Steroid-Sparing Properties of Emollients in Dermatology

Sara Harcharik and Jason Emer, MD

The Mount Sinai School of Medicine, Department of Dermatology, New York, NY, US A

Conflict of interest: No conflicts of interest
ABSTRACT

Topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs) are very effective treatments in inflammatory dermatoses, but carry risks with long-term use. TCS are associated with cutaneous atrophy and tachyphylaxis and TCIs can be irritating and contain a black box warning of an increased risk of cancers including lymphoma and non-melanomatous skin cancers. Nevertheless, they are appropriate treatments for inflammatory conditions such as psoriasis and atopic dermatitis (AD) and should be used more often with disease flares and less as maintenance therapy. Given the associated risks of long-term continuous use with these pharmacologic agents, alternatives are needed with similar anti-inflammatory and barrier repair properties that can be used indefinitely without risk. Some over-the-counter (OTC) ingredients such as colloidal oatmeal and petrolatum, as well as anti-inflammatory prescription moisturizers (medical device creams), have demonstrated efficacy with little complications in skin barrier repair and symptom relief in steroid-responsive conditions. With regimented application, these non-drug options are safe and effective and can limit the long-term continuous use of TCS or TCIs.

Key Words:
atopic dermatitis, emollients, eczema, skin barrier repair, moisturizers, topical corticosteroids, topical calcineurin inhibitors

Introduction

Topical corticosteroids (TCS) are the cornerstone of treatment for inflammatory dermatoses, particularly for the swift resolution of acute flares, as TCS can calm inflamed and irritated skin due to rapid absorption and action.¹ A wide range of potencies and vehicles enables tailoring of therapy to be site-specific and considerate of patient preference. Long-term continuous therapy with TCS can lead to localized side effects such as cutaneous atrophy, telangiectasias, acne and rosacea exacerbation, and tachyphylaxis, as well as systemic absorption if used on large surface areas causing hypothalamic-pituitary-adrenal (HPA) axis suppression, growth retardation in children, and cataract and glaucoma formation in adults.^2-6 Thus, intermittent therapy should be supplemented with alternative treatments that can help limit localized side effects and provide epidermal barrier dysfunction improvement.⁷

Topical calcineurin inhibitors (TCIs; tacrolimus ointment/ Protopic®; pimecrolimus cream/Elidel®) represent secondline therapies for the short-term and non-continuous chronic treatment of moderate-to-severe atopic dermatitis (AD) in non-immunocompromised adults and children who have failed to respond adequately to or are not suitable for other topical prescription AD treatments.^8,9 TCIs inhibit calcineurin in T-cells, reducing the production of interleukin (IL)-2 and related proinflammatory cytokines. Clinical studies have demonstrated longterm efficacy, minimal systemic absorption, and few transient side effects, such as localized irritation, with the use of these agents.^10-12 TCIs do not induce skin atrophy or inhibit collagen synthesis, enabling their use on the face, neck and intertriginous areas.¹³ In 2006 the United States Food and Drug Administration (USFDA) placed a black box warning on TCIs based on safety concerns over the possible risk of systemic absorption and on data from transplantation research reporting systemic immune suppression with oral calcineurin inhibitors (tacrolimus and cyclosporine) is associated with an increased cancer risk.¹⁴ To date, this risk remains theoretical and is based mainly on the drug’s mechanism of action, data from animal studies and a few single case reports of lymphoma and skin cancer in patients treated with TCIs.

Recently, medical device creams (Table 1), which are nonsteroidal agents with emollient, anti-inflammatory and antipruritic properties, have entered the marketplace for the treatment of inflammatory dermatoses to help treat epidermal barrier dysfunction as well as limit potential long-term use of TCS and TCIs. Atopiclair® is a hydrolipidic cream containing Butyrospermum parkii (shea tree), glycyrrhetinic acid (licorice), Vitis vinifera (grapevine) extract, bisabolol (German chamomile), hyaluronic acid and tocopheryl acetate (vitamin E), and is thought to have moisturizing, anti-inflammatory and antioxidant properties.¹⁵ It also contains telmesteine, which inhibits elastase, collagenase and matrix metalloproteinases, helping to prevent epidermal breakdown. MimyX™ contains lipid components that mimic the normal skin barrier (triglycerides, phospholipids, and squalene) along with the anti-inflammatory cannabinoid N-palmitoylethanolamine (N-PEA), an endogenous fatty acid amide thought to target the peroxisome proliferator-activated receptor-alpha (PPAR-α).¹⁶ Other added ingredients such as purified water, olive oil, glycerin, pentylene glycol, vegetable oil, and hydrogenated lecithin have humectant and emollient effects. EpiCeram® is a microencapsulation system emulsion of ceramide, conjugated linoleic acid, cholesterol and palmitic acid formulated with Euphorbia cerifera (candelilla) wax, corn syrup solids, squalene, glycerin, petrolatum, and dimethicone.^17,18 Eletone® has a high lipid content dispersed in an outer aqueous phase (Hydrolipid Technology™) in petrolatum, purified water, and mineral oil.¹⁹ Hylatopic Plus® is an emollient cream and foam containing Theobroma grandiflorum seed butter (a skin conditioning butter made from the fruit of a the Cupuaçu tree that is native to Brazil), hyaluronic acid, glycerin, dimethicone, petrolatum, and tocopheryl acetate (vitamin E).²⁰ All of the medical device creams are indicated for the treatment of various dermatoses such as AD, allergic contact dermatitis, and radiation dermatitis, which are associated with symptoms of itching, burning, and pain.

