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Clinical Updates

Eric L. Simpson, M.D.

Skin Barrier Therapy and Atopic Dermatitis

Eric Simpson

Friday, June 20, 2008


The Structure and Function of the Skin Barrier

The wonderful complexities researchers are uncovering about the functioning of the skin barrier in health and disease make the previous notions of the stratum corneum as an inert membrane outdated. The term "skin barrier function" refers to the role that the stratum corneum plays in permeability homeostasis. Far from an inert dead skin layer, the stratum corneum has multiple defensive functions beyond permeability homeostasis including mechanical resistance, innate immune defenses, allergen and irritant exclusion, UV protection, sensory functions, thermal protection and the initiation of immunological responses.1

The structure of the stratum corneum has been described as a "brick and mortar" model with flattened protein-rich keratinocytes representing the bricks enveloped by a lipid-rich matrix representing the mortar. The process of stratum corneum development begins with lamellar body secretion by keratinocytes. Lamellar bodies contain lipids that organize into bilayers and surround the lipid-depleted corneocytes creating the so-called cornified envelope. The lipid-depleted corneocytes, meanwhile, become flattened due to aggregation of their keratin scaffolding by the protein filaggrin. In addition, fillaggrin is also later proteolytically processed into small amino acids that attract water into the corneocyte.

The formation and regulation of the skin barrier is a dynamic process and the composition and function of the stratum corneum can change in response to various stimuli. Several environmental insults such as changes in pH or humidity can alter key processes such as filaggrin processing and lipid biosynthesis. Genetic factors alone, or in combination with environmental insults, can disrupt the structure and function of the skin barrier leading to chronic skin diseases such as atopic dermatitis (AD).

The Skin Barrier in Atopic Dermatitis

Evidence for skin barrier dysfunction in AD includes increased water permeability, decreased water content, an increased susceptibility to skin irritants and chronic staphylococcal colonization.2-4 Increased transepidermal water loss (TEWL) can be found in clinically involved and uninvolved skin in patients with atopic dermatitis.3 TEWL levels correlate with disease activity, and have been shown to normalize once AD lesions are clear for 5 years.5 Skin capacitance, a direct measure of stratum corneum hydration, is also diminished in AD.

Until recently, the underlying cause of the defective skin barrier in AD was not well understood. Genetic studies suggested that polymorphisms in stratum corneum processing enzymes may play a role. Studies of skin lipids suggested that a reduction in ceramides, an important stratum corneum lipid, may be responsible for the skin barrier defect in AD.6,7 The cause of the ceramide deficiency reported in the lesional skin of AD is not fully known.

In 2006, a major advance into understanding the nature of skin barrier dysfunction in AD occurred when Palmer and colleagues reported mutations in the skin barrier gene, filaggrin, to be major risk factors for AD.8 These findings have now been replicated on an unprecedented scale in Europe, Asia and the United States. A meta-analysis of nine European studies revealed that one filaggrin mutant allele increases the odds of developing AD over 4-fold. Filaggrin gene defects are the strongest genetic predictors of AD discovered to date. How a defective filaggrin gene leads to the observed inflammatory phenotype of AD remains to be clarified. These findings strengthen the view that the skin barrier plays a central role in AD pathogenesis and developing therapies that target the skin barrier may hold great promise.

Improving the Skin Barrier in AD

Emollients

Studies in both healthy and diseased skin have shown that most oil-in-water emollients improve skin barrier function.10-12 Emollients' protective effect on the skin barrier translates to improved clinical outcomes with reduced pruritus and prolonged remission for patients.13  Emollients are first-line therapy for the treatment of mild AD and have a significant steroid sparing effect when added to the treatment regimen.13-15 The efficacy of an emollient is formulation-dependent and some emollients and oils have actually been shown to worsen the skin barrier.16 Water itself has also been shown to be a skin irritant, making emollients high in water content (e.g., lotions) less appealing for AD therapy.17,18

Recently, several new emollients have emerged containing additives purported to have beneficial effects on the skin barrier. The most recent additives to emollients targeting AD are ceramide lipid species. Ceramides constitute the major intercellular lipid in the stratum corneum and are required for a functional skin barrier. A study of a ceramide-rich emollient, Triceram (Osmotics), suggested that it is more effective in improving TEWL levels and disease scores than routine emollients; however, this study did not include rigorous control methods.19  This product is commercially available but its formulation contains a formaldehyde-releasing preservative, which may cause the development of allergic contact dermatitis. CeraVe (Coria Laboratories), a moisturizer containing ceramides and hyaluronic acid, is available in a convenient 16-ounce tub. Ceratopic (SkinMedica) is another over-the-counter moisturizer containing ceramides that is promoted primarily as an aesthetic product and is not yet available in large enough quantities or priced appropriately for everyday use in AD. The Aveeno Eczema Care Moisturizing Cream contains ceramides and oat extracts and was the first product to gain the National Eczema Association Seal of Acceptance.

