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Allergy Asthma Respir Dis. 2020 Jan;8(1):9-14. Korean.
Published online Jan 31, 2020.  https://doi.org/10.4168/aard.2020.8.1.9
© 2020 The Korean Academy of Pediatric Allergy and Respiratory Disease; The Korean Academy of Asthma, Allergy and Clinical Immunology
Phenotypes and endotypes of atopic dermatitis: Clinical implications
Minji Kim,1 and Jihyun Kim2,3
1Department of Pediatrics, Hallym University Dongtan Sacred Heart Hospital, Hallym University School of Medicine, Dongtan, Korea.
2Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
3Environmental Health Center for Atopic Diseases, Samsung Medical Center, Seoul, Korea.

Correspondence to: Jihyun Kim. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. Tel: +82-2-3410-3539, Fax: +82-2-3410-0805, Email: jhlovechild@gmail.com
Received May 30, 2019; Revised Aug 06, 2019; Accepted Aug 06, 2019.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/).


Abstract

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, characterized by a complex pathophysiology and a variety of clinical phenotypes. However, heterogeneous clinical phenotypes are generally not considered in treating AD. To date, phenotypes and endotypes have been proposed to classify AD mainly based on differences in age, IgE, severity, race, skin barrier dysfunction, immune (Th2/Th17/Th22) polarization, and skin microbiome. Various biologics to target polarized immune pathways, including dupilumab, have been newly developed for the personalized treatment of moderate-to-severe AD. Further understanding of AD pathophysiology and identification of novel biomarkers will not only allow clinically useful stratification of AD and but also achieve precision medicine for the prevention and treatment of AD.

Keywords: Atopic dermatitis; Biomarker; Endotype; Phenotype; Precision medicine

Figures


Fig. 1
Overview of atopic dermatitis phenotypes and endotypes. Th, T-helper type; IFN, interferon; IL, interleukin; TSLP, thymic stromal lymphopoietin. S. aureus, Staphylococcus aureus.
Click for larger imageDownload as PowerPoint slide

Notes

This study was funded by the Environmental Health Center Project of the Ministry of Environment, Republic of Korea.

