Analysis of miRNA expression in patients with rheumatoid arthritis during remission and relapse after a 5-year trial of tofacitinib treatment

The physiopathology of rheumatoid arthritis (RA) is mediated by proinflammatory cytokines, some of which are regulated by the JAK/STAT pathway. Tofacitinib is a JAK inhibitor, but its role in the regulation of microRNAs (miRNAs) is unknown. There is also no information regarding the role of miRNAs in the clinical relapse/remission of RA. The present project aims to identify a signature profile of miRNA expression in a subgroup of RA patients who had to discontinue tofacitinib treatment (because of the ending of a 5-year open-label clinical trial) and to describe the expression of miRNAs during RA remission or flare-up. The relative expression of 61 miRNAs was determined in serum samples with the Firefly (TM) BioWorks assay. Statistical analysis was performed by means of Students t-test and heatmap analysis was performed with Firefly (TM) Analysis Workbench software and in the software GraphPad (R) Prism v5.0. Target prediction and Gene Ontology analysis were carried out using bioinformatic tools. We found a distinctive signature of miRNA expression associated with relapse, featuring upregulated expression of hsa-miR-432-5p (p < 0.05). We also found upregulation of hsa-miR-194-5p (p < 0.05) in samples of patients with RA flare-up. Gene Ontology analysis of the target genes for hsa-miR-432-5p was performed to identify relevant pathways associated with relapse; the implications of these pathways in the physiopathology of RA are discussed. Tofacitinib treatment does not have a direct effect on the expression of measured miRNAs. The changes in hsa-miR-432-5p and hsa-miR-194-5p are associated with the regulation of proinflammatory pathways and RA flare-up.