Phenotypes and endotypes of atopic dermatitis: Clinical implications

Minji Kim; Jihyun Kim

doi:10.4168/aard.2020.8.1.9

Journal List > Allergy Asthma Respir Dis > v.8(1) > 1141948

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Kim and Kim: Phenotypes and endotypes of atopic dermatitis: Clinical implications

Review

Allergy Asthma Respir Dis 2020;8(1):9-14.

Published online: 12 January 2020

DOI: https://doi.org/10.4168/aard.2020.8.1.9

Phenotypes and endotypes of atopic dermatitis: Clinical implications

Minji Kim¹, Jihyun Kim^2,³

^¹Department of Pediatrics, Hallym University Dongtan Sacred Heart Hospital, Hallym University School of Medicine, Dongtan

^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 https://orcid.org/0000-0001-8493-2881 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, E-mail: jhlovechild@gmail.com

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

Received 30 May 2019 Revised 6 August 2019 Accepted 6 August 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/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

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; 32:1645–51.

3. Kim BE, Leung DYM. Significance of skin barrier dysfunction in atopic dermatitis. Allergy Asthma Immunol Res. 2018; 10:207–15.

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; 134:1941–50.

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; 53:2755–66.

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, Schäp-pi 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):S58–64.

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; 35:161–83.

10. Williams HC, Strachan DP. The natural history of childhood eczema: observations from the British 1958 birth cohort study. Br J Dermatol. 1998; 139:834–9.

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; 171:655–62.

12. Tanei R, Katsuoka K. Clinical analyses of atopic dermatitis in the aged. J Dermatol. 2008; 35:562–9.

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 endopheno-typic profiling of adult and childhood atopic dermatitis. J Eur Acad Dermatol Venereol. 2016; 30:1930–8.

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; 138:1639–51.

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; 18:93–6.

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; 118:214–9.

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; 132:361–70.

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; 181:7420–7.

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; 117:836–41.

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; 113:925–31.

25. Silverberg JI, Simpson EL. Association between severe eczema in children and multiple comorbid conditions and increased healthcare utilization. Pediatr Allergy Immunol. 2013; 24:476–86.

26. Thijs JL, Nierkens S, Herath A, Bruijnzeel-Koomen CA, Knol EF, Giovan-none 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, Bruijn-zeel-Koomen C, et al. Biomarkers for atopic dermatitis: a systematic review and metaanalysis. Curr Opin Allergy Clin Immunol. 2015; 15:453–60.

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; 136:1265–7.

30. Heimall J, Spergel JM. Filaggrin mutations and atopy: consequences for future therapeutics. Expert Rev Clin Immunol. 2012; 8:189–97.

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; 131:982–4.

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; 25:816–8.

33. Akiyama M. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics. Br J Dermatol. 2010; 162:472–7.

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; 136:1254–64.

35. Damsker JM, Hansen AM, Caspi RR. Th1 and Th17 cells: adversaries and collaborators. Ann N Y Acad Sci. 2010; 1183:211–21.

36. Kim BE, Leung DY. Epidermal barrier in atopic dermatitis. Allergy Asthma Immunol Res. 2012; 4:12–6.

37. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011; 365:1315–27.

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; 121:1337–43.

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; 120:150–5.

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; 21:104–10.

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; 123:1361–70.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; 118:737–8.e1.

43. O'Regan GM, Sandilands A, McLean WHI, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2008; 122:689–93.

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; 127:773–86.e1–7.

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; 163:659–61.

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; 347:1151–60.

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; 115:406–13.

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:e125–7.

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. 22(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; 134:818–23.

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; 136:941–51.e3.

52. Boguniewicz M. Biologic therapy for atopic dermatitis: moving beyond the practice parameter and guidelines. J Allergy Clin Immunol Pract. 2017; 5:1477–87.

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):R7–12.

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; 129:426–33. 433. e1–8.

56. Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol. 2008; 128:2625–30.

57. Tan Q, Yang H, Liu E, Wang H. P38/ERK MAPK signaling pathways are involved in the regulation of filaggrin and involucrin by IL-17. Mol Med Rep. 2017; 16:8863–7.

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; 119:3573–85.

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; 123:1244–52.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; 134:1293–300.

61. Snast I, Reiter O, Hodak E, Friedland R, Mimouni D, Leshem YA. Are biologics efficacious in atopic dermatitis? A systematic review and metaanalysis. Am J Clin Dermatol. 2018; 19:145–65.

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; 177:419–27.

64. Ong PY, Leung DY. Immune dysregulation in atopic dermatitis. Curr Allergy Asthma Rep. 2006; 6:384–9.

65. Schlievert PM, Strandberg KL, Lin YC, Peterson ML, Leung DY. Secreted virulence factor comparison between methicillin-resistant and methicil-lin-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; 138:2224–33.

67. Wollenberg A, Wetzel S, Burgdorf WH, Haas J. Viral infections in atopic dermatitis: pathogenic aspects and clinical management. J Allergy Clin Immunol. 2003; 112:667–74.

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; 124:260–9. 269.e1–7.

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; 39:3486–90.

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; 157:1178–82.

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.

TOOLS

Similar articles