{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:50:49Z","timestamp":1791874249382,"version":"4.3.4"},"reference-count":35,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T00:00:00Z","timestamp":1639094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003329","name":"Ministry of Economy, Industry and Competitiveness","doi-asserted-by":"publisher","award":["RTI2018-094120-B-I00"],"award-info":[{"award-number":["RTI2018-094120-B-I00"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies that are of paramount importance for the diagnosis and prognosis of the disease and have been implicated in its pathogenesis. Proteins resulting from post-translational modifications (PTMs) are capable of triggering autoimmune responses important for the development of RA. In this work, we investigate serum antibody reactivity in patients with an established RA against a panel of chimeric peptides derived from fibrin and filaggrin proteins and bearing from one to three PTMs (citrullination, carbamylation and acetylation) by home-designed ELISA tests (anti-AMPA autoantibodies). The role of anti-AMPAs as biomarkers linked to the presence of a more severe RA phenotype (erosive disease with radiological structural damage) and to the presence of interstitial lung disease (ILD), a severe extra-articular manifestation in RA patients entailing a high mortality, was also analyzed. In general, the association with the clinical phenotype of RA was confirmed with the different autoantibodies, and especially for IgA and IgM isotypes. The prevalence of severe joint damage was only statistically significant for the IgG isotype when working with the peptide bearing three PTMs. Furthermore, the median titers were significantly higher in patients with RA-ILD, a finding not observed for the IgG isotype when working with the single- and double-modified peptides.<\/jats:p>","DOI":"10.3390\/ijms222413290","type":"journal-article","created":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T08:17:58Z","timestamp":1639124278000},"page":"13290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Peptides Bearing Multiple Post-Translational Modifications as Antigenic Targets for Severe Rheumatoid Arthritis Patients"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3734-1437","authenticated-orcid":false,"given":"Cristina","family":"Garc\u00eda-Moreno","sequence":"first","affiliation":[{"name":"Unit of Synthesis and Biomedical Applications of Peptides, Institute of Advanced Chemistry of Catalonia, Consejo Superior de Investigaciones Cient\u00edficas (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6906-4833","authenticated-orcid":false,"given":"Mar\u00eda J.","family":"G\u00f3mara","sequence":"additional","affiliation":[{"name":"Unit of Synthesis and Biomedical Applications of Peptides, Institute of Advanced Chemistry of Catalonia, Consejo Superior de Investigaciones Cient\u00edficas (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4104-4101","authenticated-orcid":false,"given":"Ra\u00fal","family":"Castellanos-Moreira","sequence":"additional","affiliation":[{"name":"Arthritis Unit, Rheumatology Department, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raimon","family":"Sanmart\u00ed","sequence":"additional","affiliation":[{"name":"Arthritis Unit, Rheumatology Department, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8677-2340","authenticated-orcid":false,"given":"Isabel","family":"Haro","sequence":"additional","affiliation":[{"name":"Unit of Synthesis and Biomedical Applications of Peptides, Institute of Advanced Chemistry of Catalonia, Consejo Superior de Investigaciones Cient\u00edficas (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"697","DOI":"10.2174\/15680266113139990091","article-title":"Rheumatoid arthritis: Current advances in pathogenesis, diagnosis and therapy","volume":"13","author":"Haro","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mueller, A.L., Payandeh, Z., Mohammadkhani, N., Mubarak, S.M.H., Zakeri, A., Bahrami, A.A., Brockmueller, A., and Shakibaei, M. (2021). Recent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies. Cells, 10.","DOI":"10.3390\/cells10113017"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kwon, E.J., and Ju, J.H. (2021). Impact of Posttranslational modification in pathogenesis of rheumatoid arthritis: Focusing on citrullination, carbamylation, and acetylation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910576"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102400","DOI":"10.1016\/j.jaut.2019.102400","article-title":"The etiology of rheumatoid arthritis","volume":"110","author":"Scherer","year":"2020","journal-title":"J. Autoimmun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1097\/BOR.0000000000000452","article-title":"Rheumatoid arthritis and citrullination","volume":"30","author":"Darrah","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1002\/eji.200535790","article-title":"Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins","volume":"36","author":"Sebbag","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102392","DOI":"10.1016\/j.jaut.2019.102392","article-title":"An overview of autoantibodies in rheumatoid arthritis","volume":"110","author":"Huizinga","year":"2020","journal-title":"J. Autoimmun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/nm1637","article-title":"Protein carbamylation links inflammation, smoking, uremia and atherogenesis","volume":"13","author":"Wang","year":"2007","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"17372","DOI":"10.1073\/pnas.1114465108","article-title":"Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage","volume":"108","author":"Shi","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1136\/annrheumdis-2015-208870","article-title":"The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: A study exploring replication and the added value to ACPA and rheumatoid factor","volume":"76","author":"Ajeganova","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1002\/art.38969","article-title":"Malondialdehyde-acetaldehyde adducts and anti-malondialdehyde-acetaldehyde antibodies in rheumatoid arthritis","volume":"67","author":"Thiele","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1136\/annrheumdis-2014-206785","article-title":"Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis","volume":"75","author":"Juarez","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.autrev.2012.02.008","article-title":"Synthetic peptides as tools for diagnosis and therapeutic strategies to treat systemic lupus erythematous","volume":"11","author":"Muller","year":"2012","journal-title":"Autoimmun. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1002\/bip.21456","article-title":"Posttranslationally modified peptides efficiently mimicking neoantigens: A challenge for theragnostics of autoimmune diseases","volume":"94","author":"Nuti","year":"2010","journal-title":"Biopolymers"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/psc.1166","article-title":"The use of post-translationally modified peptides for detection of biomarkers of immune-mediated diseases","volume":"15","author":"Papini","year":"2009","journal-title":"J. Pept. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1021\/jm0701932","article-title":"Antibodies to citrullinated human fibrinogen synthetic peptides in diagnosing rheumatoid arthritis","volume":"50","author":"Perez","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7486","DOI":"10.1021\/jm200563u","article-title":"The use of chimeric vimentin citrullinated peptides for the diagnosis of rheumatoid arthritis","volume":"54","author":"Malakoutikhah","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Garcia-Moreno, C., Gomara, M.J., Bleda, M.J., Sanmarti, R., and Haro, I. (2019). Development of a multiplex assay based on chimeric citrullinated peptides as proof of concept for diagnosis of rheumatoid arthritis. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0215927"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R135","DOI":"10.1186\/ar2802","article-title":"Diagnostic and prognostic value of antibodies against chimeric fibrin\/filaggrin citrullinated synthetic peptides in rheumatoid arthritis","volume":"11","author":"Sanmarti","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1136\/annrheumdis-2017-211138","article-title":"A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: Comorbidity and mortality","volume":"76","author":"Hyldgaard","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/1759720X211032457","article-title":"Role of autoantibodies in the diagnosis and prognosis of interstitial lung disease in autoimmune rheumatic disorders","volume":"13","author":"Kuwana","year":"2021","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1136\/annrheumdis-2019-216709","article-title":"Anti-carbamylated proteins antibody repertoire in rheumatoid arthritis: Evidence of a new autoantibody linked to interstitial lung disease","volume":"79","author":"Gomara","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jim.2011.01.005","article-title":"Accuracy and reproducibility of a multiplex immunoassay platform: A validation study","volume":"367","author":"Bastarache","year":"2011","journal-title":"J. Immunol. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1177\/1099800411404061","article-title":"Estimating intra- and inter-assay variability in salivary cortisol","volume":"13","author":"Hanneman","year":"2011","journal-title":"Biol. Res. Nurs."},{"key":"ref_25","unstructured":"European Medicines Agency, and Committee for Medicinal Products for Human Use (2011). Guideline on Bioanalytical Method Validation, European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-bioanalytical-method-validation_en.pdf."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1016\/j.chest.2019.12.005","article-title":"IgA antibodies directed against citrullinated protein antigens are elevated in patients with idiopathic pulmonary fibrosis","volume":"157","author":"Solomon","year":"2020","journal-title":"Chest"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1002\/art.37881","article-title":"Identification of citrullinated Hsp90 isoforms as novel autoantigens in rheumatoid arthritis-associated interstitial lung disease","volume":"65","author":"Harlow","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1093\/rheumatology\/kex520","article-title":"Anti-citrullinated alpha enolase antibodies, interstitial lung disease and bone erosion in rheumatoid arthritis","volume":"57","author":"Alunno","year":"2018","journal-title":"Rheumatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1002\/art.40900","article-title":"Malondialdehyde\u2013Acetaldehyde adducts and antibody responses in rheumatoid arthritis\u2013associated interstitial lung disease","volume":"71","author":"England","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"ref_30","first-page":"264","article-title":"Using the Larsen index to assess radiographic progression in rheumatoid arthritis","volume":"27","author":"Kirwan","year":"2000","journal-title":"J. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.bbrc.2014.01.195","article-title":"Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts","volume":"444","author":"Wada","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"728610","DOI":"10.1155\/2015\/728610","article-title":"The role of citrullinated protein antibodies in predicting erosive disease in rheumatoid arthritis: A systematic literature review and meta-analysis","volume":"2015","author":"Jilani","year":"2015","journal-title":"Int. J. Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4533","DOI":"10.1007\/s10067-021-05808-2","article-title":"Serum anti-citrullinated protein antibodies and rheumatoid factor increase the risk of rheumatoid arthritis-related interstitial lung disease: A meta-analysis","volume":"40","author":"Xie","year":"2021","journal-title":"Clin. Rheumatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1002\/art.40237","article-title":"Association of the Presence of Anti-Carbamylated Protein Antibodies in Early Arthritis with a Poorer Clinical and Radiologic Outcome: Data From the French ESPOIR Cohort","volume":"69","author":"Truchetet","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e284","DOI":"10.1016\/S2665-9913(20)30381-7","article-title":"The impact of autoantibodies against citrullinated, carbamylated and acetylated peptides on radiographic progression in patients with new-onset rheumatoid arthritis: An observational cohort study","volume":"3","author":"Nijjar","year":"2021","journal-title":"Lancet Rheumatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13290\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:44:45Z","timestamp":1760168685000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13290"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,10]]},"references-count":35,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222413290"],"URL":"https:\/\/doi.org\/10.3390\/ijms222413290","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,10]]}}}