An Encompassing Review on Therapeutic Targets, Therapies and Nanostructure Based Formulations for Atopic Dermatitis

DOI:

https://doi.org/10.37285/ijpsn.2024.17.4.10

Authors

Abstract

Atopic dermatitis (AD) is a complex inflammatory skin disease that frequently develops in childhood and can last into adulthood. It can be very painful and harm a person's quality of life. The exact cause of atopic dermatitis is not fully known but is believed to be a combination of genetic disorders and environmental factors. Currently used drugs in the treatment are topical corticosteroids and topical calcineurin inhibitors. This comprehensive review summarizes the pathophysiology of atopic dermatitis, therapeutic targets, current treatment, newer and emerging therapies in AD treatment, and the role of nanoparticles in formulation development for AD treatment.

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Keywords:

Atopic dermatitis, Protein defects in AD, Newer therapies, Nanoparticles, Targets, Current drugs

Published

2024-08-15

How to Cite

1.
R M, Jawahar N, Singh J, S S. An Encompassing Review on Therapeutic Targets, Therapies and Nanostructure Based Formulations for Atopic Dermatitis. Scopus Indexed [Internet]. 2024 Aug. 15 [cited 2024 Dec. 10];17(4):7519-51. Available from: https://www.ijpsnonline.com/index.php/ijpsn/article/view/4390

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Section

Review Articles

References

Sroka-Tomaszewska J, Trzeciak M. Molecular mechanisms of atopic dermatitis pathogenesis. Int J Mol Sci. 2021;22(8):4130.

David Boothe W, Tarbox JA, Tarbox MB. Atopic dermatitis: pathophysiology. Manag Atopic Dermat Methods Chall. 2017;21–37.

Bawany F, Northcott CA, Beck LA, Pigeon WR. Sleep disturbances and atopic dermatitis: relationships, methods for assessment, and therapies. J Allergy Clin Immunol Pract. 2021;9(4):1488–500.

Egawa G, Kabashima K. Barrier dysfunction in the skin allergy. Allergol Int. 2018;67(1):3–11.

Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005;6(4):328–40.

Yang X, Kambe N, Takimoto-Ito R, Kabashima K. Advances in the pathophysiology of atopic dermatitis revealed by novel therapeutics and clinical trials. Pharmacol Ther. 2021;224:107830.

Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, 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(4):441–6.

Pellerin L, Henry J, Hsu CY, Balica S, Jean-Decoster C, Méchin MC, et al. Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. J Allergy Clin Immunol. 2013;131(4):1094–102.

Seguchi T, Chang-Yi C, Kusuda S, Takahashi M, Aisu K, Tezuka T. Decreased expression of filaggrin in atopic skin. Arch Dermatol Res. 1996;288:442–6.

Moosbrugger-Martinz V, Leprince C, Méchin MC, Simon M, Blunder S, Gruber R, et al. Revisiting the roles of filaggrin in atopic dermatitis. Int J Mol Sci. 2022;23(10):5318.

Bin L, Leung DY. Genetic and epigenetic studies of atopic dermatitis. Allergy Asthma Clin Immunol. 2016;12:1–14.

Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2009;124(3):R7–12.

Kim J, Kim BE, Leung DY. Pathophysiology of atopic dermatitis: Clinical implications. In: Allergy and asthma proceedings. OceanSide Publications; 2019. p. 84.

Barton SJ, Ngo S, Costello P, Garratt E, El-Heis S, Antoun E, et al. DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood. Clin Exp Allergy. 2017;47(12):1599–608.

Tan HTT, Ellis JA, Koplin JJ, Martino D, Dang TD, Suaini N, et al. Methylation of the filaggrin gene promoter does not affect gene expression and allergy. Pediatr Allergy Immunol Off Publ Eur Soc Pediatr Allergy Immunol. 2014;25(6):608–10.

Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3(7):673–80.

Gittler JK, Shemer A, Suárez-Fariñas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQ, et al. Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130(6):1344–54.

