Abstract

Background: Skin barrier differences and variations in the presentation of common dermatoses such as xerosis and atopic dermatitis (AD) have been reported in racial/ethnic Canadian patients. This review discusses skin barrier differences and explores the role of ceramide-containing skin care in promoting a healthy skin barrier and mitigating AD.
Methodology: A literature review and panel discussions followed by an online review were used to adopt five statements and recommendations to promote a healthy skin barrier in various racial/ethnic Canadian AD populations.
Results: The multifactorial pathogenesis of AD includes genetic and environmental factors that may vary among racial/ethnic and geographic populations. Studies comparing ethnic groups have reported variations in transepidermal water loss, skin lipid levels, and stratum corneum pH. However, these studies frequently have flaws. The panel agreed that essential skincare principles apply to all AD-affected patients regardless of racial/ethnic background.
Conclusion: Robust comparative studies are needed to help clinicians to tailor patient education and recommend routine skincare with gentle cleansers and moisturizers containing lipids for AD management regardless of disease severity and prescription treatment.

Acknowledgments: All authors participated in all the steps of the project, selection of the literature, and the review of the manuscript. All authors read and approved the final version of the manuscript.

Disclosures:
The authors disclosed receipt of an unrestricted educational grant from CeraVe Canada for support with the research of this work. The authors also received consultancy fees for their work on this project.

Keywords: Racial/ethnic skin barrier variations, skincare, atopic dermatitis

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Background

Genetic and environmental factors influence the structure and function of the stratum corneum (SC) barrier.¹ Approximately 30% of Canadians are estimated to be part of a fast-growing racial/ethnic population by 2031.² However, morphology and descriptions of dermatoses are based on White patients and the historic assumption that most residents of Canada and the United States are of Northern European descent.²

Differences in the skin barrier properties and function and the presentation of common dermatoses such as xerosis and atopic dermatitis (AD) have been observed in subjects with richly pigmented skin compared to White subjects.^1-6 Several studies have investigated SC differences between racial/ethnic skin, comparing SC properties of self-identified Black, White, and Asian skin.¹ In one such study, White subjects had an intermediate barrier strength as evidenced by tape strippings, and Asians have been demonstrated to require the least number of tape strippings to disrupt the SC barrier.¹ This finding indicates a weaker barrier strength and slower recovery from barrier damage in the Asian population, supporting the observation of sensitive skin seen in Asians.¹

There are significant disparities in the prevalence and treatment of skin conditions across Canadian populations.^2-6 The burden of AD is higher in racial/ethnic populations, and numerous barriers to treatment exist, including systemic and institutional racism, poverty, crowded housing conditions on reserves, access and cost of basic skincare regimens, and clean water access.^2-4 Promoting a healthy skin barrier remains a particular challenge for Indigenous groups, who lack access to appropriate treatments and skincare.^2-6

This review discusses skin barrier differences in various racial/ethnic Canadian populations and explores the role of ceramide-containing skin care in promoting a healthy skin barrier and mitigating AD.

Methods

A group of dermatologists assembled during the Dermatology Update conference on November 13, 2021, in Montreal, Quebec. The panel (advisors) [four Canadian dermatologists and one dermatologist from the US] reviewed skin barrier differences in various racial/ethnic Canadian groups exploring dermatology issues related to skin barrier integrity. Additionally, the advisors determined the relevance of skincare-containing ceramides comprising cleansers and moisturizers for these populations to promote a healthy skin barrier and mitigate AD. Finally, the advisors looked into patient and clinician education tools to promote a healthy skin barrier in various racial/ethnic Canadian populations.

The project used a modified Delphi process comprising face-to-face discussions followed by an online follow-up.^7-9

Literature Review

Structured literature searches on PubMed and Google Scholar as secondary source of the English-language literature (2010 – September 2021) were conducted before the meeting on September 21 and 22, 2021. We searched for guidelines, consensus papers, clinical studies, and reviews describing skin barrier properties in various racial/ethnic Canadian populations and current best-practice in promoting a healthy skin barrier and mitigation of AD using ceramides containing non-prescription skincare cleansers and moisturizers. Excluded were papers with no original data (unless a review article was deemed relevant), or not dealing with racial/ethnic Canadian or skincare, and publication language other than English.

The Nomenclature Used for the Searches

Searches were performed for the main ethnic Canadian groups [Black, White, Asian and Indigenous populations] and ethnic regions in Canada.^2-6 Indigenous is a preferred term within Canadian communities. It is an umbrella term that covers Aboriginal, Metis, and Inuit populations. The publications collected a range of demographic data, including ethnic origin. Demographic factors referred to the quantitative data relating to the study population and its composition, which allowed portions of the population to be broken down into subgroups for closer examination.^2-6 Further searches included associations between these demographic factors and the biophysical nature of racial/ethnic skin, skin care practices, and AD treatment product use.

Search Terms

The searches explored present clinical guidelines, treatment options, and therapeutic approaches addressing racial/ethnic Canadian populations using the following terms:
Racial/ethnic Canadian populations AND AD prone skin, OR Black, White, Asian and Indigenous populations in Canada AND AD, OR racial/ethnic Canadians AND skin barrier physiology OR skin barrier function/dysfunction OR racial/ethnic Canadians AND depletion of stratum corneum lipids, OR racial/ethnic Canadians AND AD prevention, OR racial/ethnic Canadians AND AD treatment, OR Black, White, Asian and Indigenous populations in Canada AND mitigation of AD, OR racial/ethnic Canadian populations with AD/AD prone skin AND skincare, OR Black, White, Asian and Indigenous people in Canada AND cleansers OR moisturizers OR emollients OR ceramides OR ce¬ramide containing skincare OR racial/ethnic Canadian AD populations AND skincare efficacy OR safety OR tolerability OR skin irritation

The searches were performed by a dermatologist and a physician/scientist (reviewers). After selection, the publicatiodns were manually reviewed for additional resources.

Priority was given to studies on SC barrier function and the benefits of skincare using cleansers and moisturizers in racial/ethnic Canadian populations with AD or AD-prone skin.

The searches yielded 248 papers, and after excluding 173 articles [duplicates, poor quality, not about Canadian racial/ethnic AD populations or skincare], 75 remained, comprising 4 epidemiology, 4 quality of life (QoL) studies, 20 guidelines, consensus papers and systematic reviews, 19 reviews, 24 clinical studies, and 4 others.

Role of the Panel

The advisors used the literature review results, clinical experience, and expertise to adopt statements and recommendations. The results were integrated into the summary statements presented and discussed during the face-to-face meeting. For example, in a workshop, advisors divided into three groups to create a final set of summary statements about Canadians’ racial/ethnic differences in SC barrier structure and function and skincare for this population, working with 12 draft messages. The final five statements integrate the combined output from the workshop groups and post-meeting online reviews from individual advisors.

Results

Statement 1: The properties and conditions of the skin vary with body site and can be influenced by factors such as skin type, ethnicity, gender, or lifestyle.
Epidemiological data indicate a higher prevalence and severity of AD in racial/ethnic Canadian populations.^6,10-13

A three months population survey of all children aged 2-12 years in the community in the First Nations reserve of Natuashish, Labrador, Canada, showed that of 182 examined children, 30 (16.5%) mainly (20/30) had moderate to severe AD.⁶ IgE levels in children with and without AD had average values at least ten-fold higher than other populations.⁶

A systematic review and meta-analysis extracted 21 studies [1990 to 2020] from three medical databases [Pubmed, Embase, and Web of Science] to examine the prevalence of AD, clinical manifestation, and risk factors among children and adolescents in the Arctic.¹⁰ The cumulative AD incidence was 23%, and the 1-year prevalence was 19%, with the highest incidence in Arctic Scandinavia, lower Greenland, and Russia.¹⁰ The review indicated that the risk for AD in indigenous children living in rural Arctic areas seems slightly lower.¹⁰ Although the systematic review looked at the Arctic regions and included indigenous peoples, it did not mention Canadians.

