New and Future Therapies

  • Ken IgawaEmail author
  • Hiroo Yokozeki


Atopic dermatitis (AD) is caused by a complex interrelationship of a variety of genetic and environmental factors, leading to the maintenance of the chronic inflammatory skin condition.

Most conventional treatments have been designed for the so-called average patient. However, because of recent advances in life science, a more precise diagnosis of individual patients can be made, and even among patients who have the same disease, detailed subgroup classification is presumably possible. The concept that treatment and prophylactic methods can be developed for each subgroup to deepen medical treatments is referred to as ‘precision medicine’.

In recent years, many previously unknown points concerning the mechanisms of the pathogenesis of AD have been elucidated, and novel treatments in line with the pathological mechanisms or based on subgroup classifications have been developed.

It is presumed that the re-establishment of medical care in the field of allergic diseases will also be based on the concept of ‘precision medicine’. Herein, we describe how future treatment strategies for atopic dermatitis can be developed on the basis of the idea of ‘precision medicine’.


Atopic dermatitis Precision medicine Novel therapeutic approach Nucleic acid drugs 


  1. 1.
    Berth-Jones J, Damstra RJ, Golsch S, et al. Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study. BMJ. 2003;326:1367.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Szczepanowska J, Reich A, Szepietowski JC. Emollients improve treatment results with topical corticosteroids in childhood atopic dermatitis: a randomized comparative study. Pediatr Allergy Immunol. 2008;19:614–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Fallon PG, Sasaki T, Sandilands A, et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet. 2009;41:602–8.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Scharschmidt TC, Man MQ, Hatano Y, et al. Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens. J Allergy Clin Immunol. 2009;124:496–506. e1–6CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Novak N, Baurecht H, Schäfer T, et al. Loss-of-function mutations in the filaggrin gene and allergic contact sensitization to nickel. J Invest Dermatol. 2008;128:1430–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Ross-Hansen K, Menné T, Johansen JD, et al. Nickel reactivity and filaggrin null mutations--evaluation of the filaggrin bypass theory in a general population. Contact Dermatitis. 2011;64:24–31.CrossRefPubMedGoogle Scholar
  7. 7.
    Horimukai K, Morita K, Narita M, et al. Application of moisturizer to neonates prevents development of atopic dermatitis. J Allergy Clin Immunol. 2014;134:824–30.e6.CrossRefPubMedGoogle Scholar
  8. 8.
    Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014;134:818–23.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Schauber J, Dorschner RA, Yamasaki K, et al. Control of the innate epithelial antimicrobial response is cell-type specific and dependent on relevant microenvironmental stimuli. Immunology. 2006;118:509–19.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Hata TR, Gallo RL. Antimicrobial peptides, skin infections, and atopic dermatitis. Semin Cutan Med Surg. 2008;27:144–50.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Schauber J, Gallo RL. Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol. 2009;124:R13–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–60.CrossRefPubMedGoogle Scholar
  13. 13.
    Nomura I, Goleva E, Howell MD, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003;171:3262–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Rieg S, Steffen H, Seeber S, et al. Deficiency of dermcidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis correlates with an impaired innate defense of human skin in vivo. J Immunol. 2005;174:8003–10.CrossRefPubMedGoogle Scholar
  15. 15.
    Macias ES, Pereira FA, Rietkerk W, et al. Superantigens in dermatology. J Am Acad Dermatol. 2011;64:455–72. quiz 73–4CrossRefPubMedGoogle Scholar
  16. 16.
