Fumaric acid esters mechanisms of action

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This study set out to identify pathways and mechanisms affected by Fumaric acid esters (FAE) treatment and to compare them with pathways affected by treatment with the anti-TNF-α biologic Enbrel (etanercept)

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Background:
Fumaric acid esters (FAE) 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 FAE 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 anti-TNF-α biologic etanercept.

Methods:
In a prospective cohort study, 50 patients with plaque psoriasis were treated with FAE 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 (>PASI-75 improvement) and non-responders (<PASI-50 improvement). Changes in gene expression profiles were analyzed 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 IL17A in psoriasis’ pathway was most significantly activated. Glutathione and Nrf2 pathway molecules were specifically induced by FAE treatment and not by etanercept treatment, representing a 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 FAE specifically regulates the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ, which are important in normal cutaneous development, Th2 and Th17 pathways, respectively.

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