{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T19:26:33Z","timestamp":1764617193482,"version":"3.46.0"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine whether any of the HLA-A*, HLA-B* and HLA-DR* alleles in seropositive rheumatoid arthritis (RA) can be associated with the extreme serum levels of rheumatoid factor (RF) and cyclic citrullinated peptide antibodies (anti-CCP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a retrospective cross-sectional study of adult patients. Demographic data, HLA typing data and RF and anti-CCP levels were collected and analysed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HLA-A*02, HLA-B*44 and HLA-DRB1*04 were more prevalent in patients from the RA cohort compared to healthy controls. Intra-cohort analysis revealed that HLA-B*44 had an increased frequency of a twenty-fold increase in anti-CCP (P\u2009=\u20090.033) and HLA-A*03 had a borderline (P\u2009=\u20090.063) frequency. HLA-A*03 was more frequent in the groups with &gt;3-fold and &gt;10-fold anti-CCP levels, while HLA-DRB1*04 was of borderline significance at &gt;3-fold anti-CCP increase (P\u2009=\u20090.053). HLA-B*08 showed a lower frequency of 3-, 10- and 20-fold increase in anti-CCP serum levels. Carriers of B*44 (OR = 5.58; P\u2009=\u20090.030), DRB1*04 (OR = 3.89; P\u2009=\u20090.027) or A*03 (OR = 2.71; P\u2009=\u20090.023) were statistically significantly more likely to have a 20-fold increase in anti-CCP levels over the diagnostic threshold. None of the alleles increased the likelihood of having high or extreme RF levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HLA-B*44 is associated with a twenty-fold increase in anti-CCP serum levels. HLA-A*03 and HLA-DRB1*04 have a positive trend towards a twenty-fold increase in anti-CCP levels. Earlier aggressive therapy in these patients can prevent such an extreme increase in antibody levels.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0334551","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T18:26:53Z","timestamp":1764613613000},"page":"e0334551","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["HLA-B*44 is associated with a more than twentyfold increase in cyclic citrullinated peptide antibody serum level in Croatian patients with seropositive rheumatoid arthritis"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9546-3777","authenticated-orcid":true,"given":"Jure","family":"Aljinovi\u0107","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8091-6347","authenticated-orcid":true,"given":"Darko","family":"Kero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"\u0160o\u0161o","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marin","family":"Petri\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Marasovi\u0107 Krstulovi\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dijana","family":"Perkovi\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esma","family":"\u010ce\u010duk-Jeli\u010di\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja","family":"Jaman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dora","family":"Dujmovi\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivanka","family":"Marinovi\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"issue":"11","key":"pone.0334551.ref001","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1002\/art.1780301102","article-title":"The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis","volume":"30","author":"PK Gregersen","year":"1987","journal-title":"Arthritis Rheum"},{"key":"pone.0334551.ref002","doi-asserted-by":"crossref","first-page":"930112","DOI":"10.3389\/fimmu.2022.930112","article-title":"How RA Associated HLA-DR Molecules Contribute to the Development of Antibodies to Citrullinated Proteins: The Hapten Carrier Model","volume":"13","author":"J Roudier","year":"2022","journal-title":"Front Immunol"},{"key":"pone.0334551.ref003","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s00508-022-02010-5","article-title":"Association of HLA-DRB1 alleles with rheumatoid arthritis in Split-Dalmatia County in southern Croatia","volume":"134","author":"I Marinovi\u0107","year":"2022","journal-title":"Wien Klin 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Arthropathies","volume":"13","author":"J Aljinovi\u0107","year":"2024","journal-title":"J Clin