The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies

Journal of Allergy and Clinical Immunology

Volumn 139, Issue 4, 2017, Pages S65-S76

  Brunner, Patrick M ^a   Guttman Yassky, Emma ^b   Leung, Donald Y M ^c  

^a ROCKEFELLER UNIVERSITY   (United States)

^b MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^c DEPARTMENT OF MEDICINE   (United States)

Author keywords

Atopic dermatitis; eczema; immune; keratinocyte; skin immune map; targeted therapy; T helper cell

Indexed keywords

ADULT DISEASE; ATOPIC DERMATITIS; CHILDHOOD DISEASE; CHRONIC DISEASE; CONTROLLED CLINICAL TRIAL (TOPIC); DERMATITIS; HUMAN; IMMUNOPATHOGENESIS; IMMUNOREACTIVITY; NONHUMAN; ONSET AGE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPE; PHENOTYPIC VARIATION; PRIORITY JOURNAL; REVIEW; SYSTEMIC DISEASE; SYSTEMIC THERAPY; TH2 CELL; ANIMAL; DERMATITIS, ATOPIC; IMMUNOLOGY; INFLAMMATION; KERATINOCYTE; METABOLISM; MOLECULARLY TARGETED THERAPY; PHYSIOLOGY; TH17 CELL;

ANTIINFLAMMATORY AGENT; CYTOKINE;

ANIMALS; ANTI-INFLAMMATORY AGENTS; CYTOKINES; DERMATITIS, ATOPIC; HUMANS; INFLAMMATION; KERATINOCYTES; MOLECULAR TARGETED THERAPY; TH17 CELLS; TH2 CELLS;

EID: 85017147273     PISSN: 00916749     EISSN: 10976825     Source Type: Journal    
DOI: 10.1016/j.jaci.2017.01.011     Document Type: Review

References (174)

1. 1 Hanifin, J.M., Reed, M.L., Eczema prevalence impact Working Group. A population-based survey of eczema prevalence in the United States. Dermatitis 18 (2007), 82–91.
2. 2 Flohr, C., Mann, J., New insights into the epidemiology of childhood atopic dermatitis. Allergy 69 (2014), 3–16.
3. 3 Weidinger, S., Novak, N., Atopic dermatitis. Lancet 387 (2016), 1109–1122.
4. 4 Bieber, T., Atopic dermatitis. Ann Dermatol 22 (2010), 125–137.
5. 5 Silverberg, J.I., Simpson, E.L., Associations of childhood eczema severity: a US population-based study. Dermatitis 25 (2014), 107–114.
6. 6 Lande, R., Botti, E., Jandus, C., Dojcinovic, D., Fanelli, G., Conrad, C., et al. The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat Commun, 5, 2014, 5621.
7. 7 Arakawa, A., Siewert, K., Stohr, J., Besgen, P., Kim, S.M., Ruhl, G., et al. Melanocyte antigen triggers autoimmunity in human psoriasis. J Exp Med 212 (2015), 2203–2212.
8. 8 Werfel, T., Allam, J.P., Biedermann, T., Eyerich, K., Gilles, S., Guttman-Yassky, E., et al. Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J Allergy Clin Immunol 138 (2016), 336–349.
9. 9 Biedermann, T., Skabytska, Y., Kaesler, S., Volz, T., Regulation of T cell immunity in atopic dermatitis by microbes: the yin and yang of cutaneous inflammation. Front Immunol, 6, 2015, 353.
10. 10 Simon, D., Wittwer, J., Kostylina, G., Buettiker, U., Simon, H.U., Yawalkar, N., Alefacept (lymphocyte function-associated molecule 3/IgG fusion protein) treatment for atopic eczema. J Allergy Clin Immunol 122 (2008), 423–424.
11. 11 Harper, E.G., Simpson, E.L., Takiguchi, R.H., Boyd, M.D., Kurtz, S.E., Bakke, A.C., et al. Efalizumab therapy for atopic dermatitis causes marked increases in circulating effector memory CD4+ T cells that express cutaneous lymphocyte antigen. J Invest Dermatol 128 (2008), 1173–1181.
12. 12 Hijnen, D.J., ten Berge, O., Timmer-de Mik, L., Bruijnzeel-Koomen, C.A., de Bruin-Weller, M.S., Efficacy and safety of long-term treatment with cyclosporin A for atopic dermatitis. J Eur Acad Dermatol Venereol 21 (2007), 85–89.
13. 13 Khattri, S., Shemer, A., Rozenblit, M., Dhingra, N., Czarnowicki, T., Finney, R., et al. Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology. J Allergy Clin Immunol 133 (2014), 1626–1634.
14. 14 Tintle, S., Shemer, A., Suarez-Farinas, M., Fujita, H., Gilleaudeau, P., Sullivan-Whalen, M., et al. Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response. J Allergy Clin Immunol 128 (2011), 583–593.