A further study [2018] showed an AD prevalence of 20.5%, with the highest prevalence recorded among grade-1 Inuit children at 25%, compared to 15.4% among mixed ethnicity and 14.3% among non-Inuit children.¹¹ The variations in prevalence and risk factors of asthma, allergic rhinitis, and AD among the different ethnicities living in the same subarctic environment may be related to genetic, gene-environment interaction, or lifestyle factors.¹¹

An international study of asthma and allergies using written questionnaires included 8334 adolescents aged 13 to 14 in Vancouver, Saskatoon, Winnipeg, Hamilton, and Halifax, Canada.¹² Although AD was significantly more prevalent in Winnipeg (1.31; 1.01-1.69) and Vancouver (1.28; 1.04-1.58), the highest prevalence rates of allergic rhinoconjunctivitis or AD were not observed in the same regions as the highest prevalence rates of wheezing, suggesting dissimilar risk factors.¹²

A cross-sectional study in Europe and Canada on AD patient-reported burden of disease showed a substantial impact (pruritus, pain, loss of sleep, higher levels of anxiety and depression) which was highest in those with severe AD.¹³

A similar high burden of AD has been shown in studies from other countries.^14-18

Statement 2: The literature suggests racial/ethnic variations in ceramide content, SC structure, and filaggrin mutations. Racial/ethnic differences in barrier structure and function have been observed between Black, White, Asian, and Indigenous populations. Differences in TEWL have also been reported, but data are conflicting, and further research is needed.

The multifactorial pathogenesis of AD includes genetic and environmental factors that may vary among racial/ethnic and geographic populations.¹⁹ Genetic and immunophenotypic differences between racial/ ethnic AD populations, such as lower rates of filaggrin gene mutations, have been described among Black populations.^20-33 Studies involving small groups of East Asian and African American patients have identified differences in cytokine expression compared to European-American patients.^20-33 A literature review on clinical and molecular features of AD found differences in filaggrin (FLG) loss-of-function mutations across various ethnic groups with AD.²⁹ The authors noted that studies in European American compared to Asian American AD populations have consistently shown a higher prevalence of FLG loss-of-function mutations in up to 50% of European and 27% of Asian American patients, respectively.^29,30 However, the association between FLG loss-of-function mutations and AD development in populations of African descent is unclear, and other genes may be involved in skin barrier dysfunction.³⁰

A higher prevalence and persistence of AD has been noted in African American children and racial/ethnic disparities in health care utilization and access to therapies.^22-30

However, most of the information on racial/ethnic and geographic AD population variations originates from the US and may only be partially applicable to Canadians.

Statement 3: Data on racial/ethnic differences in skin barrier structure and function are limited but suggest variations in some characteristics relevant to skincare.

A healthy skin barrier function depends on the complex interplay among SC pH, desquamation rate, and the appropriate ratio of intrinsic lipids.^37-40 The lipids comprise approximately twenty percent of the volume of the healthy stratum corneum (SC) and are composed of CERs (40–50%), cholesterols (20-33%), and free fatty acids (7–13%).^37-39 Further lipids include cholesterol-3-sulfate (0-7 %) and cholesteryl esters (0-20 %).^37-40

The slightly acidic surface of healthy skin is required to mature and maintain the SC barrier, inhibiting the growth of pathogenic microorganisms.³⁹ Skin acidification plays an important role in SC barrier maturation and the activation of enzymes involved in the extracellular processing of SC lipids.³⁹ The SC pH influences barrier homeostasis, integrity and cohesion, and antimicrobial defense mechanisms.³⁹

It is unclear why specific changes in CER composition do not seem to affect a healthy SC and why deficiency of specific CER species and alterations in fatty acid composition occur in certain skin diseases such as AD.^41-45

There is some evidence that the skin barrier in Black skin contains fewer CERs and that the skin barrier in Asian skin is most vulnerable to disruption.^1,19 A less cohesive skin barrier in Asian skin might help explain differences in trans-epidermal water loss in this population.^1,19 The advisors suggested that studies correlating skin barrier structure to dysfunction in Asian skin (perhaps involving tape stripping) could provide insights. Skin barrier differences (lipids, less cohesive skin barrier) may contribute to ethnic differences in the prevalence of xerosis, pruritus, and AD.

Some individuals with AD may produce inadequate amounts of certain CERs.^31,41-45 Many with AD or AD-prone skin exhibit baseline increases in TEWL even within their unaffected, normal-appearing skin.^31,41-45 Racial and ethnic differences have been reported in the SC barrier function, including CERs content and TEWL.⁴⁵

Conventional moisturizers contain occlusives, humectants, and emulsions.³⁹ Newer classes of moisturizers designed to restore skin barrier defects include distinct ratios of lipids that resemble physiological compositions, such as CERs, cholesterol, and essential fatty acids.^37-40

CER-containing moisturizers were found to benefit AD patients when used as mono, adjunctive, and maintenance treatment.^{19,37-39,46-52} Guidelines, algorithms, and consensus papers agreed that the use of moisturizers that contain lipids, such as CERs (or their precursors) reduces pruritus, helps control xerosis, and improve the dysfunctional skin barrier in AD patients.^34-39,53

Other ingredients in moisturizers (i.e., virgin coconut oil, glycyrrhetinic acid, V. vinifera, shea butter, mineral water and hyaluronic acid) have also been recommended.^54-59

A Canadian study including 47 patients with inflammatory dermatosis, applied thermal water and hyaluronic acid-containing moisturizer for 4 weeks as an adjunct to treatment and found a markedly improved skin condition.⁵⁹

A systematic review of 92 randomized controlled trials on the efficacy and safety of moisturizers for AD showed that those containing a mixture of substances (urea, glycerin or glycyrrhetinic acid, ceramides) seem to have greater effectiveness than basic emollients.⁶²

Additionally, regular moisturizer use improves pruritus frequently caused by AD.⁶³
As the mainstay of treatment, moisturizers should be liberally applied both in AD-prone skin and AD.^{34-39, 53, 60-62} The moisturizer should be used at least twice daily directly after bathing and more frequently during acute flare-ups.^{34-39, 53} Further moisturizers must be suitable for the patient’s skin type, climate, humidity, and environmental conditions.^36-39,53-55

The advisors agreed that focusing too much on minor ethnic variations in the skin barrier of AD-affected patients could interfere with essential skincare principles that apply to all skin types. Instead, concentrating on similarities while acknowledging the differences may be more helpful.

A Canadian algorithm for topical treatment of mild-to-moderate AD for adults and pediatric patients and US guidelines for topical treatment of AD include education and avoiding triggers.^34,35 Routine skincare with gentle cleansers and moisturizers is considered an integral part of AD management regardless of disease severity and prescription treatment (Table 1).^34-38

Table 1: Cleanser and moisturizer use

Statement 4: Skin barrier differences between racial/ethnic populations may contribute to variations in the prevalence and severity of atopic dermatitis, xerosis, and, pruritus. Environmental issues and disparities in access to care may also play a role.

Although some authors reported a direct relationship between the severity of AD and the degree of SC lipid depletion^41-45, the evidence demonstrating an association between CER depletion and AD is inconclusive.¹⁹ Other factors may play a role in SC lipid depletion, and the reduced CER could be an epiphenomenon of AD.¹⁹

Epidemiological data indicate a higher prevalence and severity of AD in racial/ethnic Canadian populations; while studies do not support the assumption that skin barrier differences are a factor.^26-31 It is presumed that the impact of the cold, dry climate throughout parts of Canada may play a role in skin barrier dysfunction amongst these populations at large.

Delays in diagnosis or underestimation of severity may occur in patients with richly pigmented skin due to knowledge gaps in recognizing morphologic features of AD across the spectrum of skin complexions and racial/ethnic populations.^19,64-66 Patients with richly pigmented skin may present with variations in the appearance of erythema (Figure 1). AD lesions may appear reddish-brown, violaceous, gray, or hyperchromic rather than bright red (Figure 2). Perifollicular accentuation, papules, scaling, lichenification, and pigmentary changes may be more prominent (Figure 3 and Figure 4). As a consequence, patients with SOC may present with a more advanced stage of AD severely impacting their QoL.¹⁹

Canadian Indigenous children and young adults continue to face higher rates of health disparities than their non-Indigenous counterparts.² In dermatology, this includes a high burden of AD and secondary skin infections.^2,3 Environmental factors and disparities in access to care could be a particular challenge for Indigenous groups, who frequently lack access to appropriate treatments.^2,3 A systematic review of the pediatric dermatology literature reported on systemic [finances, wait times, geography], sociocultural [culture beliefs and communication], and individual barriers [patient beliefs and health knowledge] to diagnosis, treatment, and maintenance approaches of AD and other skin conditions.⁶⁷ The identified barriers are interesting to explore further in Canadian AD populations. However, further research is needed to obtain insight into any interventions’ impact on overcoming these barriers.

