Eczema or Atopic Dermatitis

Defining eczema

Eczema is a skin condition in which patches of the skin become inflamed, itchy, red, cracked, and breakout into blisters that may bleed.¹ Atopic eczema, also known as atopic dermatitis, is the most common type of eczema, with a lifetime prevalence of up to 20% in developed countries.^1,2 Atopic eczema usually develops during childhood and is a chronic inflammatory skin disease characterized by relapsing eczematous lesions, with intense itch and discomfort.² Atopic eczema is regarded to be the initial step of the ‘atopic march’, a concept summarizing the natural history of atopic manifestations which usually begins with atopic eczema during early childhood, followed by other allergic disorders later in life.³ An estimated 50% of patients with atopic eczema will develop other allergic symptoms within the first year of life.³

Known to be identified as early as 1796, atopic eczema was believed to have been officially first described in 1933.⁴ Due to the heterogeneity of the disease, clinical features of atopic eczema can range from minimal flexural eczema, eczema limited to the hands, to erythroderma affecting almost 90% of the skin.² During early stages, the lesions in atopic eczema are poorly defined, erythematous patches with exudation, with blistering and crusting, while at later stages, these lesions undergo scaling, fissuring and lichenification.² Depending on the severity of its clinical manifestation, atopic eczema can lead to sleep disturbances, diminished self-esteem and poor performance either at work or school; all of which pose a high negative impact on the quality of life of patients.^2,4 The causes of atopic eczema have not been clearly elucidated, but is theorized to be multifactorial in nature, comprising genetic, socioeconomic and environmental factors.⁵

Recent reports have shown an increasing trend on the prevalence of atopic eczema.⁵ The global prevalence of atopic eczema has seen a 3-fold increase since the 1960s.⁵ On the national front, the prevalence of atopic eczema among Malaysian children has risen from 9.5% in 1994-1995 to 12.6% in 2002-2003, with reports of a 0.49% yearly increase.⁶ Researchers believe that the interplay between genetic and environmental factors form the basis behind the increasing prevalence of atopic eczema.⁵ In line with increasing prevalence and the chronic nature of the disease, treatment goals are focused on improving quality of life by repairing the barrier function of the skin, minimizing pruritis, and preventing exacerbations.⁴

Understanding the pathogenesis of atopic eczema

The pathogenesis of atopic eczema results from the complex interplay between impaired skin barrier function, genetics, environmental factors (ie, allergens, infectious agents), and dysfunctional immunological responses.^7,8

• Skin barrier dysfunction

The primary function of the skin is to act as a physical and chemical barrier against external elements.⁸ Patients with atopic eczema commonly demonstrate impaired skin barrier function, resulting in increased transepidermal water loss.⁷ Currently, three causes have been related to the impaired skin barrier dysfunction seen in atopic eczema, namely; defect in the expression of the filaggrin gene, decrease in skin ceramides, and overactivation of epidermal proteases.⁸

Filaggrins function by cross-linking keratin filaments into tight bundles and generating intracellular metabolites which moisturizes the stratum corneum.^7,8 These functions of filaggrins play a crucial role in maintaining the integrity of the skin barrier.⁸ Loss of function mutations in the filaggrin gene have been shown to result in dysfunction of the epidermis and reduced skin barrier function.⁸
Besides filaggrin, a deficiency in ceramide, a lipid which is important for water retention in the stratum corneum, has also been associated with impaired skin barrier function.⁸ Patients with atopic eczema have a marked reduction of ceramides compared to health individuals. Studies have shown that ceramide deficiency is associated with higher transepidermal water loss and impaired skin barrier function.⁸ However, unlike filaggrin deficiency, ceramide deficiency is not linked to genetic mutations but is rather considered to be a post-inflammatory event.⁸

Human kallikrein (KLK)-related peptidases are the key proteases involved in corneocyte desquamation.⁸ The overactivation of these epidermal proteases leads to hyper-desquamation of corneocytes, which induces atopic eczema-like dermatitis.⁸