15. 15 Gooderham, M., Lynde, C.W., Papp, K., Bourcier, M., Guenther, L., Gulliver, W., et al. Review of systemic treatment options for adult atopic dermatitis. J Cutan Med Surg, 2016 [Epub ahead of print].
16. 16 Simon, D., Bieber, T., Systemic therapy for atopic dermatitis. Allergy 69 (2014), 46–55.
17. 17 Graham, M.T., Nadeau, K.C., Lessons learned from mice and man: mimicking human allergy through mouse models. Clin Immunol 155 (2014), 1–16.
18. 18 Tanaka, A., Amagai, Y., Oida, K., Matsuda, H., Recent findings in mouse models for human atopic dermatitis. Exp Anim 61 (2012), 77–84.
19. 19 Noda, S., Krueger, J.G., Guttman-Yassky, E., The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol 135 (2015), 324–336.
20. 20 Leung, D.Y., Guttman-Yassky, E., Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol 134 (2014), 769–779.
21. 21 Brunner, P.M., Khattri, S., Garcet, S., Finney, R., Oliva, M., Dutt, R., et al. A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol 138 (2016), 169–178.
22. 22 Suarez-Farinas, M., Gittler, J.K., Shemer, A., Cardinale, I., Krueger, J.G., Guttman-Yassky, E., Residual genomic signature of atopic dermatitis despite clinical resolution with narrow-band UVB. J Allergy Clin Immunol 131 (2013), 577–579.
23. 23 Thaci, D., Simpson, E.L., Beck, L.A., Bieber, T., Blauvelt, A., Papp, K., et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet 387 (2016), 40–52.
24. 24 Hamilton, J.D., Suarez-Farinas, 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 134 (2014), 1293–1300.
25. 25 Beck, L.A., Thaci, D., Hamilton, J.D., Graham, N.M., Bieber, T., Rocklin, R., et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 371 (2014), 130–139.
26. 26 Hamid, Q., Boguniewicz, M., Leung, D.Y., Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 94 (1994), 870–876.
27. 27 Harden, J.L., Krueger, J.G., Bowcock, A.M., The immunogenetics of psoriasis: a comprehensive review. J Autoimmun 64 (2015), 66–73.
28. 28 Czarnowicki, T., Krueger, J.G., Guttman-Yassky, E., Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications. J Allergy Clin Immunol Pract 2 (2014), 371–379.
29. 29 Oliva, M., Renert-Yuval, Y., Guttman-Yassky, E., The ‘omics’ revolution: redefining the understanding and treatment of allergic skin diseases. Curr Opin Allergy Clin Immunol 16 (2016), 469–476.
30. 30 Danso, M.O., van Drongelen, V., Mulder, A., van Esch, J., Scott, H., van Smeden, J., et al. TNF-alpha and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. J Invest Dermatol 134 (2014), 1941–1950.
31. 31 Kim, B.E., Leung, D.Y., Boguniewicz, M., Howell, M.D., Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol 126 (2008), 332–337.
32. 32 Nograles, K.E., Zaba, L.C., 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 123 (2009), 1244–1252.
33. 33 Sa, S.M., Valdez, P.A., Wu, J., Jung, K., Zhong, F., Hall, L., et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J Immunol 178 (2007), 2229–2240.
34. 34 Gutowska-Owsiak, D., Schaupp, A.L., Salimi, M., Selvakumar, T.A., McPherson, T., Taylor, S., et al. IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion. Exp Dermatol 21 (2012), 104–110.
35. 35 Irvine, A.D., McLean, W.H., Leung, D.Y., Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365 (2011), 1315–1327.
36. 36 Wolk, K., Witte, E., Wallace, E., Docke, W.D., Kunz, S., Asadullah, K., et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol 36 (2006), 1309–1323.
37. 37 Hijnen, D., De Bruin-Weller, M., Oosting, B., Lebre, C., De Jong, E., Bruijnzeel-Koomen, C., et al. Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell- attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis. J Allergy Clin Immunol 113 (2004), 334–340.
38. 38 Howell, M.D., Kim, B.E., Gao, P., Grant, A.V., Boguniewicz, M., Debenedetto, A., et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 120 (2007), 150–155.
39. 39 Egawa, G., Kabashima, K., Multifactorial skin barrier deficiency and atopic dermatitis: essential topics to prevent the atopic march. J Allergy Clin Immunol 138 (2016), 350–358.
40. 40 Nomura, T., Kabashima, K., Advances in atopic dermatitis in 2015. J Allergy Clin Immunol 138 (2016), 1548–1555.
41. 41 Bruggen, M.C., Bauer, W.M., Reininger, B., Clim, E., Captarencu, C., Steiner, G.E., et al. In situ mapping of innate lymphoid cells in human skin: evidence for remarkable differences between normal and inflamed skin. J Invest Dermatol 136 (2016), 2396–2405.
42. 42 Bonefeld, C.M., Geisler, C., The role of innate lymphoid cells in healthy and inflamed skin. Immunol Lett 179 (2016), 25–28.
