Early tissue responses in psoriasis to Enbrel

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This article published in The British Journal of Dermatology sets out to to better understand the mechanism of action of Enbrel (etanercept) by examining very early changes in the lesional skin of psoriasis.

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Background:
Anti-TNF-α therapy has made a significant impact on the treatment of psoriasis. Despite being designed to neutralize TNF-α activity, the mechanism of action of these agents in the resolution of psoriasis remains unclear.

Objectives:
To better understand the mechanism of action of etanercept by examining very early changes in the lesional skin of psoriasis patients responding to etanercept.

Methods:
20 chronic plaque psoriasis patients were enrolled and received 50mg etanercept twice weekly. Skin biopsies were obtained before treatment and on days 1, 3, 7 and 14 post-treatment. Skin mRNA expression was analysed by QRT-PCR and microarray; cytokine and phosphoprotein levels were assessed using multiplexed bead arrays.

Results:
In etanercept responders, we observed no significant changes in IL-17A, IL-22 and IFN-γ mRNA or protein in the first week of treatment; however, there was a 2.5-fold down-regulation of IL17RC mRNA (p<0.05) after day 1, accompanied by decreased ERK1/2 phosphorylation. Transcriptional analysis revealed genes suppressed by etanercept significantly overlapped with IL-17A-induced genes, and a marked overlap was also observed between the genes suppressed by etanercept and by the anti-IL17A therapy ixekizumab. Finally we show that TNF-α enhances the expression of IL-17RC and shRNA inhibition of IL-17R expression abrogates synergistic gene induction by TNF and IL17A.

Conclusions:
These results suggest that the early responses of psoriasis plaques to etanercept may be due to decreased tissue responsiveness to IL-17A due to suppressed IL17RC expression in keratinocytes, blunting the strong synergy between TNF-α and IL-17, which contributes to the maintenance of psoriasis lesions.

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