Med"},{"issue":"3","key":"pone.0334551.ref007","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/iji.12117","article-title":"HLA-A, HLA-B and HLA-DRB1 allele and haplotype diversity among volunteer bone marrow donors from Croatia","volume":"41","author":"Z Grubic","year":"2014","journal-title":"Int J Immunogenet"},{"key":"pone.0334551.ref008","author":"M Marija","year":"2020"},{"issue":"7","key":"pone.0334551.ref009","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1212\/WNL.0b013e3181ed9c9c","article-title":"HLA B*44: protective effects in MS susceptibility and MRI outcome measures","volume":"75","author":"BC Healy","year":"2010","journal-title":"Neurology"},{"issue":"2","key":"pone.0334551.ref010","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1001\/archotol.127.2.184","article-title":"Close association of HLA-B52 and HLA-B44 antigens in Israeli Arab adolescents with recurrent aphthous stomatitis","volume":"127","author":"L Jaber","year":"2001","journal-title":"Arch Otolaryngol Head Neck Surg"},{"issue":"3","key":"pone.0334551.ref011","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.clim.2006.02.001","article-title":"Increased frequency of HLA-B44 in recurrent sinopulmonary infections (RESPI)","volume":"119","author":"DT Johnston","year":"2006","journal-title":"Clin Immunol"},{"issue":"5","key":"pone.0334551.ref012","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1159\/000348366","article-title":"HLA-A, B (Class I) and HLA-DR, DQ (Class II) antigens in Turkish patients with recurrent aphthous ulceration and Beh\u00e7et\u2019s disease","volume":"22","author":"FN Pekiner","year":"2013","journal-title":"Med Princ Pract"},{"issue":"10","key":"pone.0334551.ref013","first-page":"658","article-title":"Association of Crohn\u2019s disease with HLA phenotype B44, Cw5","volume":"26","author":"J Purrmann","year":"1988","journal-title":"Z Gastroenterol"},{"issue":"1","key":"pone.0334551.ref014","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.clim.2005.09.006","article-title":"HLA B44 is associated with decreased severity of autoimmune lymphoproliferative syndrome in patients with CD95 defects (ALPS type Ia)","volume":"118","author":"MM Vacek","year":"2006","journal-title":"Clin Immunol"},{"key":"pone.0334551.ref015","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/1471-2350-10-100","article-title":"Analysis of TACI mutations in CVID & RESPI patients who have inherited HLA B*44 or HLA*B8","volume":"10","author":"ML Waldrep","year":"2009","journal-title":"BMC Med Genet"},{"issue":"9","key":"pone.0334551.ref016","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1002\/art.27584","article-title":"2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology\/European League Against Rheumatism collaborative initiative","volume":"62","author":"D Aletaha","year":"2010","journal-title":"Arthritis Rheum"},{"issue":"12","key":"pone.0334551.ref017","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1136\/ard.2004.033571","article-title":"Longitudinal analysis of citrullinated protein\/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression","volume":"64","author":"J R\u00f6nnelid","year":"2005","journal-title":"Ann Rheum Dis"},{"issue":"5","key":"pone.0334551.ref018","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1002\/art.1780370511","article-title":"\u201cHomozygosity\u201d for the HLA-DR shared epitope contributes the highest risk for rheumatoid arthritis concordance in identical twins","volume":"37","author":"D Jawaheer","year":"1994","journal-title":"Arthritis Rheum"},{"issue":"5","key":"pone.0334551.ref019","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1086\/516736","article-title":"Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis","volume":"80","author":"H Kallberg","year":"2007","journal-title":"Am J Hum Genet"},{"issue":"1","key":"pone.0334551.ref020","first-page":"12","article-title":"HLA-DRB1 gene distribution in Croatian arthritis patients","volume":"52","author":"NL Zerjavi\u0107","year":"2005","journal-title":"Reumatizam"},{"issue":"6","key":"pone.0334551.ref021","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/ng.582","article-title":"Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci","volume":"42","author":"EA Stahl","year":"2010","journal-title":"Nat 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citrullinated proteins?","volume":"116","author":"N Balandraud","year":"2021","journal-title":"J