Atopic Dermatitis Endotypes: Molecular Pathways and Precision Treatment Strategies

Authors

  • Zeiad Abdulaziz Alobead
  • Asem AlMesfer
  • Ahmad Assiri

Keywords:

Atopic Dermatitis, Endotype, Precision Medicine, Biomarker, T2-High, Barrier-Defective, Th17, Th22, IL-4, IL-13, JAK-STAT, Dupilumab, JAK Inhibitors

Abstract

Background: Atopic dermatitis (AD) is a complex, heterogeneous inflammatory skin disease. Traditional phenotype-based management often fails to control moderate-to-severe disease, highlighting the limitations of a "one-size-fits-all" approach. A paradigm shift toward a mechanistically-driven understanding, centered on the concept of disease endotypes, is crucial for advancing care.

Objective: This review synthesizes the current evidence on major AD endotypes, their defining molecular pathways, and the precision treatment strategies they inform.

Methods: The databases were searched for articles published in English in 3 data bases [PubMed – Google scholar- science direct] and a comprehensive analysis of the literature was conducted, focusing on studies that utilized high-throughput 'omics' technologies, genetic associations, and clinical trial data to deconstruct AD pathophysiology. The review delineates endotypes based on distinct molecular signatures and links these drivers to emerging targeted therapies. 

Conclusion: The stratification of AD into molecular endotypes is foundational to precision dermatology. Moving beyond clinical phenotypes to define the underlying pathological drivers enables the selection of optimal targeted therapies, such as biologics and small molecules, leading to improved efficacy and personalized patient management. Future research must focus on validating practical biomarkers for routine endotype identification in clinical practice.

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References

Nutten S. Atopic dermatitis: global epidemiology and risk factors. Annals of nutrition and metabolism. 2015 Apr 1;66(Suppl. 1):8-16.

Wollenberg A, Barbarot S, Bieber T, Christen‐Zaech S, Deleuran M, Fink‐Wagner A, Gieler U, Girolomoni G, Lau S, Muraro A, Czarnecka‐Operacz M. Consensus‐based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. Journal of the European Academy of Dermatology and Venereology. 2018 May;32(5):657-82.

Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nature medicine. 2012 May;18(5):716-25.

Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature genetics. 2006 Apr 1;38(4):441-6.

Bieber T. Atopic dermatitis N Engl J Med, 358 (14): 1483-1494 [Internet]. 2008

O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annual review of medicine. 2015 Jan 14;66(1):311-28.

Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K. Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP. Nature immunology. 2002 Jul 1;3(7):673-80.

Noda S, Suárez-Fariñas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, Peng X, Estrada YD, Nakajima S, Honda T, Shin JU. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. Journal of Allergy and Clinical Immunology. 2015 Nov 1;136(5):1254-64.

Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016;375(24):2335-2348.

Gittler JK, Shemer A, Suárez-Fariñas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQ, Mitsui H, Cardinale I, de Guzman Strong C, Krueger JG, Guttman-Yassky E. Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. Journal of Allergy and Clinical Immunology. 2012 Dec 1;130(6):1344-54.

Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K. Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP. Nature immunology. 2002 Jul 1;3(7):673-80.

Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, Kukova G, Buhl T, Ikoma A, Buddenkotte J, Soumelis V. A sensory neuron–expressed IL-31 receptor mediates T helper cell–dependent itch: Involvement of TRPV1 and TRPA1. Journal of allergy and clinical immunology. 2014 Feb 1;133(2):448-60.

Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature genetics. 2006 Apr 1;38(4):441-6.

McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. Journal of Allergy and Clinical Immunology. 2013 Feb 1;131(2):280-91.

Noda S, Suárez-Fariñas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, Peng X, Estrada YD, Nakajima S, Honda T, Shin JU. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. Journal of Allergy and Clinical Immunology. 2015 Nov 1;136(5):1254-64.

Briot A, Deraison C, Lacroix M, Bonnart C, Robin A, Besson C, Dubus P, Hovnanian A. Kallikrein 5 induces atopic dermatitis–like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. Journal of Experimental Medicine. 2009 May 11;206(5):1135-47.

Van Smeden J, Janssens M, Gooris GS, Bouwstra J. The important role of stratum corneum lipids for the cutaneous barrier function. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2014 Mar 1;1841(3):295-313.

De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M. Tight junction defects in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology. 2011 Mar 1;127(3):773-86.

Guttman-Yassky E, Brunner PM, Neumann AU, Khattri S, Pavel AB, Malik K, Singer GK, Baum D, Gilleaudeau P, Sullivan-Whalen M, Rose S. 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. Journal of the American Academy of Dermatology. 2018 May 1;78(5):872-81.

Hamid Q, Boguniewicz M, Leung D. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. The Journal of clinical investigation. 1994 Aug 1;94(2):870-6.

Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, Chen S, Trier AM, Xu AZ, Tripathi SV, Luo J. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell. 2017 Sep 21;171(1):217-28.

Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Muñoz-Planillo R, Hasegawa M, Villaruz AE, Cheung GY, McGavin MJ, Travers JB, Otto M. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature. 2013 Nov 21;503(7476):397-401.

Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY. Cytokine modulation of atopic dermatitis filaggrin skin expression. Journal of Allergy and Clinical Immunology. 2009 Sep 1;124(3):R7-12.

Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, Kukova G, Buhl T, Ikoma A, Buddenkotte J, Soumelis V. A sensory neuron–expressed IL-31 receptor mediates T helper cell–dependent itch: Involvement of TRPV1 and TRPA1. Journal of allergy and clinical immunology. 2014 Feb 1;133(2):448-60.

Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, Chen S, Trier AM, Xu AZ, Tripathi SV, Luo J. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell. 2017 Sep 21;171(1):217-28.

Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K. Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP. Nature immunology. 2002 Jul 1;3(7):673-80.

Simpson EL, Parnes JR, She D, Crouch S, Rees W, Mo M, van der Merwe R. Tezepelumab, an anti–thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. Journal of the American Academy of Dermatology. 2019 Apr 1;80(4):1013-21.

O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annual review of medicine. 2015 Jan 14;66(1):311-28.

Guttman-Yassky E, Thaçi D, Pangan AL, Hong HC, Papp KA, Reich K, Beck LA, Mohamed ME, Othman AA, Anderson JK, Gu Y. Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. Journal of Allergy and Clinical Immunology. 2020 Mar 1;145(3):877-84.

Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, Silverberg JI, Deleuran M, Kataoka Y, Lacour JP, Kingo K. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. New England Journal of Medicine. 2016 Dec 15;375(24):2335-48.

Hamilton JD, Suárez-Farinas M, Dhingra N, Cardinale I, Li X, Kostic A, Ming JE, Radin AR, Krueger JG, Graham N, Yancopoulos GD. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. Journal of Allergy and Clinical Immunology. 2014 Dec 1;134(6):1293-300.

Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T, Ramon M, Bergman R, Krueger JG, Guttman-Yassky E. IL-22–producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17–producing TH17 T cells. Journal of Allergy and Clinical Immunology. 2009 Jun 1;123(6):1244-52.

Guttman-Yassky E, Brunner PM, Neumann AU, Khattri S, Pavel AB, Malik K, Singer GK, Baum D, Gilleaudeau P, Sullivan-Whalen M, Rose S. 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. Journal of the American Academy of Dermatology. 2018 May 1;78(5):872-81.

Lynde CW, Beecker J, Dutz J, Flanagan C, Guenther LC, Gulliver W, Papp K, Rahman P, Sholter D, Searles GE. Treating to target (s) with interleukin-17 inhibitors. Journal of Cutaneous Medicine and Surgery. 2019 Mar;23(2_suppl):3S-4S.

Noda S, Suárez-Fariñas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, Peng X, Estrada YD, Nakajima S, Honda T, Shin JU. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. Journal of Allergy and Clinical Immunology. 2015 Nov 1;136(5):1254-64.

Hamid Q, Boguniewicz M, Leung D. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. The Journal of clinical investigation. 1994 Aug 1;94(2):870-6.

Guttman-Yassky E, Thaçi D, Pangan AL, Hong HC, Papp KA, Reich K, Beck LA, Mohamed ME, Othman AA, Anderson JK, Gu Y. Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. Journal of Allergy and Clinical Immunology. 2020 Mar 1;145(3):877-84.

Hamilton JD, Suárez-Farinas M, Dhingra N, Cardinale I, Li X, Kostic A, Ming JE, Radin AR, Krueger JG, Graham N, Yancopoulos GD. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. Journal of Allergy and Clinical Immunology. 2014 Dec 1;134(6):1293-300.

Wollenberg A, Blauvelt A, Guttman‐Yassky E, Worm M, Lynde C, Lacour JP, Spelman L, Katoh N, Saeki H, Poulin Y, Lesiak A. Tralokinumab for moderate‐to‐severe atopic dermatitis: results from two 52‐week, randomized, double‐blind, multicentre, placebo‐controlled phase III trials (ECZTRA 1 and ECZTRA 2). British Journal of Dermatology. 2021 Mar 1;184(3):437-49.

Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I, Wollenberg A, Galus R, Etoh T, Mihara R, Yoshida H, Stewart J. Anti–interleukin-31 receptor A antibody for atopic dermatitis. New England Journal of Medicine. 2017 Mar 2;376(9):826-35.

Simpson EL, Parnes JR, She D, Crouch S, Rees W, Mo M, van der Merwe R. Tezepelumab, an anti–thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. Journal of the American Academy of Dermatology. 2019 Apr 1;80(4):1013-21.

Simpson EL, Sinclair R, Forman S, et al. 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. 2020;396(10246):255-266. doi:10.1016/S0140-6736(20)30732-7.

Guttman-Yassky E, Brunner PM, Neumann AU, Khattri S, Pavel AB, Malik K, Singer GK, Baum D, Gilleaudeau P, Sullivan-Whalen M, Rose S. 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. Journal of the American Academy of Dermatology. 2018 May 1;78(5):872-81.

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Published

2021-06-20

How to Cite

1.
Alobead ZA, AlMesfer A, Assiri A. Atopic Dermatitis Endotypes: Molecular Pathways and Precision Treatment Strategies. J Neonatal Surg [Internet]. 2021Jun.20 [cited 2025Nov.21];10:44-56. Available from: https://jneonatalsurg.com/index.php/jns/article/view/9469

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