Fragility of epidermis and its consequence in dermatology.

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DOI: 10.1111/jdv.12509

REVIEW ARTICLE

Fragility of epidermis and its consequence in dermatology J.F. Stalder,1 D. Tennstedt,2 M. Deleuran,3 G. Fabbrocini,4 R. de Lucas,5 M. Haftek,6 C. Taieb,7 D. Coustou,8 A. Mandeau,9 B. Fabre,9 H. Hernandez-Pigeon,10 M.F. Aries,10 M.F. Galliano,10 H. Duplan,10 N. Castex-Rizzi,10 S. Bessou-Touya,10 V. Mengeaud,11 C. Rouvrais,11 A.M. Schmitt,11 R. Bottino,12 K. Cottin,12 M. Saint Aroman12,a 1

Department of Dermatology, University Hospital of Nantes, Nantes, France Department of Dermatology, Saint-Luc University Clinics, Brussels, Belgium 3 Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark 4 Department of Dermatology, University Hospital of Naples, Naples, Italy 5 Department of Dermatology, University Hospital La Paz, Madrid, Spain 6 University Lyon 1, Lyon, France 7 Pierre Fabre SA, Paris, France 8 Private Dermatologist, Toulouse, France 9 Herbal Product Laboratory, Institut de Recherche Pierre Fabre, Toulouse, France 10 tique, Pharmacologie in vitro, Toulouse, France Pierre Fabre Dermo-Cosme 11 tique, European Center of Skin Research, Hôtel Dieu, Toulouse, France Pierre-Fabre Dermo-Cosme 12 tique, Lavaur, France Pierre Fabre Dermo-Cosme a Correspondence: M. Saint Aroman. E-mail: [email protected] 2

Abstract The skin is the largest organ of the body, providing a protective barrier against bacteria, chemicals and physical insults while maintaining homeostasis in the internal environment. Such a barrier function the skin ensures protection against excessive water loss. The skin’s immune defence consists of several facets, including immediate, non-specific mechanisms (innate immunity) and delayed, stimulus-specific responses (adaptive immunity), which contribute to fending off a wide range of potentially invasive microorganisms. This article is an overview of all known data about ‘fragile skin’. Fragile skin is defined as skin with lower resistance to aggressions. Fragile skin can be classified into four categories up to its origin: physiological fragile skin (age, location), pathological fragile skin (acute and chronic), circumstantial fragile skin (due to environmental extrinsic factors or intrinsic factors such as stress) and iatrogenic fragile skin. This article includes the epidemiologic data, pathologic description of fragile skin with pathophysiological bases (mechanical and immunological role of skin barrier) and clinical description of fragile skin in atopic dermatitis, in acne, in rosacea, in psoriasis, in contact dermatitis and other dermatologic pathologies. This article includes also clinical cases and differential diagnosis of fragile skin (reactive skin) in face in adult population. In conclusion, fragile skin is very frequent worldwide and its prevalence varies between 25% and 52% in Caucasian, African and Asian population. revised: 11 March 2014; Accepted: 11 March 2014

Conflicts of interests Jean-Franc ß ois Stalder gave a several lectures about atopic dermatitis/ EXOMEGA (A-DERMA, Pierre Fabre), but was not directly involved as investigator in clinical trials with this product. Mette Søndergaard Deleuran is the investigator and/or tique, Meda Pharma, Leo Pharma, and Regeneron. Preparation advisor for AbbVie A/S, MSD, Pierre Fabre Dermo-Cosme of the manuscript by Gabriella Fabbrocini has been financially supported by Pierre Fabre Dermo-Cosmétique. Preparation tique. Preparation of the l de Lucas has been financially supported by Pierre Fabre Dermo-Cosme of the manuscript by Rau tique. Charles Taieb works manuscript by Marek Haftek has been financially supported by Pierre Fabre Dermo-Cosme within the Pierre Fabre company as Director of Scientific Relations and Maintenance Market. Preparation of the manuscript tique. Anne Mandeau works in the Herbal by Didier Coustou has been financially supported by Pierre Fabre Dermo-Cosme Product Laboratory, Institut de Recherche Pierre Fabre, Toulouse, France. Bernard Fabre works in the Research Centre of le ne Hernandez-Pigeon works in the Research Centre of Pierre Fabre. Marie-Francß oise Aries works in the Pierre Fabre. He le ne Duplan Research Centre of Pierre Fabre. Marie-Florence Galliano works in the Research Centre of Pierre Fabre. He works in the Research Centre of Pierre Fabre. Nathalie Castex-Rizzi works in the Research Centre of Pierre Fabre. Sandrine rie Mengeaud is an employee of Pierre Fabre DermoBessou-Touya works in the Research Centre of Pierre Fabre. Vale tique Company. Ce line Rouvrais is an employee of Pierre Fabre Dermo-Cosme tique Company. Anne-Marie Schmitt Cosme

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© 2014 European Academy of Dermatology and Venereology

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tique Company. Roberto Bottino is a General Manager of A-DERMA, Pierre is an employee of Pierre Fabre Dermo-Cosme tique. Karine Cottin is a Marketing Manager of A-DERMA, Pierre Fabre Dermo-Cosme tique. Marke ta Fabre Dermo-Cosme Saint Aroman works within the Pierre Fabre company as Medical Director of A-DERMA.

Funding sources None declared.

Epidemiology of fragile skin A recent publication by Haftek describes the results of recent survey realized about ‘fragile skin’. Fragile skin was perceived to occur in a substantial proportion of individuals from any given country. The survey was done at 5500 people in a representative sample from the population of five countries: France, Sweden, Spain, Japan and the USA. One of the first results was that all of the respondents were able to answer the question. For them, fragile skin has a very specific meaning. The answers varied depending on the population and their phototypes. Between 25% and 30% of ‘Caucasian’ respondents (white Europeans), 42% of those with typically ‘African’ skin and 52% of those with Asian skin reported that their skin was fragile. These people are generally young (around 40% of the European sample were aged 15–34 years) and predominantly female. Fragile skin has an important link to skin pathology, as those who claim their skin is fragile are also more likely to have recently suffered a skin condition, to have acne or to have a history of atopic dermatitis (AD). Those at either end of the age spectrum (babies and elderly patients with dermatoporosis) have generally fragile skin. It can also affect people of all ages in certain areas of the body, such as the eyelids, neck, area around the mouth and areas that receive a lot of sun exposure, such as the decollete or forehead. Dermatologists know that some conditions are clearly triggered by emotional stress, such as psoriasis flare-ups, AD, recurring herpes and hair loss. Physiological studies have shown that stress, for example, during exam periods for students, reduces the skin’s barrier function, leaving it more fragile. Many treatments can also contribute to fragile skin, particularly topical or oral retinoid treatment and aesthetic dermatology procedures using lasers or chemical peels, intended to rejuvenate the skin or to treat scarring.

Pathology of ‘fragile’ skin Marek HAFTEK, MD, PhD, Research Director at CNRS, University Lyon 1 Charles TAIEB, MD, Director of Scientific Relations and Market Maintenance, Pierre Fabre SA, Paris, France Marketa SAINT AROMAN, MD, Medical Director A-DERMA, Pierre Fabre Dermo-Cosmetique, Lavaur France If one asked a dermatologist what is fragile skin, the most likely answer would be focused on skin pathology. Indeed, several inherited or acquired dermatoses manifest themselves

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through skin lesions appearing after minor traumas (Table 1). Skin proneness to physical disruption may concern every level of the skin layered structure: from the dermis to the stratum corneum (SC) and severity of the related skin lesions does logically increase with the depth at which pathology occurs. This is best illustrated by the inborn defects of expression of various constitutive skin elements (or, of the regulatory factors influencing their function). Skin fragility syndromes due to the absence of different desmosomal proteins, e.g. plakophilin 1 or desmoplakins 1/2, are characterized by superficial lesions, more or less accentuated on palms and soles, where the horny layer is thicker and repetitive mechanical insults are most frequent.1,2 In peeling skin disease, the nascent horny layer, fragilized by the absence of corneodesmosin, a protein contributing to the cohesive proprieties of SC corneodesmosomes,3,4 peels off as a whole sheet at body sites prone to rubbing.5 Epidermal exfoliation following minor trauma may also occur due to the absence of protease inhibitors, which normally protect desmosomes from premature digestion.6 The absence of key cytoskeleton proteins leads to mechanical disruption of keratinocyte cytoplasm in the upper epidermis, in case of epidermolytic hyperkeratosis (keratins 1, 2, 10)7 and in the basal layer in epidermolysis bullosa simplex (keratins 5 and 14).8 A similar phenotype may be expressed by young individuals showing mutations in transglutaminase 5, an enzyme involved in cross-linking of cytoskeletal proteins to the cornified envelopes of differentiated keratinocytes.9 A hereditary acantholytic disease, chronic benign pemphigus of Heiley-Heiley, is due to the imperfect desmosome adhesion between keratinocytes lacking important calcium pump, because calcium is essential for desmosome formation.10 The deeper is location of the structural defect involving epidermis or dermal–epidermal junction, the higher chances are for the clinical occurrence of bullae. The junctional and dystrophic types of epidermolysis bullosa, with mutations in genes encoding collagen XVII, laminin 332, or collagen VII, respectively, are severe hereditary bullous dermatoses.8 Dermal distensions and fragility are commonly present in six clinical types of Ehlers–Danlos Syndrome caused by mutations in various collagen and collagen-processing enzyme genes.11 Interestingly, wound-healing problems observed in the seventh, newly describe type, lacking dermatan 4-O-sulfotransferase 1. Miyake et al.,12 point to a potential role of dermal glycosaminoglycans in the regulation of fibroblast and keratinocyte functions.13


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Table 1 Fragile, permeable or destructured skin in human pathology. For details, see the text. Compartment Epidermis

DEJ

Dermis

INBORN causes (mutated genes)

ACQUIRED causes

● ● ● ● ●

Skin fragility syndromes (PKP1, DSP1. . .) EB simplex (KRT5/14) Epidermolytic hyperkeratosis (KRT1/2/10) Familial pemphigus Heiley-Heiley (ATP2C1) Peeling skin syndromes (CDSN, TGM5, CSTA. . .) ● Atopic dermatitis and ichthyosis vulgaris (FLG) ● Netherton syndrome (SPINK5) ● Junctional EB (LAMA5, COL17A1. . .) and dystrophic EB (COL7A1)