Autoimmun"},{"issue":"2","key":"pone.0334551.ref025","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/acr2.11630","article-title":"Anti-Peptidylarginine Deiminase 4 Autoantibodies and Disease Duration as Predictors of Treatment Response in Rheumatoid Arthritis","volume":"6","author":"LC Cappelli","year":"2024","journal-title":"ACR Open Rheumatol"},{"issue":"3","key":"pone.0334551.ref026","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1136\/ard.2007.080267","article-title":"Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity","volume":"67","author":"EH Halvorsen","year":"2008","journal-title":"Ann Rheum Dis"},{"issue":"7","key":"pone.0334551.ref027","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1002\/art.23596","article-title":"Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis","volume":"58","author":"ML Harris","year":"2008","journal-title":"Arthritis Rheum"},{"issue":"6","key":"pone.0334551.ref028","first-page":"969","article-title":"Prevalence and significance of anti-peptidylarginine deiminase 4 antibodies in rheumatoid arthritis","volume":"35","author":"J Zhao","year":"2008","journal-title":"J Rheumatol"},{"issue":"1","key":"pone.0334551.ref029","doi-asserted-by":"crossref","first-page":"15250","DOI":"10.1038\/s41598-023-42324-6","article-title":"Carriers of HLA-DRB1*04:05 have a better clinical response to abatacept in rheumatoid arthritis","volume":"13","author":"M Inoue","year":"2023","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0334551.ref030","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.1076","article-title":"Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis","volume":"44","author":"S Raychaudhuri","year":"2012","journal-title":"Nat Genet"},{"issue":"1","key":"pone.0334551.ref031","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41467-022-35264-8","article-title":"Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis","volume":"14","author":"J-S Moon","year":"2023","journal-title":"Nat Commun"},{"issue":"3","key":"pone.0334551.ref032","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/art.38273","article-title":"Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis","volume":"66","author":"MJH de Hair","year":"2014","journal-title":"Arthritis Rheumatol"},{"issue":"6","key":"pone.0334551.ref033","doi-asserted-by":"crossref","DOI":"10.1002\/cti2.1140","article-title":"Synovial fluid CD69+CD8+ T cells with tissue-resident phenotype mediate perforin-dependent citrullination in rheumatoid arthritis","volume":"9","author":"J Jung","year":"2020","journal-title":"Clin Transl Immunol"},{"issue":"178","key":"pone.0334551.ref034","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3005580","article-title":"NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis","volume":"5","author":"R Khandpur","year":"2013","journal-title":"Sci Transl Med"},{"key":"pone.0334551.ref035","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3389\/fimmu.2016.00461","article-title":"A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination","volume":"7","author":"MF Konig","year":"2016","journal-title":"Front Immunol"},{"issue":"3","key":"pone.0334551.ref036","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41584-020-0373-9","article-title":"Methotrexate and its mechanisms of action in inflammatory arthritis","volume":"16","author":"BN Cronstein","year":"2020","journal-title":"Nat Rev Rheumatol"},{"issue":"3","key":"pone.0334551.ref037","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1006\/clim.1999.4710","article-title":"Correlation of thymic pathology with HLA in myasthenia gravis","volume":"91","author":"A Machens","year":"1999","journal-title":"Clin Immunol"},{"issue":"1","key":"pone.0334551.ref038","doi-asserted-by":"crossref","first-page":"7775","DOI":"10.1038\/s41598-023-35028-4","article-title":"The ancestral haplotype markers HLA -A3 and B7 do not influence the likelihood of advanced hepatic fibrosis or cirrhosis in HFE hemochromatosis","volume":"13","author":"JK Olynyk","year":"2023","journal-title":"Sci Rep"},{"issue":"2","key":"pone.0334551.ref039","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.4049\/jimmunol.162.2.1156","article-title":"Identification of HLA-A3 and -B7-restricted CTL response to hepatitis C virus in patients with acute and chronic hepatitis 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