Vet Dermatol 2013; 24: 73–e18 DOI: 10.1111/j.1365-3164.2012.01073.

Fixing the skin barrier: past, present and future – man

and dog compared
Rosanna Marsella
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, 2015 SW 16th Avenue, University of Florida, Gainesville, FL 32610,
USA
Correspondence: Rosanna Marsella, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, 2015 SW 16th Avenue,
University of Florida, Gainesville, FL 32610, USA. E-mail: marsella@ufl.edu

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 preventa-
tive 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 pro-
posed. Despite these preliminary data and the availability of products marketed to improve the skin barrier, evi-
dence 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 gluco-
corticoids. 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. Con-
trolled, 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.

water as the main ingredient mixed with humectants to

What is known in human medicine
hydrate the stratum corneum, while emollients classically
The importance of addressing skin dryness in humans contain some form of lipid. Water itself can contribute to
with atopic dermatitis (AD) has been known for decades. dryness and worsen the skin barrier, because prolonged
A direct relationship exists between skin dryness and dis- contact with water can disrupt the stratum corneum and
ease severity in AD patients.1 Both moisturizers and emol- water rapidly evaporates after application.5 Watery lotions
lients have been shown to improve the skin barrier and can worsen the skin barrier and predispose to develop-
clinical signs.2 Skin barrier creams increase the time ment of AD.6 Therefore, ointments or thick creams rather
between flare-ups and reduce relapses by about one-third than watery lotions are preferred in humans with AD.
compared with no treatment.3 Skin care has also a preven- Ingredients used in skin repair include combinations of
tative function. Early implementation of emollient therapy petrolatum, vegetable oils, glycerin and urea.7 Petrolatum
(petrolatum based) decreases the frequency of develop- has an immediate barrier-repairing effect8 and is used in
ment of AD in high-risk children to 15%, compared with many over-the-counter products (e.g. Vaseline, Hangz-
30–50% when no skin care is done.4 Despite the fact that hou Jinque Home Product Co. Ltd, Xiaoshan, Hangzhou,
skin barrier repair has been practised for a long time, the China; Aquaphor, Beiersdorf Inc., Wilton, CT, USA; and
debate on the best ingredient to use is ongoing. Cetaphil, Galderma Laboratories L.P., Fort Worth, TX,
USA). Paraffin oil and vegetable oils penetrate into the
Emollients, moisturizers and products based on upper layers of the stratum corneum, and this is paral-
lipids ⁄ ceramides: which one is the best? leled by a decrease in transepidermal water loss (TEWL),
The terms moisturizers and emollients are frequently used with the most effective occlusion seen with petrolatum.9
interchangeably, although moisturizers typically contain Large differences exist between products, and efficacy
depends on the type of product and frequency of applica-
Accepted 11 May 2012 tion. The choice and composition of the moisturizer are
Sources of Funding: The author has received funds for research crucial in the long term. A study investigating the impact
from Sogeval and Virbac. of long-term treatment with moisturizers on skin barrier
Conflict of Interest: The author has received funds for research
function in healthy skin demonstrated that the effect is
from Sogeval and Virbac.

