TY - JOUR
T1 - Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes
AU - Zaba, Lisa C.
AU - Suárez-Fariñas, Mayte
AU - Fuentes-Duculan, Judilyn
AU - Nograles, Kristine E.
AU - Guttman-Yassky, Emma
AU - Cardinale, Irma
AU - Lowes, Michelle A.
AU - Krueger, James G.
N1 - Funding Information:
Supported by a Clinical and Translational Science Award, grant no. UL1RR024143. L.C.Z. is supported by National Institutes of Health Medical Scientist Training Program (MSTP) grant no. GM07739, and M.A.L. by K23 AR052404-01A1 and the Doris Duke Foundation. Amgen supported this study by an unrestricted research grant to Rockefeller University. J.G.K. was a visiting lecturer at Amgen and received a small honorarium.
PY - 2009/11
Y1 - 2009/11
N2 - 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.
AB - 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.
KW - TNF
KW - etanercept
KW - gene
KW - psoriasis
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U2 - 10.1016/j.jaci.2009.08.046
DO - 10.1016/j.jaci.2009.08.046
M3 - Article
C2 - 19895991
AN - SCOPUS:71749085498
SN - 0091-6749
VL - 124
SP - 1022-1030.e395
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 5
ER -