The IL-17 pathway is an established driver of psoriasis pathogenesis. We 
examined the detailed molecular and cellular effects of blockade of IL-17 
signaling in human psoriatic skin before and following treatment with 
brodalumab, a competitive inhibitor of the IL-17 Receptor A subunit. Thousands 
of aberrantly expressed genes in lesional skin normalized within 2 weeks 
following brodalumab treatment, with conversion of the lesional psoriasis 
transcriptome to resemble that seen in nonlesional skin. Keratinocyte-expressed 
genes appeared to normalize rapidly, whereas T cell-specific normalization 
occurred over six weeks. The three IL-17 ligand genes that are upregulated in 
lesional skin, IL17A, IL17C, and IL17F, were all downregulated in a 
dose-dependent manner following brodalumab treatment. Cellular measures also 
showed a similar pattern with dramatic decreases in keratinocyte hyperplasia 
within one week, and decreases in infiltrating leukocytes occurred over a longer 
timescale. Individuals with the highest brodalumab exposure showed normalization 
of both IL-17-responsive genes and the psoriasis transcriptome, whereas subjects 
with lower exposures showed transient or incomplete molecular responses. 
Clinical and molecular response appeared dependent on the extent of brodalumab 
exposure relative to the expression of IL-17 ligand genes, and reduction of 
IL-17 signaling into the nonlesional range was strongly correlated with 
normalization of the psoriasis transcriptome. These data indicate that blockade 
of IL-17 signaling in psoriatic skin leads to rapid transcriptomal changes 
initially in keratinocyte-expressed genes, followed by normalization in the 
leukocyte abnormalities, and demonstrates the essential role of the IL-17R on 
keratinocytes in driving disease pathogenesis.