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We undertook this study to understand associations between neutrophil extracellular trap (NET) formation in the lung and local ACPA generation in subjects at risk of developing RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Induced sputum was collected from 49 subjects at risk of developing RA, 12 patients with RA, and 18 controls. Sputum neutrophils were tested for ex vivo NET formation, and sputum\u2010induced NET formation of control neutrophils was measured using immunofluorescence imaging. Sputum macrophages were tested for ex vivo endocytosis of apoptotic and opsonized cells. Levels of ACPA, NET remnants, and inflammatory proteins were quantified in sputum supernatant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Spontaneous citrullinated histone H3 (Cit\u2010H3)\u2013expressing NET formation was higher in sputum neutrophils from at\u2010risk subjects and RA patients compared to controls (median 12%, 22%, and 0%, respectively; <jats:italic>P<\/jats:italic> &lt; 0.01). In at\u2010risk subjects, sputum IgA ACPA correlated with the percentage of neutrophils that underwent Cit\u2010H3+ NET formation (r = 0.49, <jats:italic>P<\/jats:italic> = 0.002) and levels of Cit\u2010H3+ NET remnants (r = 0.70, <jats:italic>P<\/jats:italic> &lt; 0.001). Reduced endocytic capacity of sputum macrophages was found in at\u2010risk subjects and RA patients compared to controls. Using a mediation model, we found that sputum inflammatory proteins were associated with sputum IgA ACPA through a pathway mediated by Cit\u2010H3+ NET remnants. Sputum\u2010induced Cit\u2010H3+ NET formation also correlated with sputum levels of interleukin\u20101\u03b2 (IL\u20101\u03b2), IL\u20106, and tumor necrosis factor in at\u2010risk subjects, suggesting a causal relationship.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data support a potential mechanism for mucosal ACPA generation in subjects at risk of developing RA, whereby inflammation leads to increased citrullinated protein\u2013expressing NETs that promote local ACPA generation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41948","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T03:11:59Z","timestamp":1628478719000},"page":"38-48","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Association of Sputum Neutrophil Extracellular Trap Subsets With IgA Anti\u2013Citrullinated Protein Antibodies in Subjects at Risk for Rheumatoid Arthritis"],"prefix":"10.1002","volume":"74","author":[{"given":"Yuko","family":"Okamoto","sequence":"first","affiliation":[{"name":"University of Colorado, Aurora, and Tokyo Women\u2019s Medical University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Devoe","sequence":"additional","affiliation":[{"name":"University of Colorado  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickie","family":"Seto","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Minarchick","sequence":"additional","affiliation":[{"name":"University of Colorado  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