• Environmental factors

The onset and development of atopic eczema can also be influenced by environmental factors such as, exposure to pollutants and allergens, microbial exposure, climate factors, and skin pH.^8,9 Studies have shown that exposure to air pollutants may directly modify the immune response in humans, thus, increasing the risk of developing atopic eczema.⁹ Additionally, various other stimuli such as tobacco smoke, contact allergens in the environment (ie, nickel, cobalt, chromium), compounds found in personal care products, and food, may also be associated in the onset of the ‘atopic march’ and subsequently to the development of atopic eczema.⁹ Climate is another environmental factor that influences the development of atopic eczema.⁸ Studies have suggested that temperature, humidity and exposure to ultraviolet (UV) radiation, play a prominent role in the disease course of atopic eczema.^8,9 While UV exposure and temperature appear to convey protective effects, high humidity and precipitation is associated with accelerated transepidermal water loss, leading to higher rates of atopic eczema.^8,9

The pH of the skin also contributes to its barrier function.⁸ The pH of the skin is acidic, and this provides a strong antibacterial effect to the skin, and also controls the desquamation of the corneocytes.⁸ An increase in the pH of the skin have been reported in patients with atopic eczema, and is associated with exacerbation of eczematous skin lesions.⁸ Personal care products such as soaps are the most common environmental agents that affect the skin’s pH.⁸ Washing the skin with soap can cause an increase in the pH of the skin, emulsification of skin surface lipids, enhancement of skin proteases, which collectively results in thinning of the stratum corneum.⁸

The skin microbiota plays an important role in the homeostasis and pathogenic conditions of the skin. Dysbiosis of the skin microbiota (dominated by Staphylococcus aureus) have been associated with exacerbations of skin inflammation in atopic eczema.⁸ Several observations have also reported the involvement of the gut microbiota in the pathogenesis of atopic eczema.⁸

• Immunological factors

Immune dysregulation has been linked to the chronic inflammatory cascade seen in the pathogenesis of atopic eczema.¹⁰ The immune component in the pathogenesis of atopic eczema involves both the adaptive and innate immune systems. Skin resident cells (ie, keratinocytes, dendritic cells, mast cells, macrophages, and innate lymphoid cells) and infiltrated immune cells (ie, T cells, plasmacytoid dendritic cells, monocytes, and granulocytes) contribute to the skin inflammation seen in atopic eczema.^8,11 The pathogenesis of atopic eczema is mainly characterized by T helper-2 (Th-2) cell-skewed responses.⁸

Co-morbidities associated with atopic eczema⁶

• Skin infection – Patients with atopic eczema are prone towards developing secondary skin infections.
• Atopy – Atopic eczema is the first step of the ‘atopic march’; thereby, rendering patients at increased risk of developing other allergic disorders such as asthma and allergic rhinitis.
• Food allergy – Food allergy is seen especially in patients with early-onset persistent atopic eczema.
• Cardiovascular disease – There have been modest associations between severe atopic eczema and angina pectoris, hypertension and peripheral arterial disease.
• Psychological and psychosocial dysfunction – Patients with atopic eczema may demonstrate psychological and psychosocial dysfunction. Atopic eczema has been associated with attention deficit hyperactivity disorder, schizophrenia and affective disorders.

Diagnosing and assessing atopic eczema
The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis is the diagnostic tool commonly used by clinicians in the local setting (Box 1).⁶

(Adapted from: Management of Atopic Eczema. Clinical Practice Guidelines. Ministry of Health Malaysia.)

Atopic eczema is diagnosed clinically, as there is no specific laboratory investigation to confirm its diagnosis.⁶ In terms of assessing the severity of atopic eczema, the preferred tools include, the Investigator’s Global Assessment, and the Dermatology Life Quality Index/Children’s Dermatology Life Quality Index.⁶

Management of atopic eczema
Topical therapy⁶
The mainstay of treatment for atopic eczema is topical therapy with emollients, topical anti-inflammatory agents, and topical antimicrobial agents.

