The results of our analysis imply that DNA methylation levels of type I IFN-related genes identified can be useful biomarkers in the evaluation and diagnosis of GD, RA, SLE, and SSc, and the biomarker panel with all DMS found on the genes involved (IFIT1, IRF7, MX1, OAS1, USP18, and RSAD2) demonstrate the best diagnostic capacity compared to each single type-I IFN related gene, which can correctly discriminate between RA or SSc patients and healthy controls. This evidence concerns the gene USP18 and rheumatoid arthritis.