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.

An anti-inflammatory diet (ITIS diet) for patients with rheumatoid arthritis

A diet that combines several strategies to decrease inflammation may represent a more realistic dietary approach for those suffering from RA. Thus, we designed the ITIS diet, an anti-inflammatory diet for a complementary therapy in RA patients. Data from an open label pilot trial conducted to evaluate the feasibility and clinical and biological outcomes of a 2-week ITIS diet trial in RA patients showed an improvement of pain and other clinical scores. Fecal microbiome and metabolome composition at baseline were associated with pain response in preliminary data

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Pain Response to theITIS Diet is associated with Different Changes in Microbiome and Metabolome.
 A-C). Changes in a-diversity of microbiome (A), fecal (B) or plasma metabolome (C) according to pain50 over the 3 timepoints. D) After diet PCoA of Unweighted UniFrac of microbiome according to pain50. E-F) After diet PCoA of Canberra distances of fecal (E) or plasma (F) metabolome according to pain50. G-I) Songbird differential ranking of microbes (G), fecal metabolites (H) and plasma metabolites (I) (association with response compared to no response as the reference). Positive values in the rank plot correspond to a positive association with response. Features presented in each plot are selected by top and bottom ranked quartiles.

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 in inflammatory 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 not only novel diagnostic or prognostic biomarkers for disease activity, but also a better understanding of the pathogenesis of rheumatoid arthritis, psoriatic arthritis, and osteoarthritis.

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