Rheumatoid arthritis (RA) is a complex disease triggered by the interaction between genetics and the environment, especially through the shared epitope (SE) and cell surface calreticulin (CSC) theory. However, the available evidence shows that genetic diversity and environmental exposure cannot explain all the clinical characteristics and heterogeneity of RA. In contrast, recent studies demonstrate that epigenetics play important roles in the pathogenesis of RA, especially DNA methylation and histone modification. DNA methylation and histone methylation are involved in innate and adaptive immune cell differentiation and migration, proliferation, apoptosis, and mesenchymal characteristics of fibroblast-like synoviocytes (FLS). Epigenetic-mediated regulation of immune-related genes and inflammation pathways explains the dynamic expression network of RA. In this review, we summarize the comprehensive evidence to show that methylation of DNA and histones is significantly involved in the pathogenesis of RA and could be applied as a promising biomarker in the disease progression and drug-response prediction. We also explain the advantages and challenges of the current epigenetics research in RA. In summary, epigenetic modules provide a possible interface through which genetic and environmental risk factors connect to contribute to the susceptibility and pathogenesis of RA. Additionally, epigenetic regulators provide promising drug targets to develop novel therapeutic drugs for RA. Finally, DNA methylation and histone modifications could be important features for providing a better RA subtype identification to accelerate personalized treatment and precision medicine.

类风湿关节炎（RA）是一种复杂的疾病，尤其是通过共享表位（SE）和细胞表面钙网蛋白（CSC）理论，由遗传学和环境之间的相互作用引发。但是，现有证据表明，遗传多样性和环境暴露不能解释RA的所有临床特征和异质性。相反，最近的研究表明表观遗传学在RA的发病机理中起着重要作用，尤其是DNA甲基化和组蛋白修饰。DNA甲基化和组蛋白甲基化涉及先天性和适应性免疫细胞的分化以及成纤维样滑膜细胞（FLS）的迁移，增殖，凋亡和间充质特征。表观遗传介导的免疫相关基因和炎症途径的调控解释了RA的动态表达网络。在这篇综述中，我们总结了全面的证据，以显示DNA和组蛋白的甲基化与RA的发病机理密切相关，并且可以用作疾病进展和药物反应预测中的有希望的生物标志物。我们还将说明RA中当前表观遗传学研究的优势和挑战。总之，表观遗传模块提供了可能的接口，通过该接口遗传和环境风险因素相互联系，有助于RA的易感性和发病机理。此外，表观遗传调节剂为开发RA的新型治疗药物提供了有希望的药物靶标。最后，