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

Objectives 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)A 2 production in human whole blood (WB) as a possible mechanism. Methods We evaluated the effects of 4 JAKis— tofacitinib, baricitinib, filgotinib, and upadacitinib (0.04-20.0 μM)—on TXB 2 biosynthesis in clotting WB from healthy subjects, serving as a marker for platelet TXA 2 generation. Additionally, we assessed the impact of these JAKis on TXB 2 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. Results All JAKis increased serum TXB 2 production in clotting WB, although not in a concentration-dependent manner. In LPS-stimulated WB, tofacitinib (1 μM) significantly increased TXB 2 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 TXB 2 in HSs (30% ± 22%, n=10). Upadacitinib showed a trend towards increased TXB 2 (46% ± 40%, n=7), while filgotinib did not (21% ± 19%, n=7). Aspirin (100 μM) almost completely reduced serum TXB 2 in the presence of all JAKis. Conclusions The enhanced biosynthesis of TXA 2 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.