Skip to main content

Advertisement

SpringerLink
Log in

Update on the Pathogenesis and Therapy of Atopic Dermatitis

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Atopic dermatitis (AD) is a common inflammatory skin disorder characterized by recurrent eczematous lesions and intense itch. Although it most often starts in infancy and affects children, it is also highly prevalent in adults. In this article, the main aspects of AD have been updated, with a focus on the pathogenetic and therapeutic aspects. The pathogenesis of AD is complex, and it is evident that a strong genetic predisposition, epidermal dysfunction, skin microbiome abnormalities, immune dysregulation, and the neuroimmune system are critical in AD development. Mutations in the genes associated with disrupted epidermal barrier, exaggerated pathological inflammation and inadequate antimicrobial peptides can promote enhanced Th2 inflammation and mediate pruritus. Current understanding of etiology highlights gut microbial diversity, NK cell deficiency, and different immunological phenotype with age and race. For topical anti-inflammatory treatment for mild-to-severe AD, phosphodiesterase 4 inhibitors (PDE-4), JAK inhibitors, and microbiome transplantation with Roseomonas mucosa provided more management selections. The treatment of moderate-to-severe AD has been limited to merely symptomatic and relatively nonspecific immunosuppressive approaches. In-depth understanding of the pathogenesis of AD has led to the development of innovative and targeted therapies, such as biologic agents targeting interleukin (IL)-4, IL-13 and JAK/STAT inhibitors. Other potential therapeutic agents for AD include agents targeting the T helper (Th) 22 and Th17/IL23 pathway. Antipruritic therapy and complementary probiotics therapy have also been reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AD:

Atopic dermatitis

AMPs:

Antimicrobial peptides

CARD14:

Caspase recruitment domain-containing protein 14

cAMP:

Cyclic adenosine monophosphate

CD200R1:

CD200 receptor 1

DOCK2:

Docking protein 2

EASI:

Eczema area and severity index

ETFAD:

European Task Force on Atopic Dermatitis

EC-MPS:

Enteric-coated mycophenolate sodium

FLG :

Filaggrin gene

H&R criteria:

Hanifin and Rajka criteria

IgE:

Immunoglobulin E

IL:

Interleukin

IL-31Rα:

IL-31 receptor α

ISGA:

Investigator static global assessment

IVIG:

Intravenous immunoglobulin

JAK:

Janus kinase

LoF:

Loss-of-function

LT:

Leukotriene

Mrgprx2:

Mas-related G protein-coupled receptor × 2

NB-UVB:

Narrow-band UVB

NK:

Natural killer

PAR2:

Proteinase-associated receptor 2

PDE-4:

Phosphodiesterase 4

R. mucosa:

Roseomonas mucosa

S. aureus:

Staphylococcus aureus

SCORAD:

SCORing of atopic dermatitis

STAT:

Transducers and activators of transcription

SYK:

Spleen tyrosine kinase

TCI:

Topical calcineurin inhibitors

TCS:

Topical corticosteroids

TEWL:

Trans-epidermal water loss

Th:

T helper

TPMT:

Thiopurine methyltransferase

TSLP:

Thymic stromal lipoprotein

UK:

Criteria UK diagnostic criteria

VAS:

Visual analog scale

References

  1. Ascott A, Mulick A, Yu AM et al (2019) Atopic eczema and major cardiovascular outcomes: a systematic review and meta-analysis of population-based studies. J Allergy Clin Immunol 143(5):1821–1829

    PubMed  PubMed Central  Google Scholar 

  2. Drucker AM, Wang AR, Li WQ et al (2017) The burden of atopic dermatitis: summary of a report for the National Eczema Association. J Invest Dermatol 137(1):26–30

    CAS  PubMed  Google Scholar 

  3. Langan SM, Irvine AD, Weidinger S (2020) Atopic dermatitis. Lancet 396(10247):345–360

    CAS  PubMed  Google Scholar 

  4. McKenzie C, Silverberg JI (2019) The prevalence and persistence of atopic dermatitis in urban United States children. Ann Allergy Asthma Immunol 123(2):173-178.e1

    PubMed  Google Scholar 

  5. Katayama I, Aihara M, Ohya Y et al (2017) Japanese guidelines for atopic dermatitis. Allergol Int 66(2):230–247

    PubMed  Google Scholar 

  6. Guo Y, Li P, Tang J et al (2016) Prevalence of atopic dermatitis in Chinese children aged 1–7 ys. Sci Rep 6:29751

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Palmer CN, Irvine AD, Terron-Kwiatkowski A et al (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38(4):441–446