● Defective expression of collagens, elastic fibres, or their regulatory factors (e.g. Ehlers–Danlos syndromes)

In some dermatological disorders, the causative links to physical insults are not evident, because of the nature of molecular changes that underlie formation of skin lesions. Impairment of the epidermal barrier function in AD makes patients’ SC leaky and results in a greater reactivity to the environmental insults. One quite recently defined culprit occurs to be filaggrin and its breakdown products, or rather their lack in a significant fraction of AD patients.14 However, several other structural and regulatory elements composing epidermal barrier may be involved in the cases of AD not dependent on FLG gene mutations. In the Netherton’s syndrome, in which atopy is characteristic, it is the loss of intercorneocyte cohesion that underlies the advent of inflammatory and scaly skin lesions. Premature corneodesmosome breakdown observed in this disease is caused by the absence or down-regulation of serine protease inhibitor LEKTI1 encoded by SPINK5 gene, and this mechanism may be also present in some variants of AD.15 SC lipids are crucial elements of the water permeability barrier and, therefore, are also good candidates for AD-focused research.16,17 Because inflammation modifies barrier function, it is important to underline that the changes in protein and lipid expression are observed in clinically non-lesional AD skin. In a similar way, dietary deficiency in essential fatty acids results in SC barrier dysregulation, increased permeability of the SC and inflammatory reaction that further impairs barrier function in a vicious circle-like process.18 This latter example of skin fragility resulting from alimentary causes well introduces acquired dermatological conditions characterized by trauma-prone, destructured or permeable integument (Table 1). In the autoimmune bullous diseases of the epidermis or the dermal–epidermal junction, spontaneous or mechanically induced blistering occurs due to the targeting of the same structural proteins that we have seen involved in the inherited forms of bullous dermatoses. In addition, skin fragility with apparition of UV-induced bullae may have metabolic background, like it is the case in porphyria cutanea tarda.19 In staphylococcal scalded

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● Autoimmune acantholysis (pemphigus: Dsg1, Dsg3, Dsc1. . .)

● Infectious: staphylococcal scalded skin syndrome (epidermolytic exotoxins A and B)

● Iatrogenic: toxic epidermal necrolysis; oral retinoids, glucocorticosteroids. . .

● Disrupture of the barrier function in alimentary deficiencies (EFA, vitamins, oligoelements. . .)

● Autoimmune bullous diseases, e.g. BP (dystonin; collagen XVII), acquired EB (collagen VII), or metabolic (PCT). . . ● Senile atrophy > skin tears ● Hormonal change-related stretch marks

skin syndrome, widespread epidermal acantholysis is provoked by bacterial exotoxins that exert proteolytic activity towards desmoglein 1,20 whereas pathogenic mechanism of drug-induced toxic epidermal necrolysis involves chemical molecule-induced T-cell activation, leading to keratinocyte apoptosis through soluble Fas ligand, perforin/granzyme B, granulysin, tumour necrosis factor-alfa, or nitric oxide.21 Skin tenderness observed during systemic treatment with retinoids is another well-known side reaction. Hormonal makeover has its say as well, since stretch marks or corticosteroid-induced dermal atrophy are frequently encountered during prolonged therapy with glucocorticoids.22 These clinical changes may be traced down to the reduction of collagen and glycosaminoglycan synthesis associated with fragmentation of elastic fibres. Indeed, experiments with transgenic animals indicate that not only fibrous components of the extracellular matrix but also, so far less studied, proteoglycans contribute significantly to the skin mechanical resistance.23 Last but not least, some forms of skin fragility may also be age related. Intrinsic ageing is often accompanied by metabolic slowdown that results in down-regulation of structural protein production and recycling, thinning of the viable skin layers and imperfect desquamation of the SC. This makes skin of the elderly prone to tears provoked by traumatisms that younger individuals would tolerate without such sequels.24 All these objective causes of skin ‘fragility’ should be confronted with the highly subjective perception of ‘fragile’ skin.25 Skin is our interface with the environment and the most visible and expended part of our body, through which we communicate. Functional modifications of its aspect are clearly visible and readily deciphered, e.g.: sweating, blushing. Occurrence of these symptoms is often linked to environmental aggression: rapid changes of temperature, ambient humidity, sun exposure, to mention just the most common ones. The influence of psychological stress must not be overlooked neither, whether associated with the presence of a visible skin dysfunction, e.g. acne, psoria-


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sis, or just related to mishaps of the everyday life, e.g. adolescence, unemployment, family problems. All these factors may overlap with the objective signs of skin ‘fragility’. They impact our perception of ourselves and most probably make us think whether our skin is ‘fragile’ or not. Alterations to the epidermal barrier caused by inflammatory dermatitis

Most types of inflammatory dermatitis involve a complex interaction between the two tissues that make up the skin – the epidermis and the dermis. For a long time, the epidermis was thought to be a passive victim of the effects of inflammation that occur in the dermis and neurovascular regions of the skin. However, in recent years this idea has been turned on its head, and the epidermis is now at the forefront of research into inflammatory dermatitis conditions.

The epidermal barrier, fragile skin and atopic dermatitis Atopic dermatitis in children Pr Mette DELEURAN, MD, DMSc, Department of Dermatology, Aarhus University Hospital, Denmark Atopic dermatitis is a chronic or chronically relapsing eczematous disease that affects between 15% and 20% of all children in affluent countries. Studies from Africa, Asia and parts of Europe have indicated that the prevalence of AD was increasing from 1990 to 2010.26 In 60% of the paediatric cases the onset of the disease is before the age of 1 year and in 85% of the cases before the age of 5. Apart from the impact on the patient, the disease also affects the patient’s family’s quality of life more than having a child with diabetes or epilepsy.27 Gil et al. found a close relation to stress in the family and severity of AD in the child,28 and recent studies indicate a higher proportion of children with AD have symptoms similar to attention-deficit/hyperactivity disorder, probably due to itch and sleep deprivation.29 This is supported by clinical experience where a child with untreated disease is often irritable, very physically active and with concentration problems. When the AD is treated and the skin is calm the child’s mental state and behaviour often changes significantly for the better. One of the major challenges in chronic diseases is adherence to treatment. Many parents are afraid of adverse effects of the treatment options, especially topical corticosteroids (TCS),30 and this may lead to poor treatment outcomes. Therefore, there is a big need for educational programmes, and a study from Germany have shown that age-related educational programmes for the control of AD in children and adolescents are effective in the long-term management of the disease.31

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There is a great clinical variation in the objective findings of the disease, but the most constant and important symptom for the patients is the atopic itch. AD is a clinical diagnosis based on visible eczema with a characteristic history. Classically the diagnosis of AD is made on the basis of the Hanifin and Rajka criterions from 1980. There are no diagnostic tests that can confirm the diagnosis. In infants suffering from AD the scalp, cheeks and extensor side of the extremities are the most commonly affected areas. Flexural areas may also be involved, especially the neck fold. At the age between 1 and 4 the most common sites for the eczema are the flexural areas of the skin, especially the cubital and knee folds, the wrists and ankles and the face and hands. The skin is dry and fissuring behind the ears or at the earlobe are characteristic signs of the disease. In older children, the flexural areas are still affected, and eczema is often present at the hands and feet. Head and neck dermatitis is part of the disease spectrum in teenagers. The eczematous lesions may be complicated by bacterial infection with Staph. Aureus, resulting in impetigo and flare-up of eczema. Severe viral infections like eczema herpeticum, and widespread molluscum contagiosum or verrucae vulgaris are also seen more often in these patients. There is a long-standing scientific discussion whether IgE-mediated allergies are part of the pathogenesis of AD, but a substantial part of patients with AD have normal serum levels of IgE. A pivotal sign of AD is dry skin, xerosis. The importance of this symptom has been underlined by the finding that approximately one third of all patients with AD carry a mutation in the gene coding for the important skin barrier protein called filaggrin.32 Lack of filaggrin results in a skin barrier defect with dry and crackled skin. The mutation in filaggrin does, however, not explain why almost all patients with AD have a skin barrier defect. In this context it is interesting that inflammatory cytokines of the TH2 subtype can down-regulate the expression of filaggrin in keratinocytes.33 The severity of AD dictates the level of treatment. In all cases, the basic therapy is moisturizers to alleviate the dry skin and the impaired skin barrier function. The use of moisturizers has also been shown to reduce the need for potent TCS.34 In mild to moderate cases topical calcineurin inhibitors or corticosteroids may be used both in a proactive manner to prevent flare-ups, and as treatment of acute eczema.35–37 In severe, treatment refractory cases systemic anti-inflammatory treatment has to be considered. In this respect, some dermatologists have a tendency to tolerate more severe disease in children than in adults before turning to systemic immunosuppressive therapy. This may be due to lack of evidence in children and fear of severe short- and long-term side-effects. A combination of topical and systemic therapy is, however, often necessary to control severe disease and to improve the quality of life for both the patients and their families. To summarize, AD is a chronic or chronically relapsing skin disease, with major challenges for the patients and their families as well as the dermatologist.



