Exploring the Complexities of Atopic Dermatitis: Pathophysiological Mechanisms and Therapeutic Approaches (original) (raw)
Abstract
Atopic dermatitis (AD) is a prevalent inflammatory skin condition impacting both children and adults globally, with a prevalence of 15-30%. It ranks as the most prevalent skin disorder based on disability-adjusted life-years by the World Health Organization. It presents with symptoms like skin irritation, redness, dryness, itchiness, and vesicular blisters and commonly coexists with other atopic symptoms like allergic rhinitis, asthma, and food allergies. The pathophysiology involves a complex interplay of genetic predispositions, immunological dysfunctions, and environmental factors leading to tissue inflammation and disrupted skin barrier integrity. Alopecia areata is characterized by nonscarring hair loss and shares correlations with AD including a higher prevalence of atopic diseases, shared intracellular mechanisms involving the JAKSTAT pathway, and potential treatment overlap such as dupilumab. These correlations could direct new areas of research and increased insight for both diseases. Treatment of AD requires a personalized approach due to its complex, multifactorial nature integrating nonpharmacological interventions like skin hydration and trigger avoidance as well as topical and systemic approaches, if necessary, with topical corticosteroids being the first line for flares; long term corticosteroid use poses risk for adverse effects like skin atrophy. Severe cases may require systemic treatments or phototherapy. Future treatment prospects include targeting the dysbiotic microbiome and identifying biomarkers for tailored therapeutic strategies, emphasizing the importance of personalized medicine in optimizing AD management.
Figures (6)
![Figure 1: Recommendations for Atopic Dermatitis Management according to the American Academy of Dermatology. This chart compiles information regarding recommendation and certainty of evidence of current treatments for Atopic Dermatitis according to the American Academy of Dermatology as of 2023. This chart is based on the “Figure 1: Adults with atopic dermatitis” of “Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies” [46] but adds on to it by providing evidence certainty based on “Guidelines of care for the management of atopic dermatitis in adults with topical therapies” [6]. Created with BioRender.com](https://figures.academia-assets.com/116989369/figure_002.jpg)
](Figure 1: Recommendations for Atopic Dermatitis Management according to the American Academy of Dermatology. This chart compiles information regarding recommendation and certainty of evidence of current treatments for Atopic Dermatitis according to the American Academy of Dermatology as of 2023. This chart is based on the “Figure 1: Adults with atopic dermatitis” of “Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies” [46] but adds on to it by providing evidence certainty based on “Guidelines of care for the management of atopic dermatitis in adults with topical therapies” [6]. Created with BioRender.com
![Figure 2: Contributing Factors of Atopic Dermatitis and Treatment Options. There are multifactorial causes of atopic dermatitis. Inflammation can cause itch that can cause scratching which can cause tissue damage. Defective skin barriers can also be caused by genetics/ epigenetics and lead to transepidermal water loss (TEWL). Moisturizers maintain skin hydration necessary for skin barrier repair. Wet wrap therapy can also prevent TEWL by providing an occlusive barrier as well as a physical barrier that prevents scratching. Inflammation can lead to itch which can be decreased with antihistamines. Itching leads to scratching. Scratching can also be reduced with education to change patient behavior. Allergens and irritants can penetrate a dysfunctional skin barrier leading to irritation and inflammation and the need for avoidance of allergens/irritants. Inflammation can be reduced with pharmacologic such as topical corticosteroids and calcineurin inhibitors. Dysbiosis microbiomes, especially ones overran with staphylococcus aureus can be reduced using antibiotics and lead to skin barrier defects. Created with Biorender.com. The most basic recommendation for management of mild to severe AD isa liberal and frequent application of moisturizer [44]. According to the American Academy of Dermatology Association, moisturizers are “strongly recommended” with “moderate strength of evidence” to reduce the severity of disease symptoms for AD [45, 46]. A systematic review of 5 studies totaling 488 participants (treatment group: 279, control group: 209) revealed a standardized mean