Understanding the effects of Janus kinase inhibitors on the cardiovascular system in comparison to main biological DMARDs in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is linked to increased cardiovascular (CV) risk, as is typical for systemic inflammation. The systemic effects of inflammatory cytokines induce vascular dysfunction, leading to thrombosis and other CV diseases. Reducing inflammation should attenuate this risk. For several decades, biologics against a single cytokine, such as TNF inhibitors and IL-6 receptor blockers seem to support this, demonstrating excellent control of RA and reduction of CV events. The Janus kinase inhibitors (JAKi) have been approved more recently. By inhibiting the JAK-STAT pathway, they can simultaneously block the function of multiple cytokines. Unlike biologics, JAKi are associated with increased risk of adverse CV events in high-risk RA patients. This review suggests biological mechanisms that could explain the worse CV outcomes with JAKi compared to biologics. Among the key pro-inflammatory cytokines, IFNγ, IL-6 and IL-23 use directly the JAK-STAT pathway, whereas IL-17, TNF and IL-1β do not, lacking JAK-related receptors. Nevertheless, these non-JAK-dependent cytokines can still influence the JAK-STAT pathway to promote vascular effects in an indirect fashion. Moreover, IL-17 and TNF specifically when combined, exert major pro-coagulant and pro-thrombotic effects on vessels independently of JAKs. As a result, JAKi might not block these pathways and even upregulate them, at high concentrations, leading to increased thrombotic risk. Finally, new research shows that JAKi cannot prevent the increase in adhesion and coagulation molecules as well as the deficiency in physiological anti-coagulant proteins triggered by TNF and IL-17 on endothelial cells. Increased efforts to control CV risk factors are critical in this context.