Pediatric Edition
Skin Barrier Repair in the Management of Atopic Dermatitis (Pediatric Edition)
STL Pediatric Volume 2
Reza Alizadehfar, MD, FRCPC
Division of Clinical Immunology and Allergy, McGill University, Montréal, QC, Canada
Montréal Children's Hospital, Montréal, QC, Canada
The term "atopy" was first coined by Cooke and Coca in 1923, derived from the Greek word atopos, which means out of place and denotes an immune reaction that is "strange or eccentric". Atopic dermatitis (AD) is a chronic, waxing and waning, often symmetric inflammatory eruption that is characterized by pruritus and xerosis (dry skin). AD frequently emerges in the first few months of life, but its prevalence decreases with increasing age. It has been reported to affect up to 15% of children worldwide1 and can persist into adulthood. This pathology is probably caused by the interplay of genetic and environmental factors.
Genetic Factors in Atopic Dermatitis
A strong genetic involvement in AD has been clearly established.
Linkage analysis studies and the examination of polymorphisms in a number of candidate genes have identified several chromosomal loci and potential genes as possible susceptibility factors.
The genetic variants in these loci and genes are postulated to be involved in
immunoglobulin E (IgE) antibody production
regulation of the immune response in the skin and mucosa
epidermal barrier dysfunction, via modulation of epidermal maturation.
Environmental Factors in Atopic Dermatitis
Genetic factors alone, however, cannot explain the results of epidemiological studies showing the recent significant increase in prevalence of atopic dermatitis, especially in industrialized countries.
Therefore, a key role for environmental factors in mediating disease expression has been suggested.
Allergic sensitization to house dust mites and some foods may play an important etiologic role in some patients.
However, non-allergic factors may also contribute to the pathophysiology of AD by influencing dysregulation, resulting in disruption of the skin barrier. These include:
low environmental humidity level
Staphylococcus aureus (S. aureus) colonization
exposure (or the absence of it) to certain microbial factors in early infancy
exposure to pollutants, detergents, and other irritants
excessive heat.
The Impairment of the Barrier Function
The epidermis of the skin functions not only as a physical and anatomical barrier, but also as a vast immunological organ.
This barrier constantly protects against the entry of different microbes, allergens, and irritants.
In AD, a dysfunctional skin barrier has been shown to provoke increased transepidermal water loss (TEWL), resulting in pronounced cutaneous dehydration.
Such a damaged barrier can allow allergens, microbes, and irritants to penetrate the skin and cause a pro-inflammatory reaction that typically characterizes AD.
The extent of barrier dysfunction strongly correlates with the degree of inflammation within AD lesions.2
The stratum corneum (SC) of the skin has been compared to a brick wall, consisting of terminally differentiated keratinocytes (bricks) that are surrounded by a matrix of specialized lipids.
The major lipids in the SC are:
ceramides (50% by mass)
cholesterol (25% by mass)
fatty acids (10-20% by mass).
These elements create a barrier that helps to
keep water within the body
prevent the entrance of pathogens and allergens.
It has been shown that AD patients have reduced levels of the SC lipids (e.g., ceramides).3,4
This barrier defect affects not only the involved, but also the uninvolved skin, which correlates with a decrease in the ceramide fraction of the SC.
Genetic abnormalities in protease inhibitor expression and reduced levels of cornified envelope proteins, such as filaggrin,5 fuel the skin damage seen in eczematoid conditions.
Stress may also aggravate this barrier dysfunction by the production of endogenous glucocorticoids, which suppress epidermal lipid synthesis.
Lastly, the intense itching and extensive scratching that is associated with AD can also be an important factor leading to the disruption of the cutaneous barrier.
Options for Management
A range of treatments exist for atopic dermatitis, depending on the severity of the disease. Successful management aimed at reducing flares requires a combination of medical treatment, non-pharmacologic therapy, and lifestyle modification.
Topical Corticosteroids
For several decades, topical corticosteroids have been the mainstay of treatment for AD flare-ups.
A number of agents are available in various vehicles, potencies, and concentrations.
Low-potency agents should be used in infants and on sensitive skin areas (e.g., face, neck, groin, and axillae) in order to minimize side-effects, such as skin atrophy, acne, and adverse systemic effects.
Topical corticosteroids should be used for the shortest duration and at the lowest potency possible, while still allowing good control of flare-ups, to limit adverse effects.
Conversely, misinformed patients and/or parents demonstrating steroid phobia should be advised that withholding appropriate treatment affects their/
their children's wellbeing and unnecessarily prolongs the course of sometimes debilitating disease.
Topical Calcineurin Inhibitors (TCIs)
TCIs are indicated in the management of
mild to moderate AD (pimecrolimus)
moderate to severe AD (tacrolimus).
TCIs inhibit T cell activation and release of cytokines involved in the pro-inflammatory cascade of AD.
Their side-effects include skin irritation and burning at the start of therapy, but usually subside with time.