Effects of Rhealbaâ Oat (Exomega DEFI by A-DERMA) on corticosteroid use and numbers of flare in children with atopic dermatitis open labelled international multicentre study Pr Jean-Francßois STALDER, MD, Department of Dermatology, University Hospital of Nantes, France Introduction

Besides inflammatory process, dryness is a constant symptom responsible for discomfort and pruritus in AD patients. According to the recent position papers the use of emollient is highly recommended in the management of AD patients. To evaluate the effect of emollient cream EXOMEGA DEFI on TCS consumption in children with stabilized AD, we performed an international open study. Pharmacology

Rhealbaâ Oats have been selected from hundreds of different varieties, and are grown in strictly controlled, quasi-pharmaceutical conditions following the principles of biological agriculture in the A-DERMA Laboratories (Pierre-Fabre Dermo-Cosmetique, Les Cauquillous, 81100 Lavaur, France). The extract is obtained using an original process and is then tested for its levels of the active principles, flavonoids and saponins, and then divested of its proteins to pose no risk of allergic reaction. In vitro, the Rhealbaâ oat plantlets extract has been shown to inhibit the production of cytokines TH2 (IL-13) and TH-1 (IL-2) by human lymphocytes, and also to inhibit the maturation and differentiation of dendritic cells. Rhealbaâ Oat plantlet extract (Pierre Fabre Medicament, Gaillac, France) also acts on Staphylococcus aureus, pathogenic bacteria that colonize the skin of most atopy patients. Exomega DEFI cream contains Rhealbaâ Oat plantlet extract and omega-6 fatty acids. To ensure complete tolerance, it exists a specific packaging system called DEFI (Device for Exclusive Formula Integrity), which means that is has been manufactured according to Pierre Fabre Laboratories’ principles for Sterile Cosmetics. Exomega DEFI is as sterile as an injectable drug, and maintains its purity throughout use, thanks to the antireflux DEFI sealing system. Thanks to progress in galenics and packaging, Exomega DEFI contains no preservatives. Clinical study

Exomega DEFI cream was tested on 108 children with AD as part of an international multicentre study. Population: Infants and children between 6 months and 6 years were included. Subjects with moderate AD were selected according to the UK Working Party criteria, whose SCORAD (Scoring System in Atopic Dermatitis) index is the following: In Acute phase: 20 < SCORAD < 40 at selection (D-14 3). In Maintenance phase: SCORAD ≤ 20 at inclusion (D1).

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Study design: 1-Stabilization phase: application of a single daily application of an appropriate TCS from 4 to 8 days until disappearance of the lesions. 2-Maintenance phase of AD: 1 application twice daily on the whole body and the face during the maintenance phase for 12 weeks. In case of flare-ups, one application on non-inflammatory skin of the face and the body was made once daily on AD management until remission. Standardized body hygiene product (soap-free emollient foaming gel face and body Exomega A-Derma [Pierre Fabre Dermo-Cosmetique, Soual, France]) was used during the maintenance phase. The analysis of the primary criterion of efficacy (represented by the total amount of TCS between D1 and the end of the maintenance phase) was made on D84. Among the secondary efficacy criteria during the maintenance phase: ● Amount of TCS consumption used by visit. ● Number of days of application of TCS by visit. ● Compliance of TCS. ● Number of flare-ups by visit. ● Time to first flare-up. ● Time between flare-ups. ● Duration of flare-ups. ● Number of relapse days at the end of the maintenance phase. ● SCORAD index and each of its components by visit. ● PO-SCORAD index by visit. Results: During this 3-month clinical study using Exomega DEFI cream twice a day, the use of dermo-corticosteroids was reduced by around half: on average 6.2 g/month in the first month, 3 g in the second month and 3.3 g in the third month. Moreover, the eczema continued to improve with Exomega DEFI treatment, and flare-ups were both fewer and shorter. Tolerance of Exomega DEFI cream was excellent. Discussion: Many health care professionals and patients overlook the importance of moisturizers and consider them not to be ‘active’ treatments. Patient adherence is a great challenge faced in the management of chronic skin diseases when the moisturizers are used in too small quantities. To obtain a good patient adherence and to avoid treatment failure, tolerance and acceptance of the product are essential. Despite the absence of a control group, this study indicates that Exomega DEFI cream as well as Exomega foaming gel A-Derma are well tolerated and provide improvement of the eczema inducing longer and stronger remission periods.

The epidermal barrier, fragile skin and psoriasis According to communication of Morad LAHFA, MD, Dermatologist, Toulouse


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Although AD is the primary form of inflammatory dermatitis in which the epidermis has a key role, it is not the only one. In psoriasis, the epidermis is abnormal, the skin appears thickened, scalloped (hyperacanthosis), the stratum granulosum is absent and the SC is much thicker. Patients are well aware that a minor mechanical trauma to the skin, such as light rubbing, can cause psoriasis lesions. This is known as the Koebner phenomenon, named after the Viennese dermatologist who described it around the end of the 19th century. Patients also know that ultraviolet rays acting on the skin’s surface are an excellent treatment for psoriasis. In reality, there is a constant exchange between keratinocytes, lymphocytes and Langerhans cells and the three essential cells in the skin’s immune system. Molecules that play an important role in psoriatic inflammation such as IL-23 and IL-17 are the target of treatments known as ‘biological therapy’ (monoclonal antibodies). These molecules act on the epidermis and its ceramide content, and reduce its ability to produce antimicrobial peptides, important elements in epidermal antiinfectious defences, and other functions. The use of emollient treatments, as this ensures optimum hydration in the epidermis, and may play a role in preventing flare-ups.

Epidermal barrier, fragile skin and contact dermatitis According to communication of Jean-Francßois NICOLAS, MD, Dermatologist, Lyon It is clear that the epidermal barrier has the most important role in all kinds of contact dermatitis. There are several different types of contact dermatitis: allergic contact eczema, caused by haptens (most commonly nickel), and orthoergic contact dermatitis caused by irritants, to which we can add AD, in which contact with proteic allergens from the environment plays an important role. Among the factors aggravating the skin, there are strong and weak aggressions, and that depending on the molecules and the dose, we may either be tolerant or sensitive to these aggressions. This is an important element in the concept of fragile skin – it can also be described as ‘dose-dependent’ or ‘aggression dependent’, independently of other individual genetic or pathological factors.

Cutaneous fragility in acne, compensation of irritating effect of retinoids Pr Gabriella Fabbrocini, MD, Department of Dermatology, University Hospital of Naples, Italy 1. Acne and the inflammatory role of P. acnes

Acne is a common inflammatory skin disease, characterized by comedones, papules, pustules and nodules, distributed on face, chest and back. It affects 88–95% of adolescents38 and 64% of adults in their twenties.38 Propionibacterium acnes (P. acnes) has been identified in acne lesions and plays, together with the sebaceous gland, an

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important role in the pathogenesis of the condition: P. acnes, in fact, secretes lipases, chemotactic factors, metalloproteases and porphyrins, inducing an inflammatory response, with production of free radicals, and causing keratinocyte damage.39 2. The ‘epidermal barrier’

Keratinocyte damage lead to an alteration of the ‘epidermal barrier’: the ‘epidermal barrier’ refers to the collective result contributed to by multiple physiologic responsibilities of the epidermis, many of which occur within the SC. These responsibilities include homeostatic control of water content and flux (permeability barrier), recognition and neutralization of microbial organisms (antimicrobial barrier), countering of reactive oxygen species (antioxidant barrier), protection from effects of ultraviolet light exposure (photoprotection barrier) and response to exogenous allergens and haptens (immunologic barrier).40 The alteration of epidermal barrier lead to a ‘fragile skin’: this is a subjective (experienced) and objective (clinically evaluated) perception of the skin’s condition that is based on constitutional factors relating to the structure and function of the epidermal barrier.25 When epidermal permeability barrier (SC) impairment persists without correction, signal amplification produces cascades that lead to clinically evident cutaneous abnormalities (i.e. xerosis, fissuring, desquamative changes, eczematous dermatitis, hyperkeratosis).25 2.1 The ‘epidermal barrier’ in acne: surface epidermis

The facial skin of acne patients differs from normal skin of people without acne for the higher sebum production and the size of sebaceous glands; for the higher TEWL (transepidermal water loss) and lower SC hydration (decreased conductance), supporting the SC permeability barrier impairment associated with acne.41 In addition, significantly reduced free sphingosine and total ceramides in their SC are reported, indicating a deficient intercellular lipid membrane correlated with impairment of the SC permeability barrier. The increase in TEWL and decrease in SC hydration (conductance) were greater in patients with acne of moderate severity as compared to those with mild acne severity.42 2.2 The ‘epidermal barrier’ in acne: follicular epidermis (epithelium)

In acne, the proliferation of P. acnes within the follicle induces several inflammatory cascades related to innate, acquired and humoral immunological responses.42 When intrafollicular and perifollicular inflammatory processes markedly intensify, attenuation of the follicular wall can lead to various degrees of rupture with subsequent leakage of sebum, keratin, bacteria into the dermis. These foreign substances to the dermis increase inflammation, inducing the emergence of a nodular or nodulocystic acne lesion.42,43



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3. Filaggrin and acne

tance, from daily hygiene to isotretinoin, to ensure complete and individualized management.52 Strategies to mitigate the altered effects of epidermal barrier functions include the importance of topical barrier repair therapy.

Filaggrin is a key protein in epidermal differentiation and contributes to the structural and functional integrity of the SC. Alteration of filaggrin expression is associated with modification in skin barrier, and lead to some skin diseases, such as AD.44 Within acne lesions, there is an increase in filaggrin expression in keratinocytes lining the follicle wall. In addition, P. acnes has been shown to increase filaggrin expression in cultured keratinocytes and also in explants of human skin. Importantly, it is not known if the changes in filaggrin expression noted in acne are primary or secondary events.45 4. Acne treatments and skin barrier

Some topical medications, systemic medications and physical procedures used to treat acne and/or acne scarring can lead to alterations in SC permeability barrier function based on documentation of increased TEWL and in some cases visible signs of xerosis. Increases in TEWL have been reported with benzoyl peroxide, tretinoin, tazarotene and isotretinoin.41,45–49 4.1 Retinoids and skin barrier

Topical retinoids induce acanthosis, hypergranulosis, a relative decrease in SC thickness and desquamation: all these conditions are associated with an alteration in permeability barrier function. Topical retinoid application also induces desmosomal shedding within the stratum spinosum, a decrease in tonofilaments and some deposition of non-mucin glycoconjugates, leading to SC loosening and upper epidermal dyscohesion.50 Changes in the SC permeability barrier associated with both topical and oral retinoid therapy are not associated to any reduction in SC lipids, comprising the intercellular lipid membrane of the SC.50 Concurrent moisturizer use to reduce the SC permeability barrier impairment induced by topical retinoid application has been evaluated with a reduction in signs and symptoms associated with retinoid dermatitis without an apparent loss of efficacy.51

5.1 Oat plantlets extract

Oat plantlets extract contain two flavonoids, isoorientin-2″-Oarabinoside and isovitexin-2″-O-arabinoside, and two saponins, avenacosides A and B, with anti-inflammatory and immunoregulatory properties: they reduce the prostaglandin F1 a production (PGF1-a), interleukin-2 (IL-2) production in activated T lymphocytes, the MHC-II expression.53 Oat plantlets extract also reduce the production of cytokines TH2 (IL-13) and TH1 (IL-2), COX 2 expression and production of inflammatory prostaglandin derivates.53 These anti-inflammatory and antiirritant properties can reduce TEWL, typically associated with acne and acne treatments, and increase stability of skin barrier; therefore, in clinical practice, these properties can be utilized to reduce irritating effects caused by retinoids in acne patients.