Awareness amongst AD patients and caretakers, specifically Indigenous groups, on the cause of AD, general treatment principles, available treatments and the role of moisturizers, and adherence to moisturizer regimens are inconsistent.⁶⁸

Statement 5: Cultural perceptions of healthy skin impact the choice of skincare.

First Nations people have been using medicinal plants for AD treatment. Natural Indigenous medicinal discoveries [safrole, salicylic acid, and ascorbic acid derived from Sassafras albidum, genus Salix trees, and Sassafras officinale] by the Iroquoian and Algonquian-speaking Peoples of North America for AD and other dermatologic conditions are mentioned in the European literature.⁷¹ Further examples are Western red cedar’s known principal active compound, β-thujaplicin, has shown efficacy in AD.⁷⁰ Another active principal compound (7-hydroxymatairesinol) of White spruce may offer benefits due to its anti-inflammatory activity.⁷⁰ Plants and algae such as hazel may also have benefits; however, studies need to confirm this.⁷¹

The effect of traditional treatments and natural remedies for AD may be of interest in managing racial/ethnic Canadian AD populations.^70,71 However, such AD treatments may result in adverse effects such as postinflammatory hyperpigmentation or keloid scarring at a higher rate than evidence-based treatment.¹⁹

Optimal management of AD is multipronged and includes patient education, prescription treatment, and skincare promoting a healthy skin barrier.^68,72-74

Nurse practitioner or physician assistant interventions may significantly increase correct and frequent moisturizer use, reducing AD.⁷⁶

The choice of skincare should be supported by evidence but is mainly a personal and individual choice.^{34,36-38,61,75}

It is important to note that there are variations in skincare norms across diverse populations; therefore, these cultural variations when providing skincare recommendations need to be considered.¹⁹ Integrating evidence-based recommendations for skin care in a culturally competent manner that aligns with the patient’s norms/preferences is key to successful outcomes across diverse populations.^2,19 More research is needed to guide culturally appropriate recommendations better.

Limitations

A detailed discussion on genetic factors of racial/ethnic Canadian AD populations is outside the scope of the review. There is an overall lack of robust studies focusing on the prevention, treatment, and maintenance of AD in racial/ethnic Canadian AD populations.

Conclusions

The multifactorial pathogenesis of AD includes genetic and environmental factors that may vary among racial/ethnic and geographic populations. Available data suggest that skincare strategies to improve AD patients’ outcomes should consider racial/ethnic differences, integrating recommendations for skin care in a culturally competent manner that aligns with the patient’s norms and preferences. Future robust comparative studies will help clinicians to tailor patient education and recommend routine skincare with gentle cleansers and moisturizers as an integral part of AD management.

Division of Dermatology, University of Toronto Dermatology, Toronto, ON
Bay Dermatology Centre, Toronto, ON

Conflict of interest: The authors have no conflicts of interest to declare.

ABSTRACT
This review summarizes and discusses the role and efficacy of moisturizers, particularly the more recently introduced ceramide-based formulations, in the skin care regimen of patients with both active and quiescent atopic dermatitis (AD). It is now well established that a complex interplay of environmental and genetic factors are responsible for disease onset and chronicity. Indeed, several novel genetic mechanisms have been recently discovered to be associated with AD pathogenesis. Moreover, it is increasingly recognized that the epidermal barrier plays a critical role in the initiation, perpetuation, and exacerbation of AD. The skin of patients with AD harbors several defects in epidermal barrier function, including filaggrin and ceramides. An improved understanding of these etiopathogenic factors has led to the development of topical ceramide-dominant moisturizers to replace the deficient molecules and re-establish the integrity of barrier defenses. Some of these products have demonstrated efficacy in the treatment of adult and childhood AD that are similar to mid-potency topical steroids. More importantly, they have been shown to be safe with very few associated side-effects. We recommend the addition of such new agents as both the first step of treatment and in the maintenance of clinically quiescent skin of patients with AD.

Key Words:
atopic dermatitis, ceramides, eczema, emollients, epidermal barrier, lipids, transepidermal water loss

Introduction

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic skin disease of increasing prevalence (affecting 15-30% of children and 2-10% of adults).¹ AD is considered by many to be the first step in the “atopic march” that can progress to include asthma and allergic rhinitis, as well as be a precursor to, rather than a consequence of, food allergies.¹ The precise sequence of biochemical events leading to the development of AD has still not been fully elucidated, but most experts agree that it involves a complex interplay of environmental and genetic factors that induce derangements in the structure and function of the epidermal barrier and immune system. Diagnosis can be challenging, as the variability of clinical presentation can be confounding. Morphology alone cannot reliably confirm the diagnosis and the spectrum of features associated with AD must be considered. While several sets of diagnostic criteria for AD have been proposed and validated, the traditionally used being that of Hanifin and Rajka, full agreement amongst clinicians and uniformity of criteria are still lacking.²

Epidermal Barrier Dysfunction

Traditionally, it was thought that the primary pathogenic mechanism of atopic dermatitis was initiated by immune dysfunction leading to a Th2 cytokine imbalance, increased inflammation, and secondary disruption of the epidermal barrier.^1,3 However, accumulating evidence suggests that rather than merely having a bystander effect, a primary defect in the stratum corneum plays a major role in driving the pathogenesis of atopic dermatitis that leads to sustained cytokine release, recruitment of pro-inflammatory molecules, and stimulation of a Th2 response.^3,4 Moreover, further barrier disruption in the chronic stages of AD, through mechanical scratching, not only perpetuates but alters the response to a mostly Th1 type.⁵ In addition, while several other cytokines and T cell subsets like IL-31 and Th2,⁶ respectively, have recently been identified within the skin of patients with AD, the role of the skin barrier influencing their expression remains unclear.⁷

AD has been separated into two different subtypes, i.e., intrinsic and extrinsic, which were derived on the basis of the extrinsic subtype stemming from allergic sensitization to an external antigen with subsequent allergen specific IgE production, and the intrinsic variant describes patients with all clinical features of AD, but no detectable allergen specific IgE. However, these subtypes may actually represent different stages of evolution based on the relative degree of sensitization. Under this view, AD in infancy is thought to begin as “intrinsic” or non-atopic dermatitis, and over time it progresses to “true” atopy in the majority of cases via allergen exposure through what is now being more widely recognized as a primarily defective epidermal barrier function.^1,2

It is well established that the first line of defense within the epidermal barrier is the stratum corneum, which serves several fundamental roles in maintaining protection from the environment as well as preventing water loss. This “outside-in” theory views a primary defect in the stratum corneum as a key condition that drives the inflammatory cascade of AD, predisposing to increased transepidermal water loss (TEWL), penetration of irritants, allergens, secondary infection, and increased inflammation.⁸ Several lines of evidence demonstrate the capacity of the cutaneous barrier to initiate and perpetuate AD including observations that:

1. the defects in the barrier result in elevated pH that activates
   proteases capable of directly inducing a Th2 inflammatory
   response,⁹
2. the severity of the barrier defect parallels AD severity,^10,11
3. the barrier defect persists longer than both the clinical lesions
   and the underlying inflammation,¹¹
4. several genetic disorders with skin lesions similar to AD
   implicate abnormal gene coding that affect the epidermal
   barrier, and lastly,¹²
5. therapeutic strategies aimed at repairing the epidermal
   barrier, as further discussed below, also ameliorates both the
   inflammation and the clinically involved skin.¹³

Morphological Changes in Epidermal Lipids in AD

The stratum corneum represents a multicellular vertically stacked layer of cells embedded within a hydrophobic extracellular matrix. This matrix is derived from the secretion of lipid precursors and lipid hydrolases, both of which are secreted from lamellar bodies in the stratum granulosum. These hydrolases cleave the precursors to form essential and non-essential fatty acids, cholesterol, and at least 10 different ceramides, which self-organize into multilayered lamellar bilayers between the corneocytes (“bricks”), resulting in the formation of watertight “mortar”, thus, maintaining skin hydration.¹² In physiological balance, the approximate proportions of the lipid component are predominantly composed of 50% ceramides, 25% cholesterol, and 10-20% free fatty acids.⁸ In atopic dermatitis, there is a decrease in all three key lipids, especially ceramides, which are found in both lesional and non-lesional skin.¹ A lipid imbalance and inadequate amounts of ceramides contribute to defective formation of the corneocyte lipid envelope and lipid mortar, which correlates with increased TEWL and enhanced barrier permeability.