ª 2013 The Author. Veterinary Dermatology

ª 2013 ESVD and ACVD, Veterinary Dermatology, 24, 73–e18. 73
Marsella

determined by the composition of the moisturizer.10 the betamethasone-treated skin had inconsistent extra-
Moisturizers have the ability to affect epidermal mRNA cellular by-layers and only partly filled lamellar bodies.
expression of genes for involucrin, transglutaminase 1 These results are consistent with the cutaneous atrophy
and kallikrein 5 and 7, either improving or worsening skin observed clinically with betamethasone use, indicating
barrier function.11 that pimecrolimus is more appropriate for long-term ther-
Urea, a common moisturizing agent, is an endogenous apy in terms of preservation of skin barrier. Pimecrolimus
metabolite that enhances stratum corneum hydration and can also beneficially modulate expression of several
has antimicrobial activity.12 Topical application reduces genes involved directly in the skin barrier.27 Tacrolimus,
dryness13 and decreases TEWL.14 Urea is not merely a on the contrary, was reported to have negative effects on
passive metabolite, but a small-molecule regulator of epi- the skin barrier, including permeability and antimicrobial
dermal structure and function by enhancing the expres- functions.28 These effects were mediated by decreasing
sion of antimicrobial peptides, a property beneficial in epidermal lipid synthesis, lamellar body secretion and
patients with AD.15 expression of antimicrobial peptides.
In recent years, several no-steroidal barrier creams
have been approved for AD treatment. EpiCeram (Pura-
What is known in dogs
CapTM; Pharmaceutical LCC, South Plainfield, NJ, USA)
contains a combination of ceramides, cholesterol and Skin barrier dysfunction exists in AD29,30 and may
fatty acids and was approved by the Federal Drug Admin- increase the risk of allergic sensitization.31 Decreased
istration (USA) in 2006.16 Its efficacy was documented in ceramides32,33 and abnormal stratum corneum ultrastruc-
a case series17 and in a trial in patients with moderate-to- ture have been described.34,35 An increase in free and
severe AD.18 Remission of disease as established by the protein-bound glycosylceramides suggests an abnormal-
investigator under the global assessment was achieved ity in metabolism of ceramides.36 A significant decrease
by 58% of subjects after 3 weeks. Pruritus decreased and altered metabolism of sphingosine-1-phosphate are
markedly from baseline to week 3, regardless of severity described in lesional atopic skin compared with healthy
at baseline. The efficacy of EpiCeram was comparable skin.37 All these studies emphasize the relevance of
to that observed with fluticasone propionate cream.19 exploring skin barrier repair in veterinary medicine.
EpiCeram reduced clinical disease severity and pruritus In dogs, the skin barrier is often assessed by TEWL,
and improved sleep habits after both 14 and 28 days of although the reliability of this methodology is not good.38
therapy. Although the fluticasone group showed greater A relationship between deficiency of ceramides and an
improvement at 14 days, improvement with EpiCeram increase in TEWL has been described,39 while a relation-
did not differ significantly from fluticasone by 28 days. ship between disease severity and skin barrier dysfunc-
Atopiclair (Galderma S.A., Lausanne, Switzerland) tion measured by TEWL has yet to be proved in dogs.40
contains a combination of plant extracts, including glyc- Thus, while it is reasonable to speculate that restoration
yrrhetinic acid and Vitis vinifera. Atopiclair is effective in of lipid deficiency should improve skin barrier function, it
the treatment of AD and has antipruritic properties in is still largely unknown whether skin barrier repair would
patients with mild-to-moderate AD.20 Glycyrrhetinic acid, directly translate into an improvement of clinical signs.
abundant in liquorice, can inhibit pruritus elicited by prote-
ase-activated receptor-2 agonists.21 Humans with AD Lipid ⁄ ceramide-rich products
have higher levels of protease-activated receptor-2,22 and Topical application of ceramides, free fatty acids and cho-
this leads to increased permeability, barrier dysfunction, lesterol (Allerderm spot-on; Virbac Animal Health, Fort
itching and inflammation.23 Besides being antipruritic, Worth, TX, USA) improves the ultrastructure of the stra-
glycyrrhetinic acid has antibacterial and antifungal proper- tum corneum and increases the number of lipid lamel-
ties that are beneficial in patients with AD.24 lae.41 Three weeks of topical application led to an
A recent study stirred debate because it showed a lack increase in ceramide content and decrease in glucosyl-
of significant difference in the clinical efficacy between a ceramides. Normalization of protein-bound lipid content
glycyrrhetinic acid-containing barrier repair cream (Atopi- was also observed.42 While these two studies showed a
clair), a ceramide-dominant barrier repair cream (EpiCe- positive effect on lipid composition, demonstration of clin-
ram) and an over-the-counter petroleum-based skin ical benefit is still limited. An open study in dogs with
protectant moisturizer (Aquaphor Healing Ointment) chronic AD showed clinical improvement with twice-
applied three times daily for 3 weeks in children with mild- weekly application for 12 weeks, with a significant
to-moderate AD.25 These results clearly demonstrated improvement of erythema noticeable after 6 weeks.43
that there are multiple valid approaches to skin repair. Although these results are promising, the impact of this
study is limited by the small number of patients and the
Topical glucocorticoids and calcineurin inhibitors lack of a control group. A yet unpublished double-blinded,
As inflammation worsens the skin barrier, it is reasonable placebo-controlled study, applying the same emulsion
to propose that control of inflammation improves skin three times weekly for 4 weeks, reported a significant
barrier function. Indeed, both topical calcineurin inhibitors decrease of clinical signs when compared with the con-
and topical glucocorticoids (e.g. betamethasone) improve trol group, although the results on TEWL were mixed.44
TEWL.26 While both treatments decreased TEWL, elec- The lack of significant improvement in TEWL may be an
tron microscopy of the skin after 3 weeks showed that indication of poor reliability of TEWL measurements
only pimecrolimus-treated patients had an ordered stra- rather than lack of skin barrier amelioration in light of the
tum corneum with regular lamellar body extrusion, while ultrastructural studies, although the ultrastructural studies
ª 2013 The Author. Veterinary Dermatology
74 ª 2013 ESVD and ACVD, Veterinary Dermatology, 24, 73–e18.
 Restoration of skin barrier

