Beyond skin deep: Immune targets in atopic dermatitis therapy
Jake Bambrough - Senior Medical Writer March 25, 2022
Atopic dermatitis (AD), also known as eczema, is the most common inflammatory skin disease in the world, with a lifetime prevalence of up to 20%.
Atopic dermatitis (AD), also known as eczema, is the most common inflammatory skin disease in the world, with a lifetime prevalence of up to 20%.1 It is an autoimmune condition characterized by intensely itchy skin lesions.
While topical therapies such as emollients and steroid creams are the mainstay of therapy for all patients with AD,2 treatment options have been much more limited for patients with moderate-to-severe disease, who do not respond to or cannot use topical therapy.
In recent years, much attention has been directed at the development of novel therapies that target elements of the immune system that are overactive in AD. To mark the 2022 American Academy of Dermatology (AAD) Annual Meeting, which starts this week, here we review some of the key characteristics of the disease and explore some of these newer therapeutic approaches that may help patients ditch the itch and clear their skin for good.
Disease overview
AD is a complex disease, with a chronic and flaring course, caused by multiple interrelated factors including immune dysregulation, skin barrier dysfunction, genetic mutations, and environmental triggers.1
Typically, AD presents as inflamed, dry/flaky skin with skin thickening, and lesions that can ooze and crust. In patients with lighter skin types, inflammation due to AD is usually a pink or red shade;1,3-5 while in patients with skin of color or darker skin types (a special topic at this year’s AAD meeting), inflammation can appear purple, light brown or ashen grey, and typical signs can include scattered hard bumps on the skin, particularly around the follicles.6-9 Pigmentary changes in the skin can also occur in patients with skin of color following inflammation due to AD, which can be highly distressing.6-8
Regardless of race or ethnicity, itch is the cardinal symptom of atopic dermatitis. Itch leads to scratching and painful skin, and is the cause of significant patient burden:
- Among patients with moderate-to-severe disease,86% have reported itch every day10
- Severe or unbearable itch was reported by 61% of patients, and 42% reported itching for 18 hours a day or more10
AD can also have a profound impact on the quality of life of patients:
- Disturbed sleep has been reported by 80% of patients with AD11
- 73% of patients with AD reported worrying about their appearance12
- Almost 1 in 4 patients with AD suffer from depressive symptoms, significantly higher than the general population13
Biologic therapies
In AD, immune dysfunction is characterized by the upregulation of numerous type 2 cytokines, some of which have been targeted by (injectable) biologic drugs.
Interleukin-4
Interleukin-4 (IL-4) stimulates immunoglobin E (IgE) production and class switching, which may contribute to the allergic reactivity and flaring disease pattern seen in many AD patients.1,14,15 It also contributes to the dysregulation of the skin barrier by downregulating genes that encode structural proteins and lipids in the skin, as well as inhibiting skin defence mechanisms, such as antimicrobial peptides, leading to skin microbiota dysbiosis; AD patients are prone to skin infections as a result of this.1,15,16
Interleukin-13
Like IL-4, IL-13 is also involved in downregulating genes involved in skin barrier function, IgE class switching, and inhibition of anti-microbial peptide production.16 Additionally, IL-13 causes collagen degradation and leads to collagen deposition, leading to the tough, thickened skin seen in many patients with chronic AD.16 In mouse models of AD, both IL-4 and IL-13 have been shown to be involved in tissue inflammation and to act on sensory neurons in the skin to elicit itch,15 and recent research has shown that IL-13 amplifies excitability in human sensory neurons and potentiates responses in itch pathways.17
Interleukin-31
IL-31 has been implicated in the severe itch and skin hypersensitivity associated with AD.18 Receptors with which IL-31 interacts are expressed on peripheral sensory neurons, suggesting IL-31 can directly stimulate itch.1,18 It is also associated with neural branching in the skin.1
Small molecule therapies
As well as biologic therapies, several small molecule drugs have been investigated in AD. These orala therapies target intracellular downstream signalling and can inhibit a broad spectrum of immune processes associated with AD.
One of the most active areas of investigation in recent years (and another special topic at this year’s AAD meeting) are Janus kinase inhibitors (JAKi), which prevent intracellular signalling through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway.
