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

• Published in: Journal of allergy and clinical immunology 2009-11, Vol.124 (5), p.1022-1030.e395
• Main Authors: Zaba, Lisa C., MD, PhD, Suárez-Fariñas, Mayte, PhD, Fuentes-Duculan, Judilyn, MD, Nograles, Kristine E., MD, Guttman-Yassky, Emma, MD, MSc, Cardinale, Irma, MS, Lowes, Michelle A., MBBS, PhD, Krueger, James G., MD, PhD
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biological and medical sciences; CD1c antigen; Clinical trials; Crohn's disease; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dermatology; Down-Regulation - drug effects; Down-Regulation - genetics; Down-Regulation - immunology; Drugs; Etanercept; Fundamental and applied biological sciences. Psychology; Fundamental immunology; gene; Gene Expression - drug effects; Gene Expression Profiling; genomics; Helper cells; Humans; Immunoglobulin G - administration & dosage; Immunoglobulin G - therapeutic use; Immunopathology; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin 1; Interleukin 17; Interleukin 8; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - immunology; Interleukin-17 - metabolism; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - immunology; Interleukin-1beta - metabolism; Interleukin-8 - antagonists & inhibitors; Interleukin-8 - immunology; Interleukin-8 - metabolism; Lymphocytes T; Medical sciences; Myeloid Cells - drug effects; Myeloid Cells - immunology; Myeloid Cells - metabolism; Oligonucleotide Array Sequence Analysis; Psoriasis; Psoriasis - drug therapy; Psoriasis - genetics; Psoriasis - immunology; psoriasis vulgaris; Psoriasis. Parapsoriasis. Lichen; Receptors, Tumor Necrosis Factor - administration & dosage; Receptors, Tumor Necrosis Factor - therapeutic use; Rheumatoid arthritis; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sepsis; Signal Transduction; Skin - drug effects; Skin - immunology; Skin - pathology; Skin diseases; T H1; T H17; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; TNF; Tumor necrosis factor; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Up-Regulation - drug effects; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2009.08.046

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 TH 17 immune response.