Janus kinase inhibitors enhance prostanoid biosynthesis in human whole blood in vitro: implications for cardiovascular side effects and prevention strategies.

Abstract

Janus kinase inhibitors (JAKis) effectively treat chronic inflammatory diseases but are associated with cardiovascular side effects through unknown mechanisms. This study aimed to investigate the impact of JAKis on prothrombotic thromboxane (TX)A₂ production in human whole blood (WB) as a possible mechanism. We evaluated the effects of 4 JAKis- tofacitinib, baricitinib, filgotinib, and upadacitinib (0.04-20.0 μM)-on TXB₂ biosynthesis in clotting WB from healthy subjects, serving as a marker for platelet TXA₂ generation. Additionally, we assessed the impact of these JAKis on TXB₂ production in WB from healthy subjects, patients with systemic lupus erythematosus (SLE), and treatment-naïve patients with axial spondyloarthritis (axSpA) after 24-hour lipopolysaccharide (LPS) stimulation, as a marker of platelet and leukocyte prostanoid biosynthesis. All JAKis increased serum TXB₂ production in clotting WB, although not in a concentration-dependent manner. In LPS-stimulated WB, tofacitinib (1 μM) significantly increased TXB₂ production in healthy subjects (HSs) (42% ± 33%, n = 17), patients with SLE (57% ± 39%, n = 12), and patients with axSpA (31% ± 23%, n = 15). Baricitinib (1 μM) also increased TXB₂ in HSs (30% ± 22%, n = 10). Upadacitinib showed a trend towards increased TXB₂ (46% ± 40%, n = 7), while filgotinib did not (21% ± 19%, n = 7). Aspirin (100 μM) almost completely reduced serum TXB₂ in the presence of all JAKis. The enhanced biosynthesis of TXA₂ in platelets, with a minor contribution from leukocytes, may contribute to the increased cardiovascular risk associated with JAKis. Low-dose aspirin may offer a protective effect, warranting further investigations.