Regulated genes in psoriatic skin during treatment with fumaric acid esters

Background Fumaric acid esters (FAEs) are widely used in Europe for the treatment of psoriasis because of their clinical efficacy and favourable safety profile. However, the mechanisms of action by which FAEs improve psoriasis remain largely unknown. Objectives To identify pathways and mechanisms affected by FAE treatment and to compare these with pathways affected by treatment with the antitumour necrosis factor (anti-TNF)-α biologic etanercept. Methods In a prospective cohort study, 50 patients with plaque psoriasis were treated with FAEs for 20 weeks. Nine patients were randomly selected for gene expression profiling of plaque biopsies from week 0 and week 12. The groups consisted of FAE responders [> Psoriasis Area and Severity Index (PASI)-75 improvement] and nonresponders (< PASI-50 improvement). Changes in gene expression profiles were analysed using Ingenuity Pathway Analysis (IPA) and the outcome was compared with gene expression affected by etanercept. Results Response to FAE treatment was associated with a ≥ 2-fold change (P < 0·05) in the expression of 458 genes. In FAE responders the role of interleukin-17A in the psoriasis pathway was most significantly activated. Glutathione and Nrf2 pathway molecules were specifically induced by FAE treatment and not by etanercept treatment, representing an FAE-specific effect in psoriatic skin. In addition, FAE treatment specifically induced the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ in responding patients. Conclusions FAE treatment induces glutathione and Nrf2 pathway genes in lesional skin of patients with psoriasis. In responders, FAEs specifically regulate the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ, which are important in normal cutaneous development, and the T-helper (Th)2 and Th17 pathways, respectively. What's already known about this topic? Fumaric acid esters (FAEs) are used in the treatment of psoriasis, but the mechanisms of action are poorly known. In vitro actions of FAEs include inhibition of keratinocyte proliferation and inhibition of dendritic cell maturation. What does this study add? FAE treatment of patients with psoriasis specifically induces activation of the Nrf2 and glutathione pathways in psoriatic skin. GATA3 and NFκBIZ are FAE-specific molecules related to treatment response and these transcription factors are important in the T-helper (Th)2 and Th17 pathways, respectively.

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