Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients
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....
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MDPI AG
2022-11-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/11/2012 |
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| author | Amin Ravaei Lia Pulsatelli Elisa Assirelli Riccardo Meliconi Jacopo Ciaffi Elisa Gremese Barbara Tolusso Carlo Salvarani Marcello Govoni Michele Rubini |
| author_facet | Amin Ravaei Lia Pulsatelli Elisa Assirelli Riccardo Meliconi Jacopo Ciaffi Elisa Gremese Barbara Tolusso Carlo Salvarani Marcello Govoni Michele Rubini |
| author_sort | Amin Ravaei |
| collection | DOAJ |
| description | 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 naïve 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 (<i>p</i>-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (<i>p</i>-value: 0.01). Conclusion: The LINE-1 methylation level in PBMCs of naïve 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. |
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| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T19:03:43Z |
| publishDate | 2022-11-01 |
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| series | Genes |
| spelling | doaj.art-98ede6bdffea493e9af2d99441e94dbf2023-11-24T04:48:24ZengMDPI AGGenes2073-44252022-11-011311201210.3390/genes13112012Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis PatientsAmin Ravaei0Lia Pulsatelli1Elisa Assirelli2Riccardo Meliconi3Jacopo Ciaffi4Elisa Gremese5Barbara Tolusso6Carlo Salvarani7Marcello Govoni8Michele Rubini9Medical Genetics Laboratory, Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, ItalyLaboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalyMedicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalyMedicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalyMedicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalyDivision of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDivision of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDivision of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, ItalySection of Hematology and Rheumatology, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, ItalyMedical Genetics Laboratory, Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, ItalyBackground: 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 naïve 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 (<i>p</i>-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (<i>p</i>-value: 0.01). Conclusion: The LINE-1 methylation level in PBMCs of naïve 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.https://www.mdpi.com/2073-4425/13/11/2012rheumatoid arthritisLINE-1DNA methylationmethotrexatebiomarkersrheumatoid factor |
| spellingShingle | Amin Ravaei Lia Pulsatelli Elisa Assirelli Riccardo Meliconi Jacopo Ciaffi Elisa Gremese Barbara Tolusso Carlo Salvarani Marcello Govoni Michele Rubini Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients Genes rheumatoid arthritis LINE-1 DNA methylation methotrexate biomarkers rheumatoid factor |
| title | Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients |
| title_full | Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients |
| title_fullStr | Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients |
| title_full_unstemmed | Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients |
| title_short | Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early Rheumatoid Arthritis Patients |
| title_sort | seropositivity dependent association between line 1 methylation and response to methotrexate therapy in early rheumatoid arthritis patients |
| topic | rheumatoid arthritis LINE-1 DNA methylation methotrexate biomarkers rheumatoid factor |
| url | https://www.mdpi.com/2073-4425/13/11/2012 |
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