Redness-prone skin and its fragility Ra ul de Lucas, MD, Department of Dermatology, University Hospital La Paz, Madrid, Spain The dermatologists start to be aware about the fragile skin. Fragile skin is a term which is easily used by patients. Is it the same for the doctors? I would like to prove that the fragile skin exists, and our patients with this clinical finding need us to help them. I think that fragile skin is a clinical feature, with certain clinical manifestations and concrete pathophysiological mechanisms. The main clinical manifestation is the redness-prone skin. However, our patients need treatment and first of all we must know what the fragile skin is.

4.2 Isotretinoin and skin barrier

Oral isotretinoin can alter the structure, function, immunology and bacteriology of the skin: it causes increased epidermal turnover and skin fragility, with propensity for intraepidermal separation; loss of desmosomes and decrease in tonofilaments occurs. Oral isotretinoin causes easier separation of corneocytes of the outermost SC, accounting for the superficial desquamative changes that are frequently observed in treated patients.40 5 Dermo-cosmetic approach to acne

Cosmetics contribute to the success of antiacne treatments, by providing optimal hygiene, and compensating the irritation and dryness induced by medications. Overall, cosmetology is considered by the dermatologist as part of the management of acne devoid of notable side-effects. This mode of operation is part of a true health care protocol in which each part has its impor-

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Concept

Within the concept of fragile skin there is a reactive skin entity which is a condition of subjective cutaneous hyperreactivity to environmental and others factors like cosmetics or emotional triggers. The patients complain of severe skin irritation with burning, stinging, etc. without cutaneous disease. Classical patient’s symptoms are light erythema, mild scaling or the appearance of almost imperceptible papules. It is clear that a patient with acne, rosacea, AD, seborrhoeic dermatitis may have fragile skin, but many patients do not report the symptoms and they suffer these dermatoses. It’s possible that fragile skin might get worse by a simultaneous dermatosis. The problem is that fragile skin has usually been considered as a ‘mother symptom’ of these diseases. Reactive skin (sometimes called also sensitive skin) is a state of hyperreactivity to many triggers presenting with a clinical


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picture, and usually represents a combination of conditions with redness-prone skin.

receptor potential V1 is involved in hyperalgesia and neurogenic inflammation is stimulated in patients with reactive skin (sensitive skin).59

Epidemiological data

It is clear that the prevalence of reactive skin (sensitive skin) is very high in our society and it is a frequent reason for collateral consultation in dermatology. Recent studies56 show that a total of 4506 people, 37.6% had reactive skin (sensitive skin). In Spain, 11 million people had reactive skin (sensitive skin), more that 30% of the total of population.56 Regarding gender, the differences are not clear in the incidence of disease among men and women, although women’s self-perception is considerably higher compared to that of males.54 On the other hand, investigators have not found ethnic differences significant enough in the statistics data.55 Cultural and psychological factors are more likely55 responsible in the development of the disease such as the type of food, cosmetic use, hygienic habits, etc. Regarding the age, reactive skin (sensitive skin) is more common in young people, but surprisingly has not been considered yet in the differential diagnosis of childhood dermatoses. In my experience, reactive skin (sensitive skin) can explain many of the consultations in paediatric dermatology. Future studies are necessary to determine the real incidence of reactive skin (sensitive skin) in children. My patient had reactive skin (sensitive skin). How do I suspect the diagnosis?

‘You should ask him/her what the symptoms are, physical examination is required and ask him/her about triggers’. Reactive skin (sensitive skin) may represent the tip of the iceberg, other dermatoses might be hidden, such as rosacea, AD, seborrhoeic dermatitis, allergic or irritant contact dermatitis56 or pathology of mental sphere, for example, body dysmorphic disorder.57 It is important to have a detailed medical history, a thorough physical examination and sometimes look beyond the skin to reach the mind of our patients so we can help them. Why some patients, do they have redness-prone skin?

The pathophysiology to explain the mechanism is complex. There are several factors involved: Immunological and oral allergic mechanisms, impaired barrier function (TEWL increase) and neurosensory impairment. Abnormal penetration of irritants due to a disruption in skin barrier and abnormal nervous response can explain the physiopathology of reactive skin (sensitive skin). It has been proved an increase of permeability of the SC, because it is thinner in these patients. Besides, intercellular lipids, especially ceramides, are altered, as in AD and seborrhoeic dermatitis. The nerve endings are less protected by the intercellular lipids. So, it is possible that the patient feel discomfort with most of the tactile sensations.58 Recent studies proven that the transient

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What are the clinical manifestations of reactive skin and sensitive skin syndrome (SSS)60?

The complaints of most patients are: ● Subjective discomfort, with few visible symptoms like lack of flexibility, tightness, warmth, stinging, itching and pain. ● Association with others dermatosis is very common, especially rosacea, acne, AD and cosmetic procedures. ● Erythema, telangiectasia and scaling are the most frequent signs. ● Main areas affected are nasolabial folds, malar eminence, chin, front and upper lip. It is important to explore other body locations, since not only the facial region may be affected. Studies show that the scalp, hands and feet are frequently involved areas.61 Is there any objective diagnostic test?

It is necessary to think first about this clinical condition to make a diagnosis of reactive skin (=SSS). Generally, we used only clinical criteria. We suspect this disease when a patient has a weak, easily irritable and redness-prone skin. It is necessary to rule out other dermatoses, in spite of the reactive skin could mean a state of predisposition to inflammatory dermatoses such rosacea. Classically it is used the ‘stinging test’62 that consists of application of lactic acid solution in nasolabial fold and its comparison with saline solution in the contralateral fold to demonstrate the existence of reactive skin (sensitive skin). How the patient with reactive (sensitive) and rednessprone skin should be treated?

The patient should identify a list of triggers. The dermatologist must choose products that contain pure ingredients and are fragrance free. We must have one safe cosmetic line. It’s necessary to protect skin from temperature changes, wind, heat and sunlight and avoid soap. Avoid excessive alcohol, coffee and spices consumption. If the patient does not feel improvement or if symptoms are weird: remember body dysmorphic disorder.

Fragile facial skin in adults: clinical symptoms, diagnosis and complications Pr Dominique Tennstedt, MD, Department of Dermatology, SaintLuc University Clinics, Brussels, Belgium Introduction

Fragile facial skin in adults, also referred to as reactive skin, sensitive skin, irritable skin and even intolerant skin, was first described by Frosch and Thiers approximately 35 years ago.62,63



There would appear to be an alteration of the skin barrier causing minimal cases of irritant dermatitis, essentially revealed by subjective symptoms. This is without question a relatively complex and multifactorial syndrome, for which no universal consensus has been reached. Commonly employed term for this syndrome should be ‘reactive skin’. The term ‘sensitive skin’, however, should be abandoned since it causes confusion among many patients (and even dermatologists) finding it difficult to distinguish it from sensitized skin in the context of allergology and immunology. The term ‘sensitive skin’ is therefore often confused with the term ‘sensitized skin’ (sensitized by an allergen). Clinical symptoms:

The clinical symptoms of reactive skin are extremely numerous and diverse. Primarily, there are very specific subjective symptoms that can alert clinicians to this diagnosis. These subjective sensations are generally perceived on the face, and more rarely the neck or scalp. They include sensations of tingling and tightness, ‘pins and needles’ and sometimes burning, always in varying degrees of intensity, both in terms of chronological occurrence during the day and severity. In principle, few patients experience pruritus as such.64 These subjective symptoms are usually triggered by several ‘stimuli’ which, depending on the situation, can range from the application of a cosmetic product and from heat and cold exposure, to exposure to particular climatic conditions or UV rays. The influence of stress or the hormone cycle is a classic cause. In terms of objective signs, there is often a mild case of erythema, mostly accompanied by skin dryness and some couperose lesions but also sometimes a flare-up of seborrhoeic dermatitis or even other more irritant lesions. In some cases, there are no visible lesions. The syndrome of reactive (sensitive) skin is, in our society, essentially feminine, but can occasionally occur in men as well. The onset of this syndrome varies where age is concerned, but in most cases occurs between 25 and 45 years old. Seasonal variations are the norm.65–68 Most patients who claim to have reactive (sensitive) skin indicate numerous exogenous factors that can help trigger or exacerbate their subjective symptoms69–71: ● application of cosmetics, sunscreens, various unsuitable cleansing products (soaps in particular), ● method of shaving and application of aftershave, ● use of dermatological products containing primary irritants (benzoyl peroxide, salicylic acid, propylene glycol, etc.), ● ingestion of hot drinks, alcohol, products containing caffeine and other stimulants, ● irradiation by UV rays (natural or artificial), ● change in atmospheric temperature (going from a warm room to a colder one or vice versa),

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● working in an air conditioned environment ● working outdoors, ● previous ‘cosmetic’ surgical procedure: chemical peel, dermabrasion, etc.

