, Gerald McGwin, Terry A. McNearney, Rashmi Maganti, Prashanth Sunkureddi, Trisha Parekh, Michael Tarantino, Ehtisham Akhter, Hong FangEmilio B. Gonzalez, Walter R. Binder, Gary L. Norman, Zakera Shums, Marius Teodorescu, John D. Reveille, Michelle Petri, Silvia S. Pierangeli

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Abstract

Objective: To examine the prevalence of isolated IgA anti- β2-glycoprotein 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 3 patient groups and to evaluate the pathogenicity of IgA anti-β2GPI 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 of 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 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.

Original languageEnglish (US)
Pages (from-to)3186-3193
Number of pages8
JournalArthritis and Rheumatism
Volume65
Issue number12
DOIs
StatePublished - Dec 1 2013

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

Murthy, V., Willis, R., Romay-Penabad, Z., Ruiz-Limõn, P., Martínez-Martínez, L. A., Jatwani, S., Jajoria, P., Seif, A., Alarcõn, G. S., Papalardo, E., Liu, J., Vilá, L. M., McGwin, G., McNearney, T. A., Maganti, R., Sunkureddi, P., Parekh, T., Tarantino, M., Akhter, E., ... Pierangeli, S. S. (2013). Value of isolated IgA anti-β2-glycoprotein i positivity in the diagnosis of the antiphospholipid syndrome. Arthritis and Rheumatism, 65(12), 3186-3193. https://doi.org/10.1002/art.38131