Filaggrin Mutations and Exogenous Factors in AD Contribute to Epidermal Barrier Dysfunction

There has been a large focus on the role of genetic abnormalities leading to defects in key structural components of the epidermal barrier. Perhaps the best example of this is a loss of function mutation in the filaggrin gene, which encodes for the filament aggregating protein (FLG), found in up to 60% of AD patients.¹² While there are various other candidate genes that lead to increased susceptibility, including KLK7, SPINK5, and CSTA, FLG remains by far the most prominent.¹⁴ Although filaggrin is certainly one of the most important single genes involved in AD susceptibility, inherent redundancy in the epidermal differentiation complex with several other similar genes may mitigate the negative effect of filaggrin mutations and explain the incomplete penetrance in AD. As such, patients carrying a mutation in the FLG gene display a wide spectrum of disease, ranging from mildly dry skin to more severe manifestations of ichthyosis vulgaris.¹⁵ Moreover, since only 44% of AD patients carry the heterozygous mutation and 76% of homozygous or compound heterozygous FLG mutation carrying patients suffer from AD,¹⁶ this further implicates the role of other genes and the environment in disease pathogenesis. Nevertheless, complete absence of FLG, either as a homozygous mutation or a compound heterozygote mutation, clearly disrupts the epidermal barrier, as all of these patients to date have been shown to present with a clinical picture of ichthyosis vulgaris.^17,18

Filaggrin normally assists in cytoskeletal aggregation and formation of the cornified cell envelope (CCE), providing additional strength and structure. It is required for normal lamellar body formation and content secretion. Furthermore, as corneocytes mature and start losing water, FLG dissociates from the CCE and is processed into acidic metabolites acting as osmolytes that help to retain hydration and keep the pH below the threshold required for the activation of Th2-inducing endogenous serine proteases.⁹ Therefore, a FLG mutation contributes to a disrupted epidermal barrier, increased water loss, and inflammation. There are also many exogenous factors that can exacerbate barrier dysfunction, specifically soaps and surfactants in detergents that accelerate corneocyte and lipid degradation. Several antigens, including those from cockroaches, Staphylococcus aureus, dust mites, and scabies induce endogenous proteolytic activity, cleaving corneodesmosomal proteins and filaggrin, thus contributing further to the cycle of inflammation and pruritus.¹

Lipid Replacement Therapy in AD

Traditionally viewed as an immunological disorder, therapies for AD have included topical steroids and immunomodulators, and sometimes more aggressive immunosuppressives that do not target the underlying structural barrier abnormalities.^4,19 As well, most conventional moisturizers do not address this underlying lipid deficiency. With an improved understanding of AD etiopathogenesis, a new nonpharmacologic approach has emerged aimed at barrier repair involving the delivery of balanced proportions of stratum corneum specific lipids to assist in correcting this epidermal barrier dysfunction.

With accumulating evidence supporting barrier defect-initiated disease pathogenesis and its effects on both triggering and perpetuating AD, it is not surprising that emollients, ointments and oils thought to prevent epidermal water loss and inhibit sensitizing exogenous peptides from traversing the compromised barrier, have become the first-line/adjunctive therapy in patients with AD. While the use of sophisticated moisturizers has been shown to confer protective effects on the skin barrier by delaying onset and decreasing AD severity and flares,¹ it is not appropriate to generalize this benefit to all moisturizers, as they not only differ widely in their compositions, but are classified into subcategories based on the therapeutic properties of their key ingredients, e.g., occlusives, humectants, emollients (e.g., intercellular lipids), or some combination of the three. Within the intercellular lipids category, moisturizers contain a variable mix of ceramides, cholesterol, and free fatty acids.

One of the most promising barrier repair methods have been ceramide-dominant physiological lipid-based barrier repair topical emulsions. In contrast to traditional moisturizers, these formulations focus on physiologic lipid replacement therapy, particularly ceramides, to restore normal balance of the epidermal barrier. In comparison with other emollients (e.g., petrolatum) that form a more superficial occlusive barrier, ceramide-dominant moisturizers are thought to permeate the stratum corneum and are synthesized in the keratinocytes, processed in lamellar bodies, and secreted back into the stratum corneum to become a part of the dermal matrix.^8,20

Interestingly, while cholesterol, ceramides, and fatty acids are all required for repair, individually they encumber rather than facilitate barrier recovery.²¹ Moreover, incomplete mixtures can also result in suboptimal recovery,²² underlining the importance of proper physiological ratios of individual components to achieve maximal efficacy. Ceramide-based emulsions, such as EpiCeram® and TriCeram®, contain the physiological 3:1:1 molar ratio of ceramides, cholesterols, and free fatty acids, which emulates the endogenous composition of the stratum corneum and has been shown to repair its integrity and function.²¹ While several reports have shown that the 3:1:1 ratio seems to be important in barrier repair,^21-24 it appears that the “3” does not necessarily need to be a ceramide, as both three-fold higher ratios of a fatty acid or cholesterol rather than a ceramide can significantly improve barrier function when compared to vehicle alone.²³ Moreover, while both TriCeram® and EpiCeram® contain 2.1% of ceramides, one study showed that a dilution of 1:9 also has significant effects on barrier repair.²¹ In addition to assisting in restoration of the lipid defect in AD, these products also help to normalize the pH of the skin, which itself is separately associated with a decrease in epidermal barrier integrity, increased inflammation, and reduced antimicrobial defenses.^25,26

Although most of the early studies compared the efficacy of the three component mixtures to vehicle alone, several recent reports have shown that some ceramide-dominant formulations can, on their own, induce improvements comparable to topical steroids in the treatment of mild to moderate disease.19,27 Therefore, avoiding associated adverse effects from corticosteroid treatment and certain dosing restrictions, as therapy is suitable for patients of all ages and may be used on sensitive skin sites (e.g., face and intertriginous areas), which are prone to steroid-induced atrophy

Another ceramide-based barrier repair cream is CeraVe™, the first over-the-counter (OTC) product featuring multilamellar vesicular emulsions (MVEs), which are similar to liposomes, but facilitate a slow 24-hour controlled, time-released delivery of the contents. This delivery advance offers once-daily application, thereby encouraging adherence to a simplified regimen of moisturizer use. While no standalone trials have been conducted with MVEs, the combination of MVEs with topical fluocinonide 0.05% has recently been shown to reduce disease duration and time to clearance when compared with the same corticosteroid alone, resulting in accelerated skin barrier recovery.²⁸

Natural vs. Synthetic Ceramides

As previously discussed, ceramides are the main components of the multilayered lamellar bilayers between the corneocytes and, thus, a key factor in water retention and overall integrity of the barrier. Chemically, they are amide-linked free fatty acids with long-chain amino alcohol sphingoid bases, which are amidelinked to hydroxylated, x-hydroxylated or nonhydroxylated fatty acids, and shown to also have functions in apoptosis, cell growth, senescence, and cell cycle control.²⁹ Clinically, while many other moisturizers are important in providing short-term relief from dryness in AD, long-term benefits can only be derived through restoring adequate ceramide levels. While replacement with natural ceramides seems to represent the most logical step in the correction of the barrier, there are three important considerations connected with the use of “natural” ceramides. Firstly, there is a high cost associated with nature-identical, synthetic ceramides (e.g., $2,000-$10,000/kg).³⁰ Secondly, inexpensive naturally occurring ceramides are typically extracted from bovine central nervous system, which raises concerns about bovine spongiform encephalopathy (‘mad cow disease’). Thirdly, excess intracellular ceramides can be linked with significant toxicity and lead to cell growth retardation and apoptosis.^20,30 Synthetic ceramides are capable of overcoming most of these obstacles and are currently being explored as potential alternatives to natural ceramides.

Kang et al. showed that application of 1% K6PC-9p (a synthetic ceramide derivative of PC-9S) resulted in similar improvement of tetradecanoylphorbol acetate (TPA)-induced skin inflammation, when compared to 0.1% hydrocortisone.³¹ Moreover, application of a ceramide complex (pseudoceramides and eucalyptus leaf extract) resulted in not only improved TEWL and erythema gradings of treated AD patients when compared to vehicle control, but also increased levels of endogenous stratum corneum ceramides.³² Another study investigated a synthetic pseudoceramide and eucalyptus leaf extract formulation in patients with mild to severe AD.³³ This double-blind, within subject vehicle-controlled study of patients with AD lesions on the arms and legs assessed TEWL, global assessment, and erythema. A significant differential benefit for the ceramide complex over vehicle was shown. Additionally, the findings demonstrated that this ceramide complex of pseudoceramides appears to work similar to the endogenous ceramindes found in the skin.