43. 43 Kim, B.S., Siracusa, M.C., Saenz, S.A., Noti, M., Monticelli, L.A., Sonnenberg, G.F., et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med, 5, 2013, 170ra16.
44. 44 Halim, T.Y., Steer, C.A., Matha, L., Gold, M.J., Martinez-Gonzalez, I., McNagny, K.M., et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40 (2014), 425–435.
45. 45 Novak, N., Kruse, S., Kraft, S., Geiger, E., Kluken, H., Fimmers, R., et al. Dichotomic nature of atopic dermatitis reflected by combined analysis of monocyte immunophenotyping and single nucleotide polymorphisms of the interleukin-4/interleukin-13 receptor gene: the dichotomy of extrinsic and intrinsic atopic dermatitis. J Invest Dermatol 119 (2002), 870–875.
46. 46 He, J.Q., Chan-Yeung, M., Becker, A.B., Dimich-Ward, H., Ferguson, A.C., Manfreda, J., et al. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immun 4 (2003), 385–389.
47. 47 Lesiak, A., Kuna, P., Zakrzewski, M., van Geel, M., Bladergroen, R.S., Przybylowska, K., et al. Combined occurrence of filaggrin mutations and IL-10 or IL-13 polymorphisms predisposes to atopic dermatitis. Exp Dermatol 20 (2011), 491–495.
48. 48 Namkung, J.H., Lee, J.E., Kim, E., Kim, H.J., Seo, E.Y., Jang, H.Y., et al. Association of polymorphisms in genes encoding IL-4, IL-13 and their receptors with atopic dermatitis in a Korean population. Exp Dermatol 20 (2011), 915–919.
49. 49 Chan, L.S., Robinson, N., Xu, L., Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol 117 (2001), 977–983.
50. 50 Chen, L., Martinez, O., Overbergh, L., Mathieu, C., Prabhakar, B.S., Chan, L.S., Early up-regulation of Th2 cytokines and late surge of Th1 cytokines in an atopic dermatitis model. Clin Exp Immunol 138 (2004), 375–387.
51. 51 Zheng, T., Oh, M.H., Oh, S.Y., Schroeder, J.T., Glick, A.B., Zhu, Z., Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol 129 (2009), 742–751.
52. 52 Chen, L., Overbergh, L., Mathieu, C., Chan, L.S., The development of atopic dermatitis is independent of immunoglobulin E up-regulation in the K14-IL-4 SKH1 transgenic mouse model. Clin Exp Allergy 38 (2008), 1367–1380.
53. 53 Hamid, Q., Naseer, T., Minshall, E.M., Song, Y.L., Boguniewicz, M., Leung, D.Y., In vivo expression of IL-12 and IL-13 in atopic dermatitis. J Allergy Clin Immunol 98 (1996), 225–231.
54. 54 Sehra, S., Yao, Y., Howell, M.D., Nguyen, E.T., Kansas, G.S., Leung, D.Y., et al. IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. J Immunol 184 (2010), 3186–3190.
55. 55 Brauweiler, A.M., Goleva, E., Leung, D.Y., Th2 cytokines increase Staphylococcus aureus alpha toxin-induced keratinocyte death through the signal transducer and activator of transcription 6 (STAT6). J Invest Dermatol 134 (2014), 2114–2121.
56. 56 Kisich, K.O., Carspecken, C.W., Fieve, S., Boguniewicz, M., Leung, D.Y., Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human beta-defensin-3. J Allergy Clin Immunol 122 (2008), 62–68.
57. 57 Ong, P.Y., 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 347 (2002), 1151–1160.
58. 58 Niebuhr, M., Scharonow, H., Gathmann, M., Mamerow, D., Werfel, T., Staphylococcal exotoxins are strong inducers of IL-22: a potential role in atopic dermatitis. J Allergy Clin Immunol 126 (2010), 1176–1183.e4.
59. 59 Nakamura, Y., Oscherwitz, J., Cease, K.B., Chan, S.M., Munoz-Planillo, R., Hasegawa, M., et al. Staphylococcus delta-toxin induces allergic skin disease by activating mast cells. Nature 503 (2013), 397–401.
60. 60 Kasraie, S., Niebuhr, M., Werfel, T., Interleukin (IL)-31 induces pro-inflammatory cytokines in human monocytes and macrophages following stimulation with staphylococcal exotoxins. Allergy 65 (2010), 712–721.
61. 61 Lehmann, H.S., Heaton, T., Mallon, D., Holt, P.G., Staphylococcal enterotoxin-B-mediated stimulation of interleukin-13 production as a potential aetiologic factor in eczema in infants. Int Arch Allergy Immunol 135 (2004), 306–312.
62. 62 Eyerich, K., Pennino, D., Scarponi, C., Foerster, S., Nasorri, F., Behrendt, H., et al. IL-17 in atopic eczema: linking allergen-specific adaptive and microbial-triggered innate immune response. J Allergy Clin Immunol 123 (2009), 59–66.
