Rheumatoid arthritis (RA) is a common disease of rheumatic diseases. The aim of this study was to identify gene signatures in RA and uncover their potential mechanisms. Gene expression profiles of GSE1919, GSE55235, GSE55457, and GSE77928 were downloaded from GEO database. The above four series contained 76 samples, including 44 RA patients and 32 normal controls. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and protein-protein interaction (PPI) network of the differentially expressed genes (DEGs) was constructed by Cytoscape software. Up-regulated DEGs were significantly enriched in biological processes, including immune response, positive regulation of immune system process and regulation of immune system process, while down-regulated DEGs were significantly enriched in biological processes, including response to oxygen-containing compound, cellular lipid metabolic process, and lipid metabolic process. KEGG pathway analysis showed the up-regulated DEGs were enriched in cytokine-cytokine receptor interaction, chemokine signaling pathway, and primary immunodeficiency. The 104 hub genes, which were significantly differently expressed between patients and normal controls in at least two datasets, were identified from the PPI network, and subnetworks revealed that these genes were involved in significant pathways, including cytokine-cytokine receptor interaction, chemokine signaling pathway, and primary immunodeficiency. The present study indicated that the identified DEGs and hub genes promote our understanding of molecular mechanisms underlying the development of RA, such as C-C motif chemokine 5 (CCL5), might have a negative impact in the development of RA. CCL5 and its related genes might be the potential diagnostic biomarkers for the therapeutic strategies of RA.