Effects of JAK inhibitors on thromboxane biosynthesis in rheumatic diseases, and prostanoid profiles in axial spondyloarthritis

<p dir="ltr">Rheumatic diseases are a group of disorders that affect the joints and can also involve other organs such as the skin, blood vessels, and internal tissues. Many are driven by abnormal immune responses that lead to chronic inflammation. Targeted therapies, including Janus kinase inhibitors (JAKis), have improved treatment outcomes. However, their use has been associated with an increased risk of cardiovascular events, and the underlying mechanisms are not fully understood. Prostanoids are lipid mediators involved in inflammation, vascular function, and platelet activation. Changes in prostanoid production may contribute to cardiovascular risks.</p><p dir="ltr">The overall aim of this thesis was to investigate prostanoid biosynthesis in inflammation, with particular focus on the effects of JAKis (tofacitinib, baricitinib, upadacitinib, and filgotinib) on prothrombotic thromboxane A₂ (TXA₂), assessed by its stable metabolite thromboxane B₂ (TXB₂), and their potential cardiovascular implications. In addition, the role of prostanoids in axial spondyloarthritis (axSpA) was examined. The studies were based on lipopolysaccharide (LPS)-stimulated whole blood assay (WBA), clotting whole blood for serum thromboxane measurements, and analysis of urinary prostanoid metabolites.</p><p dir="ltr">In Paper I, JAKis increased thromboxane B₂ (TXB₂) in whole blood in vitro, as reflected by increased serum TXB₂ levels. This effect was strongly reduced by acetylsalicylic acid (ASA), suggesting a possible strategy to counteract increased thrombotic risk. Building on these findings, Paper II examined whether different JAKis showed variable effects on prostanoid production. Tofacitinib and baricitinib produced more pronounced increases in prostanoid levels, whereas other inhibitors showed more modest effects, indicating that these effects are drug-specific rather than class effects. In Paper III, prostanoid levels in treatment-naïve patients with axSpA were comparable to healthy controls and remained stable over time, with only a decrease in prostaglandin E₂ (PGE₂). This reduction may reflect long-term treatment effects. However, the absence of marked systemic changes does not exclude a role for prostanoids at the tissue level, where they may contribute to local inflammation and pain.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. Janus kinase inhibitors enhance prostanoid biosynthesis in human whole blood in vitro: implications for cardiovascular side effects and prevention strategies<b>. </b><b>Sabreen Alabbasi</b>*, Stefania Tacconelli*, Mirjam de Vries, Iva Gunnarsson, Vilija Oke, Marika Kvarnström, Alessandra De Michele, Patrizia Di Gregorio, Paola Patrignani^#, Helena Idborg^#, Per-Johan Jakobsson^#. Annals of the Rheumatic Diseases. 2025;84(9):1549-1560. *Shared first authorship. ^#Shared last authorship. <a href="https://doi.org/10.1016/j.ard.2025.03.014" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.ard.2025.03.014</a></p><p dir="ltr">II. Differential drug-specific effects of Janus kinase inhibitors on thromboxane production in vitro: implications for cardiovascular risk. <b>Sabreen Alabbasi</b>, Ming-Mei Shang, Dinesh Nirmalan, Fatima Mehdi, Aikaterini Chatzidionysiou, Mirjam de Vries, Marika Kvarnström, Per-Johan Jakobsson^#, Helena Idborg^#. ^#Shared last authorship. [Manuscript]</p><p dir="ltr">III. Prostanoid profiles are unaltered in treatment-naïve axial spondyloarthritis versus healthy controls. <b>Sabreen Alabbasi</b>, Mirjam de Vries, Sara Brolin, Marika Kvarnström, Helena Idborg^#, Per-Johan Jakobsson^#. ^#Shared last authorship. [Manuscript]</p>