Research

Metabolic targets as new therapeutic approach in rheumatoid arthritis. 

After several years of research on biological therapies and small molecules to target inflammation, we need a different strategy to further get more insights into mechanisms underlying rheumatoid arthritis pathogenesis and identify potential new treatments, as a significant proportion of patients are partial responders. In other fields such as oncology the concept of metabolic reprograming to improve immunotherapy are concepts we believe should be translated into autoimmune diseases to complement current therapies. However, there are little data about targeting metabolic changes in RA. We seek with our research a better understanding of the biology of these metabolic pathways in RA to better characterize a new approach in its therapeutic armamentarium. Specifically, we focus on two main pathways, glucose metabolism and phospholipid metabolism. We have identified two candidates (hexokinase 2 and choline kinase), as potential metabolic targets. Understanding whether these metabolic changes contribute to inflammation, synovial hypertrophy and cartilage damage will provide a novel insight of the progression and perpetuation of RA and will provide new therapeutic approaches for clinical use.

 
Metabolic alterations involved in activated cells. Activated cells take up large amounts of glucose and glutamine and divert them to the PPP and lipid biosynthesis, respectively. Coupled to an increased uptake of glycine, serine and branched chain amino acids (leucine, isoleucine and valine), which are required for protein synthesis, this generates sufficient building blocks (nucleic acids, proteins and membranes) for proliferation. The increased generation of reactive oxygen species requires appropriate levels of antioxidants, most of which originate from the PPP. Several of these pathways will be also involved in lipid components of cellular membranes. These metabolic changes generate bioactive metabolites that are secreted, and that also contribute to cell activation. Abbreviations: 3-PG, 3-phosphoglycerate; A-KG, α ketoglutarate; CoA, coenzyme A; G6P, glucose-6-phosphate; LPA, lysophosphatidic acid; R5P, ribose-5-phosphate; S1P, sphingosine-1-phosphate; PPP, pentose-phosphate pathway.

Metabolomic profiling to predict outcome in arthritis: 
Choosing the right biological earlier in the course of rheumatoid arthritis (RA) could help to reach the goal of remission. We hypothesized that characterization of patients’ metabolic profiles, utilizing high resolution 1H-nuclear magnetic resonance (NMR) may predict response to therapy prior to treatment. 


Polar metabolite profiles are significantly different between rituximab responders and non-responders. Variations in mean 1H-NMR spectral intensities indicate unique metabolite profiles between groups before (a) treatment with rituximab. Mean sera metabolites concentrations (± SD) of RA patients before (b) treatment with rituximab. Glu: Glutamate, AcAc: Acetoacetate, *p<0 **p<0.05


Role of eicosanoids as biomarkers in arthritis:

Eicosanoids, including prostaglandins and leukotrienes, are biological lipids that are implicated in various pathological processes including inflammation. We hypothesized that by defining more precisely the eicosanoid profile in arthritis patients, we might identify novel diagnostic or prognostic biomarkers for disease activity and arthritis pathogenesis.


Eicosanoid synthesis from polyunsaturated fatty acids. The enzymes involved in the synthesis are indicated. Proinflammatory/ eicosanoids are colored in red and anti-inflammatory/pro-resolving ones in green


Animal models of relapsing polychondritis
Relapsing polychondritis (RP) is an autoimmune disease of unknown etiology. It is characterized by recurrent episodes of inflammation resulting in destruction of cartilaginous tissues, especially the pinnae, nose, and tracheobranchial cartilage. Transgenic mice expressing DQ8 and DQ6, but lacking endogenous class II molecules, develop auricular chondritis and polyarthritis. We will use this animal model to gain a better understanding of relapsing polychondritis. 

   

A highly inflamed joint and chondritic ear 1 week after disease onset. Bradley DS et al. J Immunol 1998; 161: 5046-5053