References
1. Kim J, Kim BE, Leung DYM. Pathophysiology of atopic dermatitis: clinical implications. Allergy Asthma Proc 2019;40:84–92.
2. Whiteley J, Emir B, Seitzman R, Makinson G. The burden of atopic dermatitis in US adults: results from the 2013 National Health and Wellness Survey. Curr Med Res Opin 2016;32:1645–1651.
3. Kim BE, Leung DYM. Significance of skin barrier dysfunction in atopic dermatitis. Allergy Asthma Immunol Res 2018;10:207–215.
4. Danso MO, van Drongelen V, Mulder A, van Esch J, Scott H, van Smeden J, et al. TNF-α and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. J Invest Dermatol 2014;134:1941–1950.
5. Janssens M, van Smeden J, Gooris GS, Bras W, Portale G, Caspers PJ, et al. Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients. J Lipid Res 2012;53:2755–2766.
6. Yang HJ, Kim BS, Kim WK, Kim J, Kim JT, Suh DI, et al. Phenotype and endotype in pediatric asthma. Allergy Asthma Respir Dis 2014;2:85–90.
7. Bieber T, D'Erme AM, Akdis CA, Traidl-Hoffmann C, Lauener R, Schäppi G, et al. Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and where should we go? J Allergy Clin Immunol 2017;139(4S):S58–S64.
8. Garmhausen D, Hagemann T, Bieber T, Dimitriou I, Fimmers R, Diepgen T, et al. Characterization of different courses of atopic dermatitis in adolescent and adult patients. Allergy 2013;68:498–506.
9. Lyons JJ, Milner JD, Stone KD. Atopic dermatitis in children: clinical features, pathophysiology, and treatment. Immunol Allergy Clin North Am 2015;35:161–183.
10. Williams HC, Strachan DP. The natural history of childhood eczema: observations from the British 1958 birth cohort study. Br J Dermatol 1998;139:834–839.
11. Roduit C, Frei R, Depner M, Karvonen AM, Renz H, Braun-Fahrländer C, et al. Phenotypes of atopic dermatitis depending on the timing of onset and progression in childhood. JAMA Pediatr 2017;171:655–662.
12. Tanei R, Katsuoka K. Clinical analyses of atopic dermatitis in the aged. J Dermatol 2008;35:562–569.
13. Tanei R, Hasegawa Y. Atopic dermatitis in older adults: a viewpoint from geriatric dermatology. Geriatr Gerontol Int 2016;16 Suppl 1:75–86.
14. Nygaard U, Hvid M, Johansen C, Buchner M, Fölster-Holst R, Deleuran M, et al. TSLP, IL-31, IL-33 and sST2 are new biomarkers in endophenotypic profiling of adult and childhood atopic dermatitis. J Eur Acad Dermatol Venereol 2016;30:1930–1938.
15. Esaki H, Brunner PM, Renert-Yuval Y, Czarnowicki T, Huynh T, Tran G, et al. Early-onset pediatric atopic dermatitis is T(H)2 but also T(H)17 polarized in skin. J Allergy Clin Immunol 2016;138:1639–1651.
16. Lee E, Lee SH, Kwon JW, Kim YH, Cho HJ, Yang SI, et al. Atopic dermatitis phenotype with early onset and high serum IL-13 is linked to the new development of bronchial hyperresponsiveness in school children. Allergy 2016;71:692–700.
17. Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci 2010;58:1–7.
18. Choi SJ, Song MG, Sung WT, Lee DY, Lee JH, Lee ES, et al. Comparison of transepidermal water loss, capacitance and pH values in the skin between intrinsic and extrinsic atopic dermatitis patients. J Korean Med Sci 2003;18:93–96.
19. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006;118:214–219.
20. Mori T, Ishida K, Mukumoto S, Yamada Y, Imokawa G, Kabashima K, et al. Comparison of skin barrier function and sensory nerve electric current perception threshold between IgE-high extrinsic and IgE-normal intrinsic types of atopic dermatitis. Br J Dermatol 2010;162:83–90.
21. Suárez-Fariñas M, Dhingra N, Gittler J, Shemer A, Cardinale I, de Guzman Strong C, et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol 2013;132:361–370.
22. Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Zaba LC, Cardinale I, Nograles KE, et al. Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J Immunol 2008;181:7420–7427.
23. Howell MD, Wollenberg A, Gallo RL, Flaig M, Streib JE, Wong C, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol 2006;117:836–841.
24. Illi S, von Mutius E, Lau S, Nickel R, Grüber C, Niggemann B, et al. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004;113:925–931.
25. Silverberg JI, Simpson EL. Association between severe eczema in children and multiple comorbid conditions and increased healthcare utilization. Pediatr Allergy Immunol 2013;24:476–486.
26. Thijs JL, Nierkens S, Herath A, Bruijnzeel-Koomen CA, Knol EF, Giovannone B, et al. A panel of biomarkers for disease severity in atopic dermatitis. Clin Exp Allergy 2015;45:698–701.
27. Thijs J, Krastev T, Weidinger S, Buckens CF, de Bruin-Weller M, Bruijnzeel-Koomen C, et al. Biomarkers for atopic dermatitis: a systematic review and meta-analysis. Curr Opin Allergy Clin Immunol 2015;15:453–460.
28. Takayama G, Arima K, Kanaji T, Toda S, Tanaka H, Shoji S, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol 2006;118:98–104.
29. Leung DY. Atopic dermatitis: age and race do matter. J Allergy Clin Immunol 2015;136:1265–1267.
30. Heimall J, Spergel JM. Filaggrin mutations and atopy: consequences for future therapeutics. Expert Rev Clin Immunol 2012;8:189–197.
31. Cascella R, Foti Cuzzola V, Lepre T, Galli E, Moschese V, Chini L, et al. Full sequencing of the FLG gene in Italian patients with atopic eczema: evidence of new mutations, but lack of an association. J Invest Dermatol 2011;131:982–984.
32. Li K, Oh WJ, Park KY, Kim KH, Seo SJ. FLG mutations in the East Asian atopic dermatitis patients: genetic and clinical implication. Exp Dermatol 2016;25:816–818.
33. Akiyama M. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics. Br J Dermatol 2010;162:472–477.
34. Noda S, Suárez-Fariñas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol 2015;136:1254–1264.
