Full Papers
Tofacitinib attenuates IL-6-mediated endothelial tissue factor induction in vitro without affecting platelet aggregation in vivo: mechanistic insights into cardiovascular risk in rheumatoid arthritis
G. Cimmino1, D. Mauro2, M. Morello3, G. Titolo4, D. Iacono5, G. Forte6, A. Salzillo7, M. Raimondi8, F. Riccio9, I. Pantano10, G. De Rosa11, P. Cirillo12, F. Ciccia13
- Department of Translational Medical Sciences, Cardiology Section, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Precision Medicine, Rheumatology Section, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Translational Medical Sciences, Cardiology Section, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Precision Medicine, Rheumatology Section, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Precision Medicine, Rheumatology Section, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Precision Medicine, Rheumatology Section, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Precision Medicine, Rheumatology Section, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Precision Medicine, Rheumatology Section, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Precision Medicine, Rheumatology Section, University of Campania Luigi Vanvitelli, Naples, Italy.
- Department of Advanced Biomedical Sciences, Cardiology Section, University of Naples Federico II, Naples, Italy.
- Department of Advanced Biomedical Sciences, Cardiology Section, University of Naples Federico II, Naples, Italy. pcirillo@unina.it
- Department of Precision Medicine, Rheumatology Section, University of Campania Luigi Vanvitelli, Naples, Italy. francesco.ciccia@unicampania.it
CER18685
Full Papers
PMID: 41511754 [PubMed]
Received: 04/03/2025
Accepted : 07/07/2025
In Press: 05/01/2026
Abstract
OBJECTIVES:
Rheumatoid arthritis (RA) is characterised by systemic inflammation, which elevates the risk of atherothrombotic cardiovascular (CV) events. Although Janus kinase inhibitors (JAKi) are effective in controlling RA inflammation, post-marketing data (ORAL Surveillance) have suggested an increased risk of major adverse CV events (MACE) in patients receiving tofacitinib (TOFA). The pathophysiological mechanisms for these findings remain unclear, especially regarding platelet aggregation and tissue factor (TF) expression, two key drivers of thrombosis. In this study, we aimed to investigate the effects of TOFA on platelet aggregation and TF-mediated coagulation pathways to elucidate potential pro- or anti-thrombotic properties at the cellular level.
METHODS:
Platelet-rich plasma (PRP) from 12 healthy volunteers was incubated with TOFA (20 or 40 ng/mL), and maximal platelet aggregation (AGGmax) in response to ADP was measured by light transmission aggregometry (LTA) at 30, 60, and 90 minutes. In parallel, platelets from 14 RA patients were evaluated at baseline and at 1, 3, and 6 months of TOFA treatment (5 mg bid). Human umbilical vein endothelial cells (HUVECs) were exposed to TOFA (20 or 40 ng/mL) and/or IL-6 (0.5 ng/mL) to assess TF mRNA (by real-time PCR) and TF procoagulant activity (by factor Xa generation assay).
RESULTS:
TOFA did not alter ADP-induced platelet aggregation ex vivo in either healthy volunteers or RA patients. However, it significantly reduced IL-6-induced TF mRNA expression and activity in HUVECs. These in vitro results suggest that TOFA may counteract IL-6-mediated prothrombotic mechanisms at the endothelial level.
CONCLUSIONS:
Despite clinical concerns raised by ORAL Surveillance, our findings indicate no direct enhancement of platelet reactivity by TOFA. Instead, TOFA attenuated IL-6-driven TF expression in endothelial cells, pointing to a possible protective effect on vascular thrombogenic pathways. Further studies are warranted to reconcile these in vitro observations with real-world data on CV outcomes in RA.