63. 63 Howell, M.D., Gallo, R.L., Boguniewicz, M., Jones, J.F., Wong, C., Streib, J.E., et al. Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity 24 (2006), 341–348.
64. 64 Nomura, I., Goleva, E., Howell, M.D., Hamid, Q.A., Ong, P.Y., Hall, C.F., et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol 171 (2003), 3262–3269.
65. 65 Albanesi, C., Fairchild, H.R., Madonna, S., Scarponi, C., De Pita, O., Leung, D.Y., et al. IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor of cytokine signaling (SOCS)-1, and SOCS-3. J Immunol 179 (2007), 984–992.
66. 66 Gittler, J.K., Shemer, A., Suarez-Farinas, M., Fuentes-Duculan, J., Gulewicz, K.J., Wang, C.Q., et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol 130 (2012), 1344–1354.
67. 67 Dhingra, N., Guttman-Yassky, E., A possible role for IL-17A in establishing Th2 inflammation in murine models of atopic dermatitis. J Invest Dermatol 134 (2014), 2071–2074.
68. 68 Nograles, K.E., Zaba, L.C., Guttman-Yassky, E., Fuentes-Duculan, J., Suarez-Farinas, M., Cardinale, I., et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol 159 (2008), 1092–1102.
69. 69 Mansouri, Y., Guttman-Yassky, E., Immune pathways in atopic dermatitis, and definition of biomarkers through broad and targeted therapeutics. J Clin Med 4 (2015), 858–873.
70. 70 Thepen, T., Langeveld-Wildschut, E.G., Bihari, I.C., van Wichen, D.F., van Reijsen, F.C., Mudde, G.C., et al. Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocytochemical study. J Allergy Clin Immunol 97 (1996), 828–837.
71. 71 Rabenhorst, A., Hartmann, K., Interleukin-31: a novel diagnostic marker of allergic diseases. Curr Allergy Asthma Rep, 14, 2014, 423.
72. 72 Lee, C.H., Yu, H.S., Biomarkers for itch and disease severity in atopic dermatitis. Curr Probl Dermatol 41 (2011), 136–148.
73. 73 Guttman-Yassky, E., Dhingra, N., Leung, D.Y., New era of biologic therapeutics in atopic dermatitis. Expert Opin Biol Ther 13 (2013), 549–561.
74. 74 Szegedi, K., Kremer, A.E., Kezic, S., Teunissen, M.B., Bos, J.D., Luiten, R.M., et al. Increased frequencies of IL-31-producing T cells are found in chronic atopic dermatitis skin. Exp Dermatol 21 (2012), 431–436.
75. 75 Bieber, T., Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 67 (2012), 1475–1482.
76. 76 Tokura, Y., Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci 58 (2010), 1–7.
77. 77 McAleer, M.A., Irvine, A.D., The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 131 (2013), 280–291.
78. 78 Noda, S., Suarez-Farinas, M., Ungar, B., Kim, S.J., 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 136 (2015), 1254–1264.
79. 79 Suarez-Farinas, 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 132 (2013), 361–370.
80. 80 Cole, C., Kroboth, K., Schurch, N.J., Sandilands, A., Sherstnev, A., O'Regan, G.M., et al. Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis. J Allergy Clin Immunol 134 (2014), 82–91.
81. 81 Malajian, D., Guttman-Yassky, E., New pathogenic and therapeutic paradigms in atopic dermatitis. Cytokine 73 (2015), 311–318.
82. 82 Kezic, S., O'Regan, G.M., Lutter, R., Jakasa, I., Koster, E.S., Saunders, S., et al. Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency. J Allergy Clin Immunol 129 (2012), 1031–1039.
83. 83 Kono, M., Nomura, T., Ohguchi, Y., Mizuno, O., Suzuki, S., Tsujiuchi, H., et al. Comprehensive screening for a complete set of Japanese-population-specific filaggrin gene mutations. Allergy 69 (2014), 537–540.
84. 84 Margolis, D.J., Apter, A.J., Gupta, J., Hoffstad, O., Papadopoulos, M., Campbell, L.E., et al. The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol 130 (2012), 912–917.
85. 85 Akdis, C.A., Akdis, M., Immunological differences between intrinsic and extrinsic types of atopic dermatitis. Clin Exp Allergy 33 (2003), 1618–1621.
86. 86 Vachiramon, V., Tey, H.L., Thompson, A.E., Yosipovitch, G., Atopic dermatitis in African American children: addressing unmet needs of a common disease. Pediatr Dermatol 29 (2012), 395–402.
87. 87 Berardesca, E., Maibach, H., Ethnic skin: overview of structure and function. J Am Acad Dermatol 48 (2003), S139–S142.
88. 88 Berardesca, E., Pirot, F., Singh, M., Maibach, H., Differences in stratum corneum pH gradient when comparing white caucasian and black African-American skin. Br J Dermatol 139 (1998), 855–857.
