Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes

Abstract

Background TNF inhibitors have revolutionized the treatment of psoriasis vulgaris, as well as psoriatic and rheumatoid arthritis, and Crohns disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear. Objective To globally analyze the genomic effects of TNF inhibition in psoriasis patients, and compare genomic profiles of patients who responded or did not respond to treatment. Methods In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n=15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time-points during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. Patients were stratified as responders (n=11) or non-responders (n=4) based on histological disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time. Results In responders, 4 clusters of down-regulated genes and 3 clusters of up-regulated genes were identified. Genes down-modulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Up-regulated genes included stable dendritic cell population genes CD1c and CD207 (Langerin). Comparison of responders and non-responders revealed rapid down-modulation of innate IL-1β and IL-8 “sepsis cascade” cytokines in both groups, but only responders down-regulated IL-17 pathway genes to baseline levels. Conclusion While both responders and non-responders to etanercept inactivated “sepsis cascade” cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of Th17 immune response. Capsule Summary Cutaneous genes regulated during psoriasis treatment by etanercept provide a global view of response in disease tissue. Only responders down-regulated IL-17 pathway genes.