    Schauber J, Oda Y, Büchau AS, et al. Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D3. J Invest Dermatol. 2008;128:816–24.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004;173:2909–12.CrossRefPubMedGoogle Scholar
  18. 18.
    Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005;19:1067–77.CrossRefPubMedGoogle Scholar
  19. 19.
    Hata TR, Kotol P, Jackson M, et al. Administration of oral vitamin D induces cathelicidin production in atopic individuals. J Allergy Clin Immunol. 2008;122:829–31.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Javanbakht MH, Keshavarz SA, Djalali M, et al. Randomized controlled trial using vitamins E and D supplementation in atopic dermatitis. J Dermatolog Treat. 2011;22:144–50.CrossRefPubMedGoogle Scholar
  21. 21.
    Sidbury R, Sullivan AF, Thadhani RI, et al. Randomized controlled trial of vitamin D supplementation for winter-related atopic dermatitis in Boston: a pilot study. Br J Dermatol. 2008;159:245–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Segaert S. Vitamin D regulation of cathelicidin in the skin: toward a renaissance of vitamin D in dermatology? J Invest Dermatol. 2008;128:773–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007;120:150–5.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2009;124:R7–R12.CrossRefPubMedGoogle Scholar
  25. 25.
    Grewe M, Bruijnzeel-Koomen CA, Schöpf E, et al. A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis. Immunol Today. 1998;19:359–61.CrossRefPubMedGoogle Scholar
  26. 26.
    Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases. J Allergy Clin Immunol. 2003;112:252–62.CrossRefPubMedGoogle Scholar
  27. 27.
    Bieber T. Fc epsilon RI-expressing antigen-presenting cells: new players in the atopic game. Immunol Today. 1997;18:311–3.CrossRefPubMedGoogle Scholar
  28. 28.
    Hsu CL, Shiung YY, Lin BL, et al. Accumulated immune complexes of IgE and omalizumab trap allergens in an in vitro model. Int Immunopharmacol. 2010;10:533–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Vigo PG, Girgis KR, Pfuetze BL, et al. Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol. 2006;55:168–70.CrossRefPubMedGoogle Scholar
  30. 30.
    Belloni B, Ziai M, Lim A, et al. Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol. 2007;120:1223–5.CrossRefPubMedGoogle Scholar
  31. 31.
    Rackemann FM. Intrinsic Asthma. Bull N Y Acad Med. 1947;23:302–6.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Brenninkmeijer EE, Spuls PI, Legierse CM, et al. Clinical differences between atopic and atopiform dermatitis. J Am Acad Dermatol. 2008;58:407–14.CrossRefPubMedGoogle Scholar
  33. 33.
    Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci. 2010;58:1–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Wollenberg A, Reitamo S, Girolomoni G, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy. 2008;63:742–50.CrossRefGoogle Scholar
  35. 35.
    Peserico A, Städtler G, Sebastian M, et al. Reduction of relapses of atopic dermatitis with methylprednisolone aceponate cream twice weekly in addition to maintenance treatment with emollient: a multicentre, randomized, double-blind, controlled study. Br J Dermatol. 2008;158:801–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Werfel T, Heratizadeh A, Aberer W, et al. S2k guideline on diagnosis and treatment of atopic dermatitis--short version. J Dtsch Dermatol Ges. 2016;14:92–106.PubMedGoogle Scholar
  37. 37.
    Cury Martins J, Martins C, Aoki V, et al. Topical tacrolimus for atopic dermatitis. Cochrane Database Syst Rev. 2015; CD009864.Google Scholar
  38. 38.
    Legendre L, Barnetche T, Mazereeuw-Hautier J, et al. Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: a systematic review and meta-analysis. J Am Acad Dermatol. 2015;72:992–1002.CrossRefPubMedGoogle Scholar
  39. 39.
    Jacobi A, Antoni C, Manger B, et al. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol. 2005;52:522–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Buka RL, Resh B, Roberts B, et al. Etanercept is minimally effective in 2 children with atopic dermatitis. J Am Acad Dermatol. 2005;53:358–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Yokozeki H. A nucleic acid-based medication for allergic skin diseases. Jpn J Clin Immunol. 2012;35:107–11.CrossRefGoogle Scholar
