The Skin Barrier and Use of Moisturizers in Atopic Dermatitis

N, Dr Med Sc MARIE LODE

topic dermatitis, one of the most common chronic inflammatory skin diseases, is characterized by dry and itchy skin. The disease has a complex pathophysiology that includes interactions between genetic predisposition and exogenous provocation factors. Atopic dermatitis has been reported to be increasing in prevalence, with studies showing the frequency among school children to be between 15 and 20% in Northern Europe.1,2 This increase in prevalence over a rather short period of time suggests that environmental provocative factors have promoted the rise rather than genetic changes.3 Environmental influence on the disease process is complex, and the role of the stratum corneum (SC) as a biosensor, regulating the metabolic response to a variety of exogenous insults, appears to be essential.4 An understanding of current views of disease pathogenesis and the clinical efficacy of topical treatments constitute the foundation for efficient therapy of atopic eczema. Moisturizers are the obvious treatment for dry skin, and if used properly are useful treatment adjuncts in inflammatory dermatoses. Many health care professionals and patients overlook their importance and consider them not to be active treatments, not realizing that the SC abnormality may be the primary exacerbating factor of inflammatory skin diseases.4 Only a few controlled clinical studies are currently available, so additional scientific studies on the mechanism by which the SC affects dermatitis are considered indispensable. Not only the active ingredients, but also excipients in moisturizers, which are incorporated mainly to improve stability and viscosity, affect the structure and function of the skin.5 Likewise, ordinary humectants exhibit other properties in addition to their water-binding effect.5 Moisturizing creams and emollients are usually considered to be cosmetics but may be regulated as medicinal products if specifically marketed for the treatment of dry skin diseases such as atopic dermatitis. Moisturizers differ in their composition of active ingredients and excipients.5 Those marketed to the public often contain trendy ingredients accompanied by exciting
From the Research & Development Department, ACO Hud, Sweden. Address correspondence to Marie Lode n, Dr Med Sc, ACO Hud AB, Box 622, SE-194 26 Upplands Va sby, Sweden. E-mail address: marie.loden@acohud.se. 2003 by Elsevier Science Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010

names and exorbitant claims. In this review, the chemistry and function of atopic skin and moisturizers will be reviewed, with the aim of increasing understanding of the interactions between topically applied ingredients and the integument. This understanding should facilitate the tailoring of specific moisturizers for patients with atopic dermatitis.

Skin Structure and Function Morphology and Composition

Scaling and roughness are the visible features of clinically dry skin in patients with atopic dermatitis.6 Accumulation of scale on the skin surface results from increased production of corneocytes and/or delayed desquamation. Closer examination of the dry skin surface by scanning electron microscope shows a coarser morphology, with broad, irregularly running furrows and loss of minor furrows compared to normal skin.6 Measurement of surface topography in dry atopic skin reveals a decreased number of peaks and an increased distance between the peaks and valleys.7 During their life cycle, keratinocytes differentiate: they gradually flatten out, extrude lipids by exocytosis, and eventually completely cornify to become corneocytes. The end product, the corneocyte, is filled with keratin and amorphous matrix. In atopic skin, the number of SC cell layers is increased and there is increased cohesion between the cells.8The turnover time is shorter than in controls and the projected size of the corneocytes is smaller, probably reflecting increased epidermal proliferation due to a low-level ongoing dermatitis.8,9 Hydration makes the SC soft and compliant to mechanical stimuli.10 Water has a plasticizing effect, allowing the layer to bend and stretch more easily, thus avoiding cracking and fissuring. The water content of the SC must be greater than 10% for the skin to have a normal appearance and function.10 The dry-looking skin of patients with atopic dermatitis is less hydrated and less capable of binding water than normal skin.1113 The content of urea in the SC of this dry-appearing skin as well as that of affected skin is substantially reduced.14 Similarly, substances considered components of the skin natural moisturizing factor are reduced in atopic skin and in other dry skin conditions.8,1517 The reduced level of pyrrolidone carboxylic acid and water0738-081X/03/$see front matter doi:10.1016/S0738-081X(02)00373-5

