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SAT0031 Tofacitinib Regulates Synovial Inflammation in Psoriatic Arthritis, Inhibiting Stat Activation and Induction of Negative Feedback Inhibitors
  1. W. Gao,
  2. T. McGarry,
  3. C. Orr,
  4. D.J. Veale,
  5. U. Fearon
  1. Rheumatology, St.Vincent's University Hospital, Dublin, Ireland


Background 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.

Objectives To examine the effect of Tofacitinib (JAK inhibitor) on pro-inflammatory mechanisms in PsA.

Methods Primary cultures of PsA synovial fibroblasts (PsA SFC) and whole tissue PsA ex vivo synovial explants were established from PsA biopsies obtained at arthroscopy, and cultured in the presence of Tofacitinib (1μM). Phospho-STAT3 (p-STAT3), phospho-STAT1 (p-STAT1), Suppressor of Cytokine Signaling 3 (SOCS3) and Protein Inhibitor of Activated Stat 3 (PIAS3) expression was quantified by Western Blot. The effect of Tofacitinib on PsA SFC migration, invasion, matrigel network formation and MMP2/9 was quantified by wound repair assays, transwell invasion chambers and zymography. Spontaneous secretion of IL-6, IL-8, MMP3 and TIMP3 by PsA synovial explants was assessed by ELISA.

Results Tofacitinib significantly decreased p-STAT3, p-STAT1 and induced SOCS3 and PIAS3 expression in PsA SFC and synovial tissue explant cultures ex vivo (all p<0.05). Functionally, PsA SFC invasion, matrigel network formation and migration were inhibited in the presence Tofacitinib (all p<0.05). In PsA explant cultures Tofacitinib significantly decreased spontaneous secretion of IL-6 (p<0.05), IL-8 (p<0.05), MMP9/MMP2, MMP3 (p<0.05) and decreased the MMP3/TIMP3 ratio (p<0.05).

Conclusions This study demonstrates that Tofacitinib inhibits pro-inflammatory mechanisms in PsA, further supporting JAK-STAT inhibition as a therapeutic target for the treatment of PsA.

Disclosure of Interest W. Gao: None declared, T. McGarry: None declared, C. Orr: None declared, D. veale Grant/research support from: Abbvie, MSD, Pfizer, Roche, Consultant for: Pfizer, Roche, Speakers bureau: Abbott, MSD, Pfizer, Roche, U. fearon: None declared

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