{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:01:45Z","timestamp":1792620105640,"version":"4.5.0"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,12,3]],"date-time":"2019-12-03T00:00:00Z","timestamp":1575331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001218","name":"Lupus Research Institute","doi-asserted-by":"publisher","award":["519414"],"award-info":[{"award-number":["519414"]}],"id":[{"id":"10.13039\/100001218","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013382","name":"Institute of Translational Health Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013382","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Exaggerated neutrophil activation and formation of neutrophil extracellular traps (<jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s) are linked to inflammation and autoimmunity, including rheumatoid arthritis (<jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>). However, whether <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s are present in the circulation of <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients and contribute to inflammation and disease progression has not been carefully addressed. We undertook this study to assess markers of neutrophil activation and <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> formation in plasma samples, investigating whether they add clinical value in improving the determination of prognosis and monitoring in <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Markers of neutrophil activation (calprotectin) and cell death (<jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s) were analyzed, using enzyme\u2010linked immunosorbent assay, in serum and plasma obtained from patients in 3 cross\u2010sectional <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> cohorts and sex\u2010matched healthy controls. A longitudinal inception cohort (n = 247), seen for a median follow\u2010up of 8 years, was used for predictive analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Markers of neutrophil activation and cell death were increased in <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients compared to healthy individuals (<jats:italic>P<\/jats:italic> &lt; 0.0001). Calprotectin levels correlated with the Clinical Disease Activity Index (r = 0.53, <jats:italic>P<\/jats:italic> &lt; 0.0001) and could be used to distinguish between patients with disease in remission and those with active disease, an observation not seen when examining C\u2010reactive protein levels. A biomarker panel consisting of anti\u2013citrullinated protein antibody and calprotectin could predict erosive disease (odds ratio [<jats:styled-content style=\"fixed-case\">OR<\/jats:styled-content>] 7.5, <jats:italic>P<\/jats:italic> &lt; 0.0001) and joint space narrowing (<jats:styled-content style=\"fixed-case\">OR<\/jats:styled-content> 4.9, <jats:italic>P<\/jats:italic> = 0.001). <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content> levels were associated with markers of inflammation (<jats:italic>P<\/jats:italic> = 0.0002). Furthermore, <jats:styled-content style=\"fixed-case\">NET<\/jats:styled-content>s and a \u201cneutrophil activation signature\u201d biomarker panel had good predictive value in identifying patients who were developing extraarticular nodules (<jats:styled-content style=\"fixed-case\">OR<\/jats:styled-content> 5.6, <jats:italic>P<\/jats:italic> = 0.006).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Neutrophils undergo marked activation and cell death in <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>. Neutrophil biomarkers can provide added clinical value in the monitoring and prognosis of <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients and may allow for early preventive treatment intervention.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41062","type":"journal-article","created":{"date-parts":[[2019,7,29]],"date-time":"2019-07-29T01:43:36Z","timestamp":1564364616000},"page":"47-56","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["A Neutrophil Activation Biomarker Panel in Prognosis and Monitoring of Patients With Rheumatoid Arthritis"],"prefix":"10.1002","volume":"72","author":[{"given":"Mary","family":"Bach","sequence":"first","affiliation":[{"name":"University of Washington  Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeonghun","family":"Moon","sequence":"additional","affiliation":[{"name":"The Polyclinic  Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Moore","sequence":"additional","affiliation":[{"name":"University of Washington  Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Pan","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Research Center  Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Lee","family":"Nelson","sequence":"additional","affiliation":[{"name":"University of Washington and Fred Hutchinson Cancer Research Center  Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6171-1952","authenticated-orcid":false,"given":"Christian","family":"Lood","sequence":"additional","affiliation":[{"name":"University of Washington  Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201719"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4027"},{"key":"e_1_2_6_4_1","first-page":"638","article-title":"Neutrophil extracellular traps as a potential source of autoantigen in cocaine\u2010associated autoimmunity","volume":"56","author":"Lood C","year":"2017","journal-title":"Rheumatology (Oxford)"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3399"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1785"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1841"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3001201"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100450"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005580"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2014.80"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007515"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3006869"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208356"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.33432"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202765"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4579"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aag3358"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646542"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3829"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a123257"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.140628"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.103739"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0192365"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.04.007"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar1740"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4264"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39656"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1080\/03009740701874451"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1177\/0961203316655208"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0764-5"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0183420"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102404"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20161512"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/728610"},{"key":"e_1_2_6_36_1","first-page":"81","article-title":"An overview of the extraarticular involvement in rheumatoid arthritis and its management","volume":"8","author":"Das S","year":"2017","journal-title":"J Pharmacol Pharmacother"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/429878"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/828354"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3314"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)98862-9"},{"key":"e_1_2_6_41_1","first-page":"21","article-title":"Fecal calprotectin in inflammatory bowel disease","volume":"9","author":"Walsham NE","year":"2016","journal-title":"Clin Exp Gastroenterol"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.3109\/03009748809102976"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.3.1601"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502353"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909927107"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-016-0448-8"}],"container-title":["Arthritis &amp; 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