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

RA-MAP Consortium; Faye A H Cooles; Jessica Tarn; Dennis W Lendrem; Najib Naamane; Chung ma Lin; Ben Millar; Nicola J Maney; Amy E Anderson; Nishanthi Thalayasingam; Julie Diboll; Vincent Bondet; Darragh Duffy; Michael R Barnes; Graham R Smith; Sandra Ng; David Watson; Rafael Henkin; Andrew P Cope; Louise N Reynard; Arthur G Pratt; John D Isaacs

doi:10.1136/annrheumdis-2022-222370

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

RA-MAP Consortium, Faye A H Cooles^*, Jessica Tarn, Dennis W Lendrem, Najib Naamane, Chung ma Lin, Ben Millar, Nicola J Maney, Amy E Anderson, Nishanthi Thalayasingam, Julie Diboll, Vincent Bondet, Darragh Duffy, Michael R Barnes, Graham R Smith, Sandra Ng, David Watson, Rafael Henkin, Andrew P Cope, Louise N ReynardArthur G Pratt, John D Isaacs

^*Corresponding author for this work

Inflammation and Ageing

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1214-1223
Number of pages	10
Journal	Annals of the Rheumatic Diseases
Volume	81
Issue number	9
Early online date	9 Jun 2022
DOIs	https://doi.org/10.1136/annrheumdis-2022-222370
Publication status	Published - Sept 2022

Bibliographical note

Funding Information:
Funding Newcastle researchers received infrastructural support via the Versus Arthritis Research into Inflammatory Arthritis Centre (Ref 22072), funding from The Medical Research Council; Academy of Medical Sciences; British Society of Rheumatology; The Wellcome Trust; JGW Patterson Foundation; Immune-Mediated Inflammatory Disease Biobank in the UK (IMID-Bio-UK); Connect Immune Research; ANR and RTCure. This work was supported by the National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre for Ageing and Long-Term Conditions; views expressed are the authors’ and not necessarily those of the National Health Service, the National Institute of Health and Care Research or the Department of Health.

Competing interests JDI discloses research grants from Pfizer, Janssen and GSK; conference support from Eli Lilly and Gilead; speaker/consulting fees from AbbVie, BMS, Gilead, Roche and UCB. FAHC discloses speaker fees from AstraZeneca.The remaining authors have no competing interests.

Publisher Copyright:
© 2022 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

Antirheumatic agents
Arthritis
Immune system diseases
Inflammation
Rheumatoid

ASJC Scopus subject areas

Rheumatology
Immunology and Allergy
Immunology
General Biochemistry,Genetics and Molecular Biology

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RA-MAP Consortium, Cooles, F. A. H., Tarn, J., Lendrem, D. W., Naamane, N., Lin, C. M., Millar, B., Maney, N. J., Anderson, A. E., Thalayasingam, N., Diboll, J., Bondet, V., Duffy, D., Barnes, M. R., Smith, G. R., Ng, S., Watson, D., Henkin, R., Cope, A. P., ... Isaacs, J. D. (2022). Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming. Annals of the Rheumatic Diseases, 81(9), 1214-1223. https://doi.org/10.1136/annrheumdis-2022-222370

@article{095bebc66812450eb5474ff96a7bbd8b,

title = "Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming",

abstract = "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.",

keywords = "Antirheumatic agents, Arthritis, Immune system diseases, Inflammation, Rheumatoid",

author = "{RA-MAP Consortium} and Cooles, {Faye A H} and Jessica Tarn and Lendrem, {Dennis W} and Najib Naamane and Lin, {Chung ma} and Ben Millar and Maney, {Nicola J} and Anderson, {Amy E} and Nishanthi Thalayasingam and Julie Diboll and Vincent Bondet and Darragh Duffy and Barnes, {Michael R} and Smith, {Graham R} and Sandra Ng and David Watson and Rafael Henkin and Cope, {Andrew P} and Reynard, {Louise N} and Pratt, {Arthur G} and Isaacs, {John D} and Fisher, {Benjamin A}",

note = "Funding Information: Funding Newcastle researchers received infrastructural support via the Versus Arthritis Research into Inflammatory Arthritis Centre (Ref 22072), funding from The Medical Research Council; Academy of Medical Sciences; British Society of Rheumatology; The Wellcome Trust; JGW Patterson Foundation; Immune-Mediated Inflammatory Disease Biobank in the UK (IMID-Bio-UK); Connect Immune Research; ANR and RTCure. This work was supported by the National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre for Ageing and Long-Term Conditions; views expressed are the authors{\textquoteright} and not necessarily those of the National Health Service, the National Institute of Health and Care Research or the Department of Health. Competing interests JDI discloses research grants from Pfizer, Janssen and GSK; conference support from Eli Lilly and Gilead; speaker/consulting fees from AbbVie, BMS, Gilead, Roche and UCB. FAHC discloses speaker fees from AstraZeneca.The remaining authors have no competing interests. Publisher Copyright: {\textcopyright} 2022 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

month = sep,

doi = "10.1136/annrheumdis-2022-222370",

language = "English",

volume = "81",

pages = "1214--1223",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "9",

}

RA-MAP Consortium, Cooles, FAH, Tarn, J, Lendrem, DW, Naamane, N, Lin, CM, 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 2022, 'Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming', Annals of the Rheumatic Diseases, vol. 81, no. 9, pp. 1214-1223. https://doi.org/10.1136/annrheumdis-2022-222370

TY - JOUR

T1 - Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

AU - RA-MAP Consortium

AU - Cooles, Faye A H

AU - Tarn, Jessica

AU - Lendrem, Dennis W

AU - Naamane, Najib

AU - Lin, Chung ma

AU - Millar, Ben

AU - Maney, Nicola J

AU - Anderson, Amy E

AU - Thalayasingam, Nishanthi

AU - Diboll, Julie

AU - Bondet, Vincent

AU - Duffy, Darragh

AU - Barnes, Michael R

AU - Smith, Graham R

AU - Ng, Sandra

AU - Watson, David

AU - Henkin, Rafael

AU - Cope, Andrew P

AU - Reynard, Louise N

AU - Pratt, Arthur G

AU - Isaacs, John D

AU - Fisher, Benjamin A

N1 - Funding Information: Funding Newcastle researchers received infrastructural support via the Versus Arthritis Research into Inflammatory Arthritis Centre (Ref 22072), funding from The Medical Research Council; Academy of Medical Sciences; British Society of Rheumatology; The Wellcome Trust; JGW Patterson Foundation; Immune-Mediated Inflammatory Disease Biobank in the UK (IMID-Bio-UK); Connect Immune Research; ANR and RTCure. This work was supported by the National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre for Ageing and Long-Term Conditions; views expressed are the authors’ and not necessarily those of the National Health Service, the National Institute of Health and Care Research or the Department of Health. Competing interests JDI discloses research grants from Pfizer, Janssen and GSK; conference support from Eli Lilly and Gilead; speaker/consulting fees from AbbVie, BMS, Gilead, Roche and UCB. FAHC discloses speaker fees from AstraZeneca.The remaining authors have no competing interests. Publisher Copyright: © 2022 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

KW - Antirheumatic agents

KW - Arthritis

KW - Immune system diseases

KW - Inflammation

KW - Rheumatoid

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U2 - 10.1136/annrheumdis-2022-222370

DO - 10.1136/annrheumdis-2022-222370

M3 - Article

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AN - SCOPUS:85132368309

SN - 0003-4967

VL - 81

SP - 1214

EP - 1223

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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