Lee EB, Kim KW, Hong JY, Jee HM, Sohn MH, Kim KE. Increased serum thymic stromal lymphopoietin in children with atopic dermatitis. Pediatr Allergy Immunol. 2010;21(2p2):e457–60.

Li M, Messaddeq N, Teletin M, Pasquali JL, Metzger D, Chambon P. Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci. 2005;102(41):14795–800.

Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A, et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med. 2005;202(4):541–9.

Steinert PM, Marekov LN. The Proteins Elafin, Filaggrin, Keratin Intermediate Filaments, Loricrin, and Small Proline-rich Proteins 1 and 2 Are Isodipeptide Cross-linked Components of the Human Epidermal Cornified Cell Envelope (∗). J Biol Chem. 1995;270(30):17702–11.

Robinson NA, Lapic S, Welter JF, Eckert RL. S100A11, S100A10, annexin I, desmosomal proteins, small proline-rich proteins, plasminogen activator inhibitor-2, and involucrin are components of the cornified envelope of cultured human epidermal keratinocytes. J Biol Chem. 1997;272(18):12035–46.

Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126(3):332–7.

Nemes Z, Marekov LN, Fésüs L, Steinert PM. A novel function for transglutaminase 1: attachment of long-chain ømega-hydroxyceramides to involucrin by ester bond formation. Proc Natl Acad Sci. 1999;96(15):8402–7.

Howell MD, Gao P, Kim BE, Lesley LJ, Streib JE, Taylor PA, et al. The STAT6 gene increases the propensity of atopic dermatitis patients toward disseminated viral skin infections. J Allergy Clin Immunol. 2011;128(5):1006.

Byrd AL, Deming C, Cassidy SK, Harrison OJ, Ng WI, Conlan S, et al. Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis. Sci Transl Med. 2017;9(397):eaal4651.

Peters EM, Liezmann C, Spatz K, Daniltchenko M, Joachim R, Gimenez-Rivera A, et al. Nerve growth factor partially recovers inflamed skin from stress-induced worsening in allergic inflammation. J Invest Dermatol. 2011;131(3):735–43.

Bieber T. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nat Rev Drug Discov. 2022;21(1):21–40.

Haarmann-Stemmann T, Esser C, Krutmann J. The Janus-faced role of aryl hydrocarbon receptor signaling in the skin: consequences for prevention and treatment of skin disorders. J Invest Dermatol. 2015;135(11):2572–6.

Sakai T, Herrmann N, Maintz L, Nümm TJ, Welchowski T, Claus RA, et al. Serum sphingosine-1-phosphate is elevated in atopic dermatitis and associated with severity. Allergy. 2021;76(8):2592–5.

Guttman-Yassky E, Hanifin JM, Boguniewicz M, Wollenberg A, Bissonnette R, Purohit V, et al. The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition. Exp Dermatol. 2019;28(1):3–10.

Kragballe K. Topical corticosteroids: mechanisms of action. Acta Derm Venereol Suppl (Stockh). 1989;151:7–10.

Pascual JC, Fleisher AB. Tacrolimus ointment (Protopic) for atopic dermatitis. Skin Ther Lett. 2004;9(9):1–5.

Gupta AK, Chow M. Pimecrolimus: a review. J Eur Acad Dermatol Venereol. 2003;17(5):493–503.

Paton DM. Crisaborole: Phosphodiesterase inhibitor for treatment of atopic dermatitis. Drugs Today. 2017;53(4):239–45.

Ko KC, Tominaga M, Kamata Y, Umehara Y, Matsuda H, Takahashi N, et al. Possible antipruritic mechanism of cyclosporine A in atopic dermatitis. Acta Derm Venereol. 2016;96(5):624–9.

Chan ES, Cronstein BN. Molecular action of methotrexate in inflammatory diseases. Arthritis Res Ther. 2002;4(4):1–8.

Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus. 2005;14(3_suppl):2–8.

Aaronson DS, Horvath CM. A road map for those who don’t know JAK-STAT. Science. 2002;296(5573):1653–5.

