Positive and Negative Cardiovascular Effects of JAK Inhibitors in Inflammation

Chronic inflammation, characteristic of many autoimmune diseases, such as rheumatoid arthritis (RA), or myeloproliferative neoplasms (MPNs), is an independent driver of accelerated cardiovascular (CV) risk, primarily through proinflammatory cytokines that induce atherosclerosis and endothelial dysfunction. Although biologic therapies (tumor necrosis factor [TNF], interleukin [IL]-6, or IL-1 inhibitors) improve both clinical manifestations and CV outcomes, JAK inhibitors (JAKi) present a paradox. JAKi provide potent systemic inflammation control, sometimes superior to biologic therapies, this effect does not translate into a proportional CV risk reduction in all patients. Instead, JAKi have been linked to increased adverse CV events in high-risk patient populations with RA, resulting in a Food and Drug Administration safety warning. Conversely, JAKi show therapeutic benefit in patients with MPNs. In MPNs, JAKi specifically target the JAK2 mutation, reducing blood cell proliferation and the associated prothrombotic state. This review compares the distinct biologic mechanisms underlying this JAKi CV paradox, contrasting the JAK2 mutation-driven pathology in MPNs with the widespread cytokine-driven alterations in inflammatory diseases. In the latter, the observed CV risk might stem from failure of JAKi to fully inhibit prothrombotic pathways induced by cytokines (TNF and IL-17) and the potential dose-related vascular toxicity. Understanding these binary effects will provide new insights into the divergent CV impact of JAKi.