Association of Epigenetic Trajectory With Development of Clinical Rheumatoid Arthritis in Individuals With...

The presence of anti-citrullinated protein antibodies in the absence of clinical inflammatory arthritis identifies individuals at risk for rheumatoid arthritis (RA). We examined whether epigenetic remodeling of DNA methylation distinguishes those who ultimately develop RA ("converters") from individuals who remain asymptomatic ("nonconverters").

Genome-wide DNA methylation was quantified in peripheral blood mononuclear cells separated into CD4 T memory and naive cells and B cells collected at baseline and longitudinally over up to five years from converters who were anti-CCP3 positive (n = 21), nonconverters who were anti-CCP3 positive (n = 50), and controls who were anti-CCP3 negative (n = 69), as well as patients with early RA (n = 29). Differentially methylated loci (DMLs) were identified, followed by pathway enrichment analysis. Machine-learning algorithms assessed the predictive value of individual CpG sites for future RA onset.

At baseline, DMLs clearly separated converters from nonconverters and patients with early RA. Among the pathways associated with differentially methylated genes, enrichment of aberrant NOTCH signaling and DNA repair pathways was particularly prominent in B cells. Longitudinally, methylomes remained stable in controls and nonconverters but underwent progressive remodeling in converters, tracing a "RA methylome trajectory" toward the early RA methylome involving regulatory elements. Machine-learning models incorporating top CpG predictors accurately classified future converters with RA.

DNA methylation is a dynamic process that continuously remodels in individuals who were asymptomatic and anti-CCP3 positive as they progress to disease, whereas it remained relatively stable in nonconverters and controls. Progressive epigenetic remodeling during the trajectory from at risk to clinical arthritis highlights pathogenic pathways and yields biomarkers that may inform prognostic testing and preventive intervention in preclinical RA.