Epidermal Barrier Dysfunction

Defects in skin barrier function and stratum corneum hydration have been identified in a variety of inflammatory dermatoses.²¹ A functioning stratum corneum consists of corneocytes surrounded by ceramides, cholesterol, and free fatty acids – the so-called “bricks and mortar” model.²² Topical balms containing lipids and lipid-like substances have been shown to restore the barrier function of an impaired stratum corneum by replacing the deficient lipids, thereby improving skin hydration through decreasing transepidermal water loss (TEWL).²³ Further, epidermal barrier disruption results in greater density of epidermal Langerhans cells (antigen-presenting immune cells), enhanced inflammatory responses by increased foreign antigen presentation, and decreased anti-microbial proteins (AMPs), which play a role in innate skin defense (first-line skin protection).²⁴

In AD, the disturbed epidermal barrier is explained by nonsense mutations in the gene encoding filaggrin (FLG) and subsequent affect on the pro-inflammatory cascade, such as abnormal elevation in IL-1 cytokine profile in the stratum corneum.^25,26 FLG is a structural protein essential in the cornified envelope and is expressed as pro-FLG, which functions to secure keratinocytes together in the stratum corneum. Dysfunction or loss of FLG heavily influences keratinocyte adhesion, enhances TEWL, and causes dysregulation of skin pH, resulting in increased skin permeability.²⁷ Overall, this can induce persistent, recalcitrant and/or severe disease, increase the risk of cutaneous infections caused by microbes such as herpesvirus (eczema herpeticum) and Staphylococcus aureus, as well as increase the risk of sensitization to allergens and asthma.²⁸ Thus, the importance of an uncompromised skin barrier in improving inflammatory conditions cannot be over-emphasized and should be a major consideration in the treatment of acute flares as well as in longterm disease management.

It is important to note that despite the acknowledged contributions of a defective epidermal permeability barrier [i.e., FLG mutations, decreased AMPs such as human tissue kallikreins and cathelicidins (LL-37)] and dryness of eczematous skin, immunologic abnormalities such as T-helper type 2 (Th2) cytokines [i.e., IL-4 and IL-13 that influence immunoglobulin E (IgE) synthesis and adhesion molecule expression] also contribute to the pathogenesis of AD.²⁹ This suggests the development of inflammatory disorders is likely due to underlying immune dysregulation as the primary cause and epidermal dysfunction may be a secondary consequence.

Over-The-Counter Options and Clinical Studies

Petrolatum

Petrolatum – a mixture of long-chain hydrocarbons that is pale yellow in color, translucent, odorless, and hydrophobic – has been used for over 100 years as a healing ointment. Originally thought to be an occlusive moisturizer that forms a hydrophobic layer on the skin surface, petrolatum can penetrate and restore the stratum corneum by filling the spaces between desquamating corneocytes. This can reduce the appearance of fine lines and impart a soft, silky feel to the skin. Increased skin hydration is a consequence of epidermal lipogenesis and production of free sterols, sphingolipids, and free fatty acids.^30-32 Occlusives are generally not appealing to patients, due to their greasy feel, but can be very beneficial directly as a moisturizer and indirectly by reducing TEWL. A recently published study demonstrated the clinical efficacy and cost-effectiveness of a petrolatum-based moisturizer (Aquaphor® Healing) in treating mild-to-moderate AD as compared to two commonly prescribed medical device creams; one glycyrrhetinic acid-containing barrier repair cream (Atopiclair™) and another a ceramide-dominant barrier repair cream (EpiCeram®).³³ Some barrier repair creams contain petrolatum as their primary ingredient (Eletone®) and one study demonstrated comparable efficacy to a TCI (i.e., Elidel®) in the treatment of AD.³⁴

