Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis.
Atopic dermatitis (AD) is the most common inflammatory skin disease, but treatment options for moderate-to-severe disease are limited. Ustekinumab is an IL-12/IL-23p40 antagonist that suppresses Th1, Th17 and Th22 activation, commonly used for psoriasis patients. We sought to assess efficacy and safety of ustekinumab in patients with moderate-to-severe AD. In this phase II, double-blind, placebo-controlled study, 33 patients with moderate-to-severe AD were randomly assigned to either ustekinumab (n=16) or placebo (n=17), with subsequent crossover at 16 weeks, and last dose at 32 weeks. Background therapy with mild topical steroids was allowed to promote retention. Study endpoints included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies. The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (the primary endpoint) and 20 weeks compared to placebo, but the difference between groups was not significant. The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 32 weeks in the initial ustekinumab group. Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2-related AD genes was seen after 4 weeks of ustekinumab treatment (i.e. MMP12, IL-22, IL-13, IFN-γ, elafin/PI3, CXCL1 and CCL17; P<.05). Epidermal responses (K16, terminal differentiation) showed faster (4 weeks) and long-term regulation (32 weeks) from baseline in the ustekinumab group. No severe adverse events were observed. Ustekinumab had clear clinical and molecular effects, but clinical outcomes might have been obscured by a profound "placebo" effect, most likely due to background topical glucocorticosteroids and possibly insufficient dosing for AD.
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.|Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Saakshi
S
Khattri
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Patrick M
PM
Brunner
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Sandra
S
Garcet
Department of Dermatology, Jefferson Medical College, Philadelphia, PA, USA.
Robert
R
Finney
Division of Dermatology, Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA.
Steven R
SR
Cohen
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.|Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Margeaux
M
Oliva
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.|Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Riana
R
Dutt
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Judilyn
J
Fuentes-Duculan
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Xiuzhong
X
Zheng
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Xuan
X
Li
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Kathleen M
KM
Bonifacio
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Norma
N
Kunjravia
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Israel
I
Coats
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Inna
I
Cueto
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Patricia
P
Gilleaudeau
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
Mary
M
Sullivan-Whalen
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.|Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Icahn Institute for Genomics and Multiscale Biology at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mayte
M
Suárez-Fariñas
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.
James G
JG
Krueger
The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.|Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Emma
E
Guttman-Yassky
D000328:Adult; D054414:Chemokine CCL17 / Q000235:genetics; D054360:Chemokine CXCL1 / Q000235:genetics; D018592:Cross-Over Studies; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003879:Dermatologic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D053492:Elafin / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics; D012720:Severity of Illness Index; D059467:Transcriptome / Q000187:drug effects; D000069549:Ustekinumab / Q000009:adverse effects / Q000627:therapeutic use*; D000097043:Interleukin-22
D054414:Chemokine CCL17; D054360:Chemokine CXCL1; D003879:Dermatologic Agents; D053492:Elafin; D007371:Interferon-gamma; D018793:Interleukin-13; D007378:Interleukins; D053508:Matrix Metalloproteinase 12; D000069549:Ustekinumab; D000097043:Interleukin-22; C106230:CCL17 protein, human; C475829:CXCL1 protein, human; C578095:IL13 protein, human; C506806:PI3 protein, human; C507122:MMP12 protein, human
IL-12; IL-22; IL-23; atopic dermatitis; p40; ustekinumab