{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:31:29Z","timestamp":1791412289877,"version":"4.3.3"},"reference-count":22,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T00:00:00Z","timestamp":1689033600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["programma translationeel onderzoek"],"award-info":[{"award-number":["programma translationeel onderzoek"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018286","name":"Dutch Arthritis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018286","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":[[2023,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The natural trajectory of clinical arthritis progression at the tissue level remains elusive. We hypothesized that subclinical inflammation in different joint tissues (synovitis, tenosynovitis, osteitis) increases in a distinct temporal order in patients with clinically suspect arthralgia (CSA) who develop rheumatoid arthritis (RA) and subsides in a different sequence when CSA spontaneously resolves.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied 185 serial magnetic resonance images (MRIs) from CSA patients with subclinical joint inflammation from the placebo arm of the TREAT EARLIER trial: 52 MRIs from 21 RA progressors (MRIs conducted at 1 year before, at 4 months before, and upon RA development), and 133 MRIs from 35 patients with spontaneous resolution of pain (MRIs conducted at baseline and at 4, 12, and 24 months). MRIs were scored for osteitis, synovitis, and tenosynovitis. We used cross\u2010lagged models to evaluate 2 types of time patterns between pairs of inflamed tissues: a simultaneous pattern (coinciding changes) and a subsequent pattern (inflammatory changes in 1 tissue preceding changes in another tissue).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In patients who developed RA, synovitis, tenosynovitis, and osteitis increased simultaneously. Increasing osteitis occurred in the final 4 months before RA diagnosis, following incremental tenosynovitis and synovitis changes during the 1 year to 4 months before diagnosis (<jats:italic>P<\/jats:italic> &lt;\u20090.01). In anti\u2013citrullinated protein antibody (ACPA)\u2010positive and ACPA\u2010negative patients who progressed to RA, osteitis increased just before RA development. In patients with pain resolution, simultaneous decreases in synovitis, tenosynovitis, and osteitis occurred, with tenosynovitis decreasing in the first 4 months after CSA onset preceding decreasing synovitis and osteitis during 4\u201312 months (<jats:italic>P<\/jats:italic> =\u20090.02 and <jats:italic>P<\/jats:italic> &lt;\u20090.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified natural sequences of subclinical inflammation in different joint tissues, which deepens our understanding of clinical arthritis and RA development. During RA progression, increasing osteitis followed previous increases in tenosynovitis and synovitis. During pain resolution, tenosynovitis decreased first, followed by decreasing synovitis and osteitis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42527","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T17:18:45Z","timestamp":1682356725000},"page":"1512-1521","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Natural Sequence in Which Subclinical Inflamed Joint Tissues Subside or Progress to Rheumatoid Arthritis: A Study of Serial <scp>MRIs<\/scp> in the <scp>TREAT EARLIER<\/scp> Trial"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1654-1031","authenticated-orcid":false,"given":"Doortje I.","family":"Krijbolder","sequence":"first","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7332-8072","authenticated-orcid":false,"given":"Xanthe M. E.","family":"Matthijssen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5161-6791","authenticated-orcid":false,"given":"Bastiaan T.","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna W.","family":"van Steenbergen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie M.","family":"Boeters","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemiek","family":"Willemze","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology Maasstad Hospital  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne A.","family":"Schouffoer","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Leiden University Medical Center, Leiden, and Department of Rheumatology Haga Hospital  The Hague The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette H. M.","family":"van der Helm\u2010van Mil","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Leiden University Medical Center, Leiden, and Department of Rheumatology Erasmus Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.138461"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2019.102400"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208138"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-020-2102-9"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39749"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex235"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-018-1756-z"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01193-X"},{"key":"e_1_2_7_10_1","first-page":"1674","article-title":"Assessment of pain in rheumatoid arthritis: minimal clinically significant difference, predictors, and the effect of anti\u2010tumor necrosis factor therapy","volume":"34","author":"Wolfe F","year":"2007","journal-title":"J Rheumatol"},{"key":"e_1_2_7_11_1","first-page":"1385","article-title":"OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging Studies: core set of MRI acquisitions, joint pathology definitions, and the OMERACT RA\u2010MRI scoring system","volume":"30","author":"Ostergaard M","year":"2003","journal-title":"J Rheumatol"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.068361"},{"key":"e_1_2_7_13_1","first-page":"265","volume-title":"Handbook of developmental research methods","author":"Selig J","year":"2012"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1207\/S15328007SEM0803_5"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew270"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22313"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-211325"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216350"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.15150025"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00256-022-04238-8"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.105767"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212763"},{"key":"e_1_2_7_23_1","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1136\/annrheumdis-2020-eular.1697","article-title":"FRI0542 obtaining high positive predictive values for the development of clinically apparent arthritis in patients presenting with clinically suspect arthralgia; is it feasible?","volume":"79","author":"Matthijssen X","year":"2020","journal-title":"Ann Rheum Dis"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.42527","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T12:56:54Z","timestamp":1759928214000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.42527"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,11]]},"references-count":22,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1002\/art.42527"],"URL":"https:\/\/doi.org\/10.1002\/art.42527","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,11]]},"assertion":[{"value":"2023-03-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}