THU0073 THE ANTI-ANGIOGENIC ROLE OF TOFACITINIB DURING EXPERIMENTAL MODEL OF ARTHRITIS.
Authors: P. Cipriani, P. DI Benedetto, P. Ruscitti, O. Berardicurti, V. Liakouli, F. Carubbi, N. Panzera, N. Grazia, M. DI Vito Nolfi, B. DI Francesco, A. Maurizi, N. Rucci, A. Teti, F. Zazzeroni, E. Alesse, R. Giacomelli
Journal: Annals of the Rheumatic Diseases (2020)

Background: During rheumatoid arthritis (RA), a chronic autoimmune disease, the loop existing between inflammation and angiogenesis, characterised by new vessels formation associated with the increased recruitment of inflammatory cells, via the abnormal neo-angiogenesis in the synovial tissues, is considered an early important pathogenic mechanism. Tofacitinib, a potent and selective JAK inhibitor, showed a good profile of safety and efficacy in RA patients, slowing the radiographic progression of the disease. In the last years, many works confirmed that some pro-angiogenic genes are targets of STATs family, and among them, vascular endothelial growth factors (VEGF), a potent pro-angiogenic molecule, may promote the new vessels formation via JAK/STAT pathways. Objectives: The aim of this work was to investigate the inhibiting role of tofacitinib, on the angiogenic mechanisms occurring during experimental model of arthritis. Methods: Healthy control (HC) ECs were stimulated with VEGF and/or tofacitinib and assessed for tube formation and migration, by matrigel and Boyden chamber assay. Furthermore, after ethical approval the experimental model of arthritis was obtained, stimulating 32 mice with collagen (CIA) and 32 mice with PBS (control). At day-19, CIA and controls mice were divided in 16 mice receiving vehicle and 16 mice receiving tofacitinib. At day-35, the mice were scarified and the thickness of paw joints, the synovial vessels and the serum levels of VEGF and Ang-2 were evaluated Results: In vitro , after tofacitinib-treatment, HC-ECs lose their ability to form vessels and to migrate. In vivo , tofacitinib significantly prevented the increase of paw thickness induced by the collagen administration and reduced the vessel density in synovial tissues of joints, when compared to CIA that did not received tofacitinib. Furthermore, the serum levels of VEGF and Ang-2 were higher in CIA mice, than in control mice. The administration of tofacitinib was able to prevent the VEGF and Ang-2 accumulation in CIA mice. Conclusion: During the last decade, the biological analogies between solid tumors and synovial pannus, and the encouraging results of anti-angiogenic treatments in oncology, lead to increasing interest for angiogenesis as a possible therapeutic target in RA. The present study demonstrated the anti-angiogenic efficacy of tofacitinib, opening a new perspective application for this molecule and improving our therapeutic skill to control the clinical evolution of RA. References: [1]Leblond A et al. Autoimmun Rev 2017;16:594-601. [2]Fleischmann R et al. N Engl J Med 2012;367:495-507. [3]Marrelli A, Autoimmun Rev 2011;10:595-8. Disclosure of Interests: Paola Cipriani Grant/research support from: Actelion, Pfizer, Speakers bureau: Actelion, Pfizer, Paola Di Benedetto Grant/research support from: Paola Di Benedetto received grant from Dompè outside this work., Piero Ruscitti Grant/research support from: Piero Ruscitti received grant from Pfizer outside this work., Speakers bureau: Piero Ruscitti received speaker honoraria BMS, MSD, Ely Lilly, SOBI outside this work, Onorina Berardicurti: None declared, Vasiliki Liakouli Grant/research support from: Vasiliki Liakouli received grant from Pfizer outside this work., Speakers bureau: Vasiliki Liakouli received speaker honoraria from Sanofi Genzyme outside this work., Francesco Carubbi Speakers bureau: Francesco Carubbi received speaker honoraria from Abbvie and Celgene outside this work., Noemi Panzera: None declared, Nicolò Grazia: None declared, Mauro Di Vito Nolfi: None declared, Barbara Di Francesco: None declared, Antonio Maurizi: None declared, Nadia Rucci: None declared, Anna Teti: None declared, Francesca Zazzeroni: None declared, Edoardo Alesse: None declared, Roberto Giacomelli Grant/research support from: Roberto Giacomelli received research grant from Pfizer. This study was supported by an unconditioned Research grant from Pfizer., Speakers bureau: Roberto Giacomelli received speaker honoraria from Abbvie, Roche, Actelion, BMS, MSD, Ely Lilly, SOBI and Pfizer outside this work.