Anti-TNF, pan-JAK, and JAK1-selective inhibition differentially alter mechanisms of flow-mediated dilation in human...

Patients with chronic inflammatory disorders, including inflammatory bowel disease (IBD), carry an increased risk of cardiovascular disease. The 2022 ORAL Surveillance study reported that the pan-selective Janus kinase inhibitor (JAKi) tofacitinib was associated with increased risk of major adverse cardiovascular events (MACE) among patients with rheumatoid arthritis compared with antitumor necrosis factor (anti-TNF) therapy. This prompted guideline changes regarding the use of all JAKis, including upadacitinib, a JAK1-selective drug approved for use in chronic inflammatory conditions, including IBD. However, the mechanism underlying JAKi-related MACE outcomes and the significance of JAK selectivity relative to TNF inhibition remain unclear. Microvascular dysfunction (MVD) is a predictor of MACE. Flow-mediated dilation (FMD) is a measure of MVD. Using an established ex vivo model of resistance arterioles isolated from adipose tissue, we performed the first mechanistic comparison of antitumor necrosis factor (anti-TNF; infliximab), pan-JAK inhibitor (tofacitinib), and JAK1-selective (upadacitinib) therapies on human microvascular endothelial function. Arterioles were obtained from low-cardiovascular-risk subjects of both sexes. Isolated microvessels were incubated with drugs of interest. Flow-mediated dilation (FMD), an assessment of MVD, was measured before and after nitric oxide (NO) synthase inhibition or hydrogen peroxide (H₂O₂) scavenging. No therapy statistically altered FMD magnitude, yet underlying mechanisms differed. Control and infliximab-treated vessels maintained physiologic NO-mediated dilation. Tofacitinib induced a shift toward pathologic H₂O₂-mediated dilation. Upadacitinib impaired NO-dependent dilation without evidence of compensatory H₂O₂ signaling. In summary, anti-TNF therapy and selective versus nonselective JAKi differentially modulate endothelial mechanisms of vasodilation, suggesting unique microvascular phenotypes with potential implications for cardiovascular risk.NEW & NOTEWORTHY This is the first ex vivo mechanistic comparison of antitumor necrosis factor therapy (infliximab) and selective (upadacitinib) versus nonselective (tofacitinib) Janus kinase inhibition in human microvessels. Flow-mediated dilation showed no statistical differences; however, the mechanisms driving endothelial dilation varied. We report a shift from nitric oxide- to hydrogen peroxide-mediated dilation with tofacitinib, a distinct phenotype with upadacitinib, and nitric oxide-dependent dilation with infliximab, suggesting differential effects of IBD therapies on microvascular endothelial physiology.