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Objective  Epigenetic modifications have previously been associated with rheumatoid arthritis ( RA ). In this study, we aimed to determine whether differential  DNA  methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among  RA  patients.    Methods  Peripheral blood samples were obtained from 63 patients in the University of California, San Francisco  RA  cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti‐cyclic citrullinated protein). Fluorescence‐activated cell sorting was used to separate the cells into 4 immune cell subpopulations ( CD 14+ monocytes,  CD 19+ B cells,  CD 4+ naive T cells, and  CD 4+ memory T cells) per individual, and 229 epigenome‐wide  DNA  methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease,  RA  Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators.    Results  Differential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the   CYP 2E1  and   DUSP 22  gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type–specific. Evidence of independent effects on  DNA  methylation from smoking, medication use, and disease duration were also identified.    Conclusion  Methylation signatures specific to  RA  clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity.

Hypomethylation of CYP 2E1 and DUSP 22 Promoters Associated With Disease Activity and Erosive Disease Among Rheumatoid Arthritis Patients