Dimethicone

Dimethicone – a mixture of polydimethylsiloxanes and silicon dioxide sometimes called simethicone – is another occlusive (insoluble in water) used in many OTC moisturizers and found to be safe and effective at skin moisturizing, though it is not as effective as petrolatum at reducing TEWL.^35,36 Dimethicone is the first ingredient in a foam formulated for the relief of irritation from inflammatory dermatoses such as AD and allergic contact dermatitis (Neosalus™). A combination of cyclomethicone (a cyclic higher-viscosity silicone) and dimethicone are used in barrier creams designed to prevent skin sensitization to allergens and can be useful in patients with itching and burning associated with contact dermatitis (Tetrix™).^37,38 Additionally, a recent study showed significant reduction in the incidence of incontinenceassociated dermatitis in patients using dimethicone-impregnated clothes.³⁹

Colloidal Oatmeal

Colloidal oatmeal has a long-standing history of benefit in dermatologic conditions associated with itch and irritation because of the ability to soothe and protect inflamed skin.⁴⁰ It contains a variety of active components including polysaccharides, proteins, lipids, saponins, enzymes, flavonoids, vitamins and avenanthramides (polyphenol).⁴¹ In 2003, colloidal oatmeal became an approved OTC monograph ingredient.⁴⁰ Current, ready-to-use oatmeal preparations are the concentrated starch-protein fraction of the oat grain mixed with emollient. Fine particles disperse on the skin and form a protective, occlusive barrier that retards water loss and moisturizes to improve the epidermal barrier. Further, oatmeal saponins help to solubilize dirt, oil and sebaceous secretions, which may normalize the skin pH.⁴² Oats have important antioxidant, ultraviolet (UV) absorbent and anti-inflammatory properties attributed to the ferulic, caffeic and coumaric acids, as well as flavonoids and α-tocopherol (vitamin E) components.^43,44 Recent research has identified avenanthramides (phenolic compounds) as a minor component of oat grains and in vitro work has demonstrated anti-inflammatory and anti-pruritic properties by decreased production of Nuclear Factor-kappaB (NF-κB) in keratinocytes and reduced pro-inflammatory cytokine (such as IL-8) production.⁴⁵ Avenanthramides have also been reported to inhibit prostaglandin synthesis.⁴⁶ As a result, many studies have substantiated the anti-inflammatory, hydrating and anti-pruritic properties of colloidal oatmeal and their use in the management of common inflammatory dermatoses.

Ceramides

As discussed previously the ceramides – which are a family of lipid molecules composed of sphingosine and a fatty acid, and found in high concentrations within the membrane of cells in the stratum corneum – are an essential component of the normal stratum corneum and function to help maintain the integrity of the skin barrier.⁴⁷ They serve as important water-holding molecules in the extracellular space, linking corneocytes and creating a waterproof barrier. In ceraminde-deficient skin there is enhanced TEWL, dryness, and increased permeability to environmental irritants and allergens. A recent study found that the mechanisms of ceramide changes in atopic skin are due to both Th1 (accentuate) and Th2 (attenuate) cytokines, as both IL-4 and IL-6, as well as interferon (IFN)-γ and tumor necrosis factor (TNF)-α influenced ceramide content in the stratum corneum.⁴⁸ This further solidifies that immune dysregulation in AD has a multitude of pathophysiological effects on the skin.

Newer moisturizers/topical skin care products (Table 2) targeted to improve epidermal barrier dysfunction by replenishing the amount of ceramides in the skin – with ceramide and pseudoceramide products mimicking the natural physiological skin barrier – are a mainstay of adjunctive therapy for patients with AD. Although evidence on their efficacy compared to older, less expensive traditional therapies, such as occlusives and humectants, remains to be validated.⁴⁹ It is known that proper moisture therapy can reduce the frequency of flares and limit the need for TCS or TCIs, likely a result of barrier recovery, including restoration of proper permeability function and increased levels of AMPs. In one study, a ceramide-hyaluronic acid emollient foam (Hylatopic Plus®) and pimecrolimus both showed equivalent improvement in the signs and symptoms of AD.⁵⁰ In another study, a ceramide-dominant, physiologic lipid-based, barrier repair emollient (TriCeram®) showed improvement when substituted for other OTC moisturizers in 24 children also receiving standard therapy (TCS or TCIs) for recalcitrant AD, thereby demonstrating the use of a ceramide-dominant moisturizer as compared to traditional agents can elicit significant improvement in symptoms of AD.⁵¹ TriCeram® has been discontinued by the manufacturer and is no longer available on the market.

