Journal
ANNALS OF THE RHEUMATIC DISEASES
Volume 78, Issue 11, Pages 1505-1516Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2019-215355
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Funding
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2014-55942-R, SAF2017-88086-R]
- FIS grant from Institute of Health Carlos III (ISCIII) [PI17/00993]
- RETICS network grant from ISCIII (RIER), FEDER 'Una manera de hacer Europa' [RD16/0012/0013]
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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.
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