    CAS  PubMed  Google Scholar 

  8. Baurecht H, Hotze M, Brand S et al (2015) Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. Am J Hum Genet 96(1):104–120

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Luukkonen TM, Kiiski V, Ahola M et al (2017) The value of FLG null mutations in predicting treatment response in atopic dermatitis: an observational study in Finnish patients. Acta Derm Venereol 97(4):456–463

    CAS  PubMed  Google Scholar 

  10. Margolis DJ, Mitra N, Wubbenhorst B et al (2019) Association of filaggrin loss-of-function variants with race in children with atopic dermatitis. JAMA Dermatol 31;155(11):1269–1276.

  11. Zhang H, Guo Y, Wang W et al (2011) Mutations in the filaggrin gene in Han Chinese patients with atopic dermatitis. Allergy 66(3):420–427

    CAS  PubMed  Google Scholar 

  12. Li M, Liu Q, Liu J et al (2013) Mutations analysis in filaggrin gene in northern China patients with atopic dermatitis. J Eur Acad Dermatol Venereol 27(2):169–174

    CAS  PubMed  Google Scholar 

  13. Nomura T, Sandilands A, Akiyama M et al (2007) Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol 119(2):434–440

    CAS  PubMed  Google Scholar 

  14. On HR, Lee SE, Kim SE et al (2017) Filaggrin mutation in Korean patients with atopic dermatitis. Yonsei Med J 58(2):395–400

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Irvine AD, McLean WH, Leung DY (2011) Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365(14):1315–1327

    CAS  PubMed  Google Scholar 

  16. Wang IJ, Lin TJ (2015) FLG P478S polymorphisms and environmental risk factors for the atopic march in Taiwanese children: a prospective cohort study. Ann Allergy Asthma Immunol 114(1):52–57

    CAS  PubMed  Google Scholar 

  17. Elias MS, Wright SC, Remenyi J et al (2019) EMSY expression affects multiple components of the skin barrier with relevance to atopic dermatitis. J Allergy Clin Immunol 144(2):470–481

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mucha S, Baurecht H, Novak N et al (2020) Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression. J Allergy Clin Immunol 145(4):1208–1218

    CAS  PubMed  Google Scholar 

  19. Peled A, Sarig O, Sun G et al (2019) Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis. J Allergy Clin Immunol 143(1):173–181

    CAS  PubMed  Google Scholar 

  20. De Benedetto A, Rafaels NM, McGirt LY et al (2011) Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol 127(3):773–786

    PubMed  Google Scholar 

  21. Silverberg JI, Hanifin J, Simpson EL (2013) Climatic factors are associated with childhood eczema prevalence in the United States. J Invest Dermatol 133(7):1752–1759

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Blunder S, Rühl R, Moosbrugger-Martinz V et al (2017) Alterations in epidermal eicosanoid metabolism contribute to inflammation and impaired late differentiation in FLG-mutated atopic dermatitis. J Invest Dermatol 137(3):706–715

    CAS  PubMed  Google Scholar 

  23. Danso M, Boiten W, van Drongelen V et al (2017) Altered expression of epidermal lipid bio-synthesis enzymes in atopic dermatitis skin is accompanied by changes in stratum corneum lipid composition. J Dermatol Sci 88(1):57–66

    CAS  PubMed  Google Scholar 

  24. Ong PY, Leung DY (2016) Bacterial and viral infections in atopic dermatitis: a comprehensive review. Clin Rev Allergy Immunol 51(3):329–337

    CAS  PubMed  Google Scholar 

  25. Shi B, Leung DY, Taylor PA et al (2018) Methicillin-resistant Staphylococcus aureus colonization is associated with decreased skin commensal bacteria in atopic dermatitis. J Invest Dermatol 138(7):1668–1671

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Goleva E, Berdyshev E, Leung DY (2019) Epithelial barrier repair and prevention of allergy. J Clin Invest 129(4):1463–1474

    PubMed  PubMed Central  Google Scholar 

  27. Moriwaki M, Iwamoto K, Niitsu Y et al (2019) Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL-1α secretion via TLR9. Allergy 74(3):560–571

