TY - JOUR
T1 - Moving toward endotypes in atopic dermatitis
T2 - Identification of patient clusters based on serum biomarker analysis
AU - Thijs, Judith L.
AU - Strickland, Ian
AU - Bruijnzeel-Koomen, Carla A.F.M.
AU - Nierkens, Stefan
AU - Giovannone, Barbara
AU - Csomor, Eszter
AU - Sellman, Bret R.
AU - Mustelin, Tomas
AU - Sleeman, Matthew A.
AU - de Bruin-Weller, Marjolein S.
AU - Herath, Athula
AU - Drylewicz, Julia
AU - May, Richard D.
AU - Hijnen, Dirk Jan
N1 - Publisher Copyright:
© 2017 American Academy of Allergy, Asthma & Immunology
PY - 2017/9
Y1 - 2017/9
N2 - Background Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level. Objective We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators. Methods Sera from 193 adult patients with moderate-to-severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3-23.3] and 39.1 [95% CI, 37.5-40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen-specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k-means cluster analysis of the principal components. Results Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty-seven principal components described approximately 90% of the variance. Unsupervised k-means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation-regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN-α, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN-β, IL-1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13, and thymic stromal lymphopoietin. Conclusion AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics.
AB - Background Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level. Objective We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators. Methods Sera from 193 adult patients with moderate-to-severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3-23.3] and 39.1 [95% CI, 37.5-40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen-specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k-means cluster analysis of the principal components. Results Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty-seven principal components described approximately 90% of the variance. Unsupervised k-means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation-regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN-α, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN-β, IL-1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13, and thymic stromal lymphopoietin. Conclusion AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics.
KW - Atopic dermatitis
KW - clusters
KW - disease heterogeneity
KW - endotypes
KW - personalized medicine
KW - phenotypes
KW - principal component analysis
KW - unsupervised cluster analysis
UR - http://www.scopus.com/inward/record.url?scp=85019486518&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2017.03.023
DO - 10.1016/j.jaci.2017.03.023
M3 - Article
C2 - 28412391
AN - SCOPUS:85019486518
SN - 0091-6749
VL - 140
SP - 730
EP - 737
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 3
ER -