Other Non-steroidal Barrier Repair Products

While ceramide-based moisturizers clearly appear to be superior to most non-ceramide OTC moisturizers, it should be noted that a recent trial showed the use of a glycyrrhetinic acid-containing barrier repair cream (Atopiclair®) resulted in improvement of mild to moderate AD in children that was equivalent to EpiCeram®.³⁴ Similar findings were seen in another recent study that demonstrated non-superiority of topical pimecrolimus when compared to a number of different OTC creams (collectively regarded as one group),²⁵ suggesting that correction of numerous epidermal barrier derangements may be an effective way of controlling AD. As well, a multicenter, observational, uncontrolled study of 2456 AD patients aged 2-70 years showed that regular use of a barrier cream containing lipids and N-palmitoylethanolamine (MimyX®) significantly reduced AD skin symptoms (e.g., erythema, pruritus, excoriation, scaling, lichenification, and dryness), sleep disturbance, and topical steroid use.³⁵ Eletone® is another FDA-cleared 510(k) prescription medical device moisturizer that helps to improve stratum corneum impairment and restore barrier integrity. The product contains 70% oil dispersed in 30% water, but it uses a proprietary reverse emulsion technology that produces a formulary consistency of a cream with occlusive properties of an ointment, resulting in enhanced cosmetic acceptability. In a study assessing the use of twice-daily Eletone® in 133 pediatric patients with mild to moderate AD, at 4 weeks 54% of patients experienced improvement in pruritus and average body surface area involvement decreased by 43.6%. ³⁶ Whether such treatments lead to an indirect restoration of ceramide levels remains unknown and warrants further investigation.

Conclusion

AD follows a chronic relapsing course, as such, in addition to pharmacologic intervention, it is essential to maintain hydration and barrier function of the skin with daily regimented moisturizer use. Ceramide-based moisturizers have been shown to be beneficial in reducing TEWL, improving barrier function, and maintaining hydration of the stratum corneum, and thus, can be a useful component in AD management. Adequate moisturization reduces the need for drug treatments, as well as limits the severity and frequency of eczematous flares. Indeed, more studies are showing that correction of the skin barrier defects through emollient therapy inhibits downstream drivers of the inflammatory response, thereby providing the rationale for prophylactic and continuous use. Furthermore, the ceramidebased barrier repair emulsions have an excellent safety profile, without significant adverse events other than occasional transient tingling upon application, and thus, can be safely used in patients of all ages and on sensitive skin regions, including the face and intertriginous areas. Additional research is warranted and will lead to a better understanding of the optimal formulary compositions as well as development of a better treatment ladder for varying severities of AD. Also, long-term studies would be helpful in establishing whether lipid barrier replacement therapy reduces bacterial colonization or prevents progression of the atopic march.

References

1. Danby S, Cork MJ. A new understanding of atopic dermatitis: the role of epidermal barrier dysfunction and subclinical inflammation. J Clin Dermatol. 2010;1:33-46.
2. Bos JD, Brenninkmeijer EE, Schram ME, et al. Atopic eczema or atopiform dermatitis. Exp Dermatol. 2010 Apr;19(4):325-31.
3. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Allergy Asthma Rep. 2009 Jul;9(4):265-72.
4. Elias PM. An Appropriate response to the black-box warning: corrective, barrier repair therapy in atopic dermatitis. Clin Med Dermatol. 2009 Feb 9;2:1-3.
5. Matsushima H, Hayashi S, Shimada S. Skin scratching switches immune responses from Th2 to Th1 type in epicutaneously immunized mice. J Dermatol Sci. 2003 Sep;32(3):223-30.
6. Jin H, He R, Oyoshi M, et al. Animal models of atopic dermatitis. J Invest Dermatol. 2009 Jan;129(1):31-40.
7. Szegedi K, Kremer AE, Kezic S, et al. Increased frequencies of IL-31 producing T cells are found in chronic atopic dermatitis skin. Exper Dermatol. 2012 Jun; 21(6):431-6.
8. Sugarman JL. The epidermal barrier in atopic dermatitis. Semin Cutan Med Surg. 2008 Jun;27(2):108-14.
9. Briot A, Deraison C, Lacroix M, et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med. 2009 May 11;206(5):1135-47.
10. Sugarman JL, Fluhr JW, Fowler AJ, et al. The objective severity assessment of atopic dermatitis score: an objective measure using permeability barrier function and stratum corneum hydration with computer-assisted estimates for extent of disease. Arch Dermatol. 2003 Nov;139(11):1417-22.
11. Seidenari S, Giusti G. Objective assessment of the skin of children affected by atopic dermatitis: a study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin. Acta Derm Venereol. 1995 Nov;75(6):429-33.
12. Elias PM, Wakefield JS. Therapeutic implications of a barrier-based pathogenesis of atopic dermatitis. Clin Rev Allergy Immunol. 2011 Dec; 41(3):282-95.
13. Elias PM, Wood LC, Feingold KR. Epidermal pathogenesis of inflammatory dermatoses. Am J Contact Dermat. 1999 Sep;10(3):119-26.
14. Cork MJ, Danby SG, Vasilopoulos Y, et al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol. 2009 Aug;129(8):1892-908.
15. Heimall J, Spergel JM. Filaggrin mutations and atopy: consequences for future therapeutics. Expert Rev Clin Immunol. 2012 Feb;8(2):189-97.
16. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006 Apr;38(4):441-6.
17. Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006 Mar;38(3):337-42.
18. Hu Z, Xiong Z, Xu X, et al. Loss-of-function mutations in filaggrin gene associate with psoriasis vulgaris in Chinese population. Hum Genet. 2012 Jul; 131(7):1269-74.
19. Kircik LH, Del Rosso JQ, Aversa D. Evaluating clinical use of a ceramidedominant, physiologic lipid-based topical emulsion for atopic dermatitis. J Clin Aesthet Dermatol. 2011 Mar;4(3):34-40.
20. Anderson PC, Dinulos JG. Are the new moisturizers more effective? Curr Opin Pediatr. 2009 Aug;21(4):486-90.
21. Man MQ, Feingold KR, Elias PM. Exogenous lipids influence permeability barrier recovery in acetone-treated murine skin. Arch Dermatol. 1993 Jun; 129(6):728-38.
22. Man MQ, Brown BE, Wu-Pong S, et al. Exogenous nonphysiologic vs physiologic lipids. Divergent mechanisms for correction of permeability barrier dysfunction. Arch Dermatol. 1995 Jul;131(7):809-16.
23. Man MM, Feingold KR, Thornfeldt CR, et al. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol. 1996 May;106(5):1096-101.
24. Yang L, Mao-Qiang M, Taljebini M, et al. Topical stratum corneum lipids accelerate barrier repair after tape stripping, solvent treatment and some but not all types of detergent treatment. Br J Dermatol. 1995 Nov;133(5):679-85.
25. Emer JJ, Frankel A, Sohn A, et al. A bilateral comparison study of pimecrolimus cream 1% and a topical medical device cream in the treatment of patients with atopic dermatitis. J Drugs Dermatol. 2011 Jul;10(7):735-43.
26. Elias PM, Choi EH. Interactions among stratum corneum defensive functions. Exp Dermatol. 2005 Oct;14(10):719-26.
27. Sugarman JL, Parish LC. Efficacy of a lipid-based barrier repair formulation in moderate-to-severe pediatric atopic dermatitis. J Drugs Dermatol. 2009 Dec;8(12):1106-11.
28. Draelos ZD. The effect of ceramide-containing skin care products on eczema resolution duration. Cutis. 2008 Jan;81(1):87-91.
29. Sawai H, Domae N, Okazaki T. Current status and perspectives in ceramidetargeting molecular medicine. Curr Pharm Des. 2005;11(19):2479-87.
30. Uchida Y, Holleran WM, Elias PM. On the effects of topical synthetic pseudoceramides: comparison of possible keratinocyte toxicities provoked by the pseudoceramides, PC104 and BIO391, and natural ceramides. J Dermatol Sci. 2008 Jul;51(1):37-43.
31. Kang JS, Yoon WK, Youm JK, et al. Inhibition of atopic dermatitis-like skin lesions by topical application of a novel ceramide derivative, K6PC-9p, in NC/ Nga mice. Exp Dermatol. 2008 Nov;17(11):958-64.
32. Ishikawa J, Shimotoyodome Y, Chen S, et al. Eucalyptus increases ceramide levels in keratinocytes and improves stratum corneum function. Int J Cosmet Sci. 2012 Feb;34(1):17-22.
33. Ishida K, Takahashi A, Koutatsu B, et al. The ability of ceramide complex to reduce erythema and enhance barrier function of atopic skin. Poster #5433 presented at: American Academy of Dermatology 70th Annual Meeting. San Diego, CA. March 16-20, 2012.
34. Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-to-moderate atopic dermatitis: a randomized, controlled trial. J Drugs Dermatol. 2011 May;10(5):531-7.
35. Eberlein B, Eicke C, Reinhardt HW, et al. Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). J Eur Acad Dermatol Venereol. 2008 Jan;22(1):73-82.
36. Abramovits W, Alvarez-Connelly E, Breneman D, et al. A double-blind, randomized, vehicle-controlled trial to determine the efficacy and safety of hydrocortisone butyrate 0.1% lipocream in the treatment of mild to moderate atopic dermatitis in pediatric subjects. Poster presented at: 25th Anniversary Fall Clinical Dermatology Conference. Las Vegas, NV. October 6-9, 2006.