    CAS  PubMed  Google Scholar 

  28. Kennedy EA, Connolly J, Hourihane JO et al (2017) Skin microbiome before development of atopic dermatitis: early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year. J Allergy Clin Immunol 139:166–172

    PubMed  PubMed Central  Google Scholar 

  29. Song H, Yoo Y, Hwang J et al (2016) Faecalibacterium prausnitzii subspecies-level dysbiosis in the human gut microbiome underlying atopic dermatitis. J Allergy Clin Immunol 137(3):852–860

    CAS  PubMed  Google Scholar 

  30. Chng KR, Tay AS, Li C et al (2016) Whole metagenome profiling reveals skin microbiome-dependent susceptibility to atopic dermatitis flare. Nat Microbiol 11;1(9):16106.

  31. Hu XQ, Tang Y, Ju Y et al (2021) Scratching damages tight junctions through the Akt-claudin 1 axis in atopic dermatitis. Clin Exp Dermatol 46(1):74–81

    CAS  PubMed  Google Scholar 

  32. Tsakok T, Woolf R, Smith CH et al (2019) Atopic dermatitis: the skin barrier and beyond. Br J Dermatol 180(3):464–474

    CAS  PubMed  Google Scholar 

  33. Orciani M, Campanati A, Caffarini M et al (2017) T helper (Th)1, Th17 and Th2 imbalance in mesenchymal stem cells of adult patients with atopic dermatitis: at the origin of the problem. Br J Dermatol 176(6):1569–1576

    CAS  PubMed  Google Scholar 

  34. Batista DI, Perez L, Orfali RL et al (2015) Profile of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17 cytokines in adults with atopic dermatitis. J Eur Acad Dermatol Venereol 29(6):1091–1095

    CAS  PubMed  Google Scholar 

  35. Nomura T, Kabashima K, Miyachi Y (2014) The panoply of αβT cells in the skin. J Dermatol Sci 76(1):3–9

    CAS  PubMed  Google Scholar 

  36. Brunner PM, Emerson RO, Tipton C et al (2017) Nonlesional atopic dermatitis skin shares similar T-cell clones with lesional tissues. Allergy 72(12):2017–2025

    CAS  PubMed  Google Scholar 

  37. Mack MR, Brestoff JR, Berrien-Elliott MM et al (2020) Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis. Sci Transl Med. 2020 26;12(532):eaay1005.

  38. Möbus L, Rodriguez E, Harder I, et al (2020) Elevated NK-cell transcriptional signature and dysbalance of resting and activated NK cells in atopic dermatitis. J Allergy Clin Immunol Dec 31: S0091–6749(20)31640–7.

  39. Looman KIM, van Meel ER, Grosserichter-Wagener C et al (2020) Associations of Th2, Th17, Treg cells, and IgA+ memory B cells with atopic disease in children: The Generation R Study. Allergy 75(1):178–187

    CAS  PubMed  Google Scholar 

  40. Zhou L, Leonard A, Pavel AB et al (2019) Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol 144(1):144–156

    CAS  PubMed  Google Scholar 

  41. Wang S, Zhu R, Gu C et al (2020) Distinct clinical features and serum cytokine pattern of elderly atopic dermatitis in China. J Eur Acad Dermatol Venereol 34(10):2346–2352

    CAS  PubMed  Google Scholar 

  42. Noda S, Suárez-Fariñas M, Ungar B et al (2015) The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol 136(5):1254–1264

    CAS  PubMed  Google Scholar 

  43. Wen HC, Czarnowicki T, Noda S et al (2018) Serum from Asian patients with atopic dermatitis is characterized by TH2/TH22 activation, which is highly correlated with nonlesional skin measures. J Allergy Clin Immunol 142(1):324–328

    CAS  PubMed  Google Scholar 

  44. Andersen L, Nyeland ME, Nyberg F (2020) Higher self-reported severity of atopic dermatitis in adults is associated with poorer self-reported health-related quality of life in France, Germany, the U.K. and the U.S.A. Br J Dermatol 182(5):1176–1183.