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soluble amino acids has been suggested to reflect decreased profilaggrin production.16 Corneocytes in the SC are embedded in lipid bilayers consisting primarily of three classes of lipids: free sterols, free fatty acids, and ceramides. The SC lipids help maintain moisture content in corneocytes and are important determinants of skin permeability.18 22 In dry atopic skin, lipid composition is abnormal with both reduction in the amount of ceramides and altered distribution of the different ceramide types.2326 The proportion of ceramide 1 is decreased, and the level of esterified oleic acid in ceramide 1 is increased.27 Also, the level of cholesterol has been reported to be elevated in atopic dry skin.28 The changed lipid composition may account for the aberrant lipid organization in atopic skin, with an increased frequency of hexagonal packaging.29 The epidermis is an active site of lipid synthesis, largely autonomous from the influence of circulating lipids.30 Phospholipids and glycosphingolipids are hydrolyzed into ceramides and free fatty acids. In atopics, the enzyme sphingomyelin deacylase is highly upregulated. This has been suggested to cause a ceramide deficiency as a result of competition with sphingomyelinase and -glucocerebrosidase for their respective substrates, sphingomyelin and glucosylceramide.31 Skin pH has also been suggested to be a factor in the maintenance of competent skin barrier function.32 The pH is slightly higher both in uninvolved and in eczematous skin of patients with atopic dermatitis than in normal skin.33 The bodys internal environment maintains a near-neutral pH. The activity of certain enzymes in the SC is higher at acidic pH, whereas others show higher activity at neutral and basic pH.34,35 The steep change in pH (about 2 U) over the short distance through the SC has been suggested to activate enzymes that facilitate the desquamation process, which requires controlled degradation of desmosomes in the upper SC.36,37 A steep Ca2 gradient exists across the nucleated layers, with the highest concentration in the outer, differentiated layers of the epidermis.38 Disruption of the barrier depletes Ca2 from the upper epidermis and removes the gradient, which triggers secretion of lamellar bodies and barrier recovery.30,39 Application of exogenous Ca2 inhibits barrier repair by maintaining the Ca2 content in the upper epidermis.30,39 In dry atopic skin, higher levels of calcium is found throughout the layer, with a tendency to a steeper gradient than in normal skin.40 Higher values of Zn have also been found in atopic skin.41 This high Zn level has been suggested to bind to defensins and thus act on the conformational status of the natural defensins contained in the SC allowing for the free action of bacteria.41

Figure 1. Defective skin barrier function increases skin susceptibility and triggers eczema.

Permeability
One of the most important functions of the skin is to reduce the loss of body water to the environment and to prevent the entry of environmental substances. The integrity of the SC determines the diffusional rate of transepidermal water loss (TEWL). Higher TEWL is noted in the dry skin of atopic patients,12,13 whereas in completely healed atopic dermatitis the barrier function is not disturbed.42 Skin permeability is determined by the lipid composition of the SC,22 the size of the corneocytes,43,44 and the degree of hydration of this skin layer.10,45 These parameters are affected in dry atopic skin (see above). A smaller corneocyte size decreases the convoluted and tortuous diffusional pathway through the SC, which facilitates penetration43 and increases susceptibility to chemical irritation.46 The impaired barrier in atopic dermatitis skin makes it less efficient in excluding substances that come in contact with the surface (Figure 1). Whether pharmacologic or toxicological levels are reached within the skin or in the body depends on the nature of the substance, the integrity of the SC, and the dose applied. Patients with atopic dermatitis are considered more prone to acute irritant contact dermatitis than the normal population. Although several controlled studies demonstrate such a proclivity, others do not, suggesting that the mechanisms involved are complex.47 The impaired barrier function to water loss induces signals that stimulate barrier recovery. On the other hand, increased TEWL can also have pathologic effects by overstimulating cytokines that can then induce cutaneous abnormalities.4 Hence, avoiding the irritant and improving the defective barrier function both may prevent persistent dermatitis by mitigation of the cytokine cascade.4

Aggravating Factors for Atopic Patients

In patients with atopic dermatitis, the course of the disease is determined by environmental factors, such as

