Pos1023 characterization of tryptophan metabolism alteration in rheumatoid arthritis and evidence for a therapeutic potential of aadat administration in mice

Background Tryptophan metabolism alterations have been reported in inflammatory diseases, including rheumatoid arthritis. However, understanding whether these alterations participate RA development and can therefore be considered as putative therapeutic targets remain undetermined. Objectives In this study, we combined quantitative Tryptophan metabolomics in the serum of RA patients and corrective administration of a recombinant enzyme in experimental arthritis to address the question. Methods Targeted quantitative metabolomics was performed on the serum of 574 treatment naïve early untreated RA patients from the ESPOIR cohort and on 98 healthy subjects. Dosages were also conducted in serum of collagen-induced arthritis mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the collagen-antibody induced arthritis model. Results Differential analysis revealed drastic changes in Trp metabolites levels in RA patients compared to healthy controls. Amongst them, decreased levels of kynurenic (KYNA), xanthurenic (XANA) acids and indoles derivatives as well as an increased level of quinolinic acid in the serum of RA were positively correlated to disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively correlated to quality-of-Life scores. Similar alterations of metabolites of the kynurenine pathway were observed in collagen-induced arthritis. Finally, the administration of the recombinant enzyme Aminoadipate Aminotransferase (AADAT), which is responsible for the generation of XANA and KYNA, was protective in collagen-antibody induced arthritis model. Conclusion Altogether, our clinical and experimental data indicate that Trp metabolism alterations play an active role in RA pathogenesis and might be considered as new therapeutic avenue. Acknowledgements HS received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (ERC-2016-StG-71577). This project was partly funded by the Region GRAND EST, the FEDER project “Target (Translational research in ARticular and Gastroinstestinal inflammatory diseases in Grand EsT)”. Disclosure of Interests David MOULIN: None declared, Mahdia TAIEB: None declared, Chloe Michaudel: None declared, Anne Aucouturier: None declared, Luis Bermudez-Humaran: None declared, Philippe Langella: None declared, Denis Mulleman: None declared, Xavier Mariette Consultant of: AstraZeneca, Novartis, BMS, Galapagos, Pfizer, GSK, Philippe Dieudé: None declared, Jean-Yves Jouzeau: None declared, Patrick Emond: None declared, Jérémie SELLAM Consultant of: Abbvie, Fresenius Kabi, BMS, Roche Chugai, Sandoz, Lilly, Gilead, Novartis, and Janssen, Grant/research support from: Pfizer, MSD, Schwa Medico, and BMS, Harry SOKOL Shareholder of: Enterome Exeliom-Biosciences, Consultant of: Amgen, Fresenius, IPSEN, Actial, Astellas, Danone, THAC, Biose, BiomX, Eligo, Immusmol, Adare, Nestle, Ferring, MSD, Bledina, Pfizer, Biocodex, BMS, Bromatech, Gilead, Janssen, Mayoli, Roche, Sanofi, Servier, Takeda, Abbvie,