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

Lisa C. Zaba, Mayte Suárez-Fariñas, Judilyn Fuentes-Duculan, Kristine E. Nograles, Emma Guttman-Yassky, Irma Cardinale, Michelle A. Lowes, James G. Krueger

Research output: Contribution to journalArticle

214 Scopus citations

Abstract

Background: TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear. Objective: To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to 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 with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic 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 downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1β and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels. Conclusion: Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the TH17 immune response.

Original languageEnglish (US)
Pages (from-to)1022-1030.e395
JournalJournal of Allergy and Clinical Immunology
Volume124
Issue number5
DOIs
StatePublished - Nov 2009

Keywords

  • TNF
  • etanercept
  • gene
  • psoriasis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Zaba, L. C., Suárez-Fariñas, M., Fuentes-Duculan, J., Nograles, K. E., Guttman-Yassky, E., Cardinale, I., Lowes, M. A., & Krueger, J. G. (2009). Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. Journal of Allergy and Clinical Immunology, 124(5), 1022-1030.e395. https://doi.org/10.1016/j.jaci.2009.08.046