{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T07:34:58Z","timestamp":1790494498069,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2019,9,2]],"date-time":"2019-09-02T00:00:00Z","timestamp":1567382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP 77700"],"award-info":[{"award-number":["MOP 77700"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011102","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["1151422"],"award-info":[{"award-number":["1151422"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011102","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["777357"],"award-info":[{"award-number":["777357"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["435000033"],"award-info":[{"award-number":["435000033"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["435002030"],"award-info":[{"award-number":["435002030"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["90714509"],"award-info":[{"award-number":["90714509"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["91214031"],"award-info":[{"award-number":["91214031"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["91617107"],"award-info":[{"award-number":["91617107"]}],"id":[{"id":"10.13039\/501100003246","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":[[2019,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Anti\u2013citrullinated protein antibodies (ACPAs) are disease\u2010specific biomarkers in rheumatoid arthritis (RA). More than 90% of IgG ACPAs harbor <jats:italic>N<\/jats:italic>\u2010linked glycans in the antibody variable (V) domain. The corresponding <jats:italic>N<\/jats:italic>\u2010glycosylation sites in ACPA V\u2010region sequences result from somatic hypermutation, a T cell\u2013dependent process. As ample evidence indicates that T cells drive the maturation of the ACPA response prior to arthritis onset, we undertook this study to investigate whether the presence of glycans in IgG ACPA V domains predicts the transition from predisease autoimmunity to overt RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed 2 independent sets of serum samples obtained from 126 ACPA\u2010positive first\u2010degree relatives (FDRs) of RA patients. Both sets originated from an Indigenous North American population and comprised cross\u2010sectional and longitudinal samples of individuals who did or did not develop inflammatory arthritis. Serum IgG ACPAs were affinity\u2010purified and subjected to ultra high\u2010performance liquid chromatography\u2013based glycan analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In both data sets, FDR\u2010derived IgG ACPA displayed markedly lower levels of V domain glycans (&lt;50%) compared to IgG ACPA from RA patients. Notably, FDRs who later developed RA showed extensive V\u2010domain glycosylation before the onset of arthritis. Moreover, IgG ACPA V\u2010domain glycosylation was strongly associated with future development of RA (hazard ratio 6.07 [95% confidence interval 1.46\u201325.2]; <jats:italic>P<\/jats:italic> = 0.013).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Extensive glycosylation of the IgG ACPA V domain is present in a subset of predisposed FDRs of Indigenous North American RA patients. The presence of this feature substantially increases the risk of RA development. Based on these findings, we propose that glycosylation of the IgG ACPA V domain represents a predictive marker for RA development in ACPA\u2010positive individuals and may serve to better target prevention measures.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40920","type":"journal-article","created":{"date-parts":[[2019,5,8]],"date-time":"2019-05-08T10:06:44Z","timestamp":1557310004000},"page":"1626-1633","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["<i>N<\/i>\u2010Linked Glycans in the Variable Domain of IgG Anti\u2013Citrullinated Protein Antibodies Predict the Development of Rheumatoid Arthritis"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1622-8483","authenticated-orcid":false,"given":"Lise","family":"Hafkenscheid","sequence":"first","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"de Moel","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Smolik","sequence":"additional","affiliation":[{"name":"University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3313-9765","authenticated-orcid":false,"given":"Stacey","family":"Tanner","sequence":"additional","affiliation":[{"name":"University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Meng","sequence":"additional","affiliation":[{"name":"University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bas C.","family":"Jansen","sequence":"additional","affiliation":[{"name":"Ludger Ltd.  Oxfordshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0985-7903","authenticated-orcid":false,"given":"Albert","family":"Bondt","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Wuhrer","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom W. J.","family":"Huizinga","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene E. M.","family":"Toes","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hani","family":"El\u2010Gabalawy","sequence":"additional","affiliation":[{"name":"University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5700-5617","authenticated-orcid":false,"given":"Hans U.","family":"Scherer","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,2]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23914"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0049-0172(99)80003-1"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.080855"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.091452"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.20018"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2011.204"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2017.09.001"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.59"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.124"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/36.6.630"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-203947"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M116.062919"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206598"},{"key":"e_1_2_8_15_1","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1136\/annrheumdis-2017-212052","article-title":"B\u2010cell receptor sequencing of anti\u2010citrullinated protein antibody (ACPA) IgG\u2010expressing B cells indicates a selective advantage for the introduction of N\u2010glycosylation sites during somatic hypermutation","volume":"77","author":"Vergroesen RD","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.121016"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0665-7"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2013.07.104"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep34001"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0200280"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502136"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60826-4"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2017.185"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-012-0275-1"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2017-000479"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex340"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40062"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7681"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1076"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.40920","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.40920","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.40920","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.40920","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T20:18:34Z","timestamp":1759954714000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.40920"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,2]]},"references-count":28,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2019,10]]}},"alternative-id":["10.1002\/art.40920"],"URL":"https:\/\/doi.org\/10.1002\/art.40920","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,2]]},"assertion":[{"value":"2018-11-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-04-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}