{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T08:10:44Z","timestamp":1793175044937,"version":"4.5.0"},"reference-count":15,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T00:00:00Z","timestamp":1644710400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01\u2010AI\u2010101981"],"award-info":[{"award-number":["U01\u2010AI\u2010101981"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32\u2010AI\u2010074491"],"award-info":[{"award-number":["T32\u2010AI\u2010074491"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01\u2010AI\u201024727"],"award-info":[{"award-number":["R01\u2010AI\u201024727"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30\u2010A\u2010073750"],"award-info":[{"award-number":["P30\u2010A\u2010073750"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UM1\u2010AI\u2010144292"],"award-info":[{"award-number":["UM1\u2010AI\u2010144292"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01BX001834"],"award-info":[{"award-number":["I01BX001834"]}],"id":[{"id":"10.13039\/100000738","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":[[2022,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Patients with established rheumatoid arthritis (RA) demonstrate altered immune responses to Epstein\u2010Barr virus (EBV), but the presence and roles of EBV have not been fully explored during the pre\u2013clinical disease period. This study was undertaken to determine if EBV infection, as evidenced by an altered anti\u2010EBV antibody response, either plays an important role in driving the development of RA or is a result of expanded RA\u2010related autoimmunity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 83 subjects with RA according to the 1987 American College of Rheumatology (ACR) criteria and 83 age\u2010, sex\u2010, and race\u2010matched control subjects without RA were included in our study. We collected sera from RA subjects and matched controls during the pre\u2013RA and post\u2013RA diagnosis periods and tested the sera for the presence of 5 anti\u2010EBV antibodies (anti\u2013EBV nuclear antigen 1 IgG isotype, anti\u2013viral capsid antigen [anti\u2010VCA] isotypes IgG and IgA, and anti\u2013early antigen [EA] isotypes IgG and IgA), 7 RA\u2010related autoantibodies (rheumatoid factor measured by nephelometry [RF\u2010Neph] as well as isotype\u2010specific IgA\u2010RF, IgM\u2010RF, and IgG\u2010RF, and anti\u2013cyclic citrullinated peptide [anti\u2010CCP] antibodies, including anti\u2010CCP2, anti\u2010CCP3, and anti\u2010CCP3.1), 22 cytokines\/chemokines, 36 individual anti\u2013citrullinated protein antibodies, and IgG\u2013cytomegalovirus (CMV) antibodies. Random forest classification, mixed modeling, and joint mixed modeling were used to determine differences in anti\u2010EBV antibody levels between RA subjects and controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Random forest analysis identified the presence of preclinical EBV antibodies in the serum that differentiated RA subjects from controls without RA. Specifically, IgG\u2010EA antibody levels were higher in RA subjects (mean\u2009\u00b1\u2009SD 0.82\u2009\u00b1\u20090.72 international standardized ratio [ISR]) compared to controls (mean\u2009\u00b1\u2009SD 0.49\u2009\u00b1\u20090.28 ISR). In subjects with RA, elevated serum IgG\u2010EA levels in the preclinical period before seroconversion were significantly correlated with increased serum IgM\u2010RF levels (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.007), whereas this correlation was not seen in control subjects without RA (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.15). IgG\u2010CMV antibody levels did not differ between groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Subjects whose serum IgG\u2010EA antibody levels are elevated in the preclinical period will eventually develop RA, which suggests that EBV reactivation cycles are increased during the preclinical period of RA. A combination of RF and EBV reactivation may play an important role in the development of RA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.41994","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T20:50:34Z","timestamp":1633380634000},"page":"597-603","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Antibody Responses to\n                    <scp>Epstein\u2010Barr<\/scp>\n                    Virus in the Preclinical Period of Rheumatoid Arthritis Suggest the Presence of Increased Viral Reactivation Cycles"],"prefix":"10.1002","volume":"74","author":[{"given":"Sabrina","family":"Fechtner","sequence":"first","affiliation":[{"name":"University of Colorado  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Berens","sequence":"additional","affiliation":[{"name":"University of Colorado  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Bemis","sequence":"additional","affiliation":[{"name":"Colorado School of Public Health  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel L.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Colorado School of Public Health  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla J.","family":"Guthridge","sequence":"additional","affiliation":[{"name":"University of Oklahoma Health Sciences Center  Edmond"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nichole E.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Colorado School of Public Health  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Kristen","family":"Demoruelle","sequence":"additional","affiliation":[{"name":"University of Colorado  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Harley","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Medical Center  Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jess D.","family":"Edison","sequence":"additional","affiliation":[{"name":"Walter Reed National Military Medical Center  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A.","family":"Norris","sequence":"additional","affiliation":[{"name":"Colorado School of Public Health  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William H.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine, Stanford, California, and VA Palo Alto Health Care System  Palo Alto California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D.","family":"Deane","sequence":"additional","affiliation":[{"name":"University of Colorado  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith A.","family":"James","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. Michael","family":"Holers","sequence":"additional","affiliation":[{"name":"University of Colorado  Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,13]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-020-04731-0"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200990"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27638"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035296"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.20018"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.11223"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01857094"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202352"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.18.9918-9923.2004"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2011.04378.x"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-1031-0"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0755-6"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2007.076679"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.57.1.63"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.3109\/08916934.2011.616557"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41994","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.41994","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.41994","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T19:35:08Z","timestamp":1759952108000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.41994"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,13]]},"references-count":15,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1002\/art.41994"],"URL":"https:\/\/doi.org\/10.1002\/art.41994","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,13]]},"assertion":[{"value":"2021-03-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}