Kogame T, Egawa G, Kabashima K. Exploring the role of Janus kinase (JAK) in atopic dermatitis: a review of molecular mechanisms and therapeutic strategies. Immunol Med. 2023;1–9.

Huang I, Chung WH, Wu PC, Chen CB. JAK–STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review. Front Immunol. 2022;13:1068260.

Traidl S, Freimooser S, Werfel T. Janus kinase inhibitors for the therapy of atopic dermatitis. Allergol Sel. 2021;5:293.

Sideris N, Paschou E, Bakirtzi K, Kiritsi D, Papadimitriou I, Tsentemeidou A, et al. New and upcoming topical treatments for atopic dermatitis: a review of the literature. J Clin Med. 2022;11(17):4974.

Gatmaitan JG, Lee JH. Challenges and Future Trends in Atopic Dermatitis. Int J Mol Sci. 2023;24(14):11380.

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. 2015;136(3):667–77.

Saeki H, Ohya Y, Furuta J, Arakawa H, Ichiyama S, Katsunuma T, et al. Executive summary: Japanese guidelines for atopic dermatitis (ADGL) 2021. Allergol Int. 2022;71(4):448–58.

Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res. 2012;18(11):3008–14.

Bissonnette R, Papp KA, Poulin Y, Gooderham M, Raman M, Mallbris L, et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol. 2016;175(5):902–11.

Piscitelli SC, Pavel AB, McHale K, Jett JE, Collins J, Gillmor D, et al. A phase 1b, randomized, single-center trial of topical cerdulatinib (DMVT-502) in patients with mild-to-moderate atopic dermatitis. J Invest Dermatol. 2021;141(7):1847–51.

Landis MN, Arya M, Smith S, Draelos Z, Usdan L, Tarabar S, et al. Efficacy and safety of topical brepocitinib for the treatment of mild-to-moderate atopic dermatitis: a phase IIb, randomized, double-blind, vehicle-controlled, dose-ranging and parallel-group study. Br J Dermatol. 2022;187(6):878–87.

Guttman-Yassky E, Krueger JG. Atopic dermatitis and psoriasis: two different immune diseases or one spectrum? Curr Opin Immunol. 2017;48:68–73.

Thoma G, Duthaler RO, Waelchli R, Hauchard A, Bruno S, Strittmatter-Keller U, et al. Discovery and characterization of the topical soft JAK inhibitor CEE321 for atopic dermatitis. J Med Chem. 2023;66(3):2161–8.

He H, Guttman-Yassky E. JAK inhibitors for atopic dermatitis: an update. Am J Clin Dermatol. 2019;20:181–92.

Simpson EL, Lacour JP, Spelman L, Galimberti R, Eichenfield LF, Bissonnette R, et al. 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. 2020;183(2):242–55.

Reich K, Simpson E, Wollenberg A, Bissonnette R, Abe M, Cardillo T, et al. Efficacy of downtitration or treatment withdrawal compared with continuous dosing after successful treatment with baricitinib in patients with moderate-to-severe atopic dermatitis in a randomized substudy from the long-term extension study BREEZE-AD3. Br J Dermatol. 2023;188(2):208–17.

Napolitano M, Fabbrocini G, Cinelli E, Stingeni L, Patruno C. Profile of baricitinib and its potential in the treatment of moderate to severe atopic dermatitis: a short review on the emerging clinical evidence. J Asthma Allergy. 2020;89–94.

Chiricozzi A, Gori N, Narcisi A, Balato A, Gambardella A, Ortoncelli M, et al. Effectiveness and safety of upadacitinib in the treatment of moderate-severe atopic dermatitis: a multicentric, prospective, real-world, cohort study. Drugs RD. 2022;22(3):245–52.

Simpson EL, Sinclair R, Forman S, Wollenberg A, Aschoff R, Cork M, 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. The Lancet. 2020;396(10246):255–66.

Bissonnette R, Maari C, Forman S, Bhatia N, Lee M, Fowler J, et al. 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. 2019;181(4):733–42.

