Rheumatoid arthritis (RA) is a chronic, symmetrical, aggressive autoimmune disease involving multiple body joints. This study calculated the proportions of cell clusters, and 657 DEGs in CD16+ monocyte clusters were identified according to proportion and immune score. The interaction intensity of CD8+T cell clusters in RA was elevated, with strong interaction. The output signals of platelets, monocytes, and NK cells in RA were higher, as were the incoming signals of CD8+T cells. According to the incoming and outgoing cells, 10 ligand-receptor pairs were highly expressed in RA. Then, the association analysis of DEGs and differentially methylated genes (DMGs) was conducted, and four key genes of IFI44L (cg05696877), ISG15 (cg20062691), TAP1 (cg16853860), and TNFSF10 (cg01059398) were found. The expression analysis of these four genes in the validation set, ROC curves of the training and validation sets, and gene correlation analysis revealed an essential role in RA pathogenesis. The immune gene TNFSF10 had an AUC value > 0.9 in both the training and validation sets, indicating significant diagnostic ability. Finally, the TNFSF10 analysis in pan-cancer indicated a close relationship with the expression of various tumor patients and the degree of immune cell invasion. Therefore, this gene may be a potential target for human diseases, such as RA and tumors.