Introduction

• Atopic dermatitis (AD) or eczema is a chronic, inflammatory, pruritic skin condition of increasing prevalence that often precedes other atopic conditions such as asthma or allergic rhinitis.¹
• The lifetime prevalence of AD is estimated at up to 17% of Canadians having been affected.²
• Atopic dermatitis may account for up to 30% of dermatologic consultations in general practice.³
• Most cases of AD start in children under 5 years of age. Although 60% of patients with childhood AD are estimated to be free of symptoms in adolescence, up to half may experience adulthood recurrence.⁴
• Multiple severity scales and diagnostic criteria for AD have been adopted, but Hanifin and Rajka’s clinical criteria⁵ has been widely accepted. AD diagnosis requires the presence of at least 3 of these major criteria :
  • Characteristic lesion distribution
  • Pruritus
  • Chronic progression with recurrences
  • Personal or family history of atopy (asthma, allergic rhinitis, AD)
• Three clinical stages usually characterize AD, depending on age group:¹
  1. in infancy AD usually presents on cheeks and scalp,
  2. in childhood on the flexural areas, neck, and dorsal limbs, and
  3. in adolescence/adulthood lichenified plaques of the head, neck, and flexural areas.

Top

Pathogenesis

Filaggrin Gene

• Loss of function mutations in the filaggrin gene (also found in icthyosis vulgaris), has been identified in with patients AD.¹ Filaggrin gene defects can also be associated with increased risk of allergic rhinitis and asthma in patients with eczema.⁶
• Filaggrin normally assists in cytoskeletal aggregation and formation of the cornified cell envelope functioning to prevent water loss, creating a barrier to external insults.
• There have been several potential genes identified in AD, for example those encoding cytokines involved in IgE synthesis regulation (IL-4, IL-5, IL-12, IL-13, and GM-CSF), and gene polymorphisms involved in innate immunity contributing to imbalance between Th1 and Th2 immune responses.¹

Epidermal Barrier Dysfunction

• There is strong evidence to support that barrier abnormalities play a major role in disease pathogenesis, with recent focus on emollient and lipid replacement therapy to address barrier dysfunction and decrease inflammation.⁷
• The structure of the epidermal skin barrier, the stratum corneum, is commonly analogized to a “brick and mortar”⁸ model. The “bricks” consist of a network of compact corneocyte multilayers and the intercellular lipid matrix (composed of ceramides, cholesterol, and free fatty acids) form the “mortar”. These hydrophobic lipids function as water-retaining molecules, with their precursors secreted by the epidermal lamellar body that also deliver antimicrobial peptides and enzymes that assist in lipid generation and corneocyte shedding.⁷
• An intact stratum corneum functions to maintain skin hydration and protect against water loss.
• In AD, the pathogenic skin barrier is characterized by increased transepidermal water loss (TEWL), decreased water-binding properties, and reduced surface lipids, primarily ceramides.⁹

Top

General Treatment Principles

• Avoidance of trigger factors and optimization of the skin barrier function with emollients/moisturizers are key elements at all stages of treatment in AD.
• Increasing severity of disease calls for the addition of multiple therapeutic agents in stepwise fashion.
• Current treatment options for AD target either restoration of skin barrier function, inflammation, and/or infection/ microbial colonization.
• Production of antimicrobial peptides and molecular recognition of invading pathogens has been shown to be defective in AD.¹⁰ Colonization of the skin with Staphylococcus aureus is frequently found in AD, which in combination with a disfunctional skin barrier can result in secondary infection requiring antimicrobials, such as impetiginization, folliculitis, and cellulitis or abscesses.¹

Top

Moisturizers

• Moisturization has been shown to improve skin barrier function in AD with faster resolution of symptoms,^11,12 and continual treatment appears to reduce re-exacerbation.¹³
• Controlled clinical studies have demonstrated that moisturizers enhance topical corticosteroid efficacy. Moisturizers are also shown to have a steroid-sparing effect.⁹
• Liberal use of emollients (cream or ointment) is suggested (e.g., 500 g every 1 to 2 weeks).³
• Some emollients (e.g., containing urea, lactic acid, or propylene glycol) can cause irritation and burning, and contact dermatitis may occur in susceptible patients to certain fragrances and preservatives.¹⁴
• A reduction in lipids, particularly ceramides, correlate positively with barrier impairment in AD. Use of lipidcontaining moisturizers may be beneficial in promoting barrier recovery.^9,14

Ceramides as Moisturizers

• Patients with AD produce fewer and different lipids, and have higher ceramide degradation,¹⁰ leading to a selective reduction in the ceramide fraction.¹²
• Most current water-in-oil emollients/moisturizers do not address nor correct this underlying lipid abnormality.
• Topical mixtures containing ceramide, cholesterol, and free fatty acids have been shown to accelerate barrier repair.¹¹
• Lipid-based barrier repair cream available in Canada include CeraVe® (available over-the-counter) and EpiCeram® (prescription only).
• Ceramide-containing creams, lotions and cleansers (e.g., CeraVe®) can be delivered through time-released multilamellar vesicular emulsions (MVE).
• Such MVEs deliver ceramides, cholesterol, free fatty acids, and other moisturizing ingredients (hyaluronic acid, glycerine and dimethicone) into the skin in a 24-hour controlled, time-released manner. This delivery advance offers once-daily application, thereby encouraging adherence to a simplified regimen of moisturizer use.
• The combination of MVEs with other topical treatments has recently been shown to accelerate skin barrier recovery.¹⁵
• More education for AD patients on the benefits of ceramide creams is needed, as the use of such preparations is associated with poor patient knowledge and compliance.¹⁶
• In addition to AD, ceramide-based moisturizers may have a role in managing other cutaneous disorders that cause or exacerbate skin barrier impairment, such as acne, psoriasis, and rosacea.
• The cost comparison of various barrier repair creams may bear an impact on therapeutic decision-making.

Top

Topical Therapies

Corticosteroids and Calcineurin inhibitors

• Uninvolved skin of AD patients harbours subclinical inflammation.
• Proactive therapy, a recent therapeutic concept, aims at targeting subclinical inflammation before it flares into clinically relevant AD.
• There are two main topical modalities in anti-inflammatory treatment: corticosteroids and calcineurin inhibitors.
• With mild AD, small amounts of TCS in combination with emollients/moisturizers are sufficient to maintain an acceptable skin status without significant adverse effects.¹⁰
• Tapering of corticosteroids, in terms of progressive reduction in potency and reduction in application frequency, once the erythema has subsided is crucial.
• Topical calcineurin inhibitors (TCIs), such as topical tacrolimus or pimecrolimus, reduce proinflammatory cytokines by inhibiting the calcineurin-dependent pathway.
• Tacrolimus 0.1% ointment is similar to an intermediate potency corticosteroid and pimecrolimus 1.0% cream is slightly less potent.¹⁰
• TCIs do not cause skin atrophy, and thus, may be used on sensitive areas (e.g., face, eyelids, perioral region, genital area, axillary region, or inguinal folds).
• Health Canada has recently approved topical tacrolimus ointment twice-weekly for the prevention of eczema flares in those who experience a high frequency of flares (> 5 times per year) based on two Phase 3 multi-centre randomized clinical trials in pediatric and adult patients.^17,18
  • Preventative therapy with tacrolimus has been shown to significantly reduce treatment days and prolong intervals between flares.^17,18 Similar findings have also been reported in the use of pimecrolimus cream for flare prevention in children.¹⁹

Top

Systemic Therapy

• Numerous systemic treatments can be used in severe acute flare-ups of AD when topical therapy with immunomodulators fails to control the disease. These include phototherapy, methotrexate, azathioprine, and cyclosporine A.
• Antihistamines do not directly relieve pruritis; however, when taken before bed central sedative effects can discourage scratching and improve sleep quality.