  45. Nattkemper LA, Tey HL, Valdes-Rodriguez R et al (2018) The genetics of chronic itch: gene expression in the skin of atopic dermatitis and psoriasis patients with severe itch. J Invest Dermatol 138(6):1311–1317

    CAS  PubMed  Google Scholar 

  46. Mollanazar NK, Smith PK, Yosipovitch G (2016) Mediators of chronic pruritus in atopic dermatitis: getting the itch out? Clin Rev Allergy Immunol 51(3):263–292

    CAS  PubMed  Google Scholar 

  47. Mali SS, Bautista DM (2021) Basophils add fuel to the flame of eczema itch. Cell 184(2):294–296

    CAS  PubMed  Google Scholar 

  48. Vakharia PP, Chopra R, Silverberg JI (2018) Systematic review of diagnostic criteria used in atopic dermatitis randomized controlled trials. Am J Clin Dermatol 19(1):15–22

    PubMed  Google Scholar 

  49. Akan A, Dibek-Mısırlıoğlu E, Civelek E et al (2020) Diagnosis of atopic dermatitis in children: comparison of the Hanifin-Rajka and the United Kingdom Working Party criteria. Allergol Immunopathol (Madr) 48(2):175–181

    CAS  Google Scholar 

  50. Endre KMA, Landrø L, LeBlanc M et al (2021) Diagnosing atopic dermatitis in infancy using established diagnostic criteria: a cohort study. Br J Dermatol. https://doi.org/10.1111/bjd.19831

    Article  PubMed  Google Scholar 

  51. Cheng R, Guo Y, Huang L et al (2017) Current status in diagnosis of atopic dermatitis in China. Allergy 72(9):1277–1278

    CAS  PubMed  Google Scholar 

  52. Liu P, Zhao Y, Mu ZL et al (2016) Clinical features of adult/adolescent atopic dermatitis and Chinese criteria for atopic dermatitis. Chin Med J (Engl) 129(7):757–762

    CAS  Google Scholar 

  53. Cheng R, Zhang H, Zong W et al (2020) Development and validation of new diagnostic criteria for atopic dermatitis in children of China. J Eur Acad Dermatol Venereo l34(3):542–548.

  54. Guo Y, Zhang H, Liu Q et al (2019) Phenotypic analysis of atopic dermatitis in children aged 1–12 months: elaboration of novel diagnostic criteria for infants in China and estimation of prevalence. J Eur Acad Dermatol Venereol 33(8):1569–1576

    CAS  PubMed  Google Scholar 

  55. Son HK, Kim DH, Lee H et al (2018) Family management of childhood atopic dermatitis. J Adv Nurs 74(6):1371–1379

    PubMed  Google Scholar 

  56. Schoessler S (2019) Atopic dermatitis: management in the school setting. NASN Sch Nurse 34(6):324–328

    PubMed  Google Scholar 

  57. Cabanillas B, Brehler AC, Novak N (2017) Atopic dermatitis phenotypes and the need for personalized medicine. Curr Opin Allergy Clin Immunol 17(4):309–315

    PubMed  PubMed Central  Google Scholar 

  58. Wollenberg A, Barbarot S, Bieber T et al (2018) Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II.J Eur Acad Dermatol Venereol 32(6): 850–878.

  59. Stefanovic N, Flohr C, Irvine AD (2020) The exposome in atopic dermatitis. Allergy 75(1):63–74

    PubMed  Google Scholar 

  60. Engebretsen KA, Johansen JD, Kezic S (2016) The effect of environmental humidity and temperature on skin barrier function and dermatitis. J Eur Acad Dermatol Venereol 30(2):223–249

    CAS  PubMed  Google Scholar 

  61. Wollenberg A, Barbarot S, Bieber T et al (2018) Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. J Eur Acad Dermatol Venereol 32(5):657–682

    CAS  PubMed  Google Scholar 

  62. Wollenberg A, Christen-Zäch S, Taieb A (2020) European task force on atopic dermatitis, EADV eczema task force. ETFAD, EADV Eczema task force, et al 2020 position paper on diagnosis and treatment of atopic dermatitis in adults and children J Eur Acad Dermatol Venereol. 34(12):2717-2744

  63. Skjerven HO, Rehbinder EM, Vettukattil R et al (2020) Skin emollient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster-randomised trial. Lancet 395(10228):951–961

    PubMed  Google Scholar 

  64. du Toit G, Sayre PH, Roberts G et al (2018) Allergen specificity of early peanut consumption and effect on development of allergic disease in the Learning Early About Peanut Allergy study cohort. J Allergy Clin Immunol 141(4):1343–1353

    PubMed  Google Scholar 

  65. Hua T, Yousaf M, Gwillim E, et al (2020) Does daily bathing or showering worsen atopic dermatitis severity? A systematic review and meta-analysis. Arch Dermatol Res https://doi.org/10.1007/s00403-020-02164-0.

