Barrier function in atopic dermatitis.

What is it atopic dermatitis?

Atopic dermatitis, or eczema, is a chronic, itchy skin that is associated with dry skin. It usually begins in infancy or childhood and is often associated with other atopic conditions, such as asthma and allergic rhinoconjunctivitis (hay fever) [1].

Who gets atopic dermatitis?

Atopic dermatitis affects up to 20 to 30% in children and 2 to 10% in adults. People with a personal or family history of atopy – the tendency to develop allergic conditions – are more likely to develop atopic dermatitis [1].

What causes atopic dermatitis?

The causes of atopic dermatitis are incompletely understood. The underlying cause of atopic dermatitis is believed to be the result of a weakened skin barrier and a predisposition towards allergic inflammation [2]. Environmental triggers cause a allergic reaction, which exacerbates Symptoms of atopic dermatitis.

the immune The disturbance arises from T lymphocytes, specifically T helper (Th) type 2 (Th2) cells in the acute phase, and Th1, Th17 and Th22 cells in chronic lesions. Th2 cells produce interleukin (IL)-4 and -13 (IL-13), which regulate the production of immunoglobulin E (IgE) [3].

A theory of Pathogenesis of atopic dermatitis is the 'internal-external theory', where the primary The problem is thought to be related to the immune system, and the skin barrier becomes dysfunctional secondary to IgE sensitization [4].

Another theory is the 'outside-in theory', where the original defect is believed to be in the skin barrier, leading to increased allergen exposure and subsequent sensitization to IgE [4].

How does the skin barrier normally work?

The skin barrier provides protection against external threats such as pathogenschemical products irritantsand Allergens, which could cause an immune response if allowed to pass into the depths epidermal or dermal skin layers (see DermNet NZ page on normal skin structure).

The skin barrier also protects the body from epidermal water loss, and skin barrier function can be measured by the rate of transepidermal water loss. Increased transepidermal water loss corresponds to increased skin loss. permeability. Skin barrier function can sometimes also be measured by surface pH, the permeability of tracer compounds, and stratum corneum cohesion and hydration [2].

The stratum corneum

The stratum corneum is the highest layer of the epidermis. The stratum corneum is composed of a highly organized intercellular layer. lipid matrix, and corneocytes (flattened cells without nuclei that are full of curb filaments); This is often known as the “brick and mortar” of the skin, with corneocytes representing the bricks and mortar. lipids representing the mortar [2].

There is altered stratum corneum homeostasis in both lesional and non-lesional skin of patients with atopic dermatitis. This leads to increased water loss and increased penetration of allergens. [1].

In atopic dermatitis, the structure and composition of both the corneocytes and the intercellular lipid matrix of the stratum corneum can be affected in the following ways:

• Loss or reduced function of the protein filaggrin (FLG)
• Increased serine protease exercise
• Impaired lipid processing [1].

filaggrin protein

FLG is important for the structural integrity of the stratum corneum. FLG aggregates keratin filaments within the corneocytes and then helps form a cornified cell envelope that surrounds the corneocytes. FLG degradation products further contribute to the water retention capacity and acidic pH of the stratum corneum. Maintaining acidic pH is important to regulate the enzyme activity that leads to peeling, lipid synthesis and inflammation [2,5].

A loss of function mutation at FLG gene is the strongest genetic risk factor for atopic dermatitis. FLG mutations are associated with earlier onset of atopic dermatitis, greater disease severity, and disease persistence. Approximately 50% of cases of moderate to severe atopic dermatitis can be attributed to FLG mutations [5].

Serine protease activity and pH

The activity of serine. proteases, like kallikrein (KLK) 5 and seven, is regulated by the pH of the stratum corneum. KLK5 and KLK7 cleave extracellular corneodesmosomal proteins that bind corneocytes. Its increased activity leads to a decrease corneocyte accession and peeling [6].

The normal pH of the skin is acidic and restricts the activity of these proteases, which are more active in alkaline environments. In atopic dermatitis, the pH of the skin is elevated, and subsequently so is the activity of the serine protease. [7].

Lipid matrix function

The lipid matrix of the stratum corneum is composed of three types of lipids: cholesterol, free fatty acids and ceramides. These form a highly ordered structure of densely packed lipid layers. This intercellular lipid matrix is the main pathway for substances that travel through the skin barrier. [2].

