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This study sought to explore individual antibody responses to citrullinated and noncitrullinated proteins\/peptides in the sputum and associations with neutrophil extracellular traps (<jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s) in subjects at risk for the future development of <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Serum and sputum samples were obtained from 41 <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>\u2010free subjects who were considered at risk for the development of <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> based on familial or serologic risk factors, from 20 subjects classified as having <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>, and from 22 healthy control subjects. Samples were evaluated using a bead\u2010based array for IgG reactivity to 29 citrullinated proteins\/peptides and 21 noncitrullinated proteins\/peptides. Cutoff levels for antibody positivity were established in a separate control group. <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> levels in the sputum were measured using sandwich enzyme\u2010linked immunosorbent assays that quantitate <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>\u2013myeloperoxidase and <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>\u2013neutrophil elastase complexes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In at\u2010risk subjects, antibody responses to the citrullinated forms of fibrinogen, apolipoprotein E, and fibronectin were highly prevalent. The most citrulline\u2010specific antibodies in the sputum of at\u2010risk subjects were those to fibrinogen, vimentin, and peptides of fibrinogen A and apolipoprotein A1. Patterns of sputum autoantibody positivity differed between at\u2010risk subjects and subjects with <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>. In at\u2010risk subjects, increasing sputum <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> levels significantly correlated with several citrullinated and some noncitrullinated antibody reactivities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest that sputum antibody reactivity to particular citrullinated and noncitrullinated proteins\/peptides is specific for <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> and for subjects at risk of <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>, and the association of these proteins\/peptides with <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s may be a key feature of early <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>\u2013related autoimmunity in the lung. These results further support the hypothesis that the lung plays a role in early <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>\u2013related autoimmunity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40401","type":"journal-article","created":{"date-parts":[[2017,12,20]],"date-time":"2017-12-20T23:30:21Z","timestamp":1513812621000},"page":"516-527","source":"Crossref","is-referenced-by-count":78,"title":["Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis"],"prefix":"10.1002","volume":"70","author":[{"given":"M. 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