Fixing the skin barrier: past, present and future – man and dog compared
Skin barrier dysfunction exists in both human and canine atopic dermatitis, leading to increased water loss and potentially facilitating allergen penetration and sensitization. Both lipid (e.g. ceramides) and protein (e.g. filaggrin) abnormalities have been described. Some are genetically inherited (e.g. filaggrin mutations are one of the major risk factors in humans) and some are secondary and linked to inflammation.
In humans, numerous studies have shown efficacy of emollients and moisturizers in barrier restoration, and this approach has been for years the mainstay of therapy. Recently, this strategy has shown promise as a preventative function.
In veterinary medicine, evidence regarding skin barrier impairment is rapidly building. Decreased ceramides and filaggrin (in some subsets of dogs) have been described. Altered metabolism of ceramides has also been proposed. Despite these preliminary data and the availability of products marketed to improve the skin barrier, evidence regarding the clinical benefit of skin repair intervention is still limited. Preliminary studies have demonstrated that topical application of fatty acids and ceramides and systemic administration of fatty acids improve lipid deficiencies in the skin of dogs with atopic dermatitis, but limited clinical evidence exists.
Disease remission in humans is paralleled by an improved skin barrier, both with calcineurin inhibitors and glucocorticoids. In veterinary medicine, a preliminary study on ciclosporin and prednisone failed to detect significant improvement of water loss, while successful immunotherapy correlated with an improved skin barrier. Controlled, large studies are needed to address the question of which skin repair approach is clinically most effective and whether this can be used as a preventative strategy.
What is known in human medicine
The importance of addressing skin dryness in humans with atopic dermatitis (AD) has been known for decades. A direct relationship exists between skin dryness and disease severity in AD patients.1 Both moisturizers and emollients have been shown to improve the skin barrier and clinical signs.2 Skin barrier creams increase the time between flare-ups and reduce relapses by about one-third compared with no treatment.3 Skin care has also a preventative function. Early implementation of emollient therapy (petrolatum based) decreases the frequency of development of AD in high-risk children to 15%, compared with 30-50% when no skin care is done.4 Despite the fact that skin barrier repair has been practised for a long time, the debate on the best ingredient to use is ongoing.
Emollients, moisturizers and products based on lipids/ceramides: which one is the best?
The terms moisturizers and emollients are frequently used interchangeably, although moisturizers typically contain water as the main ingredient mixed with humectants to hydrate the stratum corneum, while emollients classically contain some form of lipid. Water itself can contribute to dryness and worsen the skin barrier, because prolonged contact with water can disrupt the stratum corneum and water rapidly evaporates after application.5 Watery lotions can worsen the skin barrier and predispose to development of AD.6 Therefore, ointments or thick creams rather than watery lotions are preferred in humans with AD.
Ingredients used in skin repair include combinations of petrolatum, vegetable oils, glycerin and urea.7 Petrolatum has an immediate barrier-repairing effect8 and is used in many over-the-counter products (e.g. Vaseline®, Hangzhou Jinque Home Product Co. Ltd, Xiaoshan, Hangzhou, China; Aquaphor®, Beiersdorf Inc., Wilton, CT, USA; and Cetaphil®, Galderma Laboratories L.P., Fort Worth, TX, USA). Paraffin oil and vegetable oils penetrate into the upper layers of the stratum corneum, and this is paralleled by a decrease in transepidermal water loss (TEWL), with the most effective occlusion seen with petrolatum.9
Large differences exist between products, and efficacy depends on the type of product and frequency of application. The choice and composition of the moisturizer are crucial in the long term. A study investigating the impact of long-term treatment with moisturizers on skin barrier function in healthy skin demonstrated that the effect is determined by the composition of the moisturizer.10 Moisturizers have the ability to affect epidermal mRNA expression of genes for involucrin, transglutaminase 1 and kallikrein 5 and 7, either improving or worsening skin barrier function.11
Urea, a common moisturizing agent, is an endogenous metabolite that enhances stratum corneum hydration and has antimicrobial activity.12 Topical application reduces dryness13 and decreases TEWL.14 Urea is not merely a passive metabolite, but a small-molecule regulator of epidermal structure and function by enhancing the expression of antimicrobial peptides, a property beneficial in patients with AD.15
In recent years, several no-steroidal barrier creams have been approved for AD treatment. EpiCeram® (Pura-Cap™; Pharmaceutical LCC, South Plainfield, NJ, USA) contains a combination of ceramides, cholesterol and fatty acids and was approved by the Federal Drug Administration (USA) in 2006.16 Its efficacy was documented in a case series17 and in a trial in patients with moderate-to-severe AD.18 Remission of disease as established by the investigator under the global assessment was achieved by 58% of subjects after 3 weeks. Pruritus decreased markedly from baseline to week 3, regardless of severity at baseline. The efficacy of EpiCeram® was comparable to that observed with fluticasone propionate cream.19 EpiCeram® reduced clinical disease severity and pruritus and improved sleep habits after both 14 and 28 days of therapy. Although the fluticasone group showed greater improvement at 14 days, improvement with EpiCeram® did not differ significantly from fluticasone by 28 days.
Atopiclair® (Galderma S.A., Lausanne, Switzerland) contains a combination of plant extracts, including glycyrrhetinic acid and Vitis vinifera. Atopiclair® is effective in the treatment of AD and has antipruritic properties in patients with mild-to-moderate AD.20 Glycyrrhetinic acid, abundant in liquorice, can inhibit pruritus elicited by protease-activated receptor-2 agonists.21 Humans with AD have higher levels of protease-activated receptor-2,22 and this leads to increased permeability, barrier dysfunction, itching and inflammation.23 Besides being antipruritic, glycyrrhetinic acid has antibacterial and antifungal properties that are beneficial in patients with AD.24
A recent study stirred debate because it showed a lack of significant difference in the clinical efficacy between a glycyrrhetinic acid-containing barrier repair cream (Atopiclair®), a ceramide-dominant barrier repair cream (EpiCeram®) and an over-the-counter petroleum-based skin protectant moisturizer (Aquaphor Healing Ointment®) applied three times daily for 3 weeks in children with mild-to-moderate AD.25 These results clearly demonstrated that there are multiple valid approaches to skin repair.
Topical glucocorticoids and calcineurin inhibitors
As inflammation worsens the skin barrier, it is reasonable to propose that control of inflammation improves skin barrier function. Indeed, both topical calcineurin inhibitors and topical glucocorticoids (e.g. betamethasone) improve TEWL.26 While both treatments decreased TEWL, electron microscopy of the skin after 3 weeks showed that only pimecrolimus-treated patients had an ordered stratum corneum with regular lamellar body extrusion, while the betamethasone-treated skin had inconsistent extracellular by-layers and only partly filled lamellar bodies. These results are consistent with the cutaneous atrophy observed clinically with betamethasone use, indicating that pimecrolimus is more appropriate for long-term therapy in terms of preservation of skin barrier. Pimecrolimus can also beneficially modulate expression of several genes involved directly in the skin barrier.27