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Inflammatory cytokines shape a changing DNA methylome in monocytes mirroring disease activity in rheumatoid arthritis
  1. Javier Rodríguez-Ubreva1,2,
  2. Carlos de la Calle-Fabregat1,2,
  3. Tianlu Li1,2,
  4. Laura Ciudad1,2,
  5. Maria L Ballestar3,
  6. Francesc Català-Moll1,2,
  7. Octavio Morante-Palacios1,2,
  8. Antonio Garcia-Gomez1,2,
  9. Raquel Celis4,
  10. Frances Humby5,
  11. Alessandra Nerviani5,
  12. Javier Martin6,
  13. Costantino Pitzalis5,
  14. Juan D Cañete4,
  15. Esteban Ballestar1,2
  1. 1 Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
  2. 2 Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Barcelona, Spain
  3. 3 Nursing Department, Faculty of Nursing and Podiatry, University of Valencia, Valencia, Comunitat Valenciana, Spain
  4. 4 Rheumatology Service, Hospital Clinic and IDIBAPS, Barcelona, Spain
  5. 5 Centre for Experimental Medicine and Rheumatology, The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  6. 6 Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Parque Tecnológico de La Salud (PTS), Granada, Spain
  1. Correspondence to Dr Esteban Ballestar, Bellvitge Institute for Biomedical Research, Barcelona, Spain; eballestar{at}


Objective Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that mainly targets joints. Monocytes and macrophages are critical in RA pathogenesis and contribute to inflammatory lesions. These extremely plastic cells respond to extracellular signals which cause epigenomic changes that define their pathogenic phenotype. Here, we interrogated how DNA methylation alterations in RA monocytes are determined by extracellular signals.

Methods High-throughput DNA methylation analyses of patients with RA and controls and in vitro cytokine stimulation were used to investigate the underlying mechanisms behind DNA methylation alterations in RA as well as their relationship with clinical parameters, including RA disease activity.

Results The DNA methylomes of peripheral blood monocytes displayed significant changes and increased variability in patients with RA with respect to healthy controls. Changes in the monocyte methylome correlate with DAS28, in which high-activity patients are divergent from healthy controls in contrast to remission patients whose methylome is virtually identical to healthy controls. Indeed, the notion of a changing monocyte methylome is supported after comparing the profiles of same individuals at different stages of activity. We show how these changes are mediated by an increase in disease activity-associated cytokines, such as tumour necrosis factor alpha and interferons, as they recapitulate the DNA methylation changes observed in patients in vitro.

Conclusion We demonstrate a direct link between RA disease activity and the monocyte methylome through the action of inflammation-associated cytokines. Finally, we have obtained a DNA methylation-based mathematical formula that predicts inflammation-mediated disease activity for RA and other chronic immune-mediated inflammatory diseases.

  • DNA methylation
  • TNFa
  • rheumatoid arthritis
  • disease activity
  • DAS28

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  • Handling editor Josef S Smolen

  • JR-U and CdlC-F contributed equally.

  • Contributors J.R-U, CC-F, JDC and EB conceived experiments. JR-U, CC-F, TL and LC performed experiments. JR-U, CC-F, TL, FC-M and OM-P performed biocomputing analysis; JRU, CC-F and MLB performed statistical analysis. RC, FH, AN, CP and JDC performed patient selection, provided samples and analysed the data. JR-U, CC-F, FC-M, AG-G, RC, JM, JDC and EB analysed the data. AG-G illustrated graphical representations. EB, JR-U and CC-F wrote the paper. All authors read and approved the final manuscript.

  • Funding We thank CERCA Programme/Generalitat de Catalunya for institutional support. EB was funded by the Spanish Ministry of Economy and Competitiveness (MINECO; grant numbers SAF2014-55942-R and SAF2017-88086-R). JDC was funded by FIS grant (PI17/00993) from Institute of Health Carlos III (ISCIII). JDC, JM and EB are supported by RETICS network grant from ISCIII (RIER, RD16/0012/0013), FEDER 'Una manera de hacer Europa'.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Bellvitge Ethics Committee (approval number PR284/14 and PR275/17).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request.