Top

Other Tips

Patient Education

• A survey¹⁶ of 422 patients with chronic skin conditions and compromised skin barrier function revealed general underuse of moisturizers. The survey also emphasized that patient education is important in promoting compliance and clinicians should provide more information on the essential role of moisturizers and cleansers in skin barrier repair.
  • Cleansers containing ceramides and emollients can minimize any barrier disturbance by simultaneously replacing lipids that are lost during washing.
• Explaining the nature and course of atopic dermatitis, trigger avoidance and lifestyle changes, and therapeutic options, as well as demonstrating proper use of treatment are key to management. Supplemental educational brochures and a written plan of care that is reinforced at follow-up visits may also be helpful.³

Lifestyle Modifications

• Identify and avoid triggers
  • Common triggers or exacerbating factors include sweating, hot baths, stress, wool clothing, dry environments, harsh soaps, and detergents
• Avoid scratching
• Keep nails trimmed, wear gloves at night to avoid scratching and enhance penetration of topical therapies
• Cool wet compresses can provide temporary relief
• Wear cotton clothing
• Choose fragrance-free skin care products and laundry detergent
• Double rinse clothing
• Short (>15 minutes) lukewarm baths followed by moisturization
• Moisturize regularly

Top

Conclusion

AD follows a chronic relapsing course. As such, in addition to pharmacologic intervention, it is essential to maintain hydration and barrier function of the skin with daily regimented moisturizer use. Ceramide-based moisturizers have been shown to be beneficial in reducing TEWL, improving barrier function, and maintaining hydration of the stratum corneum, and thus, can be a useful component in AD management. Adequate moisturization reduces the need for drug treatments, as well as limits the severity and frequency of eczematous flares.

References

1. Bieber T. Atopic dermatitis. N Engl J Med 358(14):1483-94 (2008 Apr 3).
2. Eczema prevalence in Canada. Ipsos-Insight Health (2003).
3. Nicol NH. Use of moisturizers in dermatologic disease: the role of healthcare providers in optimizing treatment outcomes. Cutis 76(6 Suppl):26-31 (2005 Dec).
4. Williams HC. Clinical practice. Atopic dermatitis. N Engl J Med 352(22): 2314-24 (2005 Jun 2).
5. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 92(suppl):44-47 (1980).
6. van den Oord RA, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and metaanalysis. BMJ 339:b2433 (2009).
7. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol 9(5):437-46 (2009 Oct).
8. Draelos ZD. Concepts in skin care maintenance. Cutis 76(6 Suppl):19-25 (2005 Dec).
9. Lebwohl M, Herrmann LG. Impaired skin barrier function in dermatologic disease and repair with moisturization. Cutis 76(6 Suppl):7-12 (2005 Dec).
10. Wollenberg A, Schnopp C. Evolution of conventional therapy in atopic dermatitis. Immunol Allergy Clin North Am 30(3):351-68 (2010 Aug).
11. Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 47(2):198-208 (2002 Aug).
12. Loden M, Andersson AC, Lindberg M. Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Canoderm). Br J Dermatol 140(2):264-7 (1999 Feb).
13. Billmann-Eberwein C, Rippke F, Ruzicka T, et al. Modulation of atopy patch test reactions by topical treatment of human skin with a fatty acid-rich emollient. Skin Pharmacol Appl Skin Physiol 15(2):100-4 (2002 Mar-Apr).
14. Ghali FE. Improved clinical outcomes with moisturization in dermatologic disease. Cutis 76(6 Suppl):13-8 (2005 Dec).
15. Draelos ZD. The effect of ceramide-containing skin care products on eczema resolution duration. Cutis 81(1):87-91 (2008 Jan).
16. Berson D. Recommendation of moisturizers and cleansers: a study of unmet needs among dermatology patients. Cutis 76(6 Suppl):3-6 (2005 Dec).
17. Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy 63(6):742-50 (2008 Jun).
18. Thaci D, Reitamo S, Gonzalez Ensenat MA, et al. Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study. Br J Dermatol 159(6):1348-56 (2008 Dec).
19. Sigurgeirsson B, Ho V, Ferrandiz C, et al. Effectiveness and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis. J Eur Acad Dermatol Venereol 22(11):1290-301 (2008 Nov).

Division of Dermatology, University of Toronto, Toronto, ON, Canada
Bay Dermatology Centre, Toronto, ON, Canada

Introduction

• Atopic dermatitis (AD) or eczema is a chronic, inflammatory, pruritic skin condition of increasing prevalence that often precedes other atopic conditions such as asthma or allergic rhinitis.¹
• The lifetime prevalence of AD is estimated at up to 17% of Canadians having been affected.²
• Atopic dermatitis may account for up to 30% of dermatologic consultations in general practice.³
• Most cases of AD start in children under 5 years of age. Although 60% of patients with childhood AD are estimated to be free of symptoms in adolescence, up to half may experience adulthood recurrence.⁴
• Multiple severity scales and diagnostic criteria for AD have been adopted, but Hanifin and Rajka’s clinical criteria⁵ has been widely accepted. AD diagnosis requires the presence of at least 3 of these major criteria :
  • Characteristic lesion distribution
  • Pruritus
  • Chronic progression with recurrences
  • Personal or family history of atopy (asthma, allergic rhinitis, AD)
• Three clinical stages usually characterize AD, depending on age group:¹
  1. in infancy AD usually presents on cheeks and scalp,
  2. in childhood on the flexural areas, neck, and dorsal limbs, and
  3. in adolescence/adulthood lichenified plaques of the head, neck, and flexural areas.

Pathogenesis

Filaggrin Gene

• Loss of function mutations in the filaggrin gene (also found in icthyosis vulgaris), has been identified in with patients AD.¹ Filaggrin gene defects can also be associated with increased risk of allergic rhinitis and asthma in patients with eczema.⁶
• Filaggrin normally assists in cytoskeletal aggregation and formation of the cornified cell envelope functioning to prevent water loss, creating a barrier to external insults.
• There have been several potential genes identified in AD, for example those encoding cytokines involved in IgE synthesis regulation (IL-4, IL-5, IL-12, IL-13, and GM-CSF), and gene polymorphisms involved in innate immunity contributing to imbalance between Th1 and Th2 immune responses.¹

Epidermal Barrier Dysfunction

• There is strong evidence to support that barrier abnormalities play a major role in disease pathogenesis, with recent focus on emollient and lipid replacement therapy to address barrier dysfunction and decrease inflammation.⁷
• The structure of the epidermal skin barrier, the stratum corneum, is commonly analogized to a “brick and mortar”⁸ model. The “bricks” consist of a network of compact corneocyte multilayers and the intercellular lipid matrix (composed of ceramides, cholesterol, and free fatty acids) form the “mortar”. These hydrophobic lipids function as water-retaining molecules, with their precursors secreted by the epidermal lamellar body that also deliver antimicrobial peptides and enzymes that assist in lipid generation and corneocyte shedding.⁷
• An intact stratum corneum functions to maintain skin hydration and protect against water loss.
• In AD, the pathogenic skin barrier is characterized by increased transepidermal water loss (TEWL), decreased water-binding properties, and reduced surface lipids, primarily ceramides.⁹

General Treatment Principles

• Avoidance of trigger factors and optimization of the skin barrier function with emollients/moisturizers are key elements at all stages of treatment in AD.
• Increasing severity of disease calls for the addition of multiple therapeutic agents in stepwise fashion.
• Current treatment options for AD target either restoration of skin barrier function, inflammation, and/or infection/ microbial colonization.
• Production of antimicrobial peptides and molecular recognition of invading pathogens has been shown to be defective in AD.¹⁰ Colonization of the skin with Staphylococcus aureus is frequently found in AD, which in combination with a disfunctional skin barrier can result in secondary infection requiring antimicrobials, such as impetiginization, folliculitis, and cellulitis or abscesses.¹

