Understanding Cardiovascular Events With JAK Inhibitors: Similarities and Differences of the Vascular Effects Between Different JAK Inhibitors on Endothelial Cells Exposed to Inflammatory Cytokines

Objective A cardiovascular safety issue has been associated with JAK inhibitors (JAKi). This study compares the effects of distinct approved JAKi on endothelial cell (EC) dysfunction and apoptosis during inflammation. Methods Massive inflammation was induced in human vascular ECs by tumor necrosis factor (TNF) with interleukin‐17A (IL‐17A) treated or not treated with tofacitinib, baricitinib, upadacitinib, peficitinib, ruxolitinib, and fedratinib at 1 or 10 μ M . Levels of IL‐6 and IL‐8 were measured by enzyme‐linked immunosorbent assay. Variations in gene expression of adhesion molecules and factors of blood coagulation and fibrinolysis pathways were quantified by quantitative reverse transcriptase–polymerase chain reaction. Endothelial apoptosis was measured by Annexin V staining. Results All JAKi decreased IL‐6 release of ECs stimulated with TNF+IL‐17A. In contrast, only baricitinib and fedratinib decreased IL‐8 overproduction, from 1 μ M . Fedratinib decreased the up‐regulation of vascular adhesion molecule 1 (VCAM‐1) and E‐selectin expression at 1 and 10 μ M . Tofacitinib reduced intercellular adhesion molecule 1 (ICAM‐1) and E‐selectin induction at 1 μ M . However, at 10 μ M , tofacitinib, baricitinib, upadacitinib, peficitinib, and ruxolitinib enhanced induction of VCAM‐1 and ICAM‐1 triggered by TNF+IL‐17A. Peficitinib and fedratinib at 1 and 10 μ M decreased tissue factor up‐regulation induced by TNF+IL‐17A, whereas ruxolitinib was effective only at 1 μ M . None of the JAKi could prevent the down‐regulation of the anticoagulant molecule thrombomodulin. Fedratinib and peficitinib were both proapoptotic and cytotoxic for ECs. Conclusion All JAKi reduced EC inflammation but most JAKi could not prevent the up‐regulation of adhesion molecules or the increase in procoagulant and the decrease in anticoagulant factors triggered by proinflammatory cytokines. Peficitinib and fedratinib exhibited cytotoxic effects causing EC apoptosis.