did not evaluate the correlation between ultrastructure Concluding remarks

and TEWL measurements.41
An open study using a spot-on (once weekly) and a spray Skin barrier repair is a promising yet still incompletely
(once daily) containing essential oils and unsaturated fatty explored approach to the management of canine AD. This
acids (Dermoscent Essential; Laboratoire de Dermo- approach could prove to be very beneficial when initiated
Cosmetique Animale, Castres, France) for 8 weeks45 early on in life and could possibly alter the course and
showed a significant decrease of clinical scores and minimize development of allergic sensitization. However,
pruritus in both groups, with no difference between this approach needs to be evaluated carefully, because
groups. No improvement on TEWL was found. Oral admi- the choice of the wrong ingredients could have negative
nistration of essential fatty acids [omega-6 (linoleic acid long-term effects and ultimately worsen an already
350 mg ⁄ mL and c-linolenic acid 45 mg ⁄ mL) and omega-3 impaired skin barrier. Thus, large controlled studies are
(eicosapentaenoic acid 25 mg ⁄ mL and docosahexaenoic still needed to identify the best treatment and the long-
acid 28 mg ⁄ mL), mixed 5:1 (v ⁄ v); Megaderm ⁄ EFA-Z term effects on skin barrier function.
(Virbac S.A., Carros, France)] for 2 months also improved
the ultrastructure and increased the lipid content in the References
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tion and enhanced metabolism of sphingosine-1-phosphate in

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 Restoration of skin barrier

Résumé
Des anomalies de barrière cutanée existent dans la dermatite atopique humaine et canine, menant à une
augmentation de la perte hydrique et facilitant potentiellement la pénétration des allergènes et la sensibili-
sation. A la fois, les anomalies des lipides (e.g. les céramides) et des protéines (e.g.la filaggrine) ont été
décrites. Certaines sont génétiques (e.g. les mutations de la filaggrine sont un des facteurs de risque prin-
cipaux chez l’homme) et certains sont secondaires et liés à l’inflammation.
Chez l’homme, de nombreuses études ont montré l’efficacité des émollients et hydratants dans la res-
tauration de barrière et cette approche a été pendant des années un pilier de la thérapie. Récemment,
cette stratégie s’est avérée prometteuse en prévention.
En médecine vétérinaire, les preuves concernant les défauts de barrière cutanée se développent rapi-
dement. Une diminution des céramides et de la filaggrine (chez certaines catégories de chiens) ont été
décrites. Un métabolisme modifié des céramides a également été proposé. Malgré ces données prélimi-
naires et la disponibilité des produits commercialisés afin d’améliorer la barrière cutanée, les preuves d’effi-
cacité clinique de réparation cutanée est encore limitée. Des études préliminaires ont démontré que
l’application topique d’acides gras et de céramides ainsi que l’administration systémique d’acides gras
améliorent les défauts de lipides dans la peau de chiens atteints de dermatite atopique mais peu de pre-
uves cliniques existent.
La rémission de la maladie chez l’homme est accompagnée par une amélioration de la barrière cutanée
à la fois par les inhibiteurs de la calcineurine et par les glucocorticoı̈des. En médecine vétérinaire, une étude
préliminaire sur la cyclosporine et la prednisone n’a pas permis de détecter une amélioration significative
de la perte hydrique alors qu’une immunothérapie efficace corrélait avec une amélioration de la barrière
cutanée. De larges études contrôlées sont nécessaires pour savoir quelle approche de réparation cutanée
serait la plus efficace et si cela peut être utilisé comme une stratégie préventive.