● previous application of topical products containing corticosteroids. This last point requires particular investigation into patient history, since ceasing the application of this type of preparation frequently causes an aggravation of the subjective sensations experienced by the patient! Rebound effects are very common and difficult to avoid or eliminate. Numerous endogenous factors can also aggravate the syndrome of reactive (sensitive) skin: ● all pre-existing skin conditions must be taken into consideration: history of, or current AD, seborrhoeic dermatitis, couperose-prone skin, rosacea, etc. ● stress and various other psychological factors can certainly play a role in the aggravation of subjective symptoms in fragile skin. In the same way, these subjective sensations can become so intolerable that, in some extreme cases, they can trigger or worsen a state of anxiety or even depression, making it difficult to determine whether it is a cause or a consequence. It is a certainty that all these trigger factors, whether endogenous or exogenous, can combine or merge themselves in a very subtle manner. This is another instance where the line between cause and consequence becomes blurred. Clinical forms:

When simplified, the various types of reactive (sensitive) facial skin in adults can be summarized in table form (Table I). Type 1 reactive skin (general)

Type 2 reactive skin (environmental)

Type 3 reactive skin (cosmetic)

-Skin extremely reactive (sensitive) to: ● topical treatments, ● environmental factors, ● stress -Dry skin – combination or oily -Extreme intolerance

-Skin highly ‘environmentally’ reactive (sensitive) to: ● heat, ● cold, ● changes in temperature, ● cigarette smoke, ● alcohol, etc. -Dry skin -Frequent flushes -Minimal couperose with exacerbated subjective sensations

-Moderately reactive (sensitive) skin: ● reacting to unsuitable topical treatments, ● reacting to irritant ingredients -An overview of allergies is essential to detect minimal sensitization (or transferred by hand)


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Another classification concerning reactive skin can be suggested and is essentially useful regarding the trigger factor(s). Of course this classification is probably ‘simplistic’, and several subtypes could be defined according to external trigger elements that are often involved (Table II). Other classification for reactive skin Type 1: role of food substances (alcohol in particular), stress, emotions, variations in temperature Type 2: role of cold, wind, air conditioning Type 3: role of cosmetics, water, soap Type 4: role of the menstrual cycle

In total, it is evident that the diagnosis to be announced must never be a diagnosis of probability and must be put forward only after extensive questioning to evaluate trigger factors or factors related to caring for reactive (sensitive) skin. Furthermore, a meticulous examination of teguments remains essential when in search of any underlying dermatitis (most often minimally present): AD, seborrhoeic dermatitis, contact dermatitis, etc. Any possibilities of pure irritant dermatitis or real cases of primary or additional allergic contact dermatitis must always be identified. In the last two cases, pruritus is most often dominant, and clinical analysis, in principle, helps shine a light on one or more of these conditions. In daily practice, making the distinction between these various conditions in adults is often difficult and clinical diagnosis can vary based on consultations. We must of course remember that reactive facial skin in adults could certainly encourage appearances of additional cases of irritant dermatitis, or even a real case of allergic contact dermatitis. This is a very common occurrence and can also be the consequence of several applications of various topical products that patients (most often female patients) apply to the face. It is therefore not uncommon to observe a cumulative effect of several skin disorders. If ever there is any doubt, extensive patch testing must be proposed as a method of finding any potential contact sensitization. These tests must include not only an extended series of standard tests, of cosmetics and/or preservatives but in addition, patch tests must also be systematically proposed, including all personal products used by the patient, to have as thorough an approach as possible. Recommendations and therapy72

It should be recommended that only a small number of cosmetic products be applied, selected based on their hypoallergenicity profile, while carefully avoiding any products causing contact allergies that might have been detected. Perfumes and cosmetic products containing fragrance must be avoided as a rule.

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Another recommendation to be made is that no detergent products be used to wash the face. In principle, no-rinse cleansing lotions or even water sprays are recommended. The application of a so-called light moisturizing cream, or a more emollient cream depending on the case, must be recommended on a case-by-case basis, in accordance with skin tolerance and the skin type in question. All ‘aggressive’ treatments including exfoliants, and all masks for unblocking pores or products made from fruit acid or vitamin A derivatives must be prohibited. Other recommendations against excessively hot or cold atmospheres and the ingestion of spicy foods or alcohol must of course be promulgated based on the case and on patient history. Conclusions

Fragile facial skin (reactive skin, sensitive skin) in adults can also be multifaceted! The various clinical appearances of these skin types, and also the different trigger causes, are to be carefully sought out, without neglecting the variable environmental context, individual patient psyche, and also the potential existence of underlying dermatosis (particularly allergic dermatosis). Nevertheless, it is difficult to ‘classify’ these types of reactive (sensitive) facial skin, especially since this classification does not necessarily provide a solution for the individual patient. Treatment of these reactive (sensitive) skin types is always completed on a ‘case-by-case’ basis, listening attentively to the patient and combining their experience with that of the practitioner. Moreover, changes in the condition of these reactive (sensitive) skin types are not predictable. They can become severely irritant or allergic or prove to be couperose or eczematous, etc., and may conceal minimal cases of dermatosis. It is therefore necessary to follow the history of these patients and to carry out useful experiments to guarantee the type of skin fragility or reactiveness.

Fragile skin in dermatological clinical practice Didier Coustou, MD, Dermatologist, Toulouse, France Situations which lead patients to come see a dermatologist are various. Whatever they suffer from progressive dermatosis, whatever they come for screening for skin cancer, whatever they come for monitoring of nevi or whatever they come for an aesthetic procedure, all patients coming to dermatologic consultation have one thing in common: they all have fragile skin. They all have a skin that has a lower resistance to aggressions. Depending on the cause or causes of this fragility, we can distinguish four types of fragile skin. Constitutional fragile skin

Fragile skin may be related to age: in fact, the two extremes of life are characterized by the fragility of their skin. The



skin of the newborn or infant does not have any maturity and toddlers are frequently brought into consultation for neonatal acne, cutis marmorata, a toxic erythema. . . The same, seniors come very often to see the dermatologist. They come for ‘senile’ skin which represents the entire chapter in textbooks of dermatology. Keratoses, skin carcinomas and pruritus are probably three reasons for consulting the most frequent in this age group and reflect a weakness acquired for many years. Fragile skin may be related to localization: the face and eyelids especially constitute an area of fragile skin: how many allergens are, for example, in contact with the entire integument but that will really trigger the eczema of eyelids? Circumstantial fragile skin

Circumstantial fragile skin is normal skins which, under the effect of different factors, will become fragile. These extrinsic factors are as follows: climate, pollution. The intrinsic factors are stress, hormones. . . The reactive skin, irritant dermatitis and orthoergic and cholinergic urticaria are the most common examples. Pathological fragile skin

Pathological fragile skin matches with all skin diseases, where the skin has a lower resistance to aggression. The epidermolysis responds very strictly to this definition. AD is also a model of skin fragility since it is a skin which presents delayed hypersensitivity to environmental allergens. Iatrogenic fragile skin

Iatrogenic fragile skin represents the last type of classification of fragile skins. Drugs, such as oral isotretinoin treatment or long corticosteroid therapy are the classical examples of iatrogenic fragile skin. Interventional dermatologic acts, such as peeling and laser, will be followed by a period in which the skin is fragile and should be particularly protected by specific care so-called ‘post-act’ care. In all these situations, the fragile skin is related to the alteration of the barrier function of the epidermis. Individually, the mechanical and/or immunological role (including innate immunity) of the epidermal barrier that can be altered. This is why the fragile skins require special care to enhance their natural protective properties and to limit the aggressions which they might suffer. They require sometimes direct protection measures (use of gloves) or avoidance of allergens, irritants or sun. Hygiene or care products which will be applied on fragile skin should be adapted to this condition and should have as objective the restoration of epidermal barrier with its mechanical and immunological functions. A-DERMA dermo-cosmetics topical products are based on Rhealbaâ Oat. They all target the treatment and care of fragile skins: AD (EXOMEGA), irritative and contact dermatitis (DERMALIBOUR+), superficial wound healing and pos-

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tact of vascular laser (EPITHELIALE AH), acne (PHYS-AC), reactive skin (RHEACALM), rosacea (SENSIPHASE AR).

Rhealbaâ Oat, for fragile skin Daniel Wallach, MD, Paris, France Rhealbaâ Oat plantlets are one of the most successful actives developed by the Pierre Fabre Laboratories for A-DERMA. The aim of the research in this brand (also known as ‘Botanical Expertise’) is to select plants containing active principles with properties that are useful for pharmaceutical products, such as the Madagascan periwinkle for use in anticancer drugs, or the Rhealbaâ Oat. It is one of the most ubiquitous plant actives among traditional forms of medicine in Europe and Asia, and a daily food source across the USA and Canada in the form of oatmeal. Oats and their colloidal extract have featured in the Pharmacopoeia for centuries. Pierre Fabre Laboratories and A-DERMA have studied the oat for over 30 years, specifically the Rhea or Rhealbaâ Oat, which is especially rich in active principles. Rhealbaâ Oats have been selected from hundreds of different varieties, and are grown in strictly controlled, quasi-pharmaceutical conditions by partner growers, following the principles of biological agriculture. The most recent discovery is the usefulness of the ‘plantlets’, which are harvested at the ‘ear formation’ stage, the timing of which is based on daily monitoring of the plants’ flavonoid levels and defined as the point at which the young plant produces the maximum in active principles. The extract is obtained using an original process and is then tested for its levels of the active principles, flavonoids and saponins, and then divested of its proteins. This last process is essential for the active’s use in A-DERMA products, to pose no risk of allergic reaction, including for people with cereal intolerance, as has been proven. The excellent tolerance of A-DERMA’s products is brought by cosmetovigilance data gathered by Pierre Fabre laboratories since 1993.

New models of human “fragile skin” developed in vitro and in vivo Marie-Florence Galliano, Celine Rouvrais, Helene HernandezPigeon, Cedric Carrasco, Helene Duplan, Nathalie Castex-Rizzi, Valerie Mengeaud, Sandrine Bessou-Touya Pierre Fabre Dermo-Cosmetique, Pharmacologie in vitro, Toulouse, France Pierre-Fabre Dermo-Cosmetique, European Center of Skin Research, Hôtel Dieu, Toulouse, France A recent study had shown that “fragile skin” is perceived to occur in a substantial proportion of individuals from any given country, particularly in the age range of 15–34 years, regardless of skin type25.


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The current survey demonstrated that fragile skin is worth being considered and requires appropriate management and skin care products. To our knowledge, there is no specific or discriminating in vitro and in vivo model of “fragile skin”. We hypothesized that barrier dysfunction in fragile skin influences sensitivity to any stresses, i.e. fragile skin is less resistant to an additional, environmental stress. As a consequence, fragile skin response is amplified.