  66. Majewski S, Bhattacharya T, Asztalos M et al (2019) Sodium hypochlorite body wash in the management of Staphylococcus aureus-colonized moderate-to-severe atopic dermatitis in infants, children, and adolescents. Pediatr Dermatol 36(4):442–447

    PubMed  PubMed Central  Google Scholar 

  67. Shi VY, Foolad N, Ornelas JN et al (2016) Comparing the effect of bleach and water baths on skin barrier function in atopic dermatitis: a split-body randomized controlled trial. Br J Dermatol 175(1):212–214

    CAS  PubMed  Google Scholar 

  68. Wollenberg A, Wetzel S, Burgdorf WH et al (2003) Viral infections in atopic dermatitis: pathogenic aspects and clinical management. J Allergy Clin Immunol 112(4):667–674

    PubMed  Google Scholar 

  69. van Smeden J, Boiten WA, Hankemeier T et al (2014) Combined LC/MS-platform for analysis of all major stratum corneum lipids, and the profiling of skin substitutes. Biochim Biophys Acta 1841(1):70–79

    PubMed  Google Scholar 

  70. Ishida K, Takahashi A, Bito K et al (2020) Treatment with synthetic pseudoceramide improves atopic skin, switching the ceramide profile to a healthy skin phenotype. J Invest Dermatol 140(9):1762-1770.e8

    CAS  PubMed  Google Scholar 

  71. McClanahan D, Wong A, Kezic S et al (2019) A randomized controlled trial of an emollient with ceramide and filaggrin-associated amino acids for the primary prevention of atopic dermatitis in high-risk infants. J Eur Acad Dermatol Venereol 33(11):2087–2094

    CAS  PubMed  Google Scholar 

  72. Chalmers JR, Haines RH, Bradshaw LE et al (2020) Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial. Lancet 395(10228):962–972

    PubMed  PubMed Central  Google Scholar 

  73. Chong M, Fonacier L (2016) Treatment of eczema: corticosteroids and beyond. Clin Rev Allergy Immunol 51(3):249–262

    CAS  PubMed  Google Scholar 

  74. Pavel AB, Zhou L, Diaz A et al (2020) The proteomic skin profile of moderate-to-severe atopic dermatitis patients shows an inflammatory signature. J Am Acad Dermatol 82(3):690–699

    CAS  PubMed  Google Scholar 

  75. Nicol NH, Boguniewicz M, Strand M et al (2014) Wet wrap therapy in children with moderate to severe atopic dermatitis in a multidisciplinary treatment program. J Allergy Clin Immunol Pract 2(4):400–406

    PubMed  Google Scholar 

  76. Ellison JA, Patel L, Ray DW et al (2000) Hypothalamic-pituitary-adrenal function and glucocorticoid sensitivity in atopic dermatitis. Pediatrics 105(4 Pt 1):794–799

    CAS  PubMed  Google Scholar 

  77. Broeders JA, Ahmed Ali U, Fischer G (2016) Systematic review and meta-analysis of randomized clinical trials (RCTs) comparing topical calcineurin inhibitors with topical corticosteroids for atopic dermatitis: a 15-year experience. J Am Acad Dermatol 75(2):410–419

    CAS  PubMed  Google Scholar 

  78. Deleuran M, Vestergaard C, Vølund A et al (2016) Topical calcineurin inhibitors, topical glucocorticoids and cancer in children: a nationwide study. Acta Derm Venereol 96(6):834–835

    CAS  PubMed  Google Scholar 

  79. Kempers S, Boguniewicz M, Carter E et al (2004) A randomized investigator-blinded study comparing pimecrolimus cream 1% with tacrolimus ointment 0.03% in the treatment of pediatric patients with moderate atopic dermatitis. J Am Acad Dermatol 51(4):515–525.

