Abstract Text: Biologic therapies, including the IL-4 receptor blocker dupilumab and JAK inhibitors like upadacitinib, have revolutionized the management of atopic dermatitis (AD). However, prolonged treatment is necessary to sustain disease remission. While both therapies are clinically effective, only dupilumab has demonstrated successful dose reduction, suggesting potential disease-modifying effects. This study aimed to investigate the long-term effects of dupilumab or upadacitinib treatment on the epigenetic profile of pathogenic skin-homing T cells in AD.
Using flow cytometry, CD4+CLA+ memory T cells were isolated from AD patients at baseline and after 52 weeks of dupilumab or upadacitinib treatment. DNA methylome and RNA transcriptome analyses were conducted using the EPIC array and RNA sequencing, respectively. Non-atopic healthy controls were included.
Our analysis identified 408 differentially methylated regions (DMRs) between non-atopic individuals and AD patients, involving pathways like cytokine-cytokine receptor interactions, NF-kB, and T cell receptor signaling. Some of these DMRs were associated with a respective change in the transcriptome. Following treatments, dupilumab modulated 6 AD-related DMRs, with 4 rectifying in the direction of healthy controls. On the other hand, upadacitinib modulated 40 AD-related DMRs, the majority of which shifted further towards the AD profile. Interestingly, we identified 240 DMRs and 12 DMRs that were modulated in response to upadacitinib and dupilumab, respectively, independent of AD-related DMRs.
In conclusion, our analysis highlights distinctive effects of dupilumab and upadacitinib treatment on the epigenetic level. The observed discrepancy in the direction of modification between treatments may suggest disease-modifying properties with clinical consequences upon therapy cessation.