In vitro models of “fragile skin” Our first approach was to generate and characterize cellular and tissue models of « fragile skin » using normal human keratinocytes and reconstructed human epidermis based on a new method of applying a double stress. We firstly generated models of barrier–weakened cells or skin tissue by treatment with a chemical stress and we secondarily exposed them to an environmental stress of dehydration. We showed that barrier permeability was compromised after treatment with the first stress, thereby cells were weakened regarding barrier protection and defence. The last stressor impact was then investigated by monitoring the expression of key structural proteins, inflammation, barrier function and fence properties. We observed that in those “fragile cells” secondarily exposed to a dehydration stress, inflammation was dramatically increased and barrier function was also severely hindered, as compared to individual stresses. The specific amplified response, observed after the last stress, could hence be considered as a hallmark of fragile-skin. With these models, we were able to demonstrate the protective effect of Rhealbaâ oat plantlets extract. Rhealbaâ oat plantlets strongly protected against barrier dysfunction and modulated the inflammatory response. This extract could be beneficial for preventing the “fragile skin” to move towards severe homeostasis imbalance.

tion could be divided in two groups “fragile skin” and “non fragile skin”. Secondly, we performed a randomized controlled study on the forearm of 19 healthy women mean age 33.26 years in order to evaluate the efficacy of a topical product containing Rhealbaâ oat extract compared to Vaseline (as control). The SDS Insult Test was done on 3 areas with 1 area non treated by SDS. The products were applied just after the SDS Insult Test, and TEWL was measured before, immediately after SDS Insult Test and 24 hours later. The fragile skin model showed that 31% of the population studied has “fragile skin” which is in agreement with the survey data of Haftek et al. We also showed that in comparison to Vaseline, an application of a product containing Rhealbaâ oat extract significantly reduced skin barrier dysfunction of “fragile skin “ subjects ( p=0.0005). The present study describes the development of a standardized method to determine « fragile skin” in vivo. We used this model in a randomized controlled study showing a significant decrease of fragile skin reactivity with a product containing Rhealbaâ oat extract versus Vaseline. The complete data of theses studies will be published in chosen journal later.

(Isoorientin-2"-O-arabinoside): R = OH; (Isovitexin-2"-O-arabinoside) R = H

A clinical model for fragile skin Our second approach was to develop a relevant methodology for determining “fragile skin” in humans and to use this model to evaluate the effect of products containing Rhealbaâ oat extract. Firstly, a chemical skin stress model was developed using 0.25 % sodium dodecyl sulfate under occlusion for 24 hours (SDS Insult Test) on the forearm of 58 healthy women, mean age 30.54 years. Published data show that 0.25% SDS stress increases Transepidermal Water Loss (TEWL) by 30% in comparison to non treated skin (Tupker, Willis, Berardesca, Lef, Fartasch, Agner, Serup. Guidelines on Sodium Lauryl Sulfate (SLS) exposure tests. Contact dermatitis 1997, 37, 53-69). We calculated a SDS stress reaction ratio in each volonteer (i.e [TEWL SDS SKIN treated - TEWL SDS non treated skin] / TEWL SDS non treated skin) and hypothesized that a TEWL ratio above 1.3 (either 30% increase) is indicative of “fragile skin”. In this way, our popula-

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(Avenacoside A) R = H; (Avenacoside B) R = Glu

Figure 1



13

% Inhibition of IL13 production

A Rhealba® oat plantlets extract

3 μg/ml

22%

10 μg/ml

26% 43%

30 μg/ml

17%

1 μg/ml

Avenacoside B

Saponins

24% 23%

1 μg/ml

Avenacoside A

IL-13

23%

3 μg/ml 10 μg/ml

29%

3 μg/ml 10 μg/ml

27% 39%

Cyclosporin 10 ng/ml 0

10

20

30

% Inhibition of IL2 production

B Rhealba® oat plantlets extract

16%*

3 μg/ml

27%**

10 μg/ml

31%**

30 μg/ml

12%

1 μg/ml

Figure 2 Effect of Rhealbaâ Oat plantlets extract and isolated saponins on IL13 production (a) and on the percentage of CD4+IL-2+ T lymphocytes (b). These results are representative of three independent experiments. *P < 0.05; **P < 0.001.

Avenacoside B

Saponins

3 μg/ml

13%

10 μg/ml

13%

1 μg/ml

Avenacoside A

IL-2

9%

3 μg/ml

23%** 32%**

10 μg/ml

->74%**

Cyclosporin 10 ng/ml

Rhealbaâ oat plantlets: a good example of Botanical Expertise Pierre Fabre Mandeau A., Aries M.F., Teysseyre V., Panel A., Crebassa V., Boe J.F., Fabre B. Institut de Recherche Pierre Fabre, Herbal Product Laboratory, Toulouse, France and Pierre Fabre Dermo-Cosmetique, Pharmacologie in vitro, Toulouse, France. In traditional medicine, oat grain, mainly used topically in the form of flour or gruel, has been known since 400 BC for its emollient, anti-inflammatory and wound-healing properties in the treatment of pruritus, erythema, ulcers and burns, until nowadays where its properties are still recognized worldwide. Looking for a safer and efficient extract, we discovered recently the very interesting properties of Rhealbaâ Oat plantlets. The oat plantlets are the aerial part of oats, harvested at the elongation stage, before flowering. Atopic patients and especially children are prone to sensitization towards aero-allergens or dietary proteins (such as ovalbumin, peanut, cereal proteins, etc.). We therefore prepared an extract from Rhealbaâ Oat plantlets, the non-edible aerial parts of the plant, rich in flavonoids and avenacosides. As this extract was intended for potential use in atopic patients likely to be already sensitized to cereal proteins, we chose an organic extraction method to remove the proteins to avoid any risk of allergic reaction. We demonstrate antiinflammatory and immunomodulating properties of the plantlet extract and purified compounds: 2 flavonoids (Isoorientin-2″O-arabinoside and isovitexine-2″-O-arabinoside) and 2 saponins

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40

0

10

20

30

40

(avenacosides A and B) (Fig. 1). With the help of biochemical tools (ELISA, Western Blot), we demonstrate the lack of detected protein, with a detection limit in routine of 10 ppm. We also show the absence of cross-reaction between oat protein and plantlet protein thus allowing the use of Rhealbaâ Oat plantlet extract in atopic patients without any risk of dietary presensitization with cereal proteins (including oats). This collective work, leading to an innovative product, illustrates perfectly the approach Botanical Expertise Pierre Fabre, which is a certified1 process for the responsible development of innovative, safe and effective plant active ingredients: from the oat cultivation (organic agriculture, collaboration with local farmers in the South-West of France) to the pharmacological assessment of isolated compounds, all this ensures safety and quality for each industrial batch of Rhealbaâ Oat plantlet extract produced.

Pharmacological activities of Rhealbaâ oat plantlet extract Helene Hernandez-Pigeon*1, Marie-Francßoise Aries*1, MarieFlorence Galliano1, Clemence Vaissiere1, Isabelle Ceruti1, Antony Caruana1, Anne Mandeau2, Helene Duplan1, Nathalie CastexRizzi1, Sandrine Bessou-Touya1

1 Certified by the EFQM European label (European Foundation for Quality Management) delivered by AFNOR since 2010.


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600

Prostacyclin PGI2

500

–19%* –35%***

pg/mL

400

300

–57%***

200

–86%***

100 0 Control

A23187 5 μM

Indometacin 0.1 μM

3 μg/mL

10 μg/mL

30 μg/mL

Rhealba® oat plantlets extract

250

Prostacyclin PGI2

pg/mL

200 –31%***

150

51%*** 100 50

–56%***

–92%***

0 Control

A23187 5 μM

Indometacin 0.1 μM

3 μg/mL

10 μg/mL

30 μg/mL

Isoorientine–2"–O–arabinoside Figure 3 Effect of Rhealbaâ Oat plantlets extract and the flavonoid Isorientine-2″-O-arabinosyl on PGI2 production. These results are representative of three independent experiments. *P < 0.05; **P < 0.01 and ***P < 0.001.

% of control COX–2 or PLA2

150

COX-2 enzymatic activity

PLA2 enzymatic activity

125

100

–9% –17%

75

50

–50%*

–50%*

–59%*

–79%*

25

0 Control NS398 0,12 μM COX2/PLA2 -Inhib COX2

0,1 mg/ml

1 mg/ml

2 mg/ml


1

NDGA 130 μM -Inhib PLA2

0,1 mg/ml

Pierre Fabre Dermo-Cosmetique, Pharmacologie in vitro, Toulouse, France. 2 Institut de Recherche Pierre Fabre, Herbal Product Laboratory, Toulouse, France *These authors equally contributed to this work

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1 mg/ml

2 mg/ml


Figure 4 Effect of Rhealbaâ Oat plantlets extract on COX-2 and PLA2 enzymatic activity. These results are representative of three independent experiments. *P < 0.05.