  80. Sigurgeirsson B, Boznanski A, Todd G et al (2015) Safety and efficacy of pimecrolimus in atopic dermatitis: a 5-year randomized trial. Pediatrics 135(4):597–606

    PubMed  Google Scholar 

  81. Doherty AM (1999) Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents. Curr Opin Chem Biol 3(4):466–473

    CAS  PubMed  Google Scholar 

  82. Yang H, Wang J, Zhang X et al (2019) Application of topical phosphodiesterase 4 inhibitors in mild to moderate atopic dermatitis: a systematic review and meta-analysis. JAMA Dermatol 155(5):585–593

    PubMed  PubMed Central  Google Scholar 

  83. Paller AS, Tom WL, Lebwohl MG et al (2016) 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(3):494-503.e6

    CAS  PubMed  Google Scholar 

  84. Eichenfield LF, Call RS, Forsha DW et al (2017) Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. J Am Acad Dermatol 77:641–649

    CAS  PubMed  Google Scholar 

  85. Ahmed A, Solman L, Williams HC et al (2018) Magnitude of benefit for topical crisaborole in the treatment of atopic dermatitis in children and adults does not look promising: a critical appraisal. Br J Dermatol 178:659–662

    CAS  PubMed  Google Scholar 

  86. Bao L, Zhang H, Chan LS (2013) The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT 2(3):e24137.

  87. Nakagawa H, Nemoto O, Igarashi A et al (2020) Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J Am Acad Dermatol 82:823–831

    CAS  PubMed  Google Scholar 

  88. Kim BS, Howell MD, Sun K et al (2020) Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J Allergy Clin Immunol 145(2):572–582

    CAS  PubMed  Google Scholar 

  89. Bissonnette R, Papp KA, Poulin Y et al (2016) Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol 175(5):902–911

    CAS  PubMed  Google Scholar 

  90. Myles IA, Earland NJ, Anderson ED et al (2018) First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI Insight 3(9):e120608.

  91. Myles IA, Castillo CR, Barbian KD et al (2020) Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair. Sci Transl Med 12(560):eaaz8631.

  92. Rodenbeck DL, Silverberg JI, Silverberg NB (2016) Phototherapy for atopic dermatitis. Clin Dermatol 34(5):607–613

    PubMed  Google Scholar 

  93. Pacifico A, Iacovelli P, Damiani G et al (2019) ‘High dose’ vs. ‘medium dose’ UVA1 phototherapy in italian patients with severe atopic dermatitis. J Eur Acad Dermatol Venereol 33(4):718–724.

  94. He A, Feldman SR, Fleischer AB Jr (2018) An assessment of the use of antihistamines in the management of atopic dermatitis. J Am Acad Dermatol 79(1):92–96

    CAS  PubMed  Google Scholar 

  95. Simpson EL, Bieber T, Guttman-Yassky E et al (2016) Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 375:2335–2348

    CAS  PubMed  Google Scholar 

  96. de Bruin-Weller M, Thaçi D, Smith CH et al (2018) Dupilumab with concomitant topical corticosteroid treatment in adults with atopic dermatitis with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo-controlled, randomized phase III clinical trial (LIBERTY AD CAFÉ). Br J Dermatol 178(5):1083–1101

    PubMed  Google Scholar 

  97. Worm M, Simpson EL, Thaçi D et al (2020) Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: a randomized clinical trial. JAMA Dermatol 156(2):131–143

    PubMed  Google Scholar 

  98. Harper JI, Ahmed I, Barclay G et al (2000) Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol 142(1):52–58

    CAS  PubMed  Google Scholar 

  99. Kim JE, Shin JM, Ko JY et al (2016) Importance of concomitant topical therapy in moderate-to-severe atopic dermatitis treated with cyclosporine. Dermatol Ther 29(2):120–125

    PubMed  Google Scholar 

  100. Goujon C, Viguier M, Staumont-Sallé D et al (2018) Methotrexate versus cyclosporine in adults with moderate-to-severe atopic dermatitis: a phase III randomized noninferiority trial. J Allergy Clin Immunol Pract 6(2):562–569

    PubMed  Google Scholar 

  101. Gerbens LAA, Hamann SAS, Brouwer MWD et al (2018) Methotrexate and azathioprine for severe atopic dermatitis: a 5-year follow-up study of a randomized controlled trial. Br J Dermatol 178(6):1288–1296

    CAS  PubMed  Google Scholar 

  102. Haeck IM, Knol MJ, Ten Berge O et al (2011) Enteric-coated mycophenolate sodium versus cyclosporin A as long-term treatment in adult patients with severe atopic dermatitis: a randomized controlled trial. J Am Acad Dermatol 64(6):1074–1084

