{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:05:36Z","timestamp":1761609936632,"version":"build-2065373602"},"reference-count":16,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T00:00:00Z","timestamp":1554854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["P30 AR053503","P30 AR070254"],"award-info":[{"award-number":["P30 AR053503","P30 AR070254"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["U54GM115458"],"award-info":[{"award-number":["U54GM115458"]}],"id":[{"id":"10.13039\/100000057","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":[[2019,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To determine if the baseline presence of autoantibodies to peptidylarginine deiminase 4 (<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>4) predicts therapeutic response to biologic and conventional disease\u2010modifying antirheumatic drugs (<jats:styled-content style=\"fixed-case\">DMARD<\/jats:styled-content>s) in patients with rheumatoid arthritis (<jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>) in whom methotrexate (<jats:styled-content style=\"fixed-case\">MTX<\/jats:styled-content>) monotherapy was unsuccessful.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Baseline serum from 282 <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients in whom <jats:styled-content style=\"fixed-case\">MTX<\/jats:styled-content> monotherapy was unsuccessful was screened for the presence of anti\u2010<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>4 antibodies by immunoprecipitation. Clinical response to either triple <jats:styled-content style=\"fixed-case\">DMARD<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">MTX<\/jats:styled-content>, sulfasalazine, and hydroxychloroquine) or <jats:styled-content style=\"fixed-case\">MTX<\/jats:styled-content>\/etanercept combination therapy was determined at 24 and 48 weeks post\u2013treatment initiation. Disease activity was measured using the Disease Activity Score 28\u2010joint assessment (<jats:styled-content style=\"fixed-case\">DAS<\/jats:styled-content>28), and erosive disease was quantified using the Sharp\/van der Heijde scoring method. Generalized estimating equations (<jats:styled-content style=\"fixed-case\">GEE<\/jats:styled-content>s) were used to model the clinical responses to treatment in patients with and those without baseline anti\u2010<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>4 antibodies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Anti\u2010<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>4 antibody positivity was associated with male sex, a history of never smoking, and anti\u2013citrullinated protein antibodies. At baseline, patients with anti\u2010<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>4 antibodies had longer disease duration and significantly more radiographic joint damage than anti\u2010<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>4\u2013negative patients, but did not differ in disease activity according to the <jats:styled-content style=\"fixed-case\">DAS<\/jats:styled-content>28. In unadjusted analyses and multivariable <jats:styled-content style=\"fixed-case\">GEE<\/jats:styled-content> models, patients with anti\u2010<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>4 antibodies exhibited greater improvements in <jats:styled-content style=\"fixed-case\">DAS<\/jats:styled-content>28 (adjusted <jats:italic>P<\/jats:italic> = 0.02 and <jats:italic>P<\/jats:italic> = 0.008, respectively) and less radiographic progression (adjusted <jats:italic>P<\/jats:italic> = 0.01 and <jats:italic>P<\/jats:italic> = 0.002, respectively) compared to anti\u2010<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content> antibody\u2013negative patients, independent of treatment received.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Although anti\u2010<jats:styled-content style=\"fixed-case\">PAD<\/jats:styled-content>4 antibodies were associated with worse baseline radiographic joint damage, suggesting a history of active or undiagnosed disease, treatment escalation therapy was more effective in reducing disease activity and slowing the progression of joint damage in this patient subset.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40791","type":"journal-article","created":{"date-parts":[[2018,12,3]],"date-time":"2018-12-03T06:04:48Z","timestamp":1543817088000},"page":"696-702","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Association of Baseline Peptidylarginine Deiminase 4 Autoantibodies With Favorable Response to Treatment Escalation in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1119-0279","authenticated-orcid":false,"given":"Erika","family":"Darrah","sequence":"first","affiliation":[{"name":"Johns Hopkins University School of Medicine  Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Yu","sequence":"additional","affiliation":[{"name":"University of Nebraska Medical Center  Omaha"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura C.","family":"Cappelli","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine  Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antony","family":"Rosen","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine  Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James R.","family":"O'Dell","sequence":"additional","affiliation":[{"name":"VA Nebraska\u2013Western Iowa Health Care System and University of Nebraska Medical Center  Omaha"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ted R.","family":"Mikuls","sequence":"additional","affiliation":[{"name":"VA Nebraska\u2013Western Iowa Health Care System and University of Nebraska Medical Center  Omaha"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,4,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.08.026"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.21641"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1303006"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200007)43:7<1473::AID-ANR9>3.0.CO;2-N"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2014.10.016"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23596"},{"key":"e_1_2_7_8_1","first-page":"969","article-title":"Prevalence and significance of anti\u2013peptidylarginine deiminase 4 antibodies in rheumatoid arthritis","volume":"35","author":"Zhao J","year":"2008","journal-title":"J Rheumatol"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2007.080267"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005370"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-1126-7"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.094490"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380107"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(89)92442-2"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0006-341X.2001.00120.x"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-018-1533-z"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27570"}],"container-title":["Arthritis &amp; 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