Interest of Rhealbaâ oat plantlet extract on atopic dermatitis treatment

Atopic dermatitis is a chronic inflammatory disease hypothesized to be the product of complex interactions among the



host’s environment, susceptibility genes, skin barrier dysfunction and immune system dysregulation. Th1 and Th2 cells which differ in their secretory patterns of cytokines, postulated in the disease process and immunosuppressive agents, are the foundation for the pharmacologic treatment of flares. Emollient application is a very beneficial complement and makes the use of topical potent immunomodulatory agents logical therapeutic considerations. The aim of this study was to evaluate the activity of Rhealbaâ Oat plantlet extract, two saponins, avenacosides A and B isolated from this extract and two flavonoids, isoorientin-2″O-arabinoside and isovitexin-2″-O-arabinoside. Immune cellular response, cutaneous inflammatory response and bacterial response were assessed. Immune cellular response was evaluated through the production by human peripheral blood mononuclear cells of interleukine 2 (Th1 cytokine) and interleukine 4, 5, and 13 (Th2 cytokines) and through the reactivity of dendritic cells (differentiation, maturation and functionality). Cutaneous inflammatory response was evaluated through the prostacyclin (PGI2, COX-2 mediator) production by human keratinocytes and COX-2 and PLA2

15

enzymatic activity in tubo. Bacterial response was evaluated through S. aureus adhesion and detachment. Rhealbaâ Oat plantlet extract and avenacoside A significantly down-regulated Th2 and Th1 cytokines by 21%, 17%, 26% on IL4, IL5, IL13 production, respectively (data not shown and Fig. 2a) and by 27% on CD4+ IL2+ cells (P < 0.001) (Fig. 2b) (with 10 lg/mL Rhealbaâ Oat plantlet extract concentration). In addition, Rhealbaâ Oat plantlet extract significantly decreased CMHII expression and CD4+ T-cell proliferation73. Rhealbaâ Oat plantlet extract and the flavonoid isoorientin-2″-O-arabinoside significantly decreased (P < 0.001) the A23187-induced PGI2 production ( 57% with 30 lg/mL of Rhealbaâ Oat plantlet extract concentration) (Fig. 3). Rhealbaâ Oat plantlet extract also inhibited COX-2 enzymatic activity but not PLA2 enzymatic activity (Fig. 4). Finally, Rhealbaâ Oat plantlet extract at 0.25% delayed significantly in a dose-dependent range the adhesion of S. aureus, while concomitantly, a significant and dose-dependent detachment of S. aureus was observed (Fig. 5). These results demonstrate that Rhealbaâ Oat plantlet extract is a potent regulator of both immunoinflammatory and bacterial response. Thus, Rhealbaâ Oat plantlets topical

A

B

Figure 5 Effect of Rhealbaâ Oat plantlets extract on Staphylococcus aureus adhesion (a) and detachment (b). These results are representative of three independent experiments.

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(a)

(b)

% of keratinocyte proliferation

70

130

+22%* 65

+32%*

HA (ng/ml)

120

+7%

60

55

110 100

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+ 30% ***

+10% **

Figure 6 Effect of Rhealbaâ Oat plantlets extract on keratinocyte proliferation (a), on hyaluronic acid (HA) production (b) and on collagen IV expression (c). These results are representative of three independent experiments. *P < 0.05, **P < 0.01 and ***P < 0.001.

preparations could represent a real interest in the treatment of AD. Interest of Rhealbaâ oat plantlet extract on epidermal restoration

Epidermal restoration is a crucial step in cutaneous repair of irritated skin occurring in AD lesions and in wound healing. It involves the combination of two cellular processes, proliferation and migration, temporally and locally orchestrated by specific molecular mediators [growth factors, cytokines, collagen, hyaluronic acid (HA). . .]. Recovery of barrier function is also

Lipid neosynthesis / % of control 180

important for epidermal restoration. During this process, differentiation programme is engaged together with expression of lipid transporters such as ABCG1 that participates in lipid barrier formation. Rhealbaâ Oat plantlets extract was evaluated on keratinocyte proliferation, on collagen IV (dermo-epidermal junction protein) expression, on hyaluronic acid (HA) synthesis and on de novo lipids synthesis. For proliferation assay, normal human keratinocytes were submitted to 48-h treatment with increasing concentrations of Rhealbaâ Oat plantlet extract. Proliferation was performed by quantifying diluted dye DiI by flow cytometry. Collagen IV expression was evaluated using immunolabelling and HA production was measured using ELISA performed on the supernatants. Transcriptome analysis was performed by realtime RT-qPCR. Finally, a cream containing Rhealbaâ Oat plantlets was topically applied twice on human reconstructed epidermis. As control of differentiation, VitC at 200 lg/mL was added into the medium. 14C-acetate was added to the medium for 2 days, and then a chase was performed for two additional days. Extracted lipids were separated by thin layer chromatography, and semiquantification was performed after autoradiography. These results showed that Rhealbaâ Oat plantlet extract was able to stimulate keratinocyte proliferation (Fig. 6a) and to enhance the expression of both HA (Fig. 6b) and collagen IV (Fig. 6c). Gene expression analysis showed that ABCG1 was up-regulated, suggesting that the Rhealbaâ Oat plantlet extract favoured barrier function restoration by enhancing lipid synthesis. This hypothesis was consistent with the effect of the Rhealbaâ Oat plantlets cream on stimulation of the neosynthesis of sphingomyelin (precursor of ceramides) ceramides/cerebrosides and free fatty acids (Fig. 7) in human reconstructed epidermis.

Control 140

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Vitamin C

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40 20

20

0

0

Sphingomyelin

Phospholipids

Polar ceramides / Cerebrosides

Cholesterol Sulfate

Free cholesterol

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Esterified fatty acids

Figure 7 Effect of Rhealbaâ Oat plantlets cream on lipid neosynthesis. These results are representative of three independent experiments. *P < 0.05; **P < 0.01 and ***P < 0.001.

JEADV 2014, 28, (Suppl. 4),1–18



Together, the present data, obtained in vitro, strongly support the positive activity of Rhealbaâ Oat plantlet extract on skin restoration.73

Acknowledgements The authors thank Dr. Daniel Wallach (Medical Writer), Dr. Morad Lahfa (Toulouse, he gave a lecture during 1st skin clinical meeting about psoriasis), Prof. Jean-Francßois Nicolas (Lyon, he gave a lecture during 1st skin clinical meeting about contact dermatitis), Valerie Teysseyre (Herbal Product Laboratory, Institut de Recherche Pierre Fabre, Toulouse, France), Alexandre Panel (Pierre Fabre Agronomie, Gaillac, France), Veronique Crebassa (Institut de Recherche Pierre Fabre, Toulouse, France), Jean-Francßois Boe (Institut de Recherche Pierre Fabre, Toulouse, France), Clemence Vaissiere (Pharmacology in vitro, Pierre Fabre Dermo-Cosmetique, Toulouse, France), Isabelle Ceruti (Pharmacology in vitro, Pierre Fabre Dermo-Cosmetique, Toulouse, France), Antony Caruana (Pharmacology in vitro, Pierre Fabre Dermo-Cosmetique, Toulouse, France), Christine Coutanceau (Responsable Medico-Marketing A-Derma).

References 1 Whittock NV, Haftek M, Angoulvant N et al. Genomic amplification of the human plakophilin 1 gene (PKP1) and detection of a new mutation in ectodermal dysplasia/skin fragility syndrome. J Invest Dermatol 2000; 115: 368–374. 2 Whittock NV, Wan H, Morley SM et al. Compound heterozygosity for nhon-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. J Invest Dermatol 2002; 118: 232–238. 3 Haftek M, Simon M, Kanitakis J et al. Expression of corneodesmosin in the granular layer and stratum corneum of normal and diseased epidermis. Br J Dermatol 1997; 137: 864–873. 4 Simon M, Jonca N, Guerrin M et al. Refined characterization of corneodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation. J Biol Chem 2001; 276: 20292– 20299. Erratum in: J Biol Chem 2001; 276(50):47742-3. 5 Oji V, Eckl KM, Aufenvenne K et al. Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease. Am J Hum Genet 2010; 87: 274–281. doi: 10.1016/j.ajhg.2010.07.005. 6 Blaydon DC, Nitoiu D, Eckl KM et al. Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion. Am J Hum Genet 2011; 89: 564–571. doi: 10.1016/j.ajhg.2011.09.001. 7 Chamcheu JC, Siddiqui IA, Syed DN, Adhami VM, Liovic M, Mukhtar H. Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys 2011; 508: 123–137. doi: 10.1016/j.abb.2010. 12.019. 8 Carulli S, Contin R, De Rosa L, Pellegrini G, De Luca M. The long and winding road that leads to a cure for epidermolysis bullosa. Regen Med 2013; 8: 467–481. doi: 10.2217/rme.13.33. 9 Kiritsi D, Cosgarea I, Franzke CW et al. Acral peeling skin syndrome with TGM5 gene mutations may resemble epidermolysis bullosa simplex in young individuals. J Invest Dermatol 2010; 130: 1741–1746. doi: 10.1038/ jid.2010.23. 10 Shull GE, Miller ML, Prasad V. Secretory pathway stress responses as possible mechanisms of disease involving Golgi Ca2+ pump dysfunction. Biofactors 2011; 37: 150–158. doi: 10.1002/biof.141. 11 Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers– Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers–Danlos

