{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T17:46:48Z","timestamp":1767116808383,"version":"3.37.3"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T00:00:00Z","timestamp":1505865600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T00:00:00Z","timestamp":1505865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Classification of patients with rheumatoid arthritis (RA) as quickly as possible improves their prognosis. This reason motivates specially dedicated early arthritis (EA) clinics. Here, we have used 1062 EA patients with two years of follow-up to explore the value of anti-carbamylated protein (anti-CarP) antibodies, a new type of RA specific autoantibodies, for classification. Specifically, we aimed to determine whether the addition of anti-CarP antibodies to IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, which are helpful in RA classification, improves it or not. Our analysis showed that incorporation of the anti-CarP antibodies to combinations of the other two antibodies (all joint by the OR Boolean operator) produces a modest increase in sensitivity (2.2% higher), at the cost of decreased specificity (8.1% lower). The cost-benefit ratio was more favorable in the patients lacking the other autoantibodies. However, it did not improve by considering different titer levels of the anti-CarP antibodies, or after exhaustively exploring other antibody combinations. Therefore, the place in RA classification of these antibodies is questionable in the context of current treatments and biomarkers. This conclusion does not exclude their potential value for stratifying patients in joint damage, disease activity, disability, or mortality categories.<\/jats:p>","DOI":"10.1038\/s41598-017-09657-5","type":"journal-article","created":{"date-parts":[[2017,9,14]],"date-time":"2017-09-14T15:59:35Z","timestamp":1505404775000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Value of Measuring Anti-Carbamylated Protein Antibodies for Classification on Early Arthritis Patients"],"prefix":"10.1038","volume":"7","author":[{"given":"Cristina","family":"Regueiro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Nu\u00f1o","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana M.","family":"Ortiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Peiteado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Villalba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dora","family":"Pascual-Salcedo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Mart\u00ednez-Feito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isidoro","family":"Gonz\u00e1lez-Alvaro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Balsa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2624-0606","authenticated-orcid":false,"given":"Antonio","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,9,20]]},"reference":[{"key":"9657_CR1","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1136\/annrheumdis-2013-204573","volume":"73","author":"JS Smolen","year":"2014","unstructured":"Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis \n                           73, 492\u2013509, doi:10.1136\/annrheumdis-2013-204573 (2014).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR2","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1002\/art.27584","volume":"62","author":"D Aletaha","year":"2010","unstructured":"Aletaha, D. et al. Rheumatoid arthritis classification criteria: an American College of Rheumatology\/European League Against Rheumatism collaborative initiative. Arthritis Rheum \n                           62, 2569\u20132581, doi:10.1002\/art.27584 (2010).","journal-title":"Arthritis Rheum"},{"key":"9657_CR3","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1002\/art.22353","volume":"55","author":"A Finckh","year":"2006","unstructured":"Finckh, A., Liang, M. H., van Herckenrode, C. M. & de Pablo, P. Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis. Arthritis Rheum \n                           55, 864\u2013872, doi:10.1002\/art.22353 (2006).","journal-title":"Arthritis Rheum"},{"key":"9657_CR4","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1002\/art.22525","volume":"56","author":"H van Dongen","year":"2007","unstructured":"van Dongen, H. et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum \n                           56, 1424\u20131432, doi:10.1002\/art.22525 (2007).","journal-title":"Arthritis Rheum"},{"key":"9657_CR5","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1136\/annrheumdis-2012-203130","volume":"73","author":"JA van Nies","year":"2014","unstructured":"van Nies, J. A. et al. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis \n                           73, 861\u2013870, doi:10.1136\/annrheumdis-2012-203130 (2014).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR6","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1136\/annrheumdis-2014-206047","volume":"74","author":"JA van Nies","year":"2015","unstructured":"van Nies, J. A., Tsonaka, R., Gaujoux-Viala, C., Fautrel, B. & van der Helm-van Mil, A. H. Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden early arthritis clinic and ESPOIR cohorts. Ann Rheum Dis \n                           74, 806\u2013812, doi:10.1136\/annrheumdis-2014-206047 (2015).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR7","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1002\/art.1780310302","volume":"31","author":"FC Arnett","year":"1988","unstructured":"Arnett, F. C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum \n                           31, 315\u2013324 (1988).","journal-title":"Arthritis Rheum"},{"key":"9657_CR8","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1136\/annrheumdis-2013-203284","volume":"73","author":"H Radner","year":"2014","unstructured":"Radner, H., Neogi, T., Smolen, J. S. & Aletaha, D. Performance of the 2010 ACR\/EULAR classification criteria for rheumatoid arthritis: a systematic literature review. Ann Rheum Dis \n                           73, 114\u2013123, doi:10.1136\/annrheumdis-2013-203284 (2014).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR9","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1136\/annrheumdis-2012-201426","volume":"71","author":"AH van der Helm-van Mil","year":"2012","unstructured":"van der Helm-van Mil, A. H. & Huizinga, T. W. The 2010 ACR\/EULAR criteria for rheumatoid arthritis: do they affect the classification or diagnosis of rheumatoid arthritis? Ann Rheum Dis \n                           71, 1596\u20131598, doi:10.1136\/annrheumdis-2012-201426 (2012).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR10","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1136\/annrheumdis-2016-209629","volume":"76","author":"AH van der Helm-van Mil","year":"2017","unstructured":"van der Helm-van Mil, A. H. & Zink, A. What is rheumatoid arthritis? Considering consequences of changed classification criteria. Ann Rheum Dis \n                           76, 315\u2013317, doi:10.1136\/annrheumdis-2016-209629 (2017).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR11","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.berh.2013.09.001","volume":"27","author":"MD Mjaavatten","year":"2013","unstructured":"Mjaavatten, M. D. & Bykerk, V. P. Early rheumatoid arthritis: the performance of the 2010 ACR\/EULAR criteria for diagnosing RA. Best Pract Res Clin Rheumatol \n                           27, 451\u2013466, doi:10.1016\/j.berh.2013.09.001 (2013).","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"9657_CR12","doi-asserted-by":"publisher","first-page":"17372","DOI":"10.1073\/pnas.1114465108","volume":"108","author":"J Shi","year":"2011","unstructured":"Shi, J. et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci USA \n                           108, 17372\u201317377, doi:10.1073\/pnas.1114465108 (2011).","journal-title":"Proc Natl Acad Sci USA"},{"key":"9657_CR13","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.1136\/annrheumdis-2013-205109","volume":"73","author":"X Jiang","year":"2014","unstructured":"Jiang, X. et al. Anti-CarP antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors, cigarette smoking and other autoantibodies. Ann Rheum Dis \n                           73, 1761\u20131768, doi:10.1136\/annrheumdis-2013-205109 (2014).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR14","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1136\/annrheumdis-2013-204154","volume":"73","author":"J Shi","year":"2014","unstructured":"Shi, J. et al. Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann Rheum Dis \n                           73, 780\u2013783, doi:10.1136\/annrheumdis-2013-204154 (2014).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR15","doi-asserted-by":"publisher","first-page":"572","DOI":"10.3899\/jrheum.140767","volume":"42","author":"RW Gan","year":"2015","unstructured":"Gan, R. W. et al. Anti-carbamylated protein antibodies are present prior to rheumatoid arthritis and are associated with its future diagnosis. J Rheumatol \n                           42, 572\u2013579, doi:10.3899\/jrheum.140767 (2015).","journal-title":"J Rheumatol"},{"key":"9657_CR16","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0536-2","volume":"17","author":"M Brink","year":"2015","unstructured":"Brink, M. et al. Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther \n                           17, 25, doi:10.1186\/s13075-015-0536-2 (2015).","journal-title":"Arthritis Res Ther"},{"key":"9657_CR17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0161141","volume":"11","author":"A Montes","year":"2016","unstructured":"Montes, A. et al. Anti-Carbamylated Protein Antibodies as a Reproducible Independent Type of Rheumatoid Arthritis Autoantibodies. PLoS One \n                           11, e0161141, doi:10.1371\/journal.pone.0161141 (2016).","journal-title":"PLoS One"},{"key":"9657_CR18","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1136\/annrheumdis-2015-207326","volume":"75","author":"JH Humphreys","year":"2016","unstructured":"Humphreys, J. H. et al. Anticarbamylated protein antibodies are associated with long-term disability and increased disease activity in patients with early inflammatory arthritis: results from the Norfolk Arthritis Register. Ann Rheum Dis \n                           75, 1139\u20131144, doi:10.1136\/annrheumdis-2015-207326 (2016).