    CAS  PubMed  Google Scholar 

  103. Phan K, Smith SD (2020) Mycophenolate mofetil and atopic dermatitis: systematic review and meta-analysis. J Dermatolog Treat 31(8):810–814

    CAS  PubMed  Google Scholar 

  104. Breslin ME, Lin JH, Roberts R et al (2016) Transient hypogammaglobulinemia and severe atopic dermatitis: open-label treatment with immunoglobulin in a case series. Allergy Rhinol (Providence) 7(2):69–73

    Google Scholar 

  105. Wong PH, White KM (2016) Impact of immunoglobulin therapy in pediatric disease: a review of immune mechanisms. Clin Rev Allergy Immunol 51(3):303–314

    CAS  PubMed  Google Scholar 

  106. Li H, Li C, Zhang H et al (2016) Effects of lidocaine on regulatory T cells in atopic dermatitis. J Allergy Clin Immunol 137(2):613–617

    CAS  PubMed  Google Scholar 

  107. Bae JM, Choi YY, Park CO et al (2013) Efficacy of allergen-specific immunotherapy for atopic dermatitis: a systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol 132(1):110–117

    PubMed  Google Scholar 

  108. Zhong H, Deng X, Song Z et al (2015) Immunological changes after ASIT in AD allergen-specific immunotherapy and their potential correlation with clinical response in patients with atopic dermatitis patients sensitized to house dust mite. J Eur Acad Dermatol Venereol 29(7):1318–1324

    CAS  PubMed  Google Scholar 

  109. Leung TH, Zhang LF, Wang J et al (2013) Topical hypochlorite ameliorates NF-κB-mediated skin diseases in mice. J Clin Invest 123(12):5361–5370

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kaffenberger BH, Mathis J, Zirwas MJ (2014) A retrospective descriptive study of oral azole antifungal agents in patients with patch test-negative head and neck predominant atopic dermatitis. J Am Acad Dermatol 71(3):480–483

    CAS  PubMed  Google Scholar 

  111. Werfel T, Layton G, Yeadon M et al (2019) Efficacy and safety of the histamine H4 receptor antagonist ZPL-3893787 in patients with atopic dermatitis. J Allergy Clin Immunol 143(5):1830–1837

    CAS  PubMed  Google Scholar 

  112. Sakata D, Uruno T, Matsubara K et al (2019) Selective role of neurokinin B in IL-31-induced itch response in mice. J Allergy Clin Immunol 144(4):1130-1133.e8

    CAS  PubMed  Google Scholar 

  113. Murakami-Satsutani N, Ito T, Nakanishi T et al (2014) IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligand. Allergol Int 63(3):443–455

    CAS  PubMed  Google Scholar 

  114. Kabashima K, Matsumura T, Komazaki H et al (2020) Nemolizumab-JP01 study group. trial of nemolizumab and topical agents for atopic dermatitis with pruritus. N Engl J Med 383(2):141–150.

  115. Simpson EL, Parnes JR, She D et al (2019) Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial. J Am Acad Dermatol 80(4):1013–1021

    CAS  PubMed  Google Scholar 

  116. Guttman-Yassky E, Pavel AB, Zhou L et al (2019) GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis. J Allergy Clin Immunol 144(2):482–493

    CAS  PubMed  Google Scholar 

  117. Chen YL, Gutowska-Owsiak D, Hardman CS et al (2019) Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis. Sci Transl Med 11(515):eaax2945.

  118. Malhotra N, Yoon J, Leyva-Castillo JM et al (2016) IL-22 derived from γδ T cells restricts Staphylococcus aureus infection of mechanically injured skin. J Allergy Clin Immunol 138(4):1098-1107.e3

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Guttman-Yassky E, Brunner PM, Neumann AU et al (2018) Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: a randomized, double-blind, phase 2a trial. J Am Acad Dermatol 78(5):872-881.e6

    CAS  PubMed  Google Scholar 

  120. Chan TC, Sanyal RD, Pavel AB et al (2018) Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features. J Allergy Clin Immunol 142:1013–1017

    PubMed  Google Scholar 

  121. Khattri S, Brunner PM, Garcet S et al (2017) Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol 26(1):28–35

    CAS  PubMed  Google Scholar 

  122. Simon D, Hösli S, Kostylina G et al (2008) Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol 121(1):122–128

    CAS  PubMed  Google Scholar 

  123. Sedivá A, Kayserová J, Vernerová E et al (2008) Anti-CD20 (rituximab) treatment for atopic eczema. J Allergy Clin Immunol 121(6):1515–1516