89. 89 Bhattacharya, T., Silverberg, J.I., Efficacy of systemic treatments for atopic dermatitis in racial and ethnic minorities in the United States. JAMA Dermatol 150 (2014), 1232–1234.
90. 90 Margolis, D.J., Gupta, J., Apter, A.J., Ganguly, T., Hoffstad, O., Papadopoulos, M., et al. Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects. J Allergy Clin Immunol 133 (2014), 784–789.
91. 91 Langley, R.G., Elewski, B.E., Lebwohl, M., Reich, K., Griffiths, C.E., Papp, K., et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med 371 (2014), 326–338.
92. 92 Lebwohl, M., Strober, B., Menter, A., Gordon, K., Weglowska, J., Puig, L., et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med 373 (2015), 1318–1328.
93. 93 Gordon, K.B., Blauvelt, A., Papp, K.A., Langley, R.G., Luger, T., Ohtsuki, M., et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med 375 (2016), 345–356.
94. 94 Shi, B., Bangayan, N.J., Curd, E., Taylor, P.A., Gallo, R.L., Leung, D.Y., et al. The skin microbiome is different in pediatric versus adult atopic dermatitis. J Allergy Clin Immunol 138 (2016), 1233–1236.
95. 95 van der Velden, V.H., Laan, M.P., Baert, M.R., de Waal Malefyt, R., Neijens, H.J., Savelkoul, H.F., Selective development of a strong Th2 cytokine profile in high-risk children who develop atopy: risk factors and regulatory role of IFN-gamma, IL-4 and IL-10. Clin Exp Allergy 31 (2001), 997–1006.
96. 96 Herberth, G., Heinrich, J., Roder, S., Figl, A., Weiss, M., Diez, U., et al. Reduced IFN-gamma- and enhanced IL-4-producing CD4+ cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life. Pediatr Allergy Immunol 21 (2010), 5–13.
97. 97 Tang, M.L., Kemp, A.S., Thorburn, J., Hill, D.J., Reduced interferon-gamma secretion in neonates and subsequent atopy. Lancet 344 (1994), 983–985.
98. 98 Kaminishi, K., Soma, Y., Kawa, Y., Mizoguchi, M., Flow cytometric analysis of IL-4, IL-13 and IFN-gamma expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease. J Dermatol Sci 29 (2002), 19–25.
99. 99 Kawamoto, N., Kaneko, H., Takemura, M., Seishima, M., Sakurai, S., Fukao, T., et al. Age-related changes in intracellular cytokine profiles and Th2 dominance in allergic children. Pediatr Allergy Immunol 17 (2006), 125–133.
100. 100 La Grutta, S., Richiusa, P., Pizzolanti, G., Mattina, A., Pajno, G.B., Citarrella, R., et al. CD4(+)IL-13(+) cells in peripheral blood well correlates with the severity of atopic dermatitis in children. Allergy 60 (2005), 391–395.
101. 101 Campbell, D.E., Fryga, A.S., Bol, S., Kemp, A.S., Intracellular interferon-gamma (IFN-gamma) production in normal children and children with atopic dermatitis. Clin Exp Immunol 115 (1999), 377–382.
102. 102 Katsunuma, T., Kawahara, H., Yuki, K., Akasawa, A., Saito, H., Impaired interferon-gamma production in a subset population of severe atopic dermatitis. Int Arch Allergy Immunol 134 (2004), 240–247.
103. 103 Machura, E., Mazur, B., Kwiecien, J., Karczewska, K., Intracellular production of IL-2, IL-4, IFN-gamma, and TNF-alpha by peripheral blood CD3+ and CD4+ T cells in children with atopic dermatitis. Eur J Pediatr 166 (2007), 789–795.
104. 104 Antunez, C., Torres, M.J., Corzo, J.L., Pena, R.R., Mayorga, C., Jurado, A., et al. Different lymphocyte markers and cytokine expression in peripheral blood mononuclear cells in children with acute atopic dermatitis. Allergol Immunopathol (Madr) 32 (2004), 252–258.
105. 105 Leonardi, S., Rotolo, N., Vitaliti, G., Spicuzza, L., La Rosa, M., IgE values and T-lymphocyte subsets in children with atopic eczema/dermatitis syndrome. Allergy Asthma Proc 28 (2007), 529–534.
106. 106 Antunez, C., Torres, M.J., Mayorga, C., Corzo, J.L., Jurado, A., Santamaria-Babi, L.F., et al. Cytokine production, activation marker, and skin homing receptor in children with atopic dermatitis and bronchial asthma. Pediatr Allergy Immunol 17 (2006), 166–174.
107. 107 Chernyshov, P.V., Expression of activation inducer molecule (CD69) on CD3+CD8+ T lymphocytes in children with atopic dermatitis correlates with SCORAD but not with the age of patients. J Eur Acad Dermatol Venereol 23 (2009), 462–463.