Numerous T helper (Th)1, Th2, Th17 and Th22 immune pathways associated with AD are modulated by JAK-STAT signalling, including IL-4, IL-13 and IL-31.19 Additional immune targets for AD therapy that can be blocked by JAKi include:
- Thymic stromal lymphoprotein (TSLP), which is an alarmin that amplifies Th2 immune responses, and whose expression by keratinocytes is increased by skin barrier dysfunction1,19
- IL-22, which contributes to skin thickening by inducing epidermal hyperplasia19
- Interferon gamma (IFN-γ), which drives keratinocyte apoptosis, worsening skin barrier dysfunction in AD19
- IL-5, which recruits eosinophils1,20
At such an exciting time for the treatment of AD, with so many new and potential therapies in the moderate-to-severe space, we look forward to seeing all the latest research presented at AAD 2022 (the first in-person congress in more than 2 years for some of our team!) and how this translates into meaningful, life-changing outcomes for patients.
aTopical formulations of JAKi have been investigated in AD, most are aimed at treating patients with mild-to-moderate disease.
References
1. Weidinger S, et al. Atopic Dermatitis. Nat Rev Dis Primers. 2018;4(1):1.
2. Wollenberg A, et al. Consensus-based European Guidelines for Treatment of Atopic Eczema (Atopic Dermatitis) in Adults and Children: Part II. J Eur Acad Dermatol Venereol. 2018;32:850-878.
3. Silverberg JI, et al. Patient Burden and Quality of Life in Atopic Dermatitis in US Adults: A Population-based cross-sectional study. Ann Allergy Asthma Immunol. 2018;121:340-347.
4. Eichenfield LF, et al. Guidelines for the Management of Atopic Dermatitis: Part 1: Diagnosis and Assessment of Atopic Dermatitis. J Am Acad Dermatol. 2014;70(2):338-351.
5. Silverberg JI. Atopic Dermatitis in Adults. Med Clin N Am. 2020;104:157-176.
6. Brunner PM and Guttman-Yassky E. Racial differences in atopic dermatitis. Ann Allergy Asthma Immunol. 2019;122:449-455.
7. Kaufman BP, et al. Atopic dermatitis in diverse racial and ethnic groups – Variations in epidemiology, genetics, clinical presentation and treatment. Exp Dermatol. 2018;27:340-357.
8. Yong A M-Y and Tay Y-K. Atopic dermatitis racial and ethnic differences. Dermatol Clin. 2017;35(3):395-402.
9. Kaufman BP, Alexis A. Eczema in skin of color: What you need to know. National Eczema Association. Available at: https://nationaleczema.org/skin-of-color/.
10. Simpson EL, et al. Patient Burden of Moderate to Severe Atopic Dermatitis (AD): Insights from a Phase 2b Clinical Trial of Dupilumab in Adults. J Am Acad Dermatol. 2016;74(3):491-498.
11. Silverberg JI, et al. Sleep Disturbance in Atopic Dermatitis in US Adults. Dermatitis. 2021 (Online ahead of print). DOI: 10.1097/DER.0000000000000731.
12. Zuberbier T, et al. Patient Perspectives on the Management of Atopic Dermatitis. J Allergy Clin Immunol. 2006;118(1):226-232.
13. Patel KR, et al. Association Between Atopic Dermatitis, Depression, and Suicidal Ideation: A systematic Review and Meta-Analysis. J Am Acad Dermatol. 2019;80(2):402-410.
14. Guttman-Yassky E and Krueger JG. Atopic Dermatitis and Psoriasis: Two Different Immune Diseases or One Spectrum. Curr Opin Immunol. 2017;48:68-73.
15. Moyle M, et al. Understanding the Immune Landscape in Atopic Dermatitis: The Era of Biologics and Emerging Therapeutic Approaches. Exp Dermatol. 2019;28:756-768.
16. Brunner PM, et al. J Allergy Clin Immunol. 2017;139(4S):S65-S76.
17. Miron Y, et al. Mechanistic Insights into the Antipruritic Effects of Lebrikizumab, an Anti-IL-13 mAb.
18. Nakashima C, et al. Interleukin-31 and Interleukin-31 Receptor: New Therapeutic Targets for Atopic Dermatitis. Exp Dermatol. 2018;27:327-331.
19. Cartron AM, et al. Janus Kinase Inhibitors for Atopic Dermatitis: A Promising Treatment Modality. Clin Exp Dermatol. 2021;46:820-824.
20. He H and Guttman-Yassky E. JAK Inhibitors for Atopic Dermatitis: An Update. Am J Clin Dermatol. 2019;20:181-192.
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