This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti–neutrophil extracellular trap (anti‐NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody–positive patients who did not have lupus.

Anti‐NET IgG/IgM levels were measured in serum samples from 389 aPL‐positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform.

We found elevated levels of anti‐NET IgG and/or IgM in 45% of the aPL‐positive patients. High anti‐NET antibody levels are associated with more circulating myeloperoxidase (MPO)–DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti‐NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti‐NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti‐NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti‐NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO–DNA complexes, and nucleosomes. Anti‐NET IgM positivity was associated with autoantibodies targeting single‐stranded DNA, double‐stranded DNA, and proliferating cell nuclear antigen.

These data reveal high levels of anti‐NET antibodies in 45% of aPL‐positive patients, where they potentially activate the complement cascade. While anti‐NET IgM may especially recognize DNA in NETs, anti‐NET IgG species appear to be more likely to target NET‐associated protein antigens.