108. 108 Wu, K.G., Li, T.H., Chen, C.J., Cheng, H.I., Wang, T.Y., Correlations of serum Interleukin-16, total IgE, eosinophil cationic protein and total eosinophil counts with disease activity in children with atopic dermatitis. Int J Immunopathol Pharmacol 24 (2011), 15–23.
109. 109 Ezzat, M.H., Hasan, Z.E., Shaheen, K.Y., Serum measurement of interleukin-31 (IL-31) in paediatric atopic dermatitis: elevated levels correlate with severity scoring. J Eur Acad Dermatol Venereol 25 (2011), 334–339.
110. 110 Nakazato, J., Kishida, M., Kuroiwa, R., Fujiwara, J., Shimoda, M., Shinomiya, N., Serum levels of Th2 chemokines, CCL17, CCL22, and CCL27, were the important markers of severity in infantile atopic dermatitis. Pediatr Allergy Immunol 19 (2008), 605–613.
111. 111 Hon, K.L., Leung, T.F., Ma, K.C., Li, A.M., Wong, Y., Fok, T.F., Serum levels of cutaneous T-cell attracting chemokine (CTACK) as a laboratory marker of the severity of atopic dermatitis in children. Clin Exp Dermatol 29 (2004), 293–296.
112. 112 Leung, T.F., Ma, K.C., Hon, K.L., Lam, C.W., Wan, H., Li, C.Y., et al. Serum concentration of macrophage-derived chemokine may be a useful inflammatory marker for assessing severity of atopic dermatitis in infants and young children. Pediatr Allergy Immunol 14 (2003), 296–301.
113. 113 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 136 (2015), 941–951.
114. 114 Esaki, H., Brunner, P.M., Renert-Yuval, Y., Czarnowicki, T., Huynh, T., Tran, G., et al. Early onset pediatric atopic dermatitis is Th2, but also Th17 polarized in skin. J Allergy Clin Immunol 138 (2016), 1639–1651.
115. 115 Witte, E., Kokolakis, G., Witte, K., Philipp, S., Doecke, W.D., Babel, N., et al. IL-19 is a component of the pathogenetic IL-23/IL-17 cascade in psoriasis. J Invest Dermatol 134 (2014), 2757–2767.
116. 116 Lande, R., Gregorio, J., Facchinetti, V., Chatterjee, B., Wang, Y.H., Homey, B., et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449 (2007), 564–569.
117. 117 Ganguly, D., Chamilos, G., Lande, R., Gregorio, J., Meller, S., Facchinetti, V., et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med 206 (2009), 1983–1994.
118. 118 Dorschner, R.A., Lin, K.H., Murakami, M., Gallo, R.L., Neonatal skin in mice and humans expresses increased levels of antimicrobial peptides: innate immunity during development of the adaptive response. Pediatr Res 53 (2003), 566–572.
119. 119 Iram, N., Mildner, M., Prior, M., Petzelbauer, P., Fiala, C., Hacker, S., et al. Age-related changes in expression and function of Toll-like receptors in human skin. Development 139 (2012), 4210–4219.
120. 120 Kim, J., Kim, B.E., Lee, J., Han, Y., Jun, H.Y., Kim, H., et al. Epidermal thymic stromal lymphopoietin predicts the development of atopic dermatitis during infancy. J Allergy Clin Immunol 137 (2016), 1282–1285.e1-4.
121. 121 Margolis, J.S., Abuabara, K., Bilker, W., Hoffstad, O., Margolis, D.J., Persistence of mild to moderate atopic dermatitis. JAMA Dermatol 150 (2014), 593–600.
122. 122 Silverberg, J.I., Persistence of childhood eczema into adulthood. JAMA Dermatol 150 (2014), 591–592.
123. 123 Czarnowicki, T., Malajian, D., Shemer, A., Fuentes-Duculan, J., Gonzalez, J., Suarez-Farinas, M., et al. Skin-homing and systemic T-cell subsets show higher activation in atopic dermatitis versus psoriasis. J Allergy Clin Immunol 136 (2015), 208–211.
124. 124 Czarnowicki, T., Gonzalez, J., Bonifacio, K.M., Shemer, A., Xiangyu, P., Kunjravia, N., et al. Diverse activation and differentiation of multiple B-cell subsets in patients with atopic dermatitis but not in patients with psoriasis. J Allergy Clin Immunol 137 (2016), 118–129.
125. 125 Alduraywish, S.A., Lodge, C.J., Campbell, B., Allen, K.J., Erbas, B., Lowe, A.J., et al. The march from early life food sensitization to allergic disease: a systematic review and meta-analyses of birth cohort studies. Allergy 71 (2016), 77–89.
126. 126 Suarez-Farinas, M., Tintle, S.J., Shemer, A., Chiricozzi, A., Nograles, K., Cardinale, I., et al. Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol 127 (2011), 954–964.