Their long-term safety is unknown and rare reports of malignancies have surfaced;6,7 however, there is no evidence of an increased rate of lymphoma when compared to the general population.8
TCIs are generally used in patients who are unresponsive or show unacceptable side-effects with classic therapy.6,7
There has been a lack of evidence supporting the use of sedative or non-sedative antihistamines for the treatment of atopic dermatitis.
The first generation antihistamines (diphenhydramine and hydroxyzine) are sometimes recommended at night for their sedative effects.
Antimicrobial Agents
Secondary superinfection with S. aureus is common and is treated with short courses of antibiotics with anti-staphylococcus coverage.
Antiseptic baths have been advocated by some experts in those chronically colonized.
Emollient therapy maintains hydration levels and epidermal barrier defenses, thereby reducing the frequency and severity of AD flares.
Emollients soften and soothe the skin.
Common emollients include petroleum jelly, animal oils, butyl stearate, cocoa butter, lanolin, lipids, mineral oil, and shea butter.
There is no strong evidence that emollients improve AD directly.
However, emollients are widely recommended because they improve the appearance and symptoms of dry skin that is commonly present in AD.7
Studies have shown that emollients may reduce the need for topical steroids and enhance the therapeutic response to them.8,9
In the absence of good studies showing the superiority of one emollient over another, patient preference should guide their usage.
Barrier Repair Creams
Given the importance of the dysregulated barrier function in AD, the use of topical agents aimed at accelerating its improvement represents a new therapeutic approach.
As important as emollients are for the alleviation of AD symptoms, these agents may be ineffective at correcting TEWL and the ceramide deficiency resulting from the defective skin barrier of AD patients.
The efficacy and tolerability of new ceramide-dominant skin repair creams with a more physiologic 3:1:1 ratio of ceramides, free fatty acids, and cholesterol have been studied in two company sponsored trials.12,13
In one multicenter, investigator-blinded, randomized pediatric study using a ceramide-dominant skin barrier cream (EpiCeram®), similar efficacy was demonstrated when compared with the mid-potency steroid fluticasone propionate 0.05%.12 No significant adverse events were observed in either treatment arms. However, 4 of 59 patients in the barrier group experienced an initial flare-up that required short-term fluticasone cream.
EpiCeram®, a steroid-free, lipid-based barrier repair cream, was approved by Health Canada in September 2009 as a Class 2 medical device and is only available by prescription.
A thin layer is applied to affected skin areas 2 times daily or as needed, massaging gently into the skin. Following application, a transient tingling sensation may persist for 10-15 minutes.
Studies on concomitant use of both topical steroids and skin barrier repair creams are not yet available.
Non-pharmacological Factors and Lifestyle Modification
Flare-ups of AD can be reduced by:
wearing soft cotton clothing
washing clothes with mild detergents
avoiding the use of fabric softeners
controlling the ambient temperature and humidity of the home
implementing avoidance measures to decrease exposure to dust mites in sensitized individuals
more rarely, avoiding specific foods in sensitized patients. If a food trigger is suspected, it may be useful to consult an allergist.
It is important to emphasize that no good evidence supports highly restrictive diets, which might have a significant psychological impact and can lead to malnutrition.
Educational programs have demonstrated significant improvement in AD severity and treatment satisfaction in intervention groups compared with control groups.14
Because of the better appreciated role of the skin barrier in AD disease pathogenesis, use of agents that can stabilize epidermal defenses may reduce the current exclusive dependence on topical steroids and immunomodulators. These barrier repair creams do not target inflammation directly, but rather act at an earlier stage in the disease process to normalize the barrier function and reduce pro-inflammatory signaling. This approach could potentially lead to better treatment outcomes with lesser side-effects.
Williams H, et al. J Allergy Clin Immunol 103(1 Pt 1):125-38 (1999 Jan).
Lebwohl M, et al. Cutis 76(6 Suppl):7-12 (2005 Dec).
Imokawa G. J Am Acad Dermatol 45(1 Suppl):S29-32 (2001 Jul).
Pilgram GS, et al. J Invest Dermatol 117(3):710-7 (2001 Sep).
Palmer CN, et al. Nat Genet 38(4):441-6 (2006 Apr).
US FDA Alert for Healthcare Professionals: Pimecrolimus.
US FDA Information for Healthcare Professionals: Tacrolimus.
Canadian Dermatology Association: Position Statement on Calcineurin Inhibitors.
Hanifin JM, et al. J Am Acad Dermatol 50(3):391-404 (2004 Mar).
Lucky AW, et al. Pediatr Dermatol 14(4):321-4 (1997 Jul-Aug).
Kantor I, et al. Today Ther Trends 11:157-66 (1993).
Chamlin SL, et al. J Am Acad Dermatol 47(2):198-208 (2002 Aug).
Sugarman JL, et al. J Drugs Dermatol 8(12):1106-11 (2009 Dec).
Staab D, et al. Pediatr Allergy Immunol 13(2):84-90 (2002 Apr).
STL Achives
Reza Alizadehfar
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