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psychologic stress,48 climate (eg, low humidity caused by cold winters and central heating), and exposure to irritants and allergens.49 The external environment involves exposures to a multitude of chemicals and other influences.50,51 Psychologic stress has been shown experimentally to retard permeability barrier recovery in humans.48 Low humidity increases cytokine expression in mice, suggesting induction of other molecules that can mediate epidermal proliferation or cutaneous inflammation. Moreover, exposure to hard water, especially to calcium in domestic water, has been found to be associated with a higher prevalence of atopic eczema in primary-school children.50 Whether this is related to the calcium ions in the skin is not known. Another factor thought to trigger atopic dermatitis is the colonization of the skin with microorganisms, such as Staphylococcus aureus (S. aureus) and Malassezia spp (formerly known as Pityrosporum ovale and orbiculare). S. aureus can release superantigenic exotoxins, which induce massive cytokine release.52 Staphylococcus enterotoxin B also induces eczema when applied directly to uninvolved atopic and normal skin.53 The severity of dermatitis has been reported to have a linear correlation with S. aureus counts.54 In young adults with atopic dermatitis, an exacerbation of the eczema of the head, neck, and shoulders, referred to as head and neck dermatitis, has been suggested to be related to the presence of Malassezia spp. Also, peroral exposure to allergens via the diet can induce systemic contact dermatitis in patients previously sensitized to topical allergens.55 Dryness of the skin is a major cause of pruritus in atopic dermatitis. Scratching facilitates the release of proinflammatory mediators that make itching worse, so a vicious itch-scratch cycle is established. Scratching also produces excoriations in the epidermis, allowing the penetration of irritating and sensitizing substances, such as superantigens produced by microorganisms. Not only can a single overwhelming external exposure cause dry skin and dermatitis, but also several small, minor insults may eventually cause visible eczema if the barrier does not recover completely between challenges (Figure 2). 51

Figure 2. Repeated exposure to several mild irritants may cause visible eczema if skin barrier recovery is impaired (adapted from Reference 51).

of humectants, the term moisturizer is used in this chapter. Moisturizers have multifunctional effects. Desired properties include reduction of clinical signs of dryness, like scaling and roughness, and decrease in perceived feelings of tightness and itching. Likewise improvement of skin barrier function is important. Sometimes moisturizers may appear to be ineffective because they are used in insufficient quantities or contain deleterious substances.

Cosmetic Properties
Application of moisturizers to the skin induces tactile and visual changes in the skin surface. The type of oils (lipids) used and the ratio between oil and water are both important determinants of product attributes. In addition, other ingredients such as emulsifiers, humectants, and preservatives influence the initial feel of the product, its spreading behavior on the skin, whether and how fast it is absorbed, and how the skin feels after its use. The ingredients fill the spaces between partially desquamated skin flakes.56,57 A dry rough surface can be expected to accept a higher application rate (mg/cm2) or products with higher amount of nonvolatile substances without feeling greasy. Beside mixing with material already present on the surface, topically applied substances may be lost from the skin by contact with other surfaces, evaporation, absorption, and metabolism. The specific combination of ingredients is important for the physical and chemical stability of the formulation as well as for its cosmetic properties. If not properly formulated, ingredients may decompose and lose efficacy, give rise to an unpleasant odor, or cause adverse effects. For example, urea increases the pH of a formulation and may form ammonia when it decomposes.58 The cosmetic properties and simplicity of use are additional parameters important for achieving the desired treatment effects. Sticky and viscous formulations are considered less attractive by most people than easily applied and rapidly absorbed emulsions. The use of

Action of Moisturizers on the Skin

The urge to apply oils to the skin is almost intuitive and may be as old as mankind itself. The term emollient implies (from the Latin derivation) a material designed to soften the skin, ie, a material that smooths the surface to the touch and makes it look smoother to the eye. The term moisturizer is often used synonymously with emollient, but the term implies the addition of water to the skin. Therefore, moisturizers usually contain humectants to enhance the water-binding capacity of the SC. Irrespective of their possible content

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Table 1. The moisture binding ability (%) of different humectants Humectant

