Background:Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. The JAK/STAT pathway has been linked to the pathogenesis of PsA. Recently, JAK/STAT inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Only a few of these inhibitors have been approved for use in PsA patients with others currently in clinical trials.Objectives:The aim of this study was to examine the effect of JAKi on primary PsA synovial fibroblasts (FLS) function.Methods:Primary PsA FLS were isolated and cultured with JAKi (Peficitinib, Filgotinib, Baricitinib and Upadacitinib) in the presence of the pro-inflammatory JAK/STAT activator - Oncostatin M (OSM). The effect of JAKi on these cells was determined by Migration and Invasion Assays, ELISA and rtPCR. PsA FLS bioenergetics was assessed using an XF24 analyser, which simultaneously quantifies two energetic pathways- glycolysis (ECAR) and Oxidative phosphorylation (OCR).Results:OSM-induced Migration and Invasion was supressed by all JAKi with Peficitinib, Filgotinib and Baracitinib showing the greatest effect. Analysis by ELISA and rtPCR showed reduction in MCP-1 and IL-6 expression in response to JAKi, in contrast, an increase in IL-8 was observed. These functional effects were accompanied by a change in the cellular bioenergetic profile of PsA FLS, where OSM significantly increased the ECAR:OCR ratio in favour of glycolysis where PsA FLS displayed a hypermetabolic phenotype. This effect was reversed in the presence of JAKi, which specifically targeted the glycolytic pathway with PsA FLS returning to a more quiescent phenotype.Conclusion:This study demonstrates that JAK/STAT signalling mediates the complex interplay between inflammation and cellular metabolism in PsA pathogenesis, inhibition of which shows effective suppression of the pathogenic phenotype of PsA FLS that drives joint destruction.References:[1]Chen M, Dai SM. A novel treatment for psoriatic arthritis: Janus kinase inhibitors. Chin Med J (Engl). 2020;133(8):959-967.Disclosure of Interests:Aisling O’ Brien: None declared, Megan Hanlon: None declared, Viviana Marzaioli: None declared, Keelin Flynn: None declared, Siobhan Wade: None declared, Douglas Veale Speakers bureau: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Consultant of: Abbvie, Janssen, Novartis, MSD, Pfizer, UCB, Grant/research support from: Janssen, Abbvie, Pfizer, UCB, Ursula Fearon Speakers bureau: Abbvie, Grant/research support from: Janssen, Abbvie, Pfizer, UCB
Janus-kinase inhibitors in rheumatoid and psoriatic arthritis and other rheumatic disease