difference of -0.51 representing a moderate effect on symptom severity reduction [45, 46]. By maintaining hydration, moisturizers reduce pruritus and aid in the repair of skin barrier defects [45, 46]. Composed of ingredients like occlusive agents, humectants, and emollients, moisturizers prevent trans- epidermal water loss (TEWL), attract water, and soften skin [47]. The formulation needed depends on the severity of skin dryness with emollients (glycol, glyceryl stearate, etc.) and humectants (hyaluronic acid, urea, etc.) usually being sufficient for normal to dry skin while occlusive agents (petrolatum, mineral oil, etc.) may be required for Skin actives like colloidal oatmeal can also be added to moisturizers or baths for their therapeutic purposes. Colloidal oatmeal is a U.S. Food and Drug Association approved skin protectant treatment for atopic dermatitis due to its anti- pruritic, anti-inflammatory and skin repairing properties [48]. Scratching an itch, one of the most common and aggravating symptoms of AD, can lead to increased pruritus and inflammation according to the “itch-scratch” cycle [49]. being sufficient for normal to dry skin while occlusive](https://figures.academia-assets.com/116989369/figure_003.jpg)
](Figure 2: Contributing Factors of Atopic Dermatitis and Treatment Options. There are multifactorial causes of atopic dermatitis. Inflammation can cause itch that can cause scratching which can cause tissue damage. Defective skin barriers can also be caused by genetics/ epigenetics and lead to transepidermal water loss (TEWL). Moisturizers maintain skin hydration necessary for skin barrier repair. Wet wrap therapy can also prevent TEWL by providing an occlusive barrier as well as a physical barrier that prevents scratching. Inflammation can lead to itch which can be decreased with antihistamines. Itching leads to scratching. Scratching can also be reduced with education to change patient behavior. Allergens and irritants can penetrate a dysfunctional skin barrier leading to irritation and inflammation and the need for avoidance of allergens/irritants. Inflammation can be reduced with pharmacologic such as topical corticosteroids and calcineurin inhibitors. Dysbiosis microbiomes, especially ones overran with staphylococcus aureus can be reduced using antibiotics and lead to skin barrier defects. Created with Biorender.com. The most basic recommendation for management of mild to severe AD isa liberal and frequent application of moisturizer [44]. According to the American Academy of Dermatology Association, moisturizers are “strongly recommended” with “moderate strength of evidence” to reduce the severity of disease symptoms for AD [45, 46]. A systematic review of 5 studies totaling 488 participants (treatment group: 279, control group: 209) revealed a standardized mean difference of -0.51 representing a moderate effect on symptom severity reduction [45, 46]. By maintaining hydration, moisturizers reduce pruritus and aid in the repair of skin barrier defects [45, 46]. Composed of ingredients like occlusive agents, humectants, and emollients, moisturizers prevent trans- epidermal water loss (TEWL), attract water, and soften skin [47]. The formulation needed depends on the severity of skin dryness with emollients (glycol, glyceryl stearate, etc.) and humectants (hyaluronic acid, urea, etc.) usually being sufficient for normal to dry skin while occlusive agents (petrolatum, mineral oil, etc.) may be required for Skin actives like colloidal oatmeal can also be added to moisturizers or baths for their therapeutic purposes. Colloidal oatmeal is a U.S. Food and Drug Association approved skin protectant treatment for atopic dermatitis due to its anti- pruritic, anti-inflammatory and skin repairing properties [48]. Scratching an itch, one of the most common and aggravating symptoms of AD, can lead to increased pruritus and inflammation according to the “itch-scratch” cycle [49]. being sufficient for normal to dry skin while occlusive
