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Adenosine metabolic signature in circulating CD4+ T cells predicts remission in rheumatoid arthritis

Lookup NU author(s): Philip Brown, Dr Amy AndersonORCiD, Najib NaamaneORCiD, Dr Dennis Lendrem, Professor John IsaacsORCiD, Dr Arthur Pratt



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Objectives Long-term outcomes in rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate (MTX) remains the first-line disease modifying therapy, however there are no biomarkers with which to identify those most likely to achieve remission. To address this unmet need we explored metabolic pathways involved in MTX mechanism of action within circulating CD4+T cells in a cohort of treatment naive patients with early RA. Methods Purified CD4+T cells were isolated from peripheral blood of 68 patients with early RA commencing MTX. The expression of a range of putative MTX metabolism and mechanism of action targets were explored by flow-cytometry and transcriptional analysis. From these data significant predictors of Disease Activity Score 28-C reactive protein (DAS28-CRP) remission (<2.4 at 6 months) were determined by logistic regression (clinical; flow-cytometry data) and linear modelling (gene expression data). Results Low baseline DAS28-CRP was associated with remission at 6 months (p=0.02). Expression of the ectonucleotidase CD39, involved in ATP-ADP conversion during adenosine synthesis, was higher on CD4+CD25 High regulatory T cells at baseline in those achieving remission (molecules of equivalent fluorescence 1264 vs 847; p=0.007). Expression of other adenosine signalling elements in CD4+T cells were also upregulated at baseline in patients achieving remission: AMPD1 (p<0.001), ADORA2b (p=0.039) and ADORA3 (p=0.047). When combined into a single predictive metric, a combination of these variables outperformed baseline DAS28-CRP in prediction of early remission (area under the curve 0.92 vs 0.67, p=0.001) Conclusions Adenosine signalling is important in the achievement of early remission with MTX in RA and biomarkers of adenosine activity may hold utility for the stratification of therapy in early disease.

Publication metadata

Author(s): Brown PM, Anderson AE, Naamane N, Lendrem DW, Morgan AW, Isaacs JD, Pratt AG

Publication type: Article

Publication status: Published

Journal: RMD Open

Year: 2024

Volume: 10

Issue: 1

Online publication date: 17/02/2024

Acceptance date: 07/02/2024

Date deposited: 04/03/2024

ISSN (electronic): 2056-5933

Publisher: BMJ Publishing Group


DOI: 10.1136/rmdopen-2023-003858

PubMed id: 38367982


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Funder referenceFunder name
Versus Arthritis (Research into inflammatory Arthritis CEntre; award reference 22072).
Wellcome Trust training Fellowship (R120782)