JEADV 2014, 28, (Suppl. 4), 1–18

17

12

13

14

15

16 17

18

19

20 21

22

23

24

25

26

27

28

29

30

National Foundation (USA) and Ehlers–Danlos Support Group (UK). Am J Med Genet 1998; 77: 31–37. Miyake N, Kosho T, Mizumoto S et al. Loss-of-function mutations of CHST14 in a new type of Ehlers–Danlos syndrome. Hum Mutat 2010; 31: 966–974. Nikolovska K, Renke JK, Jungmann O et al. A decorin-deficient matrix affects skin chondroitin/dermatan sulfate levels and keratinocyte function. Matrix Biol 2014. doi: 10.1016/j.matbio.2014.01.003 [Epub ahead of print]. McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 2013; 131: 280–291. doi: 10.1016/j. jaci.2012.12.668. Fortugno P, Furio L, Teson M et al. The 420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation: implications for atopic dermatitis. Hum Mol Genet 2012; 21: 4187–4200. doi: 10.1093/ hmg/dds243. Imokawa G. Lipid abnormalities in atopic dermatitis. J Am Acad Dermatol 2001; 45(Suppl. 1): S29–S32. van Smeden J, Janssens M, Kaye EC et al. The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients. Exp Dermatol 2014; 23: 45–52. doi: 10.1111/exd.12293. Elias PM, Brown BE, Ziboh VA. The permeability barrier in essential fatty acid deficiency: evidence for a direct role for linoleic acid in barrier function. J Invest Dermatol 1980; 74: 230–233. Phillips JD, Bergonia HA, Reilly CA, Franklin MR, Kushner JP. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci USA 2007; 104: 5079–5084. Hanakawa Y, Stanley JR. Mechanisms of blister formation by staphylococcal toxins. J Biochem 2004; 136: 747–750. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol 2013; 69: 173.e1-13; quiz 185-6. doi: 10.1016/j.jaad. 2013.05.003. Al-Himdani S, Ud-Din S, Gilmore S, Bayat A. Striae distensae: a comprehensive review and evidence-based evaluation of prophylaxis and treatment. Br J Dermatol 2014; 170: 527–547. Chakravarti S, Magnuson T, Lass JH, Jepsen KJ, LaMantia C, Carroll H. Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican. J Cell Biol 1998; 141: 1277– 1286. Leblanc K, Baranoski S, Holloway S, Langemo D, Regan M. A descriptive cross-sectional international study to explore current practices in the assessment, prevention and treatment of skin tears. Int Wound J 2014. Jan 21. doi: 10.1111/iwj.12203 [Epub ahead of print]. Haftek M, Coutanceau C, Ta€ıeb C. Epidemiology of “fragile skin”: results from a survey of different skin types. Clin Cosmet Investig Dermatol 2013; 6: 289–294. doi:10.2147/CCID.S55223. Deckers IA, McLean S, Linssen S, Mommers M, van Schayck CP, Sheikh A. Investigating international time trends in the incidence and prevalence of atopic eczema 1990-2010: a systematic review of epidemiological studies. PLoS ONE 2012; 7: e39803. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol 2006; 155: 145–151. Gil KM, Keefe FJ, Sampson HA, McCaskill CC, Rodin J, Crisson JE. The relation of stress and family environment to atopic dermatitis symptoms in children. J Psychosom Res 1987; 31: 673–684. Schmitt J, Apfelbacher C, Heinrich J, Weidinger S, Romanos M. [Association of atopic eczema and attention-deficit/hyperactivity disorder – metaanalysis of epidemiologic studies.] Z Kinder Jugendpsychiatr Psychother 2013; 41: 35–42; quiz 42-4. Moret L, Anthoine E, Aubert-Wastiaux H et al. TOPICOP(c): a new scale evaluating topical corticosteroid phobia among atopic dermatitis outpatients and their parents. PLoS ONE 2013; 8: e76493.


Stalder et al.

18

31 Staab D, Diepgen TL, Fartasch M et al. Age related, structured educational programmes for the management of atopic dermatitis in children and adolescents: multicentre, randomised controlled trial. BMJ 2006; 332: 933–938. 32 Palmer CN, Irvine AD, Terron-Kwiatkowski A et al. Common loss-offunction variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006; 38: 441–446. 33 Hvid M, Vestergaard C, Kemp K, Christensen GB, Deleuran B, Deleuran M. IL-25 in atopic dermatitis: a possible link between inflammation and skin barrier dysfunction? J Invest Dermatol 2011; 131: 150–157. 34 Grimalt R, Mengeaud V, Cambazard F; Study Investigators’ Group. The steroid-sparing effect of an emollient therapy in infants with atopic dermatitis: a randomized controlled study. Dermatology 2007; 214: 61–67. 35 Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of fluticasone propionate cream for reducing the risk of relapse in atopic dermatitis patients. Br J Dermatol 2002; 147: 528–537. 36 Thacßi 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 2008; 159: 1348–1356. 37 Wollenberg A, Reitamo S, Atzori F et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy 2008; 63: 742–750. 38 Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol 2013; 168: 474–485. doi: 10.1111/bjd.12149. 39 Beylot C, Auffret N, Poli F et al. Propionibacterium acnes: an update on its role in the pathogenesis of acne. J Eur Acad Dermatol Venereol 2014; 28: 271–278. 40 Del Rosso JQ. Clinical relevance of skin barrier changes associated with the use of oral isotretinoin: the importance of barrier repair therapy in patient management. J Drugs Dermatol 2013; 12: 626–631. 41 Thiboutot D, Del Rosso JQ. Acne vulgaris and the epidermal barrier: is acne vulgaris associated with inherent epidermal abnormalities that cause impairment of barrier functions? Do any topical acne therapies alter the structural and/or functional integrity of the epidermal barrier? J Clin Aesthet Dermatol 2013; 6: 18–24. 42 Yamamoto A, Takenouchi K, Ito M. Impaired water barrier function in acne vulgaris. Arch Dermatol Res 1995; 287: 214–218. 43 Levin J, Friedlander SF, Del Rosso JQ. Atopic dermatitis and the stratum corneum: part 2: other structural and functional characteristics of the stratum corneum barrier in atopic skin. J Clin Aesthet Dermatol 2013; 6: 49–54. 44 Kurokawa I, Mayer-da-Silva A, Gollnick H, Orfanos CE. Monoclonal antibody labeling for cytokeratins and filaggrin in the human pilosebaceous unit of normal, seborrhoeic and acne skin. J Invest Dermatol 1988; 91: 566–571. 45 Draelos ZD, Ertel KD, Berge CA. Facilitating facial retinization through barrier improvement. Cutis 2006; 78: 275–281. 46 Weber SU, Thiele JJ, Han N et al. Topical alpha-tocotrienol supplementation inhibits lipid peroxidation but fails to mitigate increased transepidermal water loss after benzoyl peroxide treatment of human skin. Free Radic Biol Med 2003; 34: 170–176. 47 Herane MI, Fuenzalida H, Zegpi E et al. Specific gel-cream as adjuvant to oral isotretinoin improved hydration and prevented TEWL increase – a double-blind, randomized, placebo-controlled study. J Cosmet Dermatol 2009; 8: 181–185. 48 St€ ucker M, Hoffman M, Altmeyer P. Instrumental evaluation of retinoidinduced skin irritation. Skin Res Technol 2002; 8: 133–140. 49 Tagami H, Tadaki T, Obata M, Koyama J. Functional assessment of the stratum corneum under the influence of oral aromatic retinoid (etreti-

JEADV 2014, 28, (Suppl. 4),1–18

50 51

52

53

54 55

56 57

58

59 60 61

62 63 64 65 66

67 68 69 70 71 72 73

nate) in guinea-pigs and humans. Comparison with topical retinoic acid treatment. Br J Dermatol 1992; 127: 470–475. Elias PM. Epidermal effects of retinoids: supramolecular observations and clinical implications. J Am Acad Dermatol 1986; 15(4 Pt 2): 797–809. Tanghetti EA. Cleanser and moisturizer use with tazarotene 0.1% cream for acne vulgaris. Poster presented at Fall Clinical Dermatology. Las Vegas, NV, 2010. Guerrero D. Dermo-cosmetic approach to acne by the dermatologist. Ann Dermatol Venereol 2010; 137(Suppl. 2): S76–S80. doi: 10.1016/ S0151-9638(10)70032-6. Aries MF, Vaissiere C, Pinelli E, Pipy B, Charveron M. Avena Rhealbaâ inhibits A23187-stimulated arachidonic acid mobilization, eicosanoid release, and cPLA2 expression in human keratinocytes: potential in cutaneous inflammatory disorders. Biol Pharm Bull 2005; 28: 601–606. Farage MA. Does sensitive skin differ between men and women? Cutan Ocul Toxicol 2010; 29: 153–163. St€ander S, Scheneider SW, Weishaupt C, Luger TA, Misery L. Putative neuronal mechanisms of sensitive skin. Exp Dermatol 2009; 18: 417–423. Misery L, Boussetta S, Nocera T, Perez-Cullel N, Taieb C. Sensitive skin in Europe. J Eur Acad Dermatol Venereol 2009; 23: 376–381. Conrado LA, Hounie AG, Diniz JB et al. Body dysmorphic disorder among dermatologic patients: prevalence and clinical features. J Am Acad Dermatol 2010; 63: 235–243. Di Nardo A, Sugino K, Wertz P, Ademola J, Maibach HI. Sodiumlauryl sulfate (SLS) induced irritant contact dermatitis: a correlation study between ceramides and in vivo parameters of irritation. Contact Dermatitis 1996; 35: 86–91. Kueper T, Krohn M, Haustedt LO, Schmaus G, Vielhaber G. Inhibition of TRPV1 for the treatment of sensitive skin. Exp Dermatol 2010; 19: 980–986. Escalas-Taberner J, Segura Rodrıguez R, Guerra Tapia A. “La piel sensible.” Mas dermatologıa 2011; 13: 4–13. Saint-Martory C, Roguedas-Contios AM, Sibaud V, Degouy A, Schmitt AM, Misery L. Sensitive skin is not limited to the face. Br J Dermatol 2008; 158: 130–133. Frosch PJ, Kligman AM. A method of a praising the stinging capacity of topically applied substances. J Soc Cosmet Chem 1977; 28: 197–209. Thiers H. Peau sensible. In Thiers H, ed. Les Cosmetiques, 2nd edn. Masson, Paris, 1986: 266–268. Misery L. Peaux reactives: mythe ou realite? Realites Therapeutiques en Dermato-Venereologie, N°157, Cahier 1, May 2006. Misery L, Martin N, Myon E, Nocera T, Taieb C. Sensitive skin: epidemiology and seasonal variations. J Invest Dermatol 2005; 125: A24. Misery L, Myon E, Martin N, Verriere F, Nocera T, Taieb C. Peaux sensibles en France: approche epidemiologique. Ann Dermatol Venereol 2005; 132: 425–429. Willis CM, Shaw S, de Lacharriere O et al. Sensitive skin: an epidemiological study. Br J Dermatol 2001; 145: 258–263. Robinson MK. Population differences in acute skin irritation response. Contact Dermatits 2002; 46: 86–93. Primavera G, Berardesca E. Sensitive skin: mechanisms and diagnosis. Int J Cosmet Sci 2005; 27: 1–10. Pons-Guiraud A. Sensitive skin: a complex and multifactorial syndrome. J Cosmet Dermatol 2004; 3: 145–148. Misery L. Les nerfs a fleur de peau. Int J Cosmet Sci 2002; 24: 111–116. Pons-Guiraud A, Vigan M. Allergies aux cosmetiques. Textbook, Edition Exp Sc Fr 2003; 37–40. Mandeau A, Aries MF, Boe JF et al. Rhealbaâ Oat plantlet extract: evidence of protein-free content and assessment of regulatory activity on immune inflammatory mediators. Planta Med 2011; 77: 900–906.


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