Jimenez PA, Sofen HL, Bissonnette R, Lee M, Fowler J, Zammit DJ, et al. Oral spleen tyrosine kinase/Janus Kinase inhibitor gusacitinib for the treatment of chronic hand eczema: Results of a randomized phase 2 study. J Am Acad Dermatol. 2023;

Liu J, Lv B, Yin H, Zhu X, Wei H, Ding Y. A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple ascending dose and food effect study to evaluate the tolerance, pharmacokinetics of Jaktinib, a new selective Janus kinase inhibitor in healthy Chinese volunteers. Front Pharmacol. 2020;11:604314.

Zhao Y, Zhang L, Ding Y, Tao X, Ji C, Dong X, et al. Efficacy and safety of SHR0302, a highly selective Janus kinase 1 inhibitor, in patients with moderate to severe atopic dermatitis: a phase II randomized clinical trial. Am J Clin Dermatol. 2021;22(6):877–89.

Furue M, Hashimoto-Hachiya A, Tsuji G. Aryl hydrocarbon receptor in atopic dermatitis and psoriasis. Int J Mol Sci. 2019;20(21):5424.

Bissonnette R, Gold LS, Rubenstein DS, Tallman AM, Armstrong A. Tapinarof in the treatment of psoriasis: A review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor–modulating agent. J Am Acad Dermatol. 2021;84(4):1059–67.

Paller AS, Gold LS, Soung J, Tallman AM, Rubenstein DS, Gooderham M. Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis. J Am Acad Dermatol. 2021;84(3): 632–8.

Napolitano M, di Vico F, Ruggiero A, Fabbrocini G, Patruno C. The hidden sentinel of the skin: An overview on the role of interleukin-13 in atopic dermatitis. Front Med. 2023;10:1165098.

Harb H, Chatila TA. Mechanisms of dupilumab. Clin Exp Allergy. 2020;50(1):5–14.

Bieber T. Interleukin-13: targeting an underestimated cytokine in atopic dermatitis. Allergy. 2020;75(1):54–62.

Wollenberg A, Blauvelt A, Guttman-Yassky E, Worm M, Lynde C, Lacour JP, et al. 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). Br J Dermatol. 2021;184(3):437–49.

Silverberg JI, Guttman-Yassky E, Thaçi D, Irvine AD, Stein Gold L, Blauvelt A, et al. Two phase 3 trials of lebrikizumab for moderate-to-severe atopic dermatitis. N Engl J Med. 2023;388(12):1080–91.

Cevikbas F, Ward A, Firth C, Veverka K. Eblasakimab, a novel IL-13 receptor alpha 1 monoclonal antibody, blocks STAT6 phosphorylation with low dose in human volunteers. Clin Immunol. 2023;109677.

Abdel-Mottaleb MMA. Nanoparticles for treatment of atopic dermatitis. In: Nanoscience in Dermatology. Elsevier; 2016. p. 167–75.

Baspinar Y, Borchert HH. Penetration and release studies of positively and negatively charged nanoemulsions—is there a benefit of the positive charge? Int J Pharm. 2012;430(1–2):247–52.

Khan AS, Shah KU, Mohaini MA, Alsalman AJ, Hawaj MAA, Alhashem YN, et al. Tacrolimus-loaded solid lipid nanoparticle gel: Formulation development and in vitro assessment for topical applications. Gels. 2022;8(2):129.

Hirai T, Yoshikawa T, Nabeshi H, Yoshida T, Tochigi S, Ichihashi K ichi, et al. Amorphous silica nanoparticles size-dependently aggravate atopic dermatitis-like skin lesions following an intradermal injection. Part Fibre Toxicol. 2012;9:1–11.

Ilves M, Palomäki J, Vippola M, Lehto M, Savolainen K, Savinko T, et al. Topically applied ZnO nanoparticles suppress allergen induced skin inflammation but induce vigorous IgE production in the atopic dermatitis mouse model. Part Fibre Toxicol. 2014;11:1–12.