![Figure 3: Mechanism of action of Topical Corticosteroids. Because of their anti- inflammatory, immunosuppressant, vasoconstrictive, and antiproliferative properties, corticosteroids are useful for a range of dermatological diseases. By attaching to phospholipids, blocking phospholipase A2 and eicosanoids, and reducing cell-mediated inflammation, they lessen the generation of inflammatory proteinoid. In addition tolowering local blood flow via vasoconstriction, they limit cytokine synthesis and decreasemast cell activation. Topical corticosteroids (TCS) are FDA-approved to reduce inflammation, pruritus, and relapses and act as the first line of treatment for AD flares after basic management with moisturizers [45]. The underlying cellular and molecular mechanisms of the effect of topical corticosteroids are shown in Figure 3. A 2023 systematic review and meta- analysis by the American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology reviewed 219 RCT (43,123 pediatric and adult participants Atopic dermatitis is part of the atopic triad; thus, patients with AD are associated with higher incidence of asthma and allergic disease as the conditions are closely linked [56]. A systematic review and meta-analysis revealed that food allergies were commonly seen in 32.7% of AD patients (4-5 times greater than healthy reference patient) and atopic dermatitis was seen in 45.3% of patients with food allergies with strongest association observed in patients with severe AD and children [57]. Elevated IgE levels are common in both AD and food allergies with common IgE triggering foods being eggs, milk, peanuts, wheat, etc. [56]. Thus, it has been theorized that elimination diets that remove chronic triggers or food allergies may have the potential to reduce the](https://figures.academia-assets.com/116989369/figure_004.jpg)
](Figure 3: Mechanism of action of Topical Corticosteroids. Because of their anti- inflammatory, immunosuppressant, vasoconstrictive, and antiproliferative properties, corticosteroids are useful for a range of dermatological diseases. By attaching to phospholipids, blocking phospholipase A2 and eicosanoids, and reducing cell-mediated inflammation, they lessen the generation of inflammatory proteinoid. In addition tolowering local blood flow via vasoconstriction, they limit cytokine synthesis and decreasemast cell activation. Topical corticosteroids (TCS) are FDA-approved to reduce inflammation, pruritus, and relapses and act as the first line of treatment for AD flares after basic management with moisturizers [45]. The underlying cellular and molecular mechanisms of the effect of topical corticosteroids are shown in Figure 3. A 2023 systematic review and meta- analysis by the American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology reviewed 219 RCT (43,123 pediatric and adult participants Atopic dermatitis is part of the atopic triad; thus, patients with AD are associated with higher incidence of asthma and allergic disease as the conditions are closely linked [56]. A systematic review and meta-analysis revealed that food allergies were commonly seen in 32.7% of AD patients (4-5 times greater than healthy reference patient) and atopic dermatitis was seen in 45.3% of patients with food allergies with strongest association observed in patients with severe AD and children [57]. Elevated IgE levels are common in both AD and food allergies with common IgE triggering foods being eggs, milk, peanuts, wheat, etc. [56]. Thus, it has been theorized that elimination diets that remove chronic triggers or food allergies may have the potential to reduce the
Figure 4: Atopic dermatitis is characterized by an increase in the activity of phosphodiesterase 4 (PDE4). PDE4 controls the synthesi of inflammatory substances by breaking down cyclic adenosine monophosphate (CAMP). Blocking PDF4 results in elevated levels of cAM inside cells, which triggers the activation of protein kinase A (PKA). PKA activation suppresses the signaling pathways of NFAT and NFkE as well as the release of downstream cytokines and chemokines. AC, Adenylyl cyclase; ATP, adenosine triphosphate; IL, interleukin; IFN-) interferon gamma; TNF-a, tumor necrosis factor-a.
Figure 5: JAK/STAT and how the medications that suppress JAK work. When cytokines bind to their receptors, they trigger the phosphorylation of JAK and STAT proteins, which are needed for signal transduction through the JAK/STAT pathway. The second set of proteins regulate inflammatory factor production through dimerization and nuclear translocation. Preventing JAK phosphorylation and STAT activation is the main function of JAK inhibitors.
Key takeaways
AI
- Atopic dermatitis (AD) affects 15-30% of the global population, ranking as the leading skin disorder by disability-adjusted life years.
- AD's pathophysiology involves genetic, immunological, and environmental factors disrupting skin barrier integrity and promoting inflammation.
- Topical corticosteroids are the first-line treatment for AD, but prolonged use carries risks such as skin atrophy.
- Emerging treatments focus on personalized medicine, targeting the microbiome, and utilizing biomarkers for tailored therapies.
- Dupilumab and JAK inhibitors show promise for AD, revealing shared mechanisms with alopecia areata, warranting further research.
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