Inflammatory Arthritis is characterised by neoangiogenesis, leukocyte infiltration and synovial hyperplasia, leading to cartilage degradation and joint destruction. Two of the most common forms of inflammatory arthritis are rheumatoid arthritis (RA) and psoriatic Arthritis (PsA). While common pathogenic features exist between RA and PsA, significant differences have been observed at the clinical, immunological, cellular and molecular levels. Specifically, the most defined differences include circulating autoantibodies, vascular morphology, synovialtissue immune cells, the pattern of periarticular inflammation and entheseal involvement. While some synthetic and biological DMARDs appear to be effective in both patient groups specific differences in response to new targeted therapies are observed that may be explained by specific molecular differences in PsA compared with RA. However, little is known about the underlying mechanisms involved in driving these pathogenic and therapeutic differences. While several studies have demonstrated differences in vascular morphology and cellular infiltrates at the site of inflammation, this has mainly been restricted to tissue-histology. This project will perform a comparative study of PsA and RA patients, along with extensive mechanistic studies using synovial-tissue and cells, focusing on (i)-single cell analysis of stromal cell subsets and activation, (ii)-functional, metabolic and transcriptional regulation, and (iii) potential new therapeutic strategies. Specifically, in well-defined RA and PsA patient cohorts we aim to, (i) perform synovial tissue single-cell analysis using advanced 30-colour flow-cytometry, single-cell RNAseq, functional assays and advanced microscopy, (ii) examine the role of metabolism in mediating synovial cell pathogenic responses in RA and PsA utilising Seahorse-technology, metabolic functional assays and FLIM analysis, and (iii) establish ‘preclinical proof-of-concept studies’ which will examine the identified pathways in RA/PsA exvivo synovial-tissue models. Discoveries from our project will provide further insight into the underlying mechanisms that distinguish RA from PsA, and will identify new disease markers and/or drug candidates for the treatment of early disease.