EpiCeram® (a prescription device) consists of a specific combination of ceramides, cholesterol and fatty acids (in the ratio of 3:1:1) that mimics those naturally found in the skin and is reported to have similar efficacy to a mid-potency topical corticosteroid.^1,52,53 It contains capric acid, cholesterol, conjugated linolenic acid, candelilla and petrolatum. In a fivecenter, investigator-blinded, randomized trial, EpiCeram® was compared to fluticasone (Cutivate®) cream in 121 patients with moderate-to-severe AD and showed reduced clinical disease severity, decreased pruritus and improved sleep habits at both 14 and 28 days after initiation of therapy. The fluticasone group improved faster – greater improvement by day 14 – but by day 28, both interventions showed equal efficacy.¹⁷ A more recent study established improvement in clinical dryness scores and skin hydration and reduction in TEWL with the use of a new moisturizer (Cetaphil® Restoraderm® Body Moisturzier; CRM) containing FLG breakdown products [natural moisturizing factor (NMF)], a ceramide precursor pseudoceramide 5 or N-(2-hydroxyhexadecanoyl) sphinganine and niacinamide (vitamin B3), at week 4 as compared to the untreated areas.⁵⁴ A significantly higher level of ceramide and a trend toward increased water content were observed in the stratum corneum of CRM-treated skin when compared to the control.

Additional Ingredients

Additional ingredients such as glycerin or glycerol, urea, hydroxy acids and propylene glycol are common humectants added to OTC ingredients to help increase the ability of the skin to absorb water; although they are typically combined with an occlusive to prevent upward migration of water from the dermis and inadvertent increased TEWL. Glycerol or glycerin are the most effective as they have the ability to activate transglutaminase activity in the stratum corneum, accelerating the maturation of corneocytes as well as increasing water channels called aquaporins (particularly aquaporin-3) in diseased skin, which ultimately increases cutaneous hydration and reduces TEWL.^55,56

Clinical Studies

Several studies have directly examined the steroid-sparing potential of OTC emollients in patients with AD. Daily hydrocortisone 2.5% cream in the morning combined with a once daily water-in-oil emollient cream in the evening (Eucerin® Creme) was equally efficacious as twice daily hydrocortisone 2.5% cream in children.⁵⁷ Similarly, once daily betamethasone diproprionate cream with Eucerin® Creme was equally efficacious as twice daily betamethasone diproprionate cream in patients with plaque psoriasis.⁵⁸ As well, in infants under 12 months of age with AD, the addition of an emollient containing water, petrolatum, shea butter, evening primrose oil, glycerin, paraffin oil, niacinamide, butylene glycol, benzoic acid, carbomer and also specific active Rhealba® oat extracts (flavonoids and saponins) (Exomega® Emolient Lotion) significantly reduced the use of topical corticosteroids (desonide 0.1% cream).⁵⁹

Prescription Alternatives: Medical Device Creams

Prescription medical device creams are not classified as drugs, but rather as medical devices that have received 510(k) FDA clearance based on a demonstrated reduction in TEWL, which is a less extensive regulatory process that focuses on safety and less on efficacy. Each device cream has ingredients with proposed moisturizing, anti-inflammatory and anti-pruritic properties that may be useful as adjunctive or maintenance therapy in inflammatory dermatoses and, thereby, may help to limit the use of TCS or TCIs. Whether these device creams are equivalent in efficacy and long-term maintenance as compared to their OTC counterparts remains to be seen. Financial burden and supply limitation (insurance approval required in the US) may create difficulty in initiating and continuing therapy, especially in cases of severe disease.

Conclusion

Epidermal barrier dysfunction is a consequence of a combination of genetic factors influenced by immune dysregulation and abnormal structural proteins. Inflammatory dermatoses require treatment with TCS and/or TCIs to control acute flares, but also necessate appropriate and adequate moisturization to mitigate structural dysfunction and insufficient skin hydration. High predisposition to recurrent and recalcitrant disease, as well as infections and sensitization to allergens, makes long-term management with the goal to prolong periods of remission and reduce the severity of flares of utmost importance. As TCS can induce long-term complications and some patients are concerned with the black box warning of TCIs, non-drug options such as OTC and/or prescription medical device creams containing active ingredients known to have moisturizing, anti-inflammatory and anti-pruritic properties, are important therapeutic adjuncts that can be used daily without the risks associated with pharmacologics. Further studies are needed to determine the long-term efficacy of these products in treating chronic inflammatory dermatoses and validate their role through the development of management guidelines.

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