Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
BACKGROUND
Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to T(H)2/T(H)22 cytokine activation. However, these models have not been tested by in vivo suppression of T-cell cytokines. Cyclosporine (CsA) is an immunosuppressant that is highly effective for severe disease, but its mechanism in AD skin lesions has not been studied.


OBJECTIVE
We sought to establish the ability of a systemic immunosuppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype and to correlate changes with clinical improvement.


METHODS
CsA's effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/d CsA for 12 weeks.


RESULTS
After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of T(H)2-, T(H)22-, and some T(H)17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures.


CONCLUSIONS
This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations, as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
Saakshi
S
Khattri
Department of Dermatology, Tel-Hashomer, Tel Aviv, Israel.
Avner
A
Shemer
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY; Center for Clinical and Translational Science, Rockefeller University, New York, NY.
Mariya
M
Rozenblit
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Columbia University College of Physicians and Surgeons, New York, NY.
Nikhil
N
Dhingra
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Center for Clinical and Translational Science, Rockefeller University, New York, NY.
Tali
T
Czarnowicki
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology, Jefferson Medical College, Philadelphia, Pa.
Robert
R
Finney
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
Patricia
P
Gilleaudeau
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
Mary
M
Sullivan-Whalen
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
Xiuzhong
X
Zheng
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
Hui
H
Xu
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
Irma
I
Cardinale
Division of Dermatology, Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St Louis, Mo.
Cristina
C
de Guzman Strong
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
Juana
J
Gonzalez
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Center for Clinical and Translational Science, Rockefeller University, New York, NY.
Mayte
M
Suárez-Fariñas
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Center for Clinical and Translational Science, Rockefeller University, New York, NY.
Jim G
JG
Krueger
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: eguttman@rockefeller.edu.
Emma
E
Guttman-Yassky
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers; D016000:Cluster Analysis; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D004817:Epidermis / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D015415:Biomarkers; D007166:Immunosuppressive Agents; D016572:Cyclosporine
Atopic dermatitis; S100 proteins; T cell; cyclosporine; epidermal abnormalities; immune