  42. 42.
    Hannon GJ. RNA interference. Nature. 2002;418:244–51.CrossRefPubMedGoogle Scholar
  43. 43.
    Morishita R, Sugimoto T, Aoki M, et al. In vivo transfection of cis element “decoy” against nuclear factor-kappaB binding site prevents myocardial infarction. Nat Med. 1997;3:894–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Nakamura H, Aoki M, Tamai K, et al. Prevention and regression of atopic dermatitis by ointment containing NF-kB decoy oligodeoxynucleotides in NC/Nga atopic mouse model. Gene Ther. 2002;9:1221–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38:441–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Suárez-Fariñas M, Dhingra N, Gittler J, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Yokozeki H, Ghoreishi M, Takagawa S, et al. Signal transducer and activator of transcription 6 is essential in the induction of contact hypersensitivity. J Exp Med. 2000;191:995–1004.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Yokozeki H, Wu MH, Sumi K, et al. In vivo transfection of a cis element ‘decoy’ against signal transducers and activators of transcription 6 (STAT6)-binding site ameliorates IgE-mediated late-phase reaction in an atopic dermatitis mouse model. Gene Ther. 2004;11:1753–62.CrossRefPubMedGoogle Scholar
  49. 49.
    Sumi K, Yokozeki H, Wu MH, et al. In vivo transfection of a cis element ‘decoy’ against signal transducers and activators of the transcription 6 (STAT6) binding site ameliorates the response of contact hypersensitivity. Gene Ther. 2004;11:1763–71.CrossRefPubMedGoogle Scholar
  50. 50.
    Miyazaki Y, Satoh T, Nishioka K, et al. STAT-6-mediated control of P-selectin by substance P and interleukin-4 in human dermal endothelial cells. Am J Pathol. 2006;169:697–707.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Igawa K, Satoh T, Hirashima M, et al. Regulatory mechanisms of galectin-9 and eotaxin-3 synthesis in epidermal keratinocytes: possible involvement of galectin-9 in dermal eosinophilia of Th1-polarized skin inflammation. Allergy. 2006;61:1385–91.CrossRefPubMedGoogle Scholar
  52. 52.
    Igawa K, Satoh T, Yokozeki H. A therapeutic effect of STAT6 decoy oligodeoxynucleotide ointment in atopic dermatitis: a pilot study in adults. Br J Dermatol. 2009;160:1124–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Hosoya K, Satoh T, Yamamoto Y, et al. Gene silencing of STAT6 with siRNA ameliorates contact hypersensitivity and allergic rhinitis. Allergy. 2011;66:124–31.CrossRefPubMedGoogle Scholar
  54. 54.
    Kim BE, Leung DY, Boguniewicz M, et al. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126:332–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Dillon SR, Sprecher C, Hammond A, et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol. 2004;5:752–60.CrossRefPubMedGoogle Scholar
  56. 56.
    Sonkoly E, Muller A, Lauerma AI, et al. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117:411–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Ikoma A, Steinhoff M, Ständer S, et al. The neurobiology of itch. Nat Rev Neurosci. 2006;7:535–47.CrossRefPubMedGoogle Scholar
  58. 58.
    Nemoto O, Furue M, Nakagawa H, 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. 2016;174:296–304.CrossRefPubMedGoogle Scholar
  59. 59.
    Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Thaçi D, Simpson EL, Beck LA, 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. 2016;387:40–52.CrossRefPubMedGoogle Scholar
  61. 61.
    Soumelis V, Reche PA, Kanzler H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–80.CrossRefPubMedGoogle Scholar
  62. 62.
    Yoo J, Omori M, Gyarmati D, et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med. 2005;202:541–9.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Wilson SR, Thé L, Batia LM, et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013;155:285–95.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of DermatologyDokkyo Medical UniversityTochigiJapan
  2. 2.Department of DermatologyTokyo Medical and Dental UniversityTokyoJapan

Personalised recommendations