{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T22:54:16Z","timestamp":1791154456242,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2008,6,24]],"date-time":"2008-06-24T00:00:00Z","timestamp":1214265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2008,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)\u2013specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD\u20104), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti\u2013PAD\u20104 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti\u2013PAD\u20104 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD\u20104 polymorphisms influence the anti\u2013PAD\u20104 autoantibody response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti\u2013PAD\u20104 autoantibodies by immunoprecipitation of in vitro\u2013translated PAD\u20104. The epitope(s) recognized by PAD\u20104 autoantibodies were mapped using various PAD\u20104 truncations. PAD\u20104 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp\/van der Heijde method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PAD\u20104 autoantibodies were found in 36\u201342% of RA patients, and were very infrequent in controls. Recognition by anti\u2013PAD\u20104 autoantibodies required the 119 N\u2010terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti\u2013PAD\u20104 immune response was associated with the RA susceptibility haplotype of <jats:italic>PADI4<\/jats:italic>. Anti\u2013PAD\u20104 antibodies were associated with more severe joint destruction in RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that anti\u2013PAD\u20104 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti\u2013PAD\u20104 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the <jats:italic>PADI4<\/jats:italic> gene influence the immune response to the PAD\u20104 protein, potentially contributing to disease propagation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.23596","type":"journal-article","created":{"date-parts":[[2008,6,24]],"date-time":"2008-06-24T13:12:23Z","timestamp":1214313143000},"page":"1958-1967","source":"Crossref","is-referenced-by-count":129,"title":["Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis"],"prefix":"10.1002","volume":"58","author":[{"given":"Michelle L.","family":"Harris","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Darrah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon K.","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan 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