Inflammatory arthritis, including rheumatoid arthritis (RA) and psoriatic arthritis (pSA), affects 2% of the population and bears a high social and economic cost. Targeted biologic therapies, including TNF inhibitors, have improved the therapeutic outcome of inflammatory arthritis, however a significant proportion of patients do not respond or respond sub-optimally, while others experience adverse events. In addition these costly biologic treatments impose a significant economic burden on healthcare systems. Therefore new and more affordable treatment strategies are required to improve outcomes. The RA joint is profoundly hypoxic due to inflammation and dysregulated angiogenesis, while hypoxia in turn drives inflammation. During hypoxia, cells must adapt to generate energy in low oxygen and therefore switch from utilising aerobic oxidative phosphorylation to anaerobic glycolysis. In addition, certain immune cells that infiltrate the inflamed joint demonstrate Warburg metabolism, utilising glycolysis even in the presence of oxygen, thereby providing essential building blocks to support their proliferation. We hypothesise that inflammation in the RA joint is fuelled by glycolysis, which is inextricably linked to hypoxia via the oxygen sensing transcription factor HIF-1α. These processes of glycolysis and hypoxia represent an opportunity for therapeutic targeting. In this study we will examine the metabolic shift within pathogenic fibroblasts and T cells in the RA joint, and their reciprocal interactions. We will also investigate the role of hypoxia in influencing the bioenergetic profiles of fibroblasts and T cells. Finally, we will utilise existing metabolic compounds, including the low cost anti-diabetic drug metformin, in order to target the process of glycolysis and thereby reduce inflammation in synovial cells and ex vivo models of RA. Metformin treatment was of benefit in pre-clinical models of autoimmunity, but has not yet been tested in cells from RA patients. This study could lead to the identification of RA as a new indication for metformin.
