title: 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 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-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels.
  
  
  CONCLUSIONS
  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 T(H)17 immune response.
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Zaba
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.forename: Judilyn
authors.initials: J
authors.lastname: Fuentes-Duculan
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Nograles
authors.forename: Emma
authors.initials: E
authors.lastname: Guttman-Yassky
authors.forename: Irma
authors.initials: I
authors.lastname: Cardinale
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lowes
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000068800:Etanercept; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D020381:Interleukin-17; D053583:Interleukin-1beta; D016209:Interleukin-8; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000068800:Etanercept