35. Damsker JM, Hansen AM, Caspi RR. Th1 and Th17 cells: adversaries and collaborators. Ann N Y Acad Sci 2010;1183:211–221.
36. Kim BE, Leung DY. Epidermal barrier in atopic dermatitis. Allergy Asthma Immunol Res 2012;4:12–16.
37. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 2011;365:1315–1327.
38. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol 2008;121:1337–1343.
39. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007;120:150–155.
40. Gutowska-Owsiak D, Schaupp AL, Salimi M, Selvakumar TA, McPherson T, Taylor S, et al. IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion. Exp Dermatol 2012;21:104–110.
41. Rodríguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell HJ, et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol 2009;123:1361–1370.e7.
42. Wan J, Mitra N, Hoffstad OJ, Margolis DJ. Influence of FLG mutations and TSLP polymorphisms on atopic dermatitis onset age. Ann Allergy Asthma Immunol 2017;118:737–738.e1.
43. O'Regan GM, Sandilands A, McLean WHI, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol 2008;122:689–693.
44. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol 2011;127:773–786. 786.e1–786.e7.
45. Hata TR, Kotol P, Boguniewicz M, Taylor P, Paik A, Jackson M, et al. History of eczema herpeticum is associated with the inability to induce human β-defensin (HBD)-2, HBD-3 and cathelicidin in the skin of patients with atopic dermatitis. Br J Dermatol 2010;163:659–661.
46. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002;347:1151–1160.
47. Hara J, Higuchi K, Okamoto R, Kawashima M, Imokawa G. High-expression of sphingomyelin deacylase is an important determinant of ceramide deficiency leading to barrier disruption in atopic dermatitis. J Invest Dermatol 2000;115:406–413.
48. Li S, Villarreal M, Stewart S, Choi J, Ganguli-Indra G, Babineau DC, et al. Altered composition of epidermal lipids correlates with Staphylococcus aureus colonization status in atopic dermatitis. Br J Dermatol 2017;177:e125–e127.
49. Berdyshev E, Goleva E, Bronova I, Dyjack N, Rios C, Jung J, et al. Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI Insight 2018;3:e98006
50. Simpson EL, Chalmers JR, Hanifin JM, Thomas KS, Cork MJ, McLean WH, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol 2014;134:818–823.
51. Czarnowicki T, Esaki H, Gonzalez J, Malajian D, Shemer A, Noda S, et al. Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)(+) TH2/TH1 cell imbalance, whereas adults acquire CLA(+) TH22/TC22 cell subsets. J Allergy Clin Immunol 2015;136:941–951.e3.
52. Boguniewicz M. Biologic therapy for atopic dermatitis: moving beyond the practice parameter and guidelines. J Allergy Clin Immunol Pract 2017;5:1477–1487.
53. Egawa G, Kabashima K. Barrier dysfunction in the skin allergy. Allergol Int 2018;67:3–11.
54. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2009;124 3 Suppl 2:R7–R12.
55. Cornelissen C, Marquardt Y, Czaja K, Wenzel J, Frank J, Lüscher-Firzlaff J, et al. IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol 2012;129:426–433. 433.e1–433.e8.
56. Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol 2008;128:2625–2630.
57. Tan Q, Yang H, Liu E, Wang H. P38/ERK MAPK signaling pathways are involved in the regulation of filaggrin and involucrin by ILXMLLink_XYZ17. Mol Med Rep 2017;16:8863–8867.
58. Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 2009;119:3573–3585.
59. Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T, et al. IL-22-producing "T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol 2009;123:1244–1252.e2.
60. Hamilton JD, Suárez-Fariñas M, Dhingra N, Cardinale I, Li X, Kostic A, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol 2014;134:1293–1300.
61. Snast I, Reiter O, Hodak E, Friedland R, Mimouni D, Leshem YA. Are biologics efficacious in atopic dermatitis? A systematic review and meta-analysis. Am J Clin Dermatol 2018;19:145–165.
62. Khattri S, Brunner PM, Garcet S, Finney R, Cohen SR, Oliva M, et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol 2017;26:28–35.
63. Saeki H, Kabashima K, Tokura Y, Murata Y, Shiraishi A, Tamamura R, et al. Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: a randomized, double-blind, placebo-controlled, phase II study. Br J Dermatol 2017;177:419–427.
64. Ong PY, Leung DY. Immune dysregulation in atopic dermatitis. Curr Allergy Asthma Rep 2006;6:384–389.
65. Schlievert PM, Strandberg KL, Lin YC, Peterson ML, Leung DY. Secreted virulence factor comparison between methicillin-resistant and methicillin-sensitive Staphylococcus aureus, and its relevance to atopic dermatitis. J Allergy Clin Immunol 2010;125:39–49.
66. Simpson EL, Villarreal M, Jepson B, Rafaels N, David G, Hanifin J, et al. Patients with atopic dermatitis colonized with Staphylococcus aureus have a distinct phenotype and endotype. J Invest Dermatol 2018;138:2224–2233.
67. Wollenberg A, Wetzel S, Burgdorf WH, Haas J. Viral infections in atopic dermatitis: pathogenic aspects and clinical management. J Allergy Clin Immunol 2003;112:667–674.
68. Beck LA, Boguniewicz M, Hata T, Schneider LC, Hanifin J, Gallo R, et al. Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol 2009;124:260–269. 269.e1–269.e7.
69. Sugita T, Suto H, Unno T, Tsuboi R, Ogawa H, Shinoda T, et al. Molecular analysis of Malassezia microflora on the skin of atopic dermatitis patients and healthy subjects. J Clin Microbiol 2001;39:3486–3490.
70. Takahata Y, Sugita T, Kato H, Nishikawa A, Hiruma M, Muto M. Cutaneous Malassezia flora in atopic dermatitis differs between adults and children. Br J Dermatol 2007;157:1178–1182.