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We sought to characterize unique peripheral blood biomarker signatures in RA that could improve RA\u2010ILD discrimination beyond clinical and genetic risk factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed a cross\u2010sectional study of participants in the Veterans Affairs Rheumatoid Arthritis Registry. ILD was validated through systematic record review. Autoantibodies (n = 14), proinflammatory cytokines\/chemokines (n = 36), adipokines (n = 3), alarmins (n = 3), and matrix metalloproteinases (n = 9) were measured from banked serum or plasma. <jats:italic>MUC5B<\/jats:italic> rs35705950 genotyping was obtained via microarray. Principal component (PC) analysis was performed to derive unique biomarker signatures. Logistic regression was used to compare models predicting RA\u2010ILD presence using combinations of clinical, peripheral biomarker, and genetic variables.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 2,001 participants with RA (88.7% male, mean age 63.7 years), 121 (6.4%) had RA\u2010ILD. A total of 15 PCs were identified, with 8 significantly associated with RA\u2010ILD after adjusting for clinical factors. These eight included biomarker themes of innate and allergic responses, autoantibodies (anti\u2013cyclic citrullinated peptide, rheumatoid factor, anti\u2013malondialdehyde\u2010acetaldehyde adduct), adipokines, alarmins, tissue remodeling, and neutrophil chemotaxis. Models with PCs (area under the receiver operating characteristic curve [AUC] 0.739) and PCs with <jats:italic>MUC5B<\/jats:italic> (AUC 0.751) outperformed clinical risk factors alone (AUC 0.630; <jats:italic>P<\/jats:italic> &lt; 0.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Peripheral biomarker signatures are associated with RA\u2010ILD and improve RA\u2010ILD identification beyond clinical risk factors. In addition to demonstrating the potential for peripheral biomarkers to aid RA\u2010ILD risk stratification, these findings suggest diverse pathways are involved in RA\u2010ILD pathogenesis.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art43149-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.43149","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T21:55:46Z","timestamp":1741643746000},"page":"971-980","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Peripheral Biomarker Signatures in Rheumatoid Arthritis\u2013Associated Interstitial Lung Disease"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8816-7782","authenticated-orcid":false,"given":"Austin M.","family":"Wheeler","sequence":"first","affiliation":[{"name":"VA Nebraska\u2010Western Iowa Health Care System and University of Nebraska Medical Center  Omaha"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua F.","family":"Baker","sequence":"additional","affiliation":[{"name":"University of Pennsylvania and Corporal Michael J. Crescenz VA Medical Center  Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0194-7562","authenticated-orcid":false,"suffix":"IV","given":"Thomas R.","family":"Riley","sequence":"additional","affiliation":[{"name":"University of Pennsylvania and Corporal Michael J. 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