Sodium-lactate Sodium-PCA Glycerin Propylene glycol Sorbitol PCA
a b

Antimicrobial Therapy
Secondary infection, facilitated by scratching, often complicates atopic dermatitis, and antimicrobial agents have become an established adjunct to topical corticosteroid therapy.81 Among antimicrobial agents, antiseptics such as gentian violet and povidone have shown efficacy.82,83 Topical antimycotics aimed at the yeast Malassezia furfur have also been suggested to benefit atopic patients with head and neck dermatitis. S. aureus is a Gram-positive bacteria which can live in the relatively dry environment of the normal skin surface. On healthy individuals it is often found in intertriginous areas, whereas in patients with atopic dermatitis it is found in 90% of isolates from chronic eczematous lesions and 70% from noninvolved areas.84 The density appears to be higher in exudative areas (107 colonies per cm2) than in lichenified plaques (about 0.5 106 colonies per cm2) or clinically normal skin (about 103 colonies per cm2).84 The severity of dermatitis has been reported to correlate with the density of S. aureus.54,85 Patients suffering from mild to moderate atopic eczema colonized with S. aureus, but without signs of active superinfection, had an improvement in their eczema after treatment with an antiseptic alone, ie, 0.3% gentian violet.83 The bacterial density decreased significantly in lesional and unaffected skin and the severity of the lesions decreased, rated by a regional severity scoring of atopic dermatitis (SCORAD).83 In patients colonized with S. aureus at an initial density of 1000 CFU/10 cm2, erythema and exudation decreased after povidone-iodine treatment.82 Antistaphylococcal treatment with cefinidir has also shown to decrease erythema and exudative lesions in atopic dermatitis along with a reduction in the density of S. aureus.86 Propylene glycol is used as inhibitor of fermentation and mold growth.87 In Sweden, moisturizers containing high concentrations (20%) of propylene glycol are approved as medicinals for the treatment of dry skin.88 Propylene glycol inhibit the growth of Trichophyton rubrum, Trichophyton mentagrophytes var. interdigitale, Epidermophyton floccosum, Malassezia, and Candida albicans, in vitro, in concentrations of 30-90 g/L.89 Propylene glycol (50%) has also shown to be useful in the treatment of tinea versicolor90 and in seborrheic dermatitis of the scalp.91 Patients with T. rubrum infections, showing therapeutic resistance to econazole, were successfully treated with econazole in combination with propylene glycol (50% in water).92 Therapeutic success probably resulted from increased absorption of econazole in combination with propylene glycol. In comparison to antibiotics and antiseptics, propylene glycol is considered to have a lower rate of contact sensitivity and less risk of bacterial resistance. The therapeutic

Humidity 5860%
66a 6163a,b 3538a,b 32a 10a 1b

Reference 66 Reference 65

moisturizers may also create some practical problems, which can discourage patients from complying with a skin care program.

Humectant Effects
Moisturizers increase SC hydration by at least two different means: a) by occlusion of the skin surface and b) by introduction of humectants, which are able to maintain the moisture in the SC. Occlusion of the surface results in reduced water loss from the outside of the skin. Hydrophobic substances (eg, lipids) in moisturizers reduce water loss, but their effect may be diminished if they are combined with other ingredients.59 62 Water contained in the applied products causes a temporary increase in skin hydration, but most of the applied water soon evaporates from the surface.60,63,64 On the other hand, evaporation lowers skin temperature, which may relieve pruritus. The inclusion of humectants in moisturizers is believed to amplify their hydrating power.65,66 Humectants widely used are urea, pyrrolidone carboxylic acid (PCA), lactic acid, glycerin, panthenol, and sorbitol (Table 1). Which of these substances most efficiently increases skin hydration is not known. Besides differences in water-binding capacity, their absorption into the skin is important for their effect. The beneficial effect of humectants on dry skin has been demonstrated in several vehicle-controlled clinical studies.6773 Another proposed effect of humectants is their influence on the crystalline arrangement of the bilayer lipids.74 In dry skin, the proportion of lipids in the solid state may be increased. Humectants may then help to maintain lipids in a liquid crystalline state at low relative humidity.74,75 For example, glycerin has been shown to maintain the liquid crystalline state of model lipids in low humidity conditions.75 Glycerin has also been proposed to aid the digestion of superficial desmosomes in subjects with dry skin and thereby ameliorate flakiness.76 Furthermore, -hydroxy acids such as lactic acid might be useful in moisturizers because of their influence on SC elasticity.77 80

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Figure 3. Disease pathogenesis and proposed therapeutic site of action of moisturizing creams and corticosteroids (modified from Reference 4).

usefulness of ordinary preservatives in moisturizers appears not to have been addressed clinically.

