Ricerc@Sapienza

Rheumatoid arthritis (RA) is a chronic, autoimmune disorder characterized by synovial inflammation; the systemic nature of RA accounts for the excess of atherosclerotic cardiovascular risk. Monocytes, and most of all, their differentiated form, macrophages, are the main driver of synovial inflammation. Moreover, monocytes are able to migrate to the atherosclerotic inflamed plaque in vessel wall where they might become foam cells. JAK-inhibitors (JAK-i), tofacitinib (JAK3/JAK1-i) and baricitinib (JAK1/JAK2-i), upadacitinib and filgotinib (JAK1-selective) are targeted synthetic anti-rheumatic drugs (tsDMARDs) approved for the treatment of RA. The molecular mechanisms of JAK-i effectiveness needs to be better elucidated. Preliminary results (unpublished data) from a collaborative study on baricitinib-treated RA patients attending our out-patients clinic demonstrated a possible role of phosphorylated STAT1, a target of Janus-kinases, in circulating Mo in distinguishing patients with a good clinical response from non-responders. Moreover, preliminary data on endothelial dysfunction, the earliest stage of atherosclerotic plaque, showed a significant improvement of flow-mediated dilation in our RA patients treated with baricitinib.
Based on these premises, the aim of the project will be to investigate the effect of inhibiting different JAK/STAT pathways on Mo phenotype and activity.
The experimental procedures will be constituted of ex vivo experiments: the analysis of the Mo profile and evaluation of its role as possible marker of treatment response, able to predict the achievement of remission/low-disease activity; the evaluation of the STAT phosphorylation status in the different Mo subsets at baseline, 3 and 12 months of follow-up. In vitro experiments will focus on the analysis of the in vitro effect of different JAK-i on Mo phenotype, STAT phosphorylation, cytokine production on Mo cultures.