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The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA\u2010LD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Eighteen patients with SJIA\u2010LD were identified. Radiographic findings included diffuse ground\u2010glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA\u2010LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, <jats:italic>P<\/jats:italic> = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, <jats:italic>P<\/jats:italic> &lt; 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, <jats:italic>P<\/jats:italic> &lt; 0.001), and had higher serum levels of interleukin\u201018 (IL\u201018) (median 27,612 pg\/ml versus 5,413 pg\/ml; <jats:italic>P<\/jats:italic> = 0.047). Patients with SJIA\u2010LD lacked genetic, serologic, or functional evidence of granulocyte\u2013macrophage colony\u2010stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA\u2010LD rarely demonstrated proteinaceous material and had less lipid\u2010laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA\u2010LD versus 66.1% in patients with primary PAP; <jats:italic>P<\/jats:italic> &lt; 0.001). BAL fluid from patients with SJIA\u2010LD contained elevated levels of IL\u201018 and the interferon\u2010\u03b3\u2013induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA\u2010LD identified up\u2010regulated type II interferon and T cell activation networks. This signature was also present in SJIA\u2010LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA\u2010LD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41073","type":"journal-article","created":{"date-parts":[[2019,8,5]],"date-time":"2019-08-05T03:48:25Z","timestamp":1564976905000},"page":"1943-1954","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":210,"title":["Systemic Juvenile Idiopathic Arthritis\u2013Associated Lung Disease: Characterization and Risk Factors"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5923-7051","authenticated-orcid":false,"given":"Grant S.","family":"Schulert","sequence":"first","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shima","family":"Yasin","sequence":"additional","affiliation":[{"name":"Cincinnati 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