Changes in plasma itaconate elevation in early rheumatoid arthritis patients elucidates disease activity associated macrophage activation

Rónán Daly, Gavin Blackburn, Cameron Best, Carl S. Goodyear, Manikhandan Mudaliar, Karl Burgess, Anne Stirling, Duncan Porter, Iain B. McInnes, Michael P. Barrett, James Dale*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Article number241
Pages (from-to)1-12
Number of pages12
JournalMetabolites
Volume10
Issue number6
DOIs
Publication statusPublished - 10 Jun 2020

Keywords / Materials (for Non-textual outputs)

  • biomarker discovery
  • DMARD
  • inflammation
  • itaconate
  • liquid chromatography–mass spectrometry (LC-MS)
  • macrophage
  • precision medicine
  • rheumatoid arthritis
  • tricarboxylic acid (TCA) cycle

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