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Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

Lookup NU author(s): Dr Faye Cooles, Dr Jessica Tarn, Dr Dennis LendremORCiD, Najib NaamaneORCiD, Alice Lin, Benjamin Millar, Dr Nicola Maney, Dr Amy AndersonORCiD, Dr Nishanthi Thalayasingam, Julie Diboll, Dr Graham Smith, Dr Louise Reynard, Dr Arthur Pratt, Professor John IsaacsORCiD



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)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Objectives: An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action. Methods: In a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes. Results: We reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α). Conclusions: Our data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.

Publication metadata

Author(s): Cooles FAH, Tarn J, Lendrem DW, Naamane N, Lin CMA, Millar B, Maney NJ, Anderson AE, Thalayasingam N, Diboll J, Bondet V, Duffy D, Barnes MR, Smith GR, Ng S, Watson D, Henkin R, Cope AP, Reynard LN, Pratt AG, Isaacs JD

Publication type: Article

Publication status: Published

Journal: Annals of the Rheumatic Diseases

Year: 2022

Pages: Epub ahead of print

Online publication date: 09/06/2022

Acceptance date: 23/05/2022

Date deposited: 06/07/2022

ISSN (print): 0003-4967

ISSN (electronic): 1468-2060

Publisher: BMJ Publishing Group


DOI: 10.1136/annrheumdis-2022-222370

PubMed id: 35680389


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Funder referenceFunder name
ANR and RTCure
Academy of Medical Sciences
British Society of Rheumatology
Connect Immune Research
JGW Patterson Foundation
Immune-Mediated Inflammatory Disease Biobank in the UK (IMID-Bio-UK)
The Wellcome Trust