Mechanisms for beneficial effect of etanercept on psoriasis unraveled
MedWire News: Study findings suggest that etanercept, an anti-tumor necrosis factor (TNF)-α therapy, exerts its effect through targeting epidermal activation, mainly through suppression of the interleukin (IL)-20 subfamily.
Etanercept was found to rapidly suppress many keratinocyte products, as well as epidermal expression of the IL-20 subfamily (IL-19, IL-20, and IL-24), which likely reduces regenerative hyperplasia.
To investigate the molecular mechanisms of etanercept, Frank Wang (University of Michigan, Ann Arbor, USA) and colleagues assessed the early (≤4 week) biochemical and cellular effects of the medication on skin lesions in 25 patients who responded to treatment prior to substantial clinical improvement.
The average Physicians' Global Assessment (PGA) of responders at baseline was 3.2 ('moderate' disease), with improvement beginning at 2 weeks (PGA=2.8) and greatest at 12 weeks (PGA=1.3), corresponding with 'minimal' disease.
Within 1 week, etanercept acutely suppressed gene expression of the IL-20 subfamily of cytokines, which were shown to be predominantly epidermis-derived and implicated in stimulating epidermal hyperplasia.
"While anti-IL-20 antibodies have thus far failed in clinical trials, this failure might be explained by the functional redundancy of the IL-20 subfamily. As such, the IL-20 subfamily, as a group, or its receptors remain therapeutic targets for psoriasis," say the researchers.
Suppression of other keratinocyte-derived products, such as chemokines and antimicrobial proteins, also occurred during this period, while suppression of epidermal regenerative hyperplasia occurred within 1-3 weeks.
Th17 inflammatory mediators including IL-23p19, IL-12p40, IL-17A, and IL-22 were suppressed by 3-4 weeks.
When the team performed in vitro assessments, they found that TNF-α and IL-17A coordinately stimulated the expression of the IL-20 subfamily in normal keratinocytes. "Suppression of dendritic cell activation, resulting from etanercept's antagonism of TNF-α, leads to dampened Th17 function," comment Wang and team.
The authors say that the ability of TNF-α to coordinate with IL-17A to regulate the IL-20 subfamily in keratinocytes and its stimulating effect on IL-23-producing DCs in conjunction with etanercept's downregulation of T-cell and DC function/activation, "support a role for Th17 elements in psoriasis pathogenesis, a concept validated by the efficacy of IL-12/23 inhibitors such as ustekinumab."
The findings are published in the British Journal of Dermatology.
By Ingrid Grasmo