@article{8cd2ee6c31cc4921ad6370ee7cd4de38,
title = "Changes in plasma itaconate elevation in early rheumatoid arthritis patients elucidates disease activity associated macrophage activation",
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.",
keywords = "biomarker discovery, DMARD, inflammation, itaconate, liquid chromatography–mass spectrometry (LC-MS), macrophage, precision medicine, rheumatoid arthritis, tricarboxylic acid (TCA) cycle",
author = "R{\'o}n{\'a}n Daly and Gavin Blackburn and Cameron Best and Goodyear, {Carl S.} and Manikhandan Mudaliar and Karl Burgess and Anne Stirling and Duncan Porter and McInnes, {Iain B.} and Barrett, {Michael P.} and James Dale",
note = "Funding Information: Conflicts of Interest: R.D., G.B., K.B., D.P., C.B., C.S.G. and M.P.B. have nothing to disclose. M.M. reports other support from CEREVANCE, LTD, outside the submitted work. A.S. reports grants from Pfizer UK, during the conduct of this survey. I.B.M. reports grants from Pfizer, grants from Chief Scientist Office, grants from Arthritis Research UK (ARUK), during the conduct of the study; grants and personal fees from Bristol Myers Squibb (BMS), personal fees from Abbvie, grants and personal fees from Union Chimique Belge (UCB), grants and personal fees from Pfizer, grants and personal fees from Janssen, personal fees from Lilly, outside the submitted work. J.D. reports grants from Chief Scientist{\textquoteright}s Office, Scottish Government and from Pfizer UK during the conduct of the study; nonfinancial support from Abbvie UK, outside the submitted work. Funding Information: The TaSER study was jointly funded by a Clinical Academic Fellowship from the Chief Scientist?s Office, Scottish Executive and an Investigator Initiated project grant from Pfizer UK. The metabolomics study was funded by an additional Investigator Initiated project grant from Pfizer UK. R.D. was funded by Wellcome (105614/Z/14/Z). M.P.B. is part of the Wellcome Centre for Molecular Parasitology funded by a core grant from Wellcome (104111/Z/14/Z). Funding Information: Funding: The TaSER study was jointly funded by a Clinical Academic Fellowship from the Chief Scientist{\textquoteright}s Office, Scottish Executive and an Investigator Initiated project grant from Pfizer UK. The metabolomics study was funded by an additional Investigator Initiated project grant from Pfizer UK. R.D. was funded by Wellcome (105614/Z/14/Z). M.P.B. is part of the Wellcome Centre for Molecular Parasitology funded by a core grant from Wellcome (104111/Z/14/Z). Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = jun,
day = "10",
doi = "10.3390/metabo10060241",
language = "English",
volume = "10",
pages = "1--12",
journal = "Metabolites",
issn = "2218-1989",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "6",
}