IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis

被引:157
作者
Callewaert, Chris [1 ,2 ]
Nakatsuji, Teruaki [3 ]
Knight, Rob [1 ,4 ,5 ,6 ]
Kosciolek, Tomasz [1 ]
Vrbanac, Alison [1 ]
Kotol, Paul [3 ]
Ardeleanu, Marius [7 ]
Hultsch, Thomas [8 ]
Guttman-Yassky, Emma [9 ]
Bissonnette, Robert [10 ]
Silverberg, Jonathan I. [11 ,12 ,13 ]
Krueger, James [14 ]
Menter, Alan [15 ]
Graham, Neil M. H. [7 ]
Pirozzi, Gianluca [16 ]
Hamilton, Jennifer D. [7 ]
Gallo, Richard L. [3 ]
机构
[1] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
[2] Univ Ghent, Ctr Microbial Ecol & Technol, Ghent, Belgium
[3] Univ Calif San Diego, Dept Dermatol, 9500 Gilman Dr,MC 0869, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Dept Comp Sci, La Jolla, CA 92093 USA
[5] Univ Calif San Diego, Dept Engn, La Jolla, CA 92093 USA
[6] Univ Calif San Diego, Ctr Microbiome Innovat, La Jolla, CA 92093 USA
[7] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA
[8] Sanofi Genzyme, Cambridge, MA USA
[9] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA
[10] Innovaderm Res Inc, Montreal, PQ, Canada
[11] Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA
[12] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA
[13] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA
[14] Rockefeller Univ, Invest Dermatol Lab, 1230 York Ave, New York, NY 10021 USA
[15] Baylor Univ, Med Ctr, Dept Dermatol, Dallas, TX USA
[16] Sanofi, Bridgewater, NJ USA
关键词
SKIN COLONIZATION; EXPRESSION; DISEASE; BARRIER; HUMANIZATION; INFLAMMATION; MECHANISMS; BIOMARKERS; MANAGEMENT; DIAGNOSIS;
D O I
10.1016/j.jid.2019.05.024
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
Dupilumab is a fully human antibody to interleukin-4 receptor alpha that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor alpha inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus.
引用
收藏
页码:191 / +
页数:19
相关论文
共 54 条
[1]   Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis [J].
Beck, Lisa A. ;
Thaci, Diamant ;
Hamilton, Jennifer D. ;
Graham, Neil M. ;
Bieber, Thomas ;
Rocklin, Ross ;
Ming, Jeffrey E. ;
Ren, Haobo ;
Kao, Richard ;
Simpson, Eric ;
Ardeleanu, Marius ;
Weinstein, Steven P. ;
Pirozzi, Gianluca ;
Guttman-Yassky, Emma ;
Suarez-Farinas, Mayte ;
Hager, Melissa D. ;
Stahl, Neil ;
Yancopoulos, George D. ;
Radin, Allen R. .
NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (02) :130-139
[2]   Lipid abnormalities in atopic skin are driven by type 2 cytokines [J].
Berdyshev, Evgeny ;
Goleva, Elena ;
Bronova, Irina ;
Dyjack, Nathan ;
Rios, Cydney ;
Jung, John ;
Taylor, Patricia ;
Jeong, Mingeum ;
Hall, Clifton F. ;
Richers, Brittany N. ;
Norquest, Kathryn A. ;
Zheng, Tao ;
Seibold, Max A. ;
Leung, Donald Y. M. .
JCI INSIGHT, 2018, 3 (04)
[3]   Mechanisms of disease: Atopic dermatitis [J].
Bieber, Thomas .
NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (14) :1483-1494
[4]   The role of the skin microbiome in atopic dermatitis: a systematic review [J].
Bjerre, R. D. ;
Bandier, J. ;
Skov, L. ;
Engstrand, L. ;
Johansen, J. D. .
BRITISH JOURNAL OF DERMATOLOGY, 2017, 177 (05) :1272-1278
[5]   Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial [J].
Blauvelt, Andrew ;
de Bruin-Weller, Marjolein ;
Gooderham, Melinda ;
Cather, Jennifer C. ;
Weisman, Jamie ;
Pariser, David ;
Simpson, Eric L. ;
Papp, Kim A. ;
Hong, H. Chih-Ho ;
Rubel, Diana ;
Foley, Peter ;
Prens, Errol ;
Griffiths, Christopher E. M. ;
Etoh, Takafumi ;
Pinto, Pedro Herranz ;
Pujol, Ramon M. ;
Szepietowski, Jacek C. ;
Ettler, Karel ;
Kemeny, Lajos ;
Zhu, Xiaoping ;
Akinlade, Bolanle ;
Hultsch, Thomas ;
Mastey, Vera ;
Gadkari, Abhijit ;
Eckert, Laurent ;
Amin, Nikhil ;
Graham, Neil M. H. ;
Pirozzi, Gianluca ;
Stahl, Neil ;
Yancopoulos, George D. ;
Shumel, Brad .
LANCET, 2017, 389 (10086) :2287-2303
[6]   Atopic dermatitis: a disease of altered skin barrier and immune dysregulation [J].
Boguniewicz, Mark ;
Leung, Donald Y. M. .
IMMUNOLOGICAL REVIEWS, 2011, 242 :233-246
[7]  
Brandt E.B., 2011, J Clin Cell Immunol, V2
[8]   Immunologic, microbial, and epithelial interactions in atopic dermatitis [J].
Brunner, Patrick M. ;
Leung, Donald Y. M. ;
Guttman-Yassky, Emma .
ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY, 2018, 120 (01) :34-41
[9]   The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins [J].
Brunner, Patrick M. ;
Suarez-Farinas, Mayte ;
He, Helen ;
Malik, Kunal ;
Wen, Huei-Chi ;
Gonzalez, Juana ;
Chan, Tom Chih-Chieh ;
Estrada, Yeriel ;
Zheng, Xiuzhong ;
Khattri, Saakshi ;
Dattola, Nancy ;
Krueger, James G. ;
Guttman-Yassky, Emma .
SCIENTIFIC REPORTS, 2017, 7
[10]   The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies [J].
Brunner, Patrick M. ;
Guttman-Yassky, Emma ;
Leung, Donald Y. M. .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2017, 139 (04) :S65-S76