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR19","doi-asserted-by":"crossref","unstructured":"Vidal-Bralo, L. et al. Anti-carbamylated protein autoantibodies associated with mortality in Spanish rheumatoid arthritis patients. PLoS One Jul 3; 12(7) (2017).","DOI":"10.1371\/journal.pone.0180144"},{"key":"9657_CR20","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1002\/art.37830","volume":"65","author":"J Shi","year":"2013","unstructured":"Shi, J. et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum \n                           65, 911\u2013915, doi:10.1002\/art.37830 (2013).","journal-title":"Arthritis Rheum"},{"key":"9657_CR21","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-015-0860-6","volume":"17","author":"J Shi","year":"2015","unstructured":"Shi, J. et al. The specificity of anti-carbamylated protein antibodies for rheumatoid arthritis in a setting of early arthritis. Arthritis Res Ther \n                           17, 339, doi:10.1186\/s13075-015-0860-6 (2015).","journal-title":"Arthritis Res Ther"},{"key":"9657_CR22","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1093\/rheumatology\/kem343","volume":"47","author":"G Orozco","year":"2008","unstructured":"Orozco, G. et al. Auto-antibodies, HLA and PTPN22: susceptibility markers for rheumatoid arthritis. Rheumatology \n                           47, 138\u2013141, doi:10.1093\/rheumatology\/kem343 (2008).","journal-title":"Rheumatology"},{"key":"9657_CR23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029492","volume":"6","author":"I Gonzalez-Alvaro","year":"2011","unstructured":"Gonzalez-Alvaro, I. et al. Interleukin 15 levels in serum may predict a severe disease course in patients with early arthritis. PLoS One \n                           6, e29492, doi:10.1371\/journal.pone.0029492 (2011).","journal-title":"PLoS One"},{"key":"9657_CR24","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1136\/ard.2010.130310","volume":"69","author":"J Funovits","year":"2010","unstructured":"Funovits, J. et al. The 2010 American College of Rheumatology\/European League Against Rheumatism classification criteria for rheumatoid arthritis: methodological report phase I. Ann Rheum Dis \n                           69, 1589\u20131595, doi:10.1136\/ard.2010.130310 (2010).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cca.2008.04.007","volume":"394","author":"R Muller","year":"2008","unstructured":"Muller, R. & Mockel, M. Logistic regression and CART in the analysis of multimarker studies. Clin Chim Acta \n                           394, 1\u20136, doi:10.1016\/j.cca.2008.04.007 (2008).","journal-title":"Clin Chim Acta"},{"key":"9657_CR26","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1136\/annrheumdis-2014-206785","volume":"75","author":"M Juarez","year":"2016","unstructured":"Juarez, M. et al. Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis. Ann Rheum Dis \n                           75, 1099\u20131107, doi:10.1136\/annrheumdis-2014-206785 (2016).","journal-title":"Ann Rheum Dis"},{"key":"9657_CR27","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1002\/art.38969","volume":"67","author":"GM Thiele","year":"2015","unstructured":"Thiele, G. M. et al. Malondialdehyde-acetaldehyde adducts and anti-malondialdehyde-acetaldehyde antibodies in rheumatoid arthritis. Arthritis Rheumatol \n                           67, 645\u2013655, doi:10.1002\/art.38969 (2015).","journal-title":"Arthritis Rheumatol"},{"key":"9657_CR28","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.autrev.2012.05.007","volume":"12","author":"LA Trouw","year":"2012","unstructured":"Trouw, L. A. & Mahler, M. Closing the serological gap: promising novel biomarkers for the early diagnosis of rheumatoid arthritis. Autoimmun Rev \n                           12, 318\u2013322, doi:10.1016\/j.autrev.2012.05.007 (2012).","journal-title":"Autoimmun Rev"},{"key":"9657_CR29","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1136\/annrheumdis-2015-208579","volume":"75","author":"S Ajeganova","year":"2016","unstructured":"Ajeganova, S. et al. Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts. Ann Rheum Dis \n                           75, 1924\u20131932, doi:10.1136\/annrheumdis-2015-208579 (2016).","journal-title":"Ann Rheum Dis"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09657-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09657-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09657-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T11:08:55Z","timestamp":1671793735000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09657-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,20]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["9657"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-09657-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2017,9,20]]},"assertion":[{"value":"19 April 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 July 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"12023"}}