Despite the emergence of ceramide-based moisturizers in the marketplace, many questions remain. Does the addition of ceramides add any clinical efficacy over traditional petrolatum-based moisturizers? A study by Loden found no benefit from a skin-identical lipid formulation over pure petrolatum in repairing the skin barrier after experimental irritant contact dermatitis.20 Does the species of ceramide added make a difference? Do the proportions of various lipids make a difference? Do different formulations work better for different types of eczema? Hopefully the pharmaceutical industry will conduct further studies in order to answer these important questions.

Anti-Inflammatory Therapies

Although the primary defect in AD may be a defective skin barrier, a cycle of skin barrier dysfunction and inflammation becomes established. Inflammatory cytokines not only result from a dysfunctional skin barrier, but may also contribute to barrier dysfunction. For example, IL-4, a Th2 cytokine found in lesional skin of AD, reduces ceramide synthesis and downregulates filaggrin.21,22 Controlling skin inflammation should therefore have beneficial effects on the skin barrier.

Controlling skin inflammation with medium-potency topical steroids provides rapid improvement in skin barrier function as measured by basal TEWL and staphylococcal colonization.23,24 Long-term use of topical steroids, however, is detrimental to the skin barrier and lead to epidermal atrophy. The negative effects on skin barrier integrity and homeostasis can be detected even after only three days of using a super-potent topical steroid; however, the clinical relevance of these assays is not known.25 There are few published studies regarding the effect of calcineurin inhibitors on skin barrier function. Tacrolimus ointment treatment reduced staphylococcal colonization in one study.26 A more recent study found tacrolimus ointment to improve barrier function in AD with potentially less detrimental effects on the epidermis than topical steroids.27

New Prescription Devices

Three new prescription creams, MimyX (Steifel Laboratories), Epiceram (Ceragenix), and Atopiclair (Graceway Pharmaceuticals), have arrived on the market that make claims of improving AD and restoring the skin barrier. These therapies were approved under the Food and Drug Administration's 510(k) registration which classifies these therapies as medical devices which, by definition, do not contain an active ingredient and serve purely as a barrier. Little clinical data regarding disease-specific efficacy is needed in 510(k) approval, therefore peer-reviewed published data evaluating these products is scant.

Atopiclair is approved for use in the United States for AD and its formulation includes licorice root extract, grapevine extract, shea butter, and hyaluronic acid, which together are claimed to have both anti-inflammatory properties and barrier-improving properties. Two clinical studies in adults revealed significant reductions in clinical scores in patients with mild-to-moderate AD. These studies have several shortcomings and inconsistencies, including a poor description of the control cream raising the question of adequate blinding. The study in Europe of 30 subjects only showed a 14% improvement in disease severity as measured by the Eczema Area and Severity Index.28  The more recent study from the United States of 218 patients revealed a 34% improvement in mean EASI score, compared with overall disease worsening in the control group.29 However, the differences seen between the control and active groups may be biased, as the control cream appears to have been irritating. Most vehicle controls in AD studies provide at least some improvement in disease severity, sometimes up to 10-20%. In this study, no improvement was seen in the control group and 40% of these subjects required rescue topical steroid therapy.

MimyX cream, similar to Atopiclair, claims to possess both skin barrier repair and anti-inflammatory properties. The lipids in MimyX include triglycerides, squalene, phospholipids, and phytosterol and are purported to mimic the lamellar lipid framework of the stratum corneum. MimyX also contains N-palmitoylthanolamine (PEA), which binds to endogenous cannabinoid receptors on mast cells has anti-inflammatory effects. Several abstracts have been presented at dermatology meetings reporting improvement in the signs and symptoms in a large number of mild-to-moderate AD as well as significantly delaying flares when used to healed sites. Unfortunately, there are no randomized controlled trials examining the efficacy of MimyX cream in the treatment of AD. These data are needed to better understand the role MimyX may play in AD management.

Epiceram, the most recently approved device for AD therapy, contains ceramides, free fatty acids, and cholesterol present in a specific molar ratio reported to be optimal for correcting the skin barrier defect in AD. A press release from the company reported the results of a clinical study involving 112 pediatric patients with AD. They report significantly improved disease scores over a 28-day treatment course and did not find a medium-potency corticosteroid to be superior to Epiceram. This study has not yet undergone the peer-review process and there are currently no other published studies of Epiceram in the treatment of AD.

Incorporating Skin Barrier Therapy into Practice

The era of skin barrier-targeted therapies for AD is still in its infancy. Despite improved understanding of the nature of the skin barrier defect in AD, we have not yet been able to translate this information into new therapies with proven superiority over traditional management strategies. Petrolatum-based emollients are still the gold-standard for improving a defective skin barrier in AD and are very effective for relapse prevention. Although intriguing, it is not yet clear that ceramide-containing emollients function any better than traditional emollients in repairing the skin barrier. In acute disease, topical steroids are still the best method of reducing inflammation quickly and this translates into skin barrier improvement in the short-term. Topical calcineurin inhibitors are useful adjunctive therapy to prevent damage to the skin barrier from long-term topical steroids. There is some evidence, although weak, that Atopiclair may be helpful for mild-moderate disease as an alternative to low-strength topical steroids or calcineurin inhibitors. Until peer-reviewed studies are available, the role of Epiceram and MimyX remains unclear in routine AD management.

Acknowledgements

Thank you to Christine Carocci for manuscript editing.

References

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