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This study was undertaken to investigate the role of neutrophils in systemic\u2010onset juvenile idiopathic arthritis (<jats:styled-content style=\"fixed-case\">JIA<\/jats:styled-content>), a prototypical multifactorial autoinflammatory disease that is characterized by arthritis and severe systemic inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fifty patients with systemic\u2010onset <jats:styled-content style=\"fixed-case\">JIA<\/jats:styled-content> who were receiving treatment with recombinant interleukin\u20101 receptor antagonist (<jats:styled-content style=\"fixed-case\">rIL<\/jats:styled-content>\u20101Ra; anakinra) were analyzed at disease onset and during remission. <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> sequencing was performed on fluorescence\u2010activated cell\u2013sorted neutrophils from 3 patients with active systemic\u2010onset <jats:styled-content style=\"fixed-case\">JIA<\/jats:styled-content> and 3 healthy controls. Expression of activation markers, apoptosis, production of reactive oxygen species (<jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content>), and degranulation of secretory vesicles from neutrophils were assessed by flow cytometry in serum samples from 17 patients with systemic\u2010onset <jats:styled-content style=\"fixed-case\">JIA<\/jats:styled-content> and 15 healthy controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Neutrophil counts were markedly increased at disease onset, and this correlated with the levels of inflammatory mediators. The neutrophil counts normalized within days after the initiation of <jats:styled-content style=\"fixed-case\">rIL<\/jats:styled-content>\u20101Ra therapy. <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010sequencing analysis revealed a substantial up\u2010regulation of inflammatory processes in neutrophils from patients with active systemic\u2010onset <jats:styled-content style=\"fixed-case\">JIA<\/jats:styled-content>, significantly overlapping with the transcriptome of sepsis. Correspondingly, neutrophils from patients with active systemic\u2010onset <jats:styled-content style=\"fixed-case\">JIA<\/jats:styled-content> displayed a primed phenotype that was characterized by increased <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content> production, <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>62L shedding, and secretory vesicle degranulation, which was reversed by <jats:styled-content style=\"fixed-case\">rIL<\/jats:styled-content>\u20101Ra treatment in patients who had achieved clinical remission. Patients with a short disease duration had high neutrophil counts, more immature neutrophils, and a complete response to <jats:styled-content style=\"fixed-case\">rIL<\/jats:styled-content>\u20101Ra, whereas patients with symptoms for &gt;1 month had normal neutrophil counts and an unsatisfactory response to <jats:styled-content style=\"fixed-case\">rIL<\/jats:styled-content>\u20101Ra. In vitro, <jats:styled-content style=\"fixed-case\">rIL<\/jats:styled-content>\u20101Ra antagonized the priming effect of <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 on neutrophils from healthy subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results strongly support the notion that neutrophils play an important role in systemic\u2010onset <jats:styled-content style=\"fixed-case\">JIA<\/jats:styled-content>, especially in the early inflammatory phase of the disease. The findings also demonstrate that neutrophil numbers and the inflammatory activity of systemic\u2010onset <jats:styled-content style=\"fixed-case\">JIA<\/jats:styled-content> are both susceptible to <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101 blockade.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40442","type":"journal-article","created":{"date-parts":[[2018,2,9]],"date-time":"2018-02-09T18:46:39Z","timestamp":1518201999000},"page":"943-956","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Reversal of Sepsis\u2010Like Features of Neutrophils by Interleukin\u20101 Blockade in Patients With Systemic\u2010Onset Juvenile Idiopathic Arthritis"],"prefix":"10.1002","volume":"70","author":[{"given":"Nienke M.","family":"ter Haar","sequence":"first","affiliation":[{"name":"University Medical Center Utrecht Wilhelmina Children's Hospital and Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Tak","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht and Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Mokry","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Wilhelmina Children's Hospital and Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne C.","family":"Scholman","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht and Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny M.","family":"Meerding","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht and Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilco","family":"de Jager","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Wilhelmina Children's Hospital and Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anouk","family":"Verwoerd","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht and Utrecht University Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Foell","sequence":"additional","affiliation":[{"name":"University of Muenster Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Vogl","sequence":"additional","affiliation":[{"name":"University of Muenster Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Roth","sequence":"additional","affiliation":[{"name":"University of Muenster Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter H. 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