The JAK-STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms

Inflammation contributes centrally to cardiovascular diseases, and anti-inflammatory treatments can reduce cardiovascular events. The JAK-STAT pathway is an emerging target in inflammation, mainly in rheumatoid arthritis (RA) and chronic myeloproliferative neoplasms (MPNs), disorders that heighten cardiovascular risk. The aim of this study was to review the international literature on the relationship between dysregulation of the JAK-STAT pathway in RA/MPNs and cardiovascular risk and on the potential cardiovascular effects of JAK-STAT inhibitors. The JAK-STAT pathway sustains inflammatory and thrombotic events in autoimmune disorders such as RA and MPNs. Here, an imbalance exists between pro- and anti-inflammatory cytokines [increased levels of interleukin (IL)-6, IL-1-beta, tumour necrosis factor-alpha, decreased levels of IL-10] and the over-expression of some prothrombotic proteins, such as protein kinase C epsilon, on the surface of activated platelets. This pathway also operates in atherosclerotic cardiovascular disease. JAK-STAT inhibitors may reduce cardiovascular events and related deaths in such conditions, but the potential of these agents requires more studies, especially with regard to cardiovascular safety, and particularly for potential prothrombotic effects. JAK-STAT inhibitors merit consideration to curb heightened cardiovascular risk in patients with RA and MPNs, with rigorous assessment of the potential benefits and risks. [GRAPHICS] Clinical effects of JAK-STAT pathway activations and JAK-STAT inhibitors. (A) Stimuli, such as mechanical stretch, pressure overload and myocardial infarction, activate the JAK2/JAK2-STAT3/STAT6 pathway. This way allows the expression of the angiotensinogen gene promoter in cardiac myocytes. Angiotensinogen eventually leads to the production of angiotensin II that in turn induces the production of cardiothropin-1, a member of the IL-6 family, ultimately producing cardiac hypertrophy. The clinical effects of this pathway are cardiac hypertrophy ormyocardial infarction (both could result in heart failure). Cardiotrophin-1 in turn allows the activation of the B-pathway. (B) Cytokines, such as IL-6, could activate the JAK2/JAK2-STAT3/STAT3 pathway in fibroblasts and endothelial cells. They are responsible for the endothelial damage that leads to atherosclerosis, with the formation of atheroma. There are several events linked to atherosclerotic cardiovascular disease, such as myocardial infarction, deep vein thrombosis and pulmonary embolism, cerebrovascular events (transient ischaemic attack, stroke), peripheral artery disease, and the formation of aortic aneurysms. JAK-STAT inhibitors, through the inhibition of the JAK-STAT pathway, may represent a way to prevent these adverse cardiovascular events. Baricitinib (JAK1/JAK2 inhibitor), tofacitinib (JAK1/JAK2/JAK3 inhibitor) and ruxolitinib (JAK1/JAK2 inhibitor) are treatment approved in RA and in MPNs that are hypothesized to have potential cardiovascular benefit.