OBJECTIVES: Rheumatoid arthritis (RA) is considered a chronic autoimmune inflammatory disease that causes great morbidity and shortens life expectancy; however, the precise pathogenesis of RA remains unclear. This study aimed to select hub genes correlated with the development of RA. METHODS: Two gene expression profiles, GSE55235 and GSE12021, obtained from the Gene Expression Omnibus (GEO) were used to identify differentially expressed genes (DEGs) in control and RA samples using GEO2R, followed by other bioinformatics methods, including functional enrichment analysis, protein-protein interaction (PPI) networks, miRNA-hub gene network, and drug-hub gene interactions. In addition, qRT-PCR was finally conducted to confirm the reliability and validity of the expression level of the novel DEGs via freshly collected heparinized blood samples of healthy controls and RA patients. RESULTS: A sum of 136 upregulated and 37 downregulated DEGs were selected. Functional enrichment analysis indicated that all the upregulated DEGs were correlated with immune response, B cell receptor signalling pathway, and adaptive immune response. KEGG pathway enrichment analysis revealed that the upregulated DEGs were mostly related to cytokine-cytokine receptor interaction, primary immunodeficiency, chemokine signalling pathways, and cell adhesion molecules (CAMs). In total, 12 hub genes (IL15, KLRK1, GZMA, CXCR6, IGHV4-38-2, IGLL5, CXCL13, CXCL11, MS4A1, SDC1, SLAMF1, and PDCD1LG2) were identified and all these hub genes were upregulated, of which IGLL5 and IGHV4-38-2 were first reported to be correlated with the pathogenic mechanism and prognosis of RA. Furthermore, we also used qRT-PCR to validate the overexpression of IGLL5 and IGHV4-38-2 in RA patients compared to the healthy controls. In the miRNA-hub gene network, hsa-miR-1185-5p and hsa-miR-3679-5p might inhibit the expression of IGLL5 during the progression of RA. The 15 most promising candidate drugs, which were all approved by the Food and Drug Administration, may assist with the treatment of RA. CONCLUSIONS: Overall, these findings may assist with developing diagnostic, prognostic, and therapeutic biomarkers for RA. Key Points • IGLL5 and IGHV4-38-2 were first reported to be correlated with the pathogenic mechanism and prognosis of RA. • Besides, hsa-miR-1185-5p and hsa-miR-3679-5p may inhibit the expression of IGLL5 during the progression of RA.