Plasma Itaconate elevation following successful cDMARD treatment in early rheumatoid arthritis patients elucidates disease activity associated macrophage activation

Objective To characterize changes in the plasma metabolic profile in newly diagnosed rheumatoid arthritis (RA) patients upon commencement of conventional disease modifying anti-rheumatic drug (cDMARD) therapy. Methods Plasma samples collected in an early RA randomized strategy study ( NCT00920478 ) that compared clinical (DAS) disease activity assessment with musculoskeletal ultrasound assessment (MSUS) to drive treatment decisions were subjected to untargeted metabolomic analysis. Metabolic profiles were collected at pre- and 3 months post commencement of non-biologic cDMARD. Metabolites that changed in association with changes in the DAS44 score were identified at the 3 month timepoint. Results A total of ten metabolites exhibited a clear correlation with reduction in DAS44 score following cDMARD commencement, particularly itaconate, its derived anhydride and a derivative of itaconate coA. Increasing itaconate correlated with improved DAS44 score and decreasing levels of CRP. Conclusion cDMARD treatment effects invoke consistent changes in plasma detectable metabolites, that in turn implicate clinical disease activity with macrophages. Such changes inform RA pathogenesis and reveal for the first time a link between itaconate production and resolution of an inflammatory disease in humans. Quantitative metabolic biomarker based tests of clinical change in state are feasible and should be developed around the itaconate pathway. Key Messages What is already known about this subject? Rheumatoid arthritis is associated with perturbations in metabolic activity, which have also been associated with response to certain treatments. In vitro work on immunometabolism has recently revealed itaconate as a key metabolite controlling macrophage activation. What does this study add? In newly diagnosed RA, commencement of csDMARD therapy is associated with changes in the levels of ten metabolites (especially itaconate and its derivatives) that correlate to a corresponding fall in disease activity Pathway analyses suggest these metabolites are associated with macrophage activation. How might this impact on clinical practice? Changes in metabolite levels in response to treatment provide additional new insights into RA pathogenesis that suggest a focus on macrophage activation state. The association of increased itaconate with decreased inflammation point to possible routes of intervention in RA.