• Emollient/moisturiser – Improves the skin barrier function and dryness resulting in alleviation of pruritis. Additionally, emollients decrease the need for topical corticosteroids.
• Topical corticosteroids (TCS) – Possesses anti-inflammatory and immunosuppressive effects. TCS is the first-line anti-inflammatory agent for atopic eczema in both children and adults. Commonly used to treat flares in atopic eczema and treatment should be monitored every 3–6 months to ascertain response and potential side effects.
• Topical calcineurin inhibitors (TCIs) – Non-steroidal immune-modulating agents that are currently licensed for use in patients aged two years and above. TCIs may be considered to treat flares in atopic eczema.
• Wet wrap therapy (WWT) – Consists of two layers of tubular bandages or garments with inner wet and outer dry layers, applied over moisturiser alone or in combination with TCS.

Bleach bath and other antiseptic baths (ie, potassium permanganate, triclosan, chlorhexidine) have also been shown to reduce bacterial colonization on the skin, alleviate the symptoms, and improve the severity of atopic eczema.

Phototherapy⁶
Phototherapy is an option for patients presenting with severe atopic eczema who either do not respond to conventional treatment or are intolerant due to side effects. This therapeutic option is known to improve the severity of atopic eczema, pruritis and sleeplessness. UVA1 may be used to control acute flares while narrow-band UV-B is used in moderate to severe chronic atopic eczema.

Systemic therapy⁶
Systemic therapy for atopic eczema includes adjunctive treatment options (ie, antihistamines and systemic antibiotics) and specific treatment options (ie, immunomodulating agents and biologics). Specific treatment options should only be used in severe cases of atopic eczema whereby other therapeutic options have failed or are inappropriate.

• Antihistamines – Prescribed to alleviate itch. Antihistamines should not substitute topical therapy or used as monotherapy.
• Immunomodulating agents – Prescribed in moderate to severe atopic eczema which are uncontrolled after treatment optimization with topical therapy and/or phototherapy. Immunomodulating agents commonly used include systemic corticosteroids, azathioprine, cyclosporin A, methotrexate, mycophenolate mofetil and enteric-coated mycophenolate sodium. Systemic corticosteroids can be considered for short-term control of severe acute exacerbation of atopic eczema, while azathioprine, cyclosporin A, methotrexate or mycophenolate can be used in the treatment of severe atopic eczema after treatment optimization with topical therapy.
• Systemic antibiotics – Prescribed when there is clinical evidence of infection.

Biologics⁶
Biologics are proteins which are designed to specifically block bioactive mediators of immune responses such as cytokine, chemokines and immunoglobulins (Igs). Immunoglobulins currently available for the management of atopic eczema include;

• Dupilumab – Monoclonal antibody that blocks interleukin-4 (IL-4) and interleukin-13 (IL-13) receptors.
• Omalizumab – Recombinant human monoclonal antibody that binds to free human IgE in the blood and IgE receptors on the surface of B-lymphocytes.
• Infliximab – Chimeric monoclonal antibody which works against tumour necrosis factor alpha (TNF-α).

Non-pharmacological interventions⁶
Non-pharmacological interventions for atopic eczema include practicing proper bathing practices (long duration of bathing has been associated with greater severity of atopic eczema), dietary interventions by avoiding certain types of food, and supplementation with fish oil, probiotics, prebiotics, minerals and vitamins. Educational interventions are also an integral part of the management of atopic eczema. Education equips both caregivers and patients with essential information to empower and enable them to better manage the disease, which subsequently reduces the frequency and severity of flares.

Figure 1. Treatment algorithm of atopic eczema⁶


Footnote: IGA, Investigators’ Global Assessment; TCS, Topical corticosteroids; TCI, Topical calcineurin inhibitors; WWT, Wet wrap therapy
(Adapted from: Management of Atopic Eczema. Clinical Practice Guidelines. Ministry of Health Malaysia.)


References:

1. What’s to know about eczema? Medical News Today. Available at: https://www.medicalnewstoday.com/articles/14417.php. Accessed 20 September 2018.
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6. Management of Atopic Eczema. Clinical Practice Guidelines. Ministry of Health Malaysia. Available at: http://www.acadmed.org.my/view_file.cfm?fileid=883. Accessed 20 September 2018.
7. McPherson T. Indian J Dermatol 2016;61:649-655.
8. Egawa G, et al. Cogent Biol 2015;1:1103459.
9. David Boothe W, et al. Adv Exp Med Biol 2017;1027:21-37.
10. Tidwell WJ, et al. J Am Acad Dermatol 2018;78:S67-S70.
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