Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

Emma Guttman-Yassky; Robert Bissonnette; Benjamin Ungar; Mayte Suárez-Fariñas; Marius Ardeleanu; Hitokazu Esaki; Maria Suprun; Yeriel Estrada; Hui Xu; Xiangyu Peng; Jonathan I. Silverberg; Alan Menter; James G. Krueger; Rick Zhang; Usman Chaudhry; Brian Swanson; Neil M.H. Graham; Gianluca Pirozzi; George D. Yancopoulos; Jennifer D. Jennifer

doi:10.1016/j.jaci.2018.08.022

Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

Emma Guttman-Yassky
, Robert Bissonnette
, Benjamin Ungar
, Mayte Suárez-Fariñas
, Marius Ardeleanu
, Hitokazu Esaki
, Maria Suprun
, Yeriel Estrada
, Hui Xu
, Xiangyu Peng
, Jonathan I. Silverberg
, Alan Menter
, James G. Krueger
, Rick Zhang
, Usman Chaudhry
, Brian Swanson
, Neil M.H. Graham
, Gianluca Pirozzi
, George D. Yancopoulos
, Jennifer D. Jennifer

Research output: Contribution to journal › Article › peer-review

624 Scopus citations

Abstract

Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and T_H17/T_H22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.

Original language	English
Pages (from-to)	155-172
Number of pages	18
Journal	Journal of Allergy and Clinical Immunology
Volume	143
Issue number	1
DOIs	https://doi.org/10.1016/j.jaci.2018.08.022
State	Published - Jan 2019

Keywords

Atopic dermatitis
IL-4 receptor α inhibition
dupilumab
epidermal pathology
gene expression
skin
transcriptome
type 2 inflammation

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10.1016/j.jaci.2018.08.022

Cite this

Guttman-Yassky, E., Bissonnette, R., Ungar, B., Suárez-Fariñas, M., Ardeleanu, M., Esaki, H., Suprun, M., Estrada, Y., Xu, H., Peng, X., Silverberg, J. I., Menter, A., Krueger, J. G., Zhang, R., Chaudhry, U., Swanson, B., Graham, N. M. H., Pirozzi, G., Yancopoulos, G. D., & Jennifer, J. D. (2019). Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology, 143(1), 155-172. https://doi.org/10.1016/j.jaci.2018.08.022

@article{7ef492f5d60b4e859bafc9f71fe55940,

title = "Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis",

abstract = "Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8\% and 110.8\% with dupilumab and −10.5\% and 55.0\% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.",

keywords = "Atopic dermatitis, IL-4 receptor α inhibition, dupilumab, epidermal pathology, gene expression, skin, transcriptome, type 2 inflammation",

author = "Emma Guttman-Yassky and Robert Bissonnette and Benjamin Ungar and Mayte Su{\'a}rez-Fari{\~n}as and Marius Ardeleanu and Hitokazu Esaki and Maria Suprun and Yeriel Estrada and Hui Xu and Xiangyu Peng and Silverberg, \{Jonathan I.\} and Alan Menter and Krueger, \{James G.\} and Rick Zhang and Usman Chaudhry and Brian Swanson and Graham, \{Neil M.H.\} and Gianluca Pirozzi and Yancopoulos, \{George D.\} and Jennifer, \{Jennifer D.\}",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2019",

month = jan,

doi = "10.1016/j.jaci.2018.08.022",

language = "English",

volume = "143",

pages = "155--172",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "1",

}

Guttman-Yassky, E, Bissonnette, R, Ungar, B , Suárez-Fariñas, M, Ardeleanu, M, Esaki, H, Suprun, M, Estrada, Y, Xu, H, Peng, X, Silverberg, JI, Menter, A, Krueger, JG, Zhang, R, Chaudhry, U, Swanson, B, Graham, NMH, Pirozzi, G, Yancopoulos, GD & Jennifer, JD 2019, 'Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis', Journal of Allergy and Clinical Immunology, vol. 143, no. 1, pp. 155-172. https://doi.org/10.1016/j.jaci.2018.08.022

TY - JOUR

T1 - Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

AU - Guttman-Yassky, Emma

AU - Bissonnette, Robert

AU - Ungar, Benjamin

AU - Suárez-Fariñas, Mayte

AU - Ardeleanu, Marius

AU - Esaki, Hitokazu

AU - Suprun, Maria

AU - Estrada, Yeriel

AU - Xu, Hui

AU - Peng, Xiangyu

AU - Silverberg, Jonathan I.

AU - Menter, Alan

AU - Krueger, James G.

AU - Zhang, Rick

AU - Chaudhry, Usman

AU - Swanson, Brian

AU - Graham, Neil M.H.

AU - Pirozzi, Gianluca

AU - Yancopoulos, George D.

AU - Jennifer, Jennifer D.

PY - 2019/1

Y1 - 2019/1

N2 - Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.

AB - Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.

KW - Atopic dermatitis

KW - IL-4 receptor α inhibition

KW - dupilumab

KW - epidermal pathology

KW - gene expression

KW - skin

KW - transcriptome

KW - type 2 inflammation

UR - https://www.scopus.com/pages/publications/85055641845

U2 - 10.1016/j.jaci.2018.08.022

DO - 10.1016/j.jaci.2018.08.022

M3 - Article

C2 - 30194992

AN - SCOPUS:85055641845

SN - 0091-6749

VL - 143

SP - 155

EP - 172

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 1

ER -

Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

Abstract

Keywords

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