Figure 4. A simplified relationship between TEWL and skin condition and reported changes in TEWL from treatment with different moisturizers on diseased skin. Locobase with 20% propylene glycol and 5% lactic acid increased TEWL in ichthyosis.111 No influence was found in wet work from Locobase,166 in atopics from Fenuril with 4% urea,114 and Keratisidin with ammonium lactate.112 Reduction in TEWL was found after treatment with Canoderm with 5% urea in atopics and SLS-irritated skin110,113 and in ichthyosis with Calmuril with 10% urea and 5% lactic acid.72

Barrier-Improving Effects
Moisturizers that improve abnormal barrier function and prevent deterioration of the normal barrier will reduce the expression of atopic eczema (Figure 3).3,4 Studies also substantiate that moisturizer therapy offers a steroid-sparing alternative to topical corticosteroids in the treatment of atopic dermatitis.93 There are multiple mechanisms by which moisturizers improve barrier function. Moisturizers reduce scratching by helping to relieve the pruritus that characterizes atopic dermatitis. Furthermore, increased skin hydration increases SC elasticity and reduce the risks of cracking and barrier disruption.10 On the other hand, excessive hydration of the SC layer may also impair its diffusional resistance by creating interfacial defects in the lipid bilayer.45,94 Thus, an increased TEWL may reflect a decreased as well as an increased level of hydration (Figure 4). Furthermore, TEWL may not necessarily predict the permeability to other substances. Topically applied lipids were previously considered to exert their effects on the skin solely by forming an inert, epicutaneous, protective membrane. Common lipids that reduce TEWL include petrolatum, beeswax, long-chain esters, fatty acids, lanolin, and mono-, di-, and triglycerides.59,60 Recent findings indicate that such lipids also may diffuse more deeply into the skin. For example, petrolatum is absorbed into the outer layer of delipidized SC. Lipids that are more physiologic have been shown to penetrate into the skin and modify endogenous epidermal lipids and the rate of barrier recovery.95104 For example, a vegetable oil-containing linoleic acid was shown to change the ceramide levels

in normal human SC.101 The smaller amounts of one ceramide found in the SC in winter were restored to the larger amounts found in summer months.101 Application of certain lipids externally, may thus assist the skin in supplying damaged SC with adequate lipids. The composition of externally applied lipids may, however, be crucial for the rate of barrier recovery.102106 Different models for diseased skin have been used in which the barrier has been abrogated, for example, by successive tape strippings or by exposure to acetone or sodium lauryl sulfate (SLS). In acetone-disrupted mouse skin, mixtures containing cholesterol, fatty acids, or ceramides as the dominant lipids delayed recovery, whereas an equimolar mixture of ceramide, fatty acid and cholesterol, or pure cholesterol allowed normal barrier recovery.104 In tape-stripped aged human skin, a lipid mixture with cholesterol as the dominant lipid accelerated barrier recovery.106 In SLS-damaged human skin, no acceleration of barrier recovery was detected after treatment with ceramide 3B in different emulsions.107 Neither did a moisturizer consisting of ceramide-3, cholesterol, and fatty acids (skin identical lipids) in a petrolatum-rich emulsion show superiority to pure petrolatum in human skin, damaged by SLS and tape-strippings.108 Accelerated barrier recovery is usually found when moisturizers are compared with untreated controls in experimentally damaged skin.105,109,110 Several clinical studies have looked at the influence of moisturizers on the TEWL of diseased skin (Figure 4). In ichthyotic skin, higher TEWL was noted after treatment with a moisturizer containing propylene glycol and lactic acid, whereas, in another study on ich-

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Table 2. List of some preservatives allowed in moisturizers in European Union (Directive 76/768) and a tentative assessment of their risk of causing contact allergy, according to de Groot159. INCI-name is the International Cosmetic Ingredient Name used on cosmetics.
Maximum authorized concentration, %
0.1% 0.5 (acid) 1 0.1 Avoid formation of nitrosoamines

