{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:53Z","timestamp":1787028233234,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T00:00:00Z","timestamp":1667347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Health Ministry","award":["RF-2010-2317168"],"award-info":[{"award-number":["RF-2010-2317168"]}]},{"name":"Italian Health Ministry","award":["FAR 2021"],"award-info":[{"award-number":["FAR 2021"]}]},{"name":"Italian Health Ministry","award":["2019"],"award-info":[{"award-number":["2019"]}]},{"DOI":"10.13039\/501100007109","name":"University of Ferrara","doi-asserted-by":"publisher","award":["RF-2010-2317168"],"award-info":[{"award-number":["RF-2010-2317168"]}],"id":[{"id":"10.13039\/501100007109","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007109","name":"University of Ferrara","doi-asserted-by":"publisher","award":["FAR 2021"],"award-info":[{"award-number":["FAR 2021"]}],"id":[{"id":"10.13039\/501100007109","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007109","name":"University of Ferrara","doi-asserted-by":"publisher","award":["2019"],"award-info":[{"award-number":["2019"]}],"id":[{"id":"10.13039\/501100007109","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondazione Roche per la Ricerca Indipendente","award":["RF-2010-2317168"],"award-info":[{"award-number":["RF-2010-2317168"]}]},{"name":"Fondazione Roche per la Ricerca Indipendente","award":["FAR 2021"],"award-info":[{"award-number":["FAR 2021"]}]},{"name":"Fondazione Roche per la Ricerca Indipendente","award":["2019"],"award-info":[{"award-number":["2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Methotrexate (MTX) is considered the first choice among disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) treatment. However, response to it varies as approximately 40% of the patients do not respond and would lose the most effective period of treatment time. Therefore, having a predictive biomarker before starting MTX treatment is of utmost importance. Methylation of long interspersed nucleotide element-1 (LINE-1) is generally considered a surrogate marker for global genomic methylation, which has been reported to associate with disease activity after MTX therapy. Methods: We performed a prospective study on 273 na\u00efve early RA (ERA) patients who were treated with MTX, followed up to 12 months, and classified according to their therapy response. The baseline LINE-1 methylation levels in peripheral blood mononuclear cells (PBMC) of cases were assessed by bisulfite pyrosequencing. Results: Baseline LINE-1 methylation level per se turned out not to predict the response to the therapy, nor did age, sex, body mass index, or smoking status. However, if cases were stratified according to positivity to rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) or seronegativity, we observed an opposite association between baseline LINE-1 methylation levels and optimal response to MTX therapy among responders. The best response to MTX therapy was associated with hypermethylated LINE-1 among double-positive ERA cases (p-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (p-value: 0.01). Conclusion: The LINE-1 methylation level in PBMCs of na\u00efve ERA cases associates with the degree of response to MTX therapy in an opposite way depending on the presence of RF and ACPA antibodies. Our results suggest LINE-1 methylation level as a new epigenetic biomarker for predicting the degree of response to MTX in both double-positive and seronegative ERA patients.<\/jats:p>","DOI":"10.3390\/genes13112012","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T03:11:21Z","timestamp":1667445081000},"page":"2012","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9050-1030","authenticated-orcid":false,"given":"Amin","family":"Ravaei","sequence":"first","affiliation":[{"name":"Medical Genetics Laboratory, Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia","family":"Pulsatelli","sequence":"additional","affiliation":[{"name":"Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Assirelli","sequence":"additional","affiliation":[{"name":"Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Meliconi","sequence":"additional","affiliation":[{"name":"Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9446-7351","authenticated-orcid":false,"given":"Jacopo","family":"Ciaffi","sequence":"additional","affiliation":[{"name":"Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Gremese","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Tolusso","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Salvarani","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"},{"name":"University Hospital of Modena, University of Modena and Reggio Emilia, 41124 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0499-5773","authenticated-orcid":false,"given":"Marcello","family":"Govoni","sequence":"additional","affiliation":[{"name":"Section of Hematology and Rheumatology, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"},{"name":"Rheumatology Unit, Sant\u2019Anna University Hospital, 44122 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1448-9516","authenticated-orcid":false,"given":"Michele","family":"Rubini","sequence":"additional","affiliation":[{"name":"Medical Genetics Laboratory, Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy"},{"name":"University Center for Studies on Gender Medicine, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1136\/ard.2010.138461","article-title":"2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology\/European League Against Rheumatism Collaborative Initiative","volume":"69","author":"Aletaha","year":"2010","journal-title":"Ann. 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