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Higher plasma concentrations of microbial transfer RNA (tRNA)\u2010derived RNA\u20101 (tDR\u20101) were previously associated with lower rheumatoid arthritis (RA) disease activity. This study examined whether tDR\u20101 concentrations differ in anticyclic citrullinated peptide\u20103 positive (CCP3+) at\u2010risk individuals (ARI), based on who later develops clinical RA, or discriminate later conversion status beyond established risk factors and if tDR\u20101 has in vitro effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Plasma tDR\u20101 concentrations were measured in CCP3+ ARI. Group differences in log\u2010transformed tDR\u20101 were assessed by lognormal Welch's\n                      <jats:italic>t<\/jats:italic>\n                      \u2010test and logistic regression. Area under the receiver operating characteristic curve (AUROC) was used to evaluate discriminatory ability. Human THP\u20101 monocyte\u2010derived macrophages were treated with tDR\u20101 versus scramble control, and gene expression was assessed by NanoString Immunology panel.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 60 CCP3+ ARI, 25 later developed clinical RA (\u201cconverters\u201d) over a mean of 2.2 years, whereas 35 did not (\u201cnonconverters\u201d) over a mean of 5.3 years. Baseline plasma tDR\u20101 concentrations were significantly higher (5.4\u2010fold) in nonconverters versus converters, even after adjustment for additional RA risk factors (shared epitope, smoking, rheumatoid factor) (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a05.1 \u00d7 10\n                      <jats:sup>\u22124<\/jats:sup>\n                      ). The AUROC improved from 0.722 for these risk factors alone to 0.902 with the addition of tDR\u20101 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.003). In vitro, tDR\u20101 significantly down\u2010regulated many type 1 interferon (IFN) response genes in THP\u20101 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Higher plasma tDR\u20101 concentrations were associated with nonconversion to clinical RA in CCP3+ ARI. tDR\u20101's reducing type 1 IFN response gene expression suggests a potential mechanism by which microbes and tDR\u20101 could affect RA development.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70264-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70264","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:55:01Z","timestamp":1782190501000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Increased Plasma Microbial\n                    <scp>tDR<\/scp>\n                    \u20101 in At\u2010Risk Individuals Is Associated With Decreased Conversion to Clinical Rheumatoid Arthritis and Reduces an In Vitro Macrophage Type 1 Interferon Response"],"prefix":"10.1002","author":[{"given":"Anastasiia","family":"Phothisane","sequence":"first","affiliation":[{"name":"Vanderbilt University Medical Center  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tulsi K.","family":"Joishy","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Ramirez\u2010Becerra","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Wu","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center  Nashville Tennessee"},{"name":"University of Virginia  Charlottesville"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5851-7246","authenticated-orcid":false,"given":"Jennifer","family":"Seifert","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie L.","family":"Feser","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill M.","family":"Norris","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2563-5155","authenticated-orcid":false,"given":"M. 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