FRI0166 Characterisation of phosphodiesterase 4 (PDE4) blockade in the synovium of psoriatic arthritis patients: a focus on synovial invasiveness and t-cell polyfunctionality

Background Owing to the multi-faceted nature of the pathogenesis of psoriatic arthritis (PsA), the development of multi-targeted agents has been an area of intensive research. Such agents include the phosphodiesterase 4 (PDE4) inhibitors, Rolipram and Apremilast, which elevate intracellular cAMP levels to modulate a number of anti-inflammatory mechanisms. However, the effect of PDE4 blockade within the complex inflammatory environment of the inflamed synovium remains to be elucidated. Objectives To characterise the effect of PDE4 blockade in PsA using ex vivo synovial whole tissue explants and synovial single cell suspensions reflective of the complex synovial micro-environment. Methods Ex-vivo PsA whole tissue synovial explants were cultured in the presence of PDE4 inhibitor, Rolipram, for 24 hour. The expression of pro-inflammatory mediators were quantified by ELISA and MSD multiplex. A 21 day synovial explant matrigel model was utilised to examine synovial fibroblast (SFC) invasiveness to allow for a long-term assessment. For the characterisation of synovial T-cells, synovial explants were digested and cultured in the presence of Rolipram for 8 hours, stimulated and stained for surface and intracellular T-cell markers. Cell surface expression of CD161 was used to identify Th17 lineage (CD161 +Th17 and exTh17 cells) or non-Th17 lineage (CD161-) Th1 cells. SPICE analysis was utilised to determine the proportions of mono- and polyfunctional T-cells, which were correlated with disease activity scores. Results Rolipram treatment inhibited the spontaneous secretion of inflammatory mediators IL-6, IL-8, MCP-1 and MMP-1 (all p Conclusions PDE4 blockade mediates broad anti-inflammatory mechanisms in PsA synovial tissue through the reduced expression of pro-inflammatory mediators, decreased invasiveness and reduced T cell polyfunctionality. We also demonstrate the feasibility of using ex vivo models to determine “ in situ like” assessments of therapeutic agents and further our understanding of disease pathogenesis. Disclosure of Interest None declared