Psoriatic arthritis monocyte DNA methylomes bridge joint and skin inflammatory pathways across rheumatoid arthritis and psoriasis

OBJECTIVES: Immune-mediated inflammatory diseases share clinical, genetic, and immunological features, but their specific molecular drivers are not fully defined. Psoriatic arthritis (PsA) exemplifies this overlap, bridging the joint pathology of rheumatoid arthritis (RA) with the skin involvement of psoriasis (PsO). We investigated shared and disease-specific epigenomic traits across the RA-PsA-PsO spectrum, focusing on monocyte DNA methylation and transcriptional programmes. METHODS: We compared genome-wide DNA methylation profiles from peripheral blood monocytes from patients with RA, PsA, PsO, undifferentiated arthritis, and matched healthy donors. We correlated DNA methylation changes with joint- and skin-associated disease activity indices (Disease activity score in 28 joints and body surface area) and analysed for transcription factor motif and pathway enrichment. Single-cell RNA sequencing datasets of monocytes from RA, PsA, and PsO were incorporated to validate and extend epigenomic findings at the transcriptional level in monocyte subsets. RESULTS: Across RA, PsA, and PsO, we identified a common methylation signature enriched in enhancers and immune regulatory pathways, implicating transcription factors such as interferon regulatory factors, signal transducer and activator of transcription proteins, Krüppel-like factors, and CCAAT/enhancer-binding proteins. PsA exhibited a dual epigenomic profile, sharing features with both RA and PsO, including Major histocompatibility complex (MHC) class II-related loci and fibroblast growth factor receptor signalling. The dual disease activity component of PsA correlated with methylation changes linked to inflammasome components, on the one hand, and cytokine signalling (interleukin [IL]-23/IL-17, IL-7, IL-2), on the other. Single-cell transcriptomic analysis confirmed convergent alterations in antigen presentation, interferon responses, nuclear factor kappa B (NF-κB) signalling, and fibroblast-associated genes, while highlighting PsA-specific transcriptional signatures. CONCLUSIONS: Monocyte epigenomes reveal shared inflammatory programmes across RA, PsA, and PsO, with PsA occupying a dual molecular state with joint and skin autoimmunity. Integration with single-cell transcriptomes underscores common and distinct pathogenic pathways in PsA, providing insights into underlying disease mechanisms and classification.