Moisturizers

• Moisturization has been shown to improve skin barrier function in AD with faster resolution of symptoms,^11,12 and continual treatment appears to reduce re-exacerbation.¹³
• Controlled clinical studies have demonstrated that moisturizers enhance topical corticosteroid efficacy. Moisturizers are also shown to have a steroid-sparing effect.⁹
• Liberal use of emollients (cream or ointment) is suggested (e.g., 500 g every 1 to 2 weeks).³
• Some emollients (e.g., containing urea, lactic acid, or propylene glycol) can cause irritation and burning, and contact dermatitis may occur in susceptible patients to certain fragrances and preservatives.¹⁴
• A reduction in lipids, particularly ceramides, correlate positively with barrier impairment in AD. Use of lipidcontaining moisturizers may be beneficial in promoting barrier recovery.^9,14

Ceramides as Moisturizers

• Patients with AD produce fewer and different lipids, and have higher ceramide degradation,¹⁰ leading to a selective reduction in the ceramide fraction.¹²
• Most current water-in-oil emollients/moisturizers do not address nor correct this underlying lipid abnormality.
• Topical mixtures containing ceramide, cholesterol, and free fatty acids have been shown to accelerate barrier repair.¹¹
• Lipid-based barrier repair cream available in Canada include CeraVe® (available over-the-counter) and EpiCeram® (prescription only).
• Ceramide-containing creams, lotions and cleansers (e.g., CeraVe®) can be delivered through time-released multilamellar vesicular emulsions (MVE).
• Such MVEs deliver ceramides, cholesterol, free fatty acids, and other moisturizing ingredients (hyaluronic acid, glycerine and dimethicone) into the skin in a 24-hour controlled, time-released manner. This delivery advance offers once-daily application, thereby encouraging adherence to a simplified regimen of moisturizer use.
• The combination of MVEs with other topical treatments has recently been shown to accelerate skin barrier recovery.¹⁵
• More education for AD patients on the benefits of ceramide creams is needed, as the use of such preparations is associated with poor patient knowledge and compliance.¹⁶
• In addition to AD, ceramide-based moisturizers may have a role in managing other cutaneous disorders that cause or exacerbate skin barrier impairment, such as acne, psoriasis, and rosacea.
• The cost comparison of various barrier repair creams may bear an impact on therapeutic decision-making.

Topical Therapies

Corticosteroids and Calcineurin inhibitors

• Uninvolved skin of AD patients harbours subclinical inflammation.
• Proactive therapy, a recent therapeutic concept, aims at targeting subclinical inflammation before it flares into clinically relevant AD.
• There are two main topical modalities in anti-inflammatory treatment: corticosteroids and calcineurin inhibitors.
• With mild AD, small amounts of TCS in combination with emollients/moisturizers are sufficient to maintain an acceptable skin status without significant adverse effects.¹⁰
• Tapering of corticosteroids, in terms of progressive reduction in potency and reduction in application frequency, once the erythema has subsided is crucial.
• Topical calcineurin inhibitors (TCIs), such as topical tacrolimus or pimecrolimus, reduce proinflammatory cytokines by inhibiting the calcineurin-dependent pathway.
• Tacrolimus 0.1% ointment is similar to an intermediate potency corticosteroid and pimecrolimus 1.0% cream is slightly less potent.¹⁰
• TCIs do not cause skin atrophy, and thus, may be used on sensitive areas (e.g., face, eyelids, perioral region, genital area, axillary region, or inguinal folds).
• Health Canada has recently approved topical tacrolimus ointment twice-weekly for the prevention of eczema flares in those who experience a high frequency of flares (> 5 times per year) based on two Phase 3 multi-centre randomized clinical trials in pediatric and adult patients.^17,18
  • Preventative therapy with tacrolimus has been shown to significantly reduce treatment days and prolong intervals between flares.^17,18 Similar findings have also been reported in the use of pimecrolimus cream for flare prevention in children.¹⁹

Systemic Therapy

• Numerous systemic treatments can be used in severe acute flare-ups of AD when topical therapy with immunomodulators fails to control the disease. These include phototherapy, methotrexate, azathioprine, and cyclosporine A.
• Antihistamines do not directly relieve pruritis; however, when taken before bed central sedative effects can discourage scratching and improve sleep quality.

Other Tips

Patient Education

• A survey¹⁶ of 422 patients with chronic skin conditions and compromised skin barrier function revealed general underuse of moisturizers. The survey also emphasized that patient education is important in promoting compliance and clinicians should provide more information on the essential role of moisturizers and cleansers in skin barrier repair.
  • Cleansers containing ceramides and emollients can minimize any barrier disturbance by simultaneously replacing lipids that are lost during washing.
• Explaining the nature and course of atopic dermatitis, trigger avoidance and lifestyle changes, and therapeutic options, as well as demonstrating proper use of treatment are key to management. Supplemental educational brochures and a written plan of care that is reinforced at follow-up visits may also be helpful.³

Lifestyle Modifications

• Identify and avoid triggers
  • Common triggers or exacerbating factors include sweating, hot baths, stress, wool clothing, dry environments, harsh soaps, and detergents
• Avoid scratching
• Keep nails trimmed, wear gloves at night to avoid scratching and enhance penetration of topical therapies
• Cool wet compresses can provide temporary relief
• Wear cotton clothing
• Choose fragrance-free skin care products and laundry detergent
• Double rinse clothing
• Short (>15 minutes) lukewarm baths followed by moisturization
• Moisturize regularly

Conclusion

AD follows a chronic relapsing course. As such, in addition to pharmacologic intervention, it is essential to maintain hydration and barrier function of the skin with daily regimented moisturizer use. Ceramide-based moisturizers have been shown to be beneficial in reducing TEWL, improving barrier function, and maintaining hydration of the stratum corneum, and thus, can be a useful component in AD management. Adequate moisturization reduces the need for drug treatments, as well as limits the severity and frequency of eczematous flares.

References

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2. Eczema prevalence in Canada. Ipsos-Insight Health (2003).
3. Nicol NH. Use of moisturizers in dermatologic disease: the role of healthcare providers in optimizing treatment outcomes. Cutis 76(6 Suppl):26-31 (2005 Dec).
4. Williams HC. Clinical practice. Atopic dermatitis. N Engl J Med 352(22): 2314-24 (2005 Jun 2).
5. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 92(suppl):44-47 (1980).
6. van den Oord RA, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and metaanalysis. BMJ 339:b2433 (2009).
7. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol 9(5):437-46 (2009 Oct).
8. Draelos ZD. Concepts in skin care maintenance. Cutis 76(6 Suppl):19-25 (2005 Dec).
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10. Wollenberg A, Schnopp C. Evolution of conventional therapy in atopic dermatitis. Immunol Allergy Clin North Am 30(3):351-68 (2010 Aug).
11. Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 47(2):198-208 (2002 Aug).
12. Loden M, Andersson AC, Lindberg M. Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Canoderm). Br J Dermatol 140(2):264-7 (1999 Feb).
13. Billmann-Eberwein C, Rippke F, Ruzicka T, et al. Modulation of atopy patch test reactions by topical treatment of human skin with a fatty acid-rich emollient. Skin Pharmacol Appl Skin Physiol 15(2):100-4 (2002 Mar-Apr).
14. Ghali FE. Improved clinical outcomes with moisturization in dermatologic disease. Cutis 76(6 Suppl):13-8 (2005 Dec).
15. Draelos ZD. The effect of ceramide-containing skin care products on eczema resolution duration. Cutis 81(1):87-91 (2008 Jan).
16. Berson D. Recommendation of moisturizers and cleansers: a study of unmet needs among dermatology patients. Cutis 76(6 Suppl):3-6 (2005 Dec).
17. Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy 63(6):742-50 (2008 Jun).
18. Thaci D, Reitamo S, Gonzalez Ensenat MA, et al. Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study. Br J Dermatol 159(6):1348-56 (2008 Dec).
19. Sigurgeirsson B, Ho V, Ferrandiz C, et al. Effectiveness and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis. J Eur Acad Dermatol Venereol 22(11):1290-301 (2008 Nov).