Abstract
Changes in the plasma metabolic profile were characterised in newly diagnosed rheumatoid arthritis (RA) patients upon commencement of conventional disease-modifying anti-rheumatic drug (cDMARD) therapy. Plasma samples collected in an early RA randomised 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 three months post-commencement of nonbiologic cDMARD. Metabolites that changed in association with changes in the DAS44 score were identified at the three-month timepoint. A total of nine metabolites exhibited a clear correlation with a 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 C-reactive protein (CRP). 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 inflammatory disease in humans. Quantitative metabolic biomarker-based tests of clinical change in state are feasible and should be developed around the itaconate pathway.
Highlights
Rheumatoid arthritis (RA) is a chronic, destructive, immune-mediated inflammatory condition that predominantly affects synovial joints
Itaconate appears to be involved in the regulation of inflammation, its elevation leading, to suppression of the inflammatory response [29] and functional roles in human inflammatory disease have yet to be reported, our studies indicate levels are elevated as inflammation is diminished
The findings suggest that further study of the itaconate pathway and macrophage activity may reveal additional important insights into immune function regulation and rheumatoid arthritis (RA) pathogenesis and may reveal new, clinically relevant, markers of disease activity and treatment response
Summary
Rheumatoid arthritis (RA) is a chronic, destructive, immune-mediated inflammatory condition that predominantly affects synovial joints. Metabolites 2020, 10, 241 to external stimuli (e.g., cigarette smoke) triggers persistent systemic autoimmunity, and subsequent inflammatory cell articular recruitment, leading to tissue damage [1]. Constitutional features, such as weight loss, malaise or fever are prevalent in RA patients and RA patients exhibit an increased resting metabolic rate [2], which may in part be related to increased immune cell activation and turnover. Chronic synovitis is associated with angiogenesis and, increased mediator release, e.g., prostanoids and chemokines that may be detected in the circulation. It is possible that changes in disease activity state may be reflected in measurable changes in biochemical activity that is demonstrated through detailed characterisation of metabolite profiles
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