{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:26:27Z","timestamp":1788459987599,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T00:00:00Z","timestamp":1660608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Rheumatoid arthritis is a highly heterogeneous autoimmune disease characterized by unpredictable disease flares and significant differences in therapeutic response to available treatments. One possible reason for poor efficacy is that it cannot be treated accurately due to no optimal stratification for RA patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aims to construct an RA classification model by m6A characters and further predict response to medication.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty m6A regulators were used to construct a random forest diagnosis model, and RNA-seq analysis was employed for external validation. The RNA modification patterns mediated by 20 m6A regulators were systematically evaluated in 1191 RA samples and explored different molecular clusters associated with other immune microenvironment characteristics and biological pathways. Then, we established an m6A score model to quantify the m6A modification patterns. The model was applied to patients at baseline to test the association between m6Ascore and infliximab responsiveness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The m6A diagnosis model showed good discriminatory ability in distinguishing RA. Patients with RA were classified into three clusters with distinct molecular and cellular signatures. Cluster A displayed strongly activated inflammatory cells and pathways. Specific innate lymphocytes occupied cluster B. Cluster C was mainly enriched in prominent adaptive lymphocytes and NK-mediated cytotoxicity signatures with the highest m6A score. Patients with a low m6Ascore exhibited significantly infliximab therapeutic benefits compared with those with a high m6Ascore (p&amp;lt; 0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study is the first to provide a comprehensive analysis of m6A modifications in RA, which provides an innovative patient stratification framework and potentially enables improved therapeutic decisions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.940918","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T07:28:47Z","timestamp":1660634927000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Predictive value of drug efficacy by M6A modification patterns in rheumatoid arthritis patients"],"prefix":"10.3389","volume":"13","author":[{"given":"Shan","family":"Song","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Xiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Feng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"ITC1","DOI":"10.7326\/AITC201901010","article-title":"Rheumatoid arthritis","volume":"170","author":"Sparks","year":"2019","journal-title":"Ann Intern Med"},{"key":"B2","doi-asserted-by":"publisher","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":"B3","doi-asserted-by":"publisher","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","article-title":"Rheumatoid arthritis","volume":"4","author":"Smolen","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2217\/epi-2016-0151","article-title":"Epigenetic alterations in rheumatoid arthritis fibroblast-like synoviocytes","volume":"9","author":"Doody","year":"2017","journal-title":"Epigenomics"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31491-5","article-title":"Novel treatment strategies in rheumatoid arthritis","volume":"389","author":"Burmester","year":"2017","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-020-01309-9","article-title":"Understanding refractory rheumatoid arthritis: Implications for a therapeutic approach","volume":"80","author":"Melville","year":"2020","journal-title":"Drugs"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1030","article-title":"MODOMICS: A database of RNA modification pathways. 2017 update","volume":"46","author":"Boccaletto","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s12943-019-1109-9","article-title":"Functions of N6-methyladenosine and its role in cancer","volume":"18","author":"He","year":"2019","journal-title":"Mol Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.014","article-title":"N(6)-methyladenosine modulates messenger RNA translation efficiency","volume":"161","author":"Wang","year":"2015","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/s12943-019-1033-z","article-title":"The role of m(6)A RNA methylation in human cancer","volume":"18","author":"Chen","year":"2019","journal-title":"Mol Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s11684-018-0654-8","article-title":"RNA m(6)A modification and its function in diseases","volume":"12","author":"Tong","year":"2018","journal-title":"Front Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2017.08.030","article-title":"Roles of RNA methylation by means of N(6)-methyladenosine (m(6)A) in human cancers","volume":"408","author":"Wang","year":"2017","journal-title":"Cancer Lett"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2018.7","article-title":"m(6)A mRNA methylation sustains treg suppressive functions","volume":"28","author":"Tong","year":"2018","journal-title":"Cell Res"},{"key":"B14","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.molimm.2017.11.009","article-title":"Potential link between m(6)A modification and systemic lupus erythematosus","volume":"93","author":"Li","year":"2018","journal-title":"Mol Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/1741-7015-12-35","article-title":"Epigenetics in the pathogenesis of rheumatoid arthritis","volume":"12","author":"Glant","year":"2014","journal-title":"BMC Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2018.00299","article-title":"Genome-wide identification of N(6)-methyladenosine (m(6)A) SNPs associated with rheumatoid arthritis","volume":"9","author":"Mo","year":"2018","journal-title":"Front Genet"},{"key":"B17","doi-asserted-by":"publisher","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 Rheum Dis"},{"key":"B18","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s12943-020-01170-0","article-title":"m(6)A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer","volume":"19","author":"Zhang","year":"2020","journal-title":"Mol Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0168-5","article-title":"Reading, writing and erasing mRNA methylation","volume":"20","author":"Zaccara","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2020.0402","article-title":"The