Resumen
Tanto en la dermatitis atópica humana como canina se observa una alteración de la función de barrera de la
piel, lo cual lleva a una perdida elevada de agua y potencialmente favorece la penetración y la sensibiliza-
ción a alergenos. Se han descrito tanto anormalidades en los lı́pidos (por ejemplo ceramidas) como en las
proteı́nas (por ejemplo filagrina). Algunos defectos son hereditarios (por ejemplo las mutaciones en la molé-
cula de filagrina son uno de los factores de riesgo principales en seres humanos) y algunas son secundarias
y ligadas a inflamación.
En seres humanos numerosos estudios han demostrado la eficacia de emolientes y de cremas hidra-
tantes en la restauración de la barrera, y este acercamiento ha sido durante años la base principal de la tera-
pia. Recientemente, esta estrategia terapéutica también ha demostrado ser prometedora como función
preventiva.
En veterinaria, existen cada vez mas evidencias respecto a la alteración de la función de barrera de la
piel. Se han descrito disminuciones en las ceramidas y la filagrina (en algunos grupos de perros). También
se ha propuesto un metabolismo alterado de las ceramidas. A pesar de estos datos preliminares y de la dis-
ponibilidad de productos para mejorar la función de barrera de la piel, las pruebas con respecto al beneficio
a nivel clı́nico de la mejora esa función de barrera son todavı́a limitadas. Estudios preliminares han demos-
trado que el uso tópico de ácidos grasos y de ceramidas y la administración sistémica de ácidos grasos
mejoran las deficiencias en los lı́pidos en la piel de perros con dermatitis atópica, pero existen mı́nimas evi-
dencias clı́nicas.
La remisión de la enfermedad en seres humanos es paralela a una mejora de la función de barrera de la
piel, en personas tratadas tanto con inhibidores de calcineurina como con glucocorticoides. En veterinaria,
un estudio preliminar utilizando ciclosporina y prednisona no pudo detectar una mejora significativa de la
pérdida de agua, mientras que la inmunoterapia se correlacionó con una función de barrera mejorada. Se
necesitan estudios controlados con mayor numero de animales para abordar la cuestión de cual es la mejor
estrategia para mejorar la alteración de la barrera de la piel y si esta estrategia podrı́a utilizarse como terapia
preventiva.

Zusammenfassung
Eine Dysfunktion der Hautbarriere besteht sowohl beim Menschen als auch bei Hunden mit atopischer
Dermatitis, was zu erhöhtem Wasserverlust führt und möglicherweise das Eindringen der Allergene und in
der Folge eine Sensibilisierung ermöglicht. Es wurden Abweichungen sowohl bei den Lipiden (z.B. bei den
Ceramiden) als auch bei Proteinen (z.B. bei Filaggrin) beschrieben. Einige sind genetisch bedingt (z.B. sind
Filaggrinmutationen unter den wichtigsten Risikofaktoren beim Menschen), einige treten sekundär auf und
stehen im Zusammenhang mit einer Entzündung.
Beim Menschen haben zahlreiche Studien die Wirksamkeit von Weichmachern und Feuchtigkeitsspen-
dern bei der Wiederherstellung der Barriere beschrieben und diese Ansicht spielte seit Jahren eine zentrale
Rolle bei der Therapie. Unlängst konnte auch gezeigt werden, dass diese Strategie auch eine präventative
Wirkung hat.

ª 2013 The Author. Veterinary Dermatology

ª 2013 ESVD and ACVD, Veterinary Dermatology, 24, 73–e18. e17
Marsella

In der Veterinärmedizin steigt die Evidenz im Bezug auf eine Beeinträchtigung der Hautbarriere dras-
tisch an. Verminderte Konzentrationen an Ceramiden und Filaggrin (in einigen Untergruppen von Hunden)
sind beschrieben. Die Hypothese eines veränderten Metabolismus der Ceramide wurde auch aufgestellt.
Trotz dieser vorläufigen Daten und der Verfügbarkeit von Produkten, die die Verbesserung der Hautbarriere
bewerben, ist die Evidenz, dass Interventionen im Bereich der Hautreparatur einen klinischen Nutzen
bringen, noch immer limitiert. Vorläuferstudien haben gezeigt, dass die topische Applikation von essentiel-
len Fettsäuren und Ceramiden, sowie die systemische Administration von essentiellen Fettsäuren die
Lipiddefizite in der Haut von Hunden mit atopischer Dermatitis, verbessern; klinische Evidenz liegt allerd-
ings nur begrenzt vor.
Die Remission der Erkrankung ist beim Menschen von einer verbesserten Hautbarriere begleitet, die
sowohl durch Calcineurin Inhibitoren wie auch durch Glukokortikoide erreicht wird. In der Veterinärmedizin
konnte eine Vorläuferstudie mit Ciclosporin und Prednisolon keine signifikanten Verbesserungen des Was-
serverlusts zeigen, während eine erfolgreiche Immuntherapie mit einer verbesserten Hautbarriere einher-
ging. Kontrollierte, große Studien sind notwendig, um abzuklären in welcher Form eine Reparatur der Haut
klinisch am effektivsten ist und ob dieses Vorgehen präventativ eingesetzt werden kann.

ª 2013 The Author. Veterinary Dermatology

e18 ª 2013 ESVD and ACVD, Veterinary Dermatology, 24, 73–e18.