Epigenetic trajectory predicts development of clinical rheumatoid arthritis in ACPA+ individuals: Targeting Immune Responses for Prevention of Rheumatoid Arthritis (TIP-RA)

The presence of anti-citrullinated protein antibodies (ACPAs) in the absence of clinically-apparent inflammatory arthritis (IA) identifies individuals "at-risk" for developing future clinical rheumatoid arthritis (RA). However, it is unclear why some ACPA+ individuals convert to clinical RA while others do not. We explored the possibility that epigenetic remodeling is part of the trajectory from an at-risk state to clinical disease. Cross-sectional differential methylation analysis at baseline revealed DMLs that distinguish the Pre-RA methylome from ACPA+ Non-converters. Genes overlapping these DMLs correspond to aberrant NOTCH signaling and DNA repair pathways in B cells. Longitudinal analysis showed that ACPA-Control and ACPA+ Non-converter methylomes are relatively constant. In contrast, the Pre-RA methylome remodeled along a dynamic "RA methylome trajectory" characterized by epigenetic changes in active regulatory elements. Machine learning revealed individual loci predictive of RA conversion. DNA methylation is a dynamic process in ACPA+ individuals at-risk for developing RA that later transition to clinical disease. In contrast, non-converters and controls have stable methylomes. The accumulation of epigenetic marks over time prior to conversion to clinical RA conforms to pathways that are associated with immunity and can be used to identify potential pathogenic pathways for therapeutic targeting and/or use as prognostic biomarkers.