m6A methylation landscape stratifies hepatocellular carcinoma into 3 subtypes with distinct metabolic characteristics","volume":"17","author":"Shen","year":"2020","journal-title":"Cancer Biol Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0436","article-title":"Tumor microenvironment characterization in gastric cancer identifies prognostic and immunotherapeutically relevant gene signatures","volume":"7","author":"Zeng","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.02007","article-title":"Heterogeneity of the type I interferon signature in rheumatoid arthritis: A potential limitation for its use as a clinical biomarker","volume":"8","author":"Rodriguez-Carrio","year":"2017","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32341-2","article-title":"Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial","volume":"397","author":"Humby","year":"2021","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3830","article-title":"The RNA helicase DDX46 inhibits innate immunity by entrapping m(6)A-demethylated antiviral transcripts in the nucleus","volume":"18","author":"Zheng","year":"2017","journal-title":"Nat Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.627893","article-title":"Regulatory role of the RNA N(6)-methyladenosine modification in immunoregulatory cells and immune-related bone homeostasis associated with rheumatoid arthritis","volume":"8","author":"Fan","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"5735279","DOI":"10.1155\/2020\/5735279","article-title":"Decreased ALKBH5, FTO, and YTHDF2 in peripheral blood are as risk factors for rheumatoid arthritis","volume":"2020","author":"Luo","year":"2020","journal-title":"BioMed Res Int"},{"key":"B27","doi-asserted-by":"publisher","first-page":"3120391","DOI":"10.1155\/2019\/3120391","article-title":"METTL3 attenuates LPS-induced inflammatory response in macrophages via NF-kappaB signaling pathway","volume":"2019","author":"Wang","year":"2019","journal-title":"Mediators Inflamm"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2755","DOI":"10.1038\/s41467-018-05044-4","article-title":"Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission","volume":"9","author":"Tasaki","year":"2018","journal-title":"Nat Commun"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113937","article-title":"Pre-treatment whole blood gene expression is associated with 14-week response assessed by dynamic contrast enhanced magnetic resonance imaging in infliximab-treated rheumatoid arthritis patients","volume":"9","author":"MacIsaac","year":"2014","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","first-page":"102373","DOI":"10.1016\/j.jaut.2019.102373","article-title":"The immunobiology of mTOR in autoimmunity","volume":"110","author":"Suto","year":"2020","journal-title":"J Autoimmun"},{"key":"B31","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/j.1365-2249.2012.04626.x","article-title":"Differential effects of infliximab on absolute circulating blood leucocyte counts of innate immune cells in early and late rheumatoid arthritis patients","volume":"170","author":"Coulthard","year":"2012","journal-title":"Clin Exp Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.11.060","article-title":"Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha","volume":"128","author":"Mitoma","year":"2005","journal-title":"Gastroenterology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1016\/j.autrev.2018.01.020","article-title":"NLRP3: A promising therapeutic target for autoimmune diseases","volume":"17","author":"Shen","year":"2018","journal-title":"Autoimmun Rev"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-020-00603-2","article-title":"NOD-like receptors in autoimmune diseases","volume":"42","author":"Chen","year":"2021","journal-title":"Acta Pharmacol Sin"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202753","article-title":"The type I IFN signature as a biomarker of preclinical rheumatoid arthritis","volume":"72","author":"Lubbers","year":"2013","journal-title":"Ann Rheum Dis"},{"key":"B36","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1002\/art.27226","article-title":"Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-beta\/alpha ratios in rheumatoid arthritis patients: A post hoc analysis of a predominantly Hispanic cohort","volume":"62","author":"Mavragani","year":"2010","journal-title":"Arthritis Rheumatol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/art.27702","article-title":"Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients","volume":"62","author":"Thurlings","year":"2010","journal-title":"Arthritis Rheumatol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.692160","article-title":"m(6)A modification mediates mucosal immune microenvironment and therapeutic response in inflammatory bowel disease","volume":"9","author":"Chen","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.642437","article-title":"N6-methyladenosine induced miR-34a-5p promotes TNF-alpha-Induced nucleus pulposus cell senescence by targeting SIRT1","volume":"9","author":"Zhu","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.7150\/thno.45178","article-title":"METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications","volume":"10","author":"Jian","year":"2020","journal-title":"Theranostics"},{"key":"B41","doi-asserted-by":"publisher","first-page":"eabd4742","DOI":"10.1126\/sciadv.abd4742","article-title":"Pooled CRISPR screening identifies m(6)A as a positive regulator of macrophage activation","volume":"7","author":"Tong","year":"2021","journal-title":"Sci Adv"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.3390\/ijms20061323","article-title":"m6A reader YTHDF2 regulates LPS-induced inflammatory response","volume":"20","author":"Yu","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-021-01818-1","article-title":"YTHDF2 is a potential target of AML1\/ETO-HIF1alpha loop-mediated cell proliferation in t (8, 21) AML","volume":"40","author":"Chen","year":"2021","journal-title":"Oncogene"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.940918\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T07:28:51Z","timestamp":1660634931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.940918\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,16]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2022.940918"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.940918","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,16]]},"article-number":"940918"}}