INCI-name (CAS-no)
Benzalkonium chloride (8001-54-5) Benzoic acid (65-85-0) Benzyl alcohol (100-51-6) 2-bromo-2-nitropropane1,3-diol (52-51-7) Butylparaben (94-26-8) Chlorhexidine (55-56-1) Chloroacetamide (79-07-2) Chloroxylenol (88-04-0, 1321-23-9) Diazolidinyl Urea (78491-02-8)

Other name/other salts

Bensalkonium bromide and - saccarinate Benzoic acid and its salts and esters Benzenmethanol, phenylcarbinol, phenylmethyl alcohol Bronopol

Notes
Labelled: Avoid contact with eyes

Risk of sensitization
Intermediate Low Low Intermediate Low Intermediate

Butylparahydroxybenzoas, butylhydroxybenzoate 0.4 Chlorhexidine and its diacetate (56-95-1) and dihydro- 0.3 chloride (3697-42-5) or didigluconate (18472-51-0) 2-chloroacetamide 0.3 4-chlor-3,5-xylenol, chlorodimethylhydroxybenzene GermallII, N-(1,3-bis (hydroxymethyl)-2,5-dioxo-5imidazolidinyl) N,N-bis(hydroxymethyl) urea, N-(Hydroxymetyl)-N-(dihydroximetyl-1,3-dioxo2,5-imidazolidinyl-4)-N-(hydroximetyl)urea 1,3-Bis (2-hydroximetyl)-5,5-dimetyl-2,4-imidazolidinedione () Formaldehyde/paraformaldehyde and its sodium salt Glutaraldehyd, 1,5-pentandial 0.5 0.5%

Labelled: Contains chloracetamide

Intermediate

Releases formaldehyde

High

DMDM Hydantoin (6440-58-0) Formaldehyde (50-00-0) Formic acid Glutaral (111-30-8)

0.6 0.2 0.5 0.1%

Low High Labelled: Contains glutaraldehyde where concentration exceeds 0.05% Releases formaldehyde Releases formaldehyde High Intermediate

Imidazolidinyl Urea (39236-46-9) Methenamine (100-97-0) Methylchloroisothiazolinone (26172-55-4) Methylisothiaz olinone (2682-20-4) Methyldibromo glutaronitrile (35691-65-7) Methylparaben (99-76-3)

Germall 115, 3,3-Bis(1-hydroximetyl-2,5-dioxoimidaxolidin-4-yl)-1,1-metylendiurea Hexamethyleneamine Kathon CG, 5-chloro-2-methyl-isothiazol-3(2H)-on and 2-methylisoyhiazol-3(2H)-on,

0.6 0.15 0.0015

Intermediate

Dibromodicyanobutane, 1,2-dibromo-2,4-dicyanobutane Metagin, Methyl hydroxybenzoate,

0.1 0.4 (acid) for 1 ester, 0,8% for mixtures of esters 0,2

High Low

p-Chloro-m-Cresol (59-50-7)

4-chloro-m-cresol, 4-chloro-5-hydroxytoluene

Phenoxyethanol (122-99-6) Pirocton olamine (68890-66-4) Propylparaben (94-13-3)

Etylenglycolmonophenyleter, 2-phenoxyetanol 1-Hydroxi-4-methyl-6(2,4,4-trimetylpentyl)2pyridone and its monoethanolamine salt Propagin, propyl hydroxy benzoate.

1 0.5% 0.4 (acid) for 1 ester, 0,8% for mixtures of esters 0.2 0.5 (acid)

Not to be used in prod- Low ucts intended to come in contact with mucous membranes Low

Low

Quaternium-15 (51229-78-8) Salicyclic acid (69-72-7)

Dowicil200, Methenamine 3-chlorallylochloride, chlorallylhexaminechloride Salicylic acid and its salts

Releases formaldehyde Not to be used in preparations for children under 3 years of age, shampoos.