127. 127 Deckert, S., Kopkow, C., Schmitt, J., Nonallergic comorbidities of atopic eczema: an overview of systematic reviews. Allergy 69 (2014), 37–45.
128. 128 Brunner, P.M., Silverberg, J.I., Guttman-Yassky, E., Paller, A.S., Kabashima, K., Amagai, M., et al. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol 137 (2017), 18–25.
129. 129 Silverberg, J.I., Association between adult atopic dermatitis, cardiovascular disease, and increased heart attacks in three population-based studies. Allergy 70 (2015), 1300–1308.
130. 130 Silverberg, J.I., Greenland, P., Eczema and cardiovascular risk factors in 2 US adult population studies. J Allergy Clin Immunol 135 (2015), 721–728.
131. 131 Zhang, A., Silverberg, J.I., Association of atopic dermatitis with being overweight and obese: a systematic review and metaanalysis. J Am Acad Dermatol 72 (2015), 606–616.
132. 132 Silverberg, J.I., Simpson, E.L., Association between obesity and eczema prevalence, severity and poorer health in US adolescents. Dermatitis 25 (2014), 172–181.
133. 133 Silverberg, J.I., Becker, L., Kwasny, M., Menter, A., Cordoro, K.M., Paller, A.S., Central obesity and high blood pressure in pediatric patients with atopic dermatitis. JAMA Dermatol 151 (2015), 144–152.
134. 134 Strom, M., Silverberg, J.I., Associations of physical activity and sedentary behavior with atopic disease in US children. J Pediatr 174 (2016), 247–253.
135. 135 Hjuler, K.F., Bottcher, M., Vestergaard, C., Deleuran, M., Raaby, L., Botker, H.E., et al. Increased prevalence of coronary artery disease in severe psoriasis and severe atopic dermatitis. Am J Med 128 (2015), 1325–1334.
136. 136 Steyers, C.M. 3rd, Miller, F.J. Jr., Endothelial dysfunction in chronic inflammatory diseases. Int J Mol Sci 15 (2014), 11324–11349.
137. 137 Vena, G.A., Vestita, M., Cassano, N., Psoriasis and cardiovascular disease. Dermatol Ther 23 (2010), 144–151.
138. 138 Kupetsky, E.A., Mathers, A.R., Ferris, L.K., Anti-cytokine therapy in the treatment of psoriasis. Cytokine 61 (2013), 704–712.
139. 139 Koga, C., Kabashima, K., Shiraishi, N., Kobayashi, M., Tokura, Y., Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol 128 (2008), 2625–2630.
140. 140 Kanda, N., Watanabe, S., Increased serum human beta-defensin-2 levels in atopic dermatitis: relationship to IL-22 and oncostatin M. Immunobiology 217 (2012), 436–445.
141. 141 Leonardi, S., Cuppari, C., Manti, S., Filippelli, M., Parisi, G.F., Borgia, F., et al. Serum interleukin 17, interleukin 23, and interleukin 10 values in children with atopic eczema/dermatitis syndrome (AEDS): association with clinical severity and phenotype. Allergy Asthma Proc 36 (2015), 74–81.
142. 142 Hayashida, S., Uchi, H., Takeuchi, S., Esaki, H., Moroi, Y., Furue, M., Significant correlation of serum IL-22 levels with CCL17 levels in atopic dermatitis. J Dermatol Sci 61 (2011), 78–79.
143. 143 Erbel, C., Chen, L., Bea, F., Wangler, S., Celik, S., Lasitschka, F., et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J Immunol 183 (2009), 8167–8175.
144. 144 Griffin, G.K., Newton, G., Tarrio, M.L., Bu, D.X., Maganto-Garcia, E., Azcutia, V., et al. IL-17 and TNF-alpha sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation. J Immunol 188 (2012), 6287–6299.
145. 145 Leung, D.Y., Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol 105 (2000), 860–876.
146. 146 Iyengar, S.R., Hoyte, E.G., Loza, A., Bonaccorso, S., Chiang, D., Umetsu, D.T., et al. Immunologic effects of omalizumab in children with severe refractory atopic dermatitis: a randomized, placebo-controlled clinical trial. Int Arch Allergy Immunol 162 (2013), 89–93.
147. 147 Heil, P.M., Maurer, D., Klein, B., Hultsch, T., Stingl, G., Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course—a randomized, placebo-controlled and double blind pilot study. J Dtsch Dermatol Ges 8 (2010), 990–998.
148. 148 Simon, D., Braathen, L.R., Simon, H.U., Eosinophils and atopic dermatitis. Allergy 59 (2004), 561–570.
149. 149 Oldhoff, J.M., Darsow, U., Werfel, T., Katzer, K., Wulf, A., Laifaoui, J., et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy 60 (2005), 693–696.
150. 150 Phipps, S., Flood-Page, P., Menzies-Gow, A., Ong, Y.E., Kay, A.B., Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin. J Invest Dermatol 122 (2004), 1406–1412.
