{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T20:21:30Z","timestamp":1776284490140,"version":"3.50.1"},"reference-count":34,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T00:00:00Z","timestamp":1664409600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004628","name":"MedImmune","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004628","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01\u2010AR\u2010050026"],"award-info":[{"award-number":["R01\u2010AR\u2010050026"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01\u2010AR\u2010069569"],"award-info":[{"award-number":["R01\u2010AR\u2010069569"]}],"id":[{"id":"10.13039\/100000069","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":[[2022,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The study of autoantibody isotypes in autoimmune diseases is useful for identifying clinically relevant endotypes. This study was undertaken to study the prevalence and clinical significance of different isotypes and IgG subclasses of anti\u2013peptidylarginine deiminase 4 (anti\u2010PAD4) autoantibodies in individuals with rheumatoid arthritis (RA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In 196 RA subjects and 64 healthy controls, anti\u2010PAD4 antibody types were determined using enzyme\u2010linked immunosorbent assay. We investigated associations between anti\u2010PAD4 antibodies and clinical outcomes, and relevant features were confirmed in an independent RA cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Anti\u2010PAD4 IgG1, anti\u2010PAD4 IgG2, anti\u2010PAD4 IgG3, anti\u2010PAD4 IgG4, anti\u2010PAD4 IgA, and anti\u2010PAD4 IgE antibodies were more frequent in RA patients than healthy controls (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). Anti\u2010PAD4 IgG1, anti\u2010PAD4 IgG3, and anti\u2010PAD4 IgE were associated with distinct clinical features. Anti\u2010PAD4 IgG1 was predictive of progressive radiographic joint damage (odds ratio [OR] 4.88, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.005), especially in RA patients without baseline joint damage (40% versus 0%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.003) or in those negative for anti\u2013cyclic citrullinated peptide and\/or rheumatoid factor (OR 32; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.009). IgG1 was also associated with higher levels of C\u2010reactive protein (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.006) and interleukin\u20106 (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.021). RA patients with anti\u2010PAD4 IgG3 had higher baseline joint damage scores (median Sharp\/van der Heijde score 13 versus 7, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.046), while those with anti\u2010PAD4 IgE had higher Disease Activity Score in 28 joints (median 4.0 versus 3.5, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.025), more frequent rheumatoid nodules (31% versus 16%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.025), and more frequent interstitial lung disease (ground\u2010glass opacification) (24% versus 9%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.014). Anti\u2010PAD4 IgG1 antibody associations with joint damage were corroborated in an independent RA cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Anti\u2010PAD4 IgG1, anti\u2010PAD4 IgG3, and anti\u2010PAD4 IgE antibodies identify discrete disease subsets in RA, suggesting that heavy chain usage drives distinct effector mechanisms of anti\u2010PAD4 antibodies in RA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42262","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T12:28:10Z","timestamp":1654691290000},"page":"1746-1754","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Heavy Chain Constant Region Usage in Antibodies to Peptidylarginine Deiminase 4 as a Marker of Disease Subsets in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"74","author":[{"given":"E.","family":"G\u00f3mez\u2010Ba\u00f1uelos","sequence":"first","affiliation":[{"name":"Division of Rheumatology Johns Hopkins University School of Medicine  Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Johns Hopkins University School of Medicine  Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Johns Hopkins University School of Medicine  Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9246-6200","authenticated-orcid":false,"given":"M. I.","family":"Danila","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology and Rheumatology University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"S. L.","family":"Bridges","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology and Rheumatology University of Alabama at Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8792-0402","authenticated-orcid":false,"given":"J. T.","family":"Giles","sequence":"additional","affiliation":[{"name":"Division of Rheumatology College of Physicians and Surgeons, Columbia University  New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. P.","family":"Sims","sequence":"additional","affiliation":[{"name":"BioPharmaceuticals R&amp;D, AstraZeneca  Gaithersburg Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3415-0704","authenticated-orcid":false,"given":"F.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Johns Hopkins University School of Medicine  Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1119-0279","authenticated-orcid":false,"given":"E.","family":"Darrah","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Johns Hopkins University School of Medicine  Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,9,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2012.134"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0061045"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.124"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0409-1"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-1126-7"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005370"},{"key":"e_1_2_8_8_1","first-page":"969","article-title":"Prevalence and significance of anti\u2010peptidylarginine deiminase 4 antibodies in rheumatoid arthritis","volume":"35","author":"Zhao J","year":"2008","journal-title":"J Rheumatol"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.170769"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.094490"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2016.03.016"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2009.09.046"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/2049-632X.12034"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00520"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3326"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/antib5010002"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-010-1671-4"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23719"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02696"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_8_21_1","first-page":"261","article-title":"How to read radiographs according to the Sharp\/van der Heijde method","volume":"27","author":"Van der Heijde D.","year":"2000","journal-title":"J Rheumatol"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380107"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200012)43:12<2751::AID-ANR15>3.0.CO;2-6"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0098794"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.20040"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy395"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu393"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-019-3118-5"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.111152"},{"key":"e_1_2_8_31_1","first-page":"2585","article-title":"Prognostic factors for joint destruction in rheumatoid arthritis: a prospective longitudinal study of 318 patients","volume":"30","author":"Guillemin F","year":"2003","journal-title":"J Rheumatol"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-015-3032-9"},{"key":"e_1_2_8_33_1","first-page":"62","article-title":"Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis","volume":"29","author":"Turesson C","year":"2002","journal-title":"J Rheumatol"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27405"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-021-02528-5"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.42262","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.42262","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.42262","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T12:21:20Z","timestamp":1759926080000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.42262"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,29]]},"references-count":34,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["10.1002\/art.42262"],"URL":"https:\/\/doi.org\/10.1002\/art.42262","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,29]]},"assertion":[{"value":"2021-04-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}