High

Sorbic acid (110-44-1) Triclosan (3380-34-5)

Sorbic acid (hexa-2,4-dienacid) and its salts Triclosan

0.6 (acid) 0.5

Low/Intermediate Low

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thyosis, a lower TEWL was found after treatment with 10% urea.72,111 In one study on dry skin in atopic and nonatopic individuals, a moisturizer containing ammonium lactate as humectant had no effect on TEWL, although clinical appearance improved.112 One moisturizer with 5% urea reduced TEWL in a study of atopic patients, but in another study, a different moisturizer with 4% urea did not reduce TEWL in atopic subjects.113,114 The same 4% urea moisturizer was superior to 20% glycerin in lowering TEWL in a recent study of dry skin of atopic patients.115 Moreover, a particular ceramide-dominant lipid mixture improved childhood atopic dermatitis, resulting in a lower disease severity score and decreased TEWL.116 Despite these findings, the use of moisturizers with urea has been questioned, especially with regard to the risk of reducing the chemical barrier function of the skin to toxic substances.117 Urea has been shown to act as a penetration-enhancer in some single-application studies.118 122 For example, in one study, the time to onset of erythema from exposure to hexyl nicotinate was shortened by 10% urea, whereas in another study no influence on the time to redness was detected.118,123 Absence of penetration enhancement has also been reported by others, and repeated applications of ureacontaining moisturizers have actually been shown to make skin less susceptible to the irritant, as well as reduce TEWL in normal skin SLS109,110,124,125 (Fig. 5). As a contrast, treating normal skin with a moisturizer without any humectant but with high lipid content had no influence on TEWL but increased skin susceptibility to SLS-induced irritation.105,126 These results emphasize the importance of other ingredients in the moisturizers so that the content of emulsifiers, lipids, and preservatives may well influence their ultimate effect. pH and the formation of ammonia in urea-containing product also have to be taken into account.

exert therapeutic effects remain unclear, but studies indicate that polyunsaturated fatty acids in the oils can be transformed enzymatically into putative antiinflammatory products by the epidermis.129 Dietary supplementation with fish oil and purified ethyl ester of eicosapentaenoic acid (20:5, n-3) from fish oil has antiinflammatory effects on ultraviolet B-induced acute inflammation.130 132 The enzyme -6-desaturase, which converts linoleic acid into -linolenic acid, might also play a role, because it has been suggested to be impaired in atopic eczema.133 Several dietary oil supplements have been suggested to improve atopic dermatitis. Some studies have also shown promising effects of evening primrose oil, a vegetable oil rich in -linolenic acid, when administered po to atopic patients.134,135 This was not confirmed in more recent double-blind, placebo-controlled studies in children and adults.136 138

Adverse Effects of Moisturizers

Moisturizers are considered very safe, especially when compared to some drugs eg, topical corticosteroids, prescribed by dermatologists. Adverse skin reactions from topical moisturizer preparations are not uncommon. Virtually any topical substance can irritate the skin, but some individuals are more susceptible than others. Atopics are particularly at risk for adverse skin reactions, due to their impaired barrier function. Facial skin is also more prone to adverse skin reactions than other body regions, possibly because of a less efficient barrier, with a smaller number of SC cell layers and the presence of large follicular pores.139 141 The most common adverse reactions are sensory or subjective sensations (no signs of inflammation) immediately after application of a topical product. Smarting, burning, and stinging sensations are examples of such reactions. Some preservatives, like benzoic acid and sorbic acid, and humectants, such as lactic acid, urea, pyrrolidone carboxylic acid, and sodium chloride, are well known to cause uncomfortable subjective sensations.142145 Facial skin and excoriated skin in general are most sensitive to stinging.144 When atopics were asked to judge the degree of adverse skin reactions to urea-containing moisturizers, 20-40% reported smarting sensations, ie, a sharp, local, superficial effect similar to the reaction caused by acidic solutions.146 Combinations containing corticosteroids do not eliminate this stinging. In fact, 12-30% of eczema patients using hydrocortisone creams with 4-20% urea reported stinging.69,147,148 Formulations without agents known to cause stinging may also induce sensory reactions. Some patients develop status cosmeticus in which every product applied to the face produces itching, burning, or stinging sensations.143 It is not known whether sensory sensations following application of moisturizers can affect the barrier properties of the skin, but it has