In atopic dermatitis, there is a reduction in total lipids, significant deficits of certain types of lipids, and changes in lipid composition. In combination, this leads to impaired skin barrier function and increased permeability of the stratum corneum [2].

The immune system and skin barrier function.

A defect in the skin barrier can facilitate the transport of allergens or haptens (molecules which only causes an allergic reaction when it binds to a protein) in the skin, inducing the release of proinflammatory cytokines causing skin inflammation [2].

At the same time, the Th2 cytokines IL-4 and IL-13, and the Th2 cytokine IL-22 downregulates the expression of FLG, causing more damage to the skin barrier [2,8].

Skin microbiome and skin barrier function

the cutaneous the microbiome is the pathogen and diner bacteria, fungi and viruses that reside in our skin and help maintain epidermal homeostasis [1].

More than 90% of patients with atopic dermatitis have colonized the skin with Staphylococcus aureus [1].

When the stratum corneum is structurally competent, with an acidic pH and a well-organized lipid matrix, it prevents colonization with pathogens such as S. aureus, a bacterium that can negatively affect the barrier function. S. aureus Surface proteins reduce the production of free fatty acids in the epidermis, which increases the permeability of the skin. In patients with atopic dermatitis, S. aureus Exotoxins with super antigenic properties stimulate the production of IgE and cause pruritus. Subsequent excoriations create more defects in the skin barrier [4].

How does understanding skin barrier function affect the treatment of atopic dermatitis?

Understanding that the skin barrier dysfunction Boosting disease activity in atopic dermatitis has led to increased interest and emphasis on treatments that improve barrier function.

Moisturizers are the main treatment for atopic dermatitis. Moisturizers that improve barrier function (barrier cream) have been shown to reduce relapse rates in atopic dermatitis with regular use [9].

Restoring the skin's barrier function can proactively prevent the development or progression of atopic dermatitis, as has been shown in a randomized trial. control essays of neonates at risk of atopic dermatitis treated with a daily moisturizer [10,11].

Moisturizing ingredients that are useful in atopic dermatitis include [2,12]:

• Physiological lipids (e.g., ceramides, cholesterol): restore the composition of lipid bilayers in the stratum corneum and reduce skin permeability
• Physiological moisturizers (urea, glycerol) that do not participate in the metabolic process of the skin, but prevent excessive water loss and keep the stratum corneum hydrated
• Anti-itch agents (e.g., Glycerol) that block the release of histamine and allow the restoration of the stratum corneum to begin
• Dexpanthenol: stimulates lipid synthesis and the epidermis. differentiation
• Occlusive agents (e.g., petroleum jelly) that reduce water evaporation
• Emollients that soften the skin (e.g., sorbolene and glycerin cream).

Bathing with water can remove irritants, allergens, and flakes (scales) in atopic dermatitis, allowing for repair of the skin barrier. It is recommended to apply moisturizer shortly after bathing. Soap-free cleansers, which are low in pH and hypoallergenic, are recommended as soap substitutes as they cause less disruption to the structure of the stratum corneum and acid mantle. [12]. Using the 'soak and smear' technique (soaking the affected area in water before smearing it on the ointment) increases the effectiveness of current medicines. Applying topical corticosteroids to damp skin immediately after bathing traps water in the stratum corneum and increases the amount of medication 10- to 100-fold. [13].

Bleach baths have been shown to be useful in reducing the clinical severity of atopic dermatitis, as a result of their antibacterial, antifungal, and anti-inflammatory properties.inflammatory properties [14]. While sodium hypochlorite (bleach) is generally alkaline (pH 11-13), it produces hypochlorous acid (pH 2-7.5) when dissolved in water [15]. It is possible that this acidity helps maintain the normal function of the skin barrier, in addition to acting as an antiseptic.

Other treatments sometimes necessary in atopic dermatitis include other topicals. anti-inflammatory treatments, such as:

• Topical calcineurin inhibitors.
• Wet wraps

• Antibiotics for secondary infections.

• Oral antihistamines for symptom relief.

In cases of severe atopic dermatitis, recommended treatments include:

• Phototherapy
• Oral corticosteroids
• Non-steroidal immunomodulators or immunosuppressants
• New biological agents led by dupilumab [16].