Background/Purpose: Psoriatic Arthritis (PsA) is a common, chronic immune-mediated inflammatory disease, characterised by synovitis, progressive destruction of articular cartilage/bone, and is associated with psoriasis. Janus Kinase and Signal Transducer and Activator of Transcription (JAK/STAT), a critical signalling pathway involved in inflammatory mechanisms, has been implicated in the pathogenesis of PsA. This study was to examine the mechanistic effect of Tofacitinib (A novel JAK inhibitor CP-690,550) on pro-inflammatory pathways using ex vivo and  in vivo models of PsA.

Methods: PsA whole tissue synovial explant cultures were established from PsA biopsies obtained under direct visualisation at arthroscopy. This explant model maintains the architecture and cell-cell contact of the synovial tissue,  spontaneously releases pro-inflammatory mediators and therefore closely reflects the in vivo inflamed microenvironment. Primary PsA synovial fibroblasts (PsASFC) were also isolated from PsA synovial biopsies.  Phospho-STAT3 (p-STAT3), phospho-STAT1 (p-STAT1), Suppressor of Cytokine Signaling 3 (SOCS3) and Protein Inhibitor of Activated Stat 3 (PIAS3) expression were quantified by Western Blot in PsA synovial explants and PsASFC following culture with Tofacitinib (1μM) or vehicle control. Cytokine expression of IL-6, IL-8 and IL-10 in ex vivo culture synovial explants in response to Tofacitinib (0.5μM-1μM) were assessed by ELISA. Furthermore the effect of Tofacitinib (0.5μM-1μM) on PsASFC migration, invasion, matrigel network formation and MMP2/9 were quantified by wound repair assays, transwell invasion chambers and zymography.

 Results: Tofacitinib significantly decreased p-STAT3 and p-STAT1 expression in PsA synovial tissue explant cultures ex vivo and in primary PsASFC (p<0.05). In contrast Tofacitinib induced SOCS3 and PIAS3 expression in both models (p<0.05). In parallel Tofacitinib significantly decreased spontaneous secretion of IL-6 (p<0.05), IL-8 (p<0.05) and induced IL-10 (p<0.05) expression in PsA explant cultures.  Functionally, PsASFC invasion, matrigel network/tube formation, migration, and pro-MMP-2/-9 activities, were inhibited in the presence of Tofacitinib (p<0.05). 

Conclusion: This is the first study to demonstrate Jak/STAT signaling and the effect of Tofacitinib on these pathways in PsA synovial tissue and  primary PsA synovial fibroblasts. Tofacitinib mediated specific JAK-STAT signaling components, inhibited key pro-inflammatory cytokines and invasion/migrational mechanisms. Thus this data further supports the use of JAK-STAT inhibition as a potential therapeutic agent for the treatment of PsA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tofacitinib-regulates-synovial-angiogenesis-in-psoriatic-arthritis-through-induction-of-negative-feedback-inhibitors/