    PubMed  Google Scholar 

  124. Oldhoff JM, Darsow U, Werfel T et al (2006) No effect of anti-interleukin-5 therapy (mepolizumab) on the atopy patch test in atopic dermatitis patients. Int Arch Allergy Immunol 141(3):290–294

    CAS  PubMed  Google Scholar 

  125. Liu FT, Goodarzi H, Chen HY (2011) IgE, mast cells, and eosinophils in atopic dermatitis. Clin Rev Allergy Immunol 41(3):298–310

    CAS  PubMed  Google Scholar 

  126. yengar SR, Hoyte EG, Loza A, et al (2013) Immunologic effects of omalizumab in children with severe refractory atopic dermatitis: a randomized, placebo-controlled clinical trial. Int Arch Allergy Immunol 162(1):89–93

    Google Scholar 

  127. Heil PM, Maurer D, Klein B et al (2010) 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(12):990–998

    PubMed  Google Scholar 

  128. Wang HH, Li YC, Huang YC (2016) Efficacy of omalizumab in patients with atopic dermatitis: a systematic review and meta-analysis. J Allergy Clin Immunol 138(6):1719–1722

    CAS  PubMed  Google Scholar 

  129. Guttman-Yassky E, Thaçi D, Pangan AL et al (2020) Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. J Allergy Clin Immunol 145(3):877–884

    CAS  PubMed  Google Scholar 

  130. Simpson EL, Lacour JP, Spelman L et al (2020) Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials. Br J Dermatol 183(2):242–255

    CAS  PubMed  Google Scholar 

  131. Guttman-Yassky E, Silverberg JI, Nemoto O et al (2019) Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J Am Acad Dermatol 80(4):913-921.e9

    CAS  PubMed  Google Scholar 

  132. Silverberg JI, Simpson EL, Thyssen JP et al (2020) Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol 156(8):863–873

    PubMed  Google Scholar 

  133. Simpson EL, Sinclair R, Forman S et al (2020) Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet 396(10246):255–266

    CAS  PubMed  Google Scholar 

  134. Bissonnette R, Maari C, Forman S et al (2019) The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate-to-severe atopic dermatitis: results from a randomized double-blind placebo-controlled study. Br J Dermatol 181(4):733–742

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Lee YW, Won CH, Jung K et al (2019) Efficacy and safety of PAC-14028 cream - a novel, topical, nonsteroidal, selective TRPV1 antagonist in patients with mild-to-moderate atopic dermatitis: a phase IIb randomized trial. Br J Dermatol 180(5):1030–1038

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Navarro-López V, Ramírez-Boscá A, Ramón-Vidal D et al (2018) Effect of oral administration of a mixture of probiotic strains on SCORAD index and use of topical steroids in young patients with moderate atopic dermatitis: a randomized clinical trial. JAMA Dermatol 154(1):37–43

    PubMed  Google Scholar 

  137. Cao L, Wang L, Yang L et al (2015) Long-term effect of early-life supplementation with probiotics on preventing atopic dermatitis: a meta-analysis. J Dermatolog Treat 26(6):537–540

    PubMed  Google Scholar 

Download references

Funding

This work was supported by funds from the National Nature Science Foundation of China (81630083, 81874252, 81703150), the most important clinical discipline in Shanghai (2017ZZ2016-02), Innovative research team of high-level local universities in Shanghai (2018), and ‘Chen Guang’ project from Shanghai Municipal Education Commission and Shanghai Education Development Foundation (17CG11).

Author information

Author notes

  1. Huaguo Li and Zhen Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Huaguo Li, Zhen Zhang, Hui Zhang, Yifeng Guo & Zhirong Yao

  2. Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Huaguo Li, Zhen Zhang, Hui Zhang, Yifeng Guo & Zhirong Yao

Authors
  1. Huaguo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yifeng Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhirong Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yifeng Guo or Zhirong Yao.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, H., Zhang, Z., Zhang, H. et al. Update on the Pathogenesis and Therapy of Atopic Dermatitis. Clinic Rev Allerg Immunol 61, 324–338 (2021). https://doi.org/10.1007/s12016-021-08880-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-021-08880-3

Keywords

Search

Navigation