Microbiota Analysis to Predict Outcomes of Rheumatoid Arthritis Patients Treated With JAK-inhibitor

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Gut microbiota is becoming an important predictor of response and tolerance with anti-cancer drugs. However, its potential of prediction in other fields has poorly been explored. Drug metabolism and concentrations of tofacitinib depend on body mass index, liver function and cytochrome P450 activity ...

Gut microbiota is becoming an important predictor of response and tolerance with anti-cancer drugs. However, its potential of prediction in other fields has poorly been explored. Drug metabolism and concentrations of tofacitinib depend on body mass index, liver function and cytochrome P450 activity (especially CYP3A4). Humans carry in their gut trillions of germs, which are now known to be key players in health and disease. Those germs can strongly impact drug metabolism and concentrations based on 3 mechanisms. First, gut bacteria possess a huge pool of enzymes which catalyzes drug metabolism reactions. Second, gut microbiota regulates bile acid metabolism which play critical role in drug metabolism. Third, gut microbiota modulates the expression of cytochrome P450, especially CYP3A4, the main enzyme catabolizing Tofacitinib (TOFA). In addition to drug metabolism, gut microbiota is a key driver of immune activation. Clinical response to CTLA-4 or anti-PD-1 strongly depends on gut microbiota in different cancers. The experiments performed to decipher the mechanisms involved suggested that microbiota composition affects immune responses, which will facilitate or not anti-tumoral efficacy of checkpoints inhibitors. RA is a heterogeneous disease with predominant inflammation pathways varying dependent on patients. Some RA seem to be more dependent on IL-6 whereas others rely more on TNF-alpha, B or T cells. Gut microbiota was shown to affect all those different targets. Assessing baseline levels of JAK STAT signaling pathway gene expression will help us to link immune activation, gut microbiota and clinical response to TOFA. We hypothesize that gut-microbiota composition impacts TOFA metabolism, immune activation, and thus clinical response and has a great potential to predict clinical outcomes in patients with RA treated with TOFA. Study objectives : Main objective To construct a model based on gut-microbiota composition, immune activation markers (JAK-STAT signalling pathway) and clinical data to predict TOFA non-response at 3 months in RA patients with inadequate response to methotrexate. Secondary objectives To construct a model based on gut-microbiota composition, immune activation markers (JAK-STAT signalling pathway) and clinical data to predict low-disease activity at 6 months of TOFA in RA patients with inadequate response to methotrexate. To compare responders and non-responders and patients with or without adverse effects on TOFA in terms of: baseline gut-microbiota TOFA concentrations at 3 months baseline JAK-STAT signalling pathway gene expression profile baseline clinical data To correlate changes in disease activity score based on 28 joint evaluation (DAS28, see annex for calculation) between month-3 and baseline with: changes in gut microbiota TOFA concentrations changes in JAK-STAT signaling

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