151. 151 Simpson, E.L., Bieber, T., Guttman-Yassky, E., Beck, L.A., Blauvelt, A., Cork, M.J., et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 375 (2016), 2335–2348.
152. 152 Nemoto, O., Furue, M., Nakagawa, H., Shiramoto, M., Hanada, R., Matsuki, S., et al. The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study. Br J Dermatol 174 (2016), 296–304.
153. 153 Wang, Y.H., Liu, Y.J., Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy 39 (2009), 798–806.
154. 154 Liu, Y.J., Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation. J Allergy Clin Immunol 120 (2007), 238–244.
155. 155 Nakajima, S., Igyarto, B.Z., Honda, T., Egawa, G., Otsuka, A., Hara-Chikuma, M., et al. Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling. J Allergy Clin Immunol 129 (2012), 1048–1055.
156. 156 Ziegler, S.F., Liu, Y.J., Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat Immunol 7 (2006), 709–714.
157. 157 Iwasaki, M., Nagata, K., Takano, S., Takahashi, K., Ishii, N., Ikezawa, Z., Association of a new-type prostaglandin D2 receptor CRTH2 with circulating T helper 2 cells in patients with atopic dermatitis. J Invest Dermatol 119 (2002), 609–616.
158. 158 He, R., Oyoshi, M.K., Wang, J.Y., Hodge, M.R., Jin, H., Geha, R.S., The prostaglandin D(2) receptor CRTH2 is important for allergic skin inflammation after epicutaneous antigen challenge. J Allergy Clin Immunol 126 (2010), 784–790.
159. 159 Ulven, T., Kostenis, E., Novel CRTH2 antagonists: a review of patents from 2006 to 2009. Expert Opin Ther Pat 20 (2010), 1505–1530.
160. 160 Cameron, L., Depner, M., Kormann, M., Klopp, N., Illig, T., von Mutius, E., et al. Genetic variation in CRTh2 influences development of allergic phenotypes. Allergy 64 (2009), 1478–1485.
161. 161 Nakajima, S., Kitoh, A., Egawa, G., Natsuaki, Y., Nakamizo, S., Moniaga, C.S., et al. IL-17A as an inducer for Th2 immune responses in murine atopic dermatitis models. J Invest Dermatol 134 (2014), 2122–2130.
162. 162 Nast, A., Jacobs, A., Rosumeck, S., Werner, R.N., Efficacy and safety of systemic long-term treatments for moderate-to-severe psoriasis: a systematic review and meta-analysis. J Invest Dermatol 135 (2015), 2641–2648.
163. 163 Khattri, S., Brunner, P.M., Garcet, S., Finney, R., Cohen, S.R., Oliva, M., et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol 26 (2016), 28–35.
164. 164 Guttman-Yassky, E., Ungar, B., Noda, S., Suprun, M., Shroff, A., Dutt, R., et al. Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism. J Allergy Clin Immunol 137 (2016), 301–304.
165. 165 Samrao, A., Berry, T.M., Goreshi, R., Simpson, E.L., A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol 148 (2012), 890–897.
166. 166 Volf, E.M., Au, S.C., Dumont, N., Scheinman, P., Gottlieb, A.B., A phase 2, open-label, investigator-initiated study to evaluate the safety and efficacy of apremilast in subjects with recalcitrant allergic contact or atopic dermatitis. J Drugs Dermatol 11 (2012), 341–346.
167. 167 Bissonnette, R., Papp, K.A., Poulin, Y., Gooderham, M., Raman, M., Mallbris, L., et al. Topical tofacitinib for atopic dermatitis: a phase 2a randomised trial. Br J Dermatol 175 (2016), 902–911.
168. 168 Levy, L.L., Urban, J., King, B.A., Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol 73 (2015), 395–399.
169. 169 De Benedetto, A., Yoshida, T., Fridy, S., Park, J.E., Kuo, I.H., Beck, L.A., Histamine and skin barrier: are histamine antagonists useful for the prevention or treatment of atopic dermatitis?. J Clin Med 4 (2015), 741–755.
170. 170 Gisondi, P., Girolomoni, G., Apremilast in the therapy of moderate-to-severe chronic plaque psoriasis. Drug Des Devel Ther 10 (2016), 1763–1770.
171. 171 Paller, A.S., Tom, W.L., Lebwohl, M.G., Blumenthal, R.L., Boguniewicz, M., Call, R.S., et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol 75 (2016), 494–503.e4.
172. 172 Amano, W., Nakajima, S., Kunugi, H., Numata, Y., Kitoh, A., Egawa, G., et al. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J Allergy Clin Immunol 136 (2015), 667–677.
173. 173 Bao, L., Zhang, H., Chan, L.S., The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT, 2, 2013, e24137.
174. 174 Glatzer, F., Gschwandtner, M., Ehling, S., Rossbach, K., Janik, K., Klos, A., et al. Histamine induces proliferation in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor. J Allergy Clin Immunol 132 (2013), 1358–1367.