DNA Methylation Discriminates Between Patients With Psoriatic Arthritis PsA, Skin Psoriasis

DNA methylation profiles in CD4+ T-cells differentiate patients with psoriasis from healthy individuals and skin psoriasis from patients with psoriatic arthritis (PsA), according to a small study published in Frontiers in Immunology.¹

“DNA methylation may represent a stable and reliable biomarker candidate for predicting disease progression from skin psoriasis to PsA, monitoring disease activity, and evaluating treatment response,” wrote first author Valentina Natoli, MD, of the University of Liverpool in the UK, and the University of Genoa in Italy, and colleagues.

The prediction of joint disease in patients with psoriasis, as well as the early and correct diagnosis of PsA in the absence of skin disease are challenging. The pathophysiology of PsA and psoriasis is not fully understood, but the role of effector CD4+ T-cells has been recognized. Epigenetic modifications are believed to be involved in the molecular pathogenesis of PsA and psoriasis. DNA methylation has been linked with pathological effector T-cell phenotypes and inflammatory cytokine expression in psoriasis. In this study, the researchers aimed to identify disease-associated DNA methylation signatures in CD4+ T-cells from patients with PsA and psoriasis which could be used as diagnostic and/or prognostic biomarkers to inform treatment.

Peripheral blood mononuclear cells were collected from 12 patients with chronic plaque psoriasis (median age 41 years, 58% male, Psoriasis Area And Severity Index [PASI] score 41.0), 8 patients with PsA (median age 56.5 years, 50% male, PASI score 6.8) and 8 healthy controls (median age 27 years, 50% male). Patients developed skin psoriasis before the onset of PsA. At the time of enrollment, patients were not taking any relevant systemic immunomodulating therapy. CD4+ T-cells were separated by fluorescence-activated cell sorting. DNA methylation profiling and bioinformatic analyses were performed. The Interferome database was used to identify genes under interferon control, and DNA Methylation Scores were calculated.

The numbers and proportions of CD4+ T-cell subsets did not vary between patients with PsA, those with skin psoriasis, and controls. The researchers identified 883 differentially methylated positions (DMPs) affecting 548 genes between “all” patients with psoriasis and controls. Further analysis separated controls from skin psoriasis and PsA. When promoter DMPs were included, Gene Ontology enrichment analysis identified hypermethylation of genes involved in “regulation of wound healing, spreading of epidermal cells,” “negative regulation of cell-substrate junction organization,” and “negative regulation of focal adhesion assembly.” When controls and “all” patients with psoriasis were compared, 69.2% of DMPs mapped to interferon-related genes. DNA methylation profiles also distinguished patients with PsA from those with skin psoriasis (2949 DMPs/1084 genes) through genes affecting “cAMP-dependent protein kinase inhibitor activity” and “cAMP-dependent protein kinase regulator activity.” Treatment with cytokine inhibitors, including for Interleukin (IL-)17 and Tumor Necrosis Factor (TNF), corrected DNA methylation patterns of IL-17/TNF-associated genes, and methylation scores were linked to PASI scores.

The future application of DNA methylation in “clinical practice requires prospective validation in independent cohorts,” the authors concluded.

Limitations of the study include its small sample size and the age differences between patient groups. Normalization techniques were applied to reduce the impact of these age differences on DNA methylation. The study was not able to assess the effect of DNA methylation on active joint counts and joint disease activity in patients with PsA, as this information was lacking, or on gene transcription, as RNA sequencing was not performed. The authors noted patients with PsA without pre-existing skin involvement will need to be studied to further understand the transition from skin psoriasis to PsA.

References

1. ^{Natoli V, Charras A, Hofmann SR, et al. DNA methylation patterns in CD4+ T-cells separate psoriasis patients from healthy controls, and skin psoriasis from psoriatic arthritis. Front Immunol. 2023;14:1245876. Published 2023 Aug 15. doi:10.3389/fimmu.2023.1245876}