Antiinflammatory Effects
There is a growing recognition that lipids in the skin function as modulators of inflammation and the immune response. Lipids in ointment bases have been found to have an antimitotic effect on the epidermis of stripped dorsal skin of hairless mice.127 One class of lipids, very important in this regard, is that of the essential fatty acids (EFA), which can be divided into two families, the omega-6 and omega-3 fatty acids, derived from linoleic and -linoleic acid, respectively. EFA influence skin physiology via their effects on skin barrier function, eicosanoid production, membrane fluidity, and cell signaling.128 The EFA are found predominantly within the epidermal phospholipids, but are also incorporated in ceramides where they play a critical role in barrier function. The most abundant EFA in the skin is linoleic acid and its metabolite arachidonic acid. The biochemical mechanisms by which EFA may

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Figure 5. Normal skin susceptibility to SLS exposure after repeated application (21-27 days) of moisturizers. The susceptibility was measured as TEWL and is expressed in percentage of the untreated control arm. The figure is adopted from values reported in the literature; the ordinary moisturizer contained 18% lipids,109 the high lipid content cream contained 70% lipids (Locobase, Yamanochi126), 20% glycerin cream in an ordinary cream base (Miniderm, ACO Hud115), 10% urea in a cream base also containing 5% lactic acid (Calmuril, Pharmacia109), and 5% urea in an ordinary cream base (Canoderm, ACO Hud110). The asterisks denote result significantly different from the control area (P .05).

been shown that lactic acid stimulates the production of ceramides and makes the skin more resistant to xerosis.149 Moisturizers are usually free from strong irritants, however repeated application of mildly irritating preparations to sensitive areas may increase TEWL and cause dermatitis (Figure 2). For example, frequent immersion of the skin in water paradoxically is counterproductive to moisturization.10,150 Classic hydrophilic ointment is stabilized with emulsifying wax (British Pharmacopoeia 1988) containing the well-known irritant SLS at a concentration of 10% as coemulsifier.151 Aqueous solutions of 1% SLS are commonly used in experimental dermatology to induce irritation.152 Also, fatty acids sometimes found in moisturizers as emulsifiers can influence skin barrier properties.153,154 Nonionic emulsifiers, because of their mildness, are the preferred stabilizers for emulsions, but TEWL measurements indicate that some of them may also produce invisible barrier damage when applied to normal skin.154 Nonionic polyethylene glycol emulsifiers are also susceptible to oxidation, inducing formation of peroxides and aldehydes.155 Propylene glycol may also cause adverse reactions in normal subjects at concentrations as low as 10% under occlusive conditions and in dermatitis patients at concentrations as low as 2%.156 158 The nature of the cutaneous response remains obscure and therefore the skin reactions to propylene glycol have been classified into four mechanisms: a) irritant contact dermatitis, b) allergic contact dermatitis, c) nonimmunologic contact urticaria, and d) subjective or sensory irrita-

tion.144,157 Propylene glycol is also regarded as a penetration enhancer. Potential allergens in moisturizers are mainly fragrances and preservatives. Virtually all moisturizers on the market contain fragrances. These have no medical role, but their inclusion into creams and lotions may enhance patient compliance. Fragrances are the most frequent sensitizers in topically applied products. The prevalence of sensitization to fragrances has increased; in eczema patients treated by dermatologists, the prevalence is between 6-14%.159,160 More than 2000 substances are used in fragrances and over 100 have been identified as allergens.159 Product labeling of moisturizers should identify the major fragrance allergens that they contain. Patch testing to individual allergens can then be performed on persons with a history of allergy to moisturizers. This would enable these patients to avoid formulations to which they might be sensitive, just as is presently done with the testing and labeling of preservatives. After fragrances, preservatives are the next most common sensitizers in skin care products. The main preservative allergens are listed in Table 2 along with a proposed assessment of their relative risk of causing contact allergy. Very rarely, humectants, emulsifiers, and oils cause contact allergy.159 Some dermatologists consider the lanolins to be a frequent cause of contact allergy, but this notion is probably a result of inappropriate testing conditions leading to false-positive reactions.159 Cosmetic acne and folliculitis resulting from blockage of the follicular orifices are rarely encountered side effects of moisturizers. Teenagers are particularly prone to this reaction. Application of the product in the direction of hair growth is sometimes recommended to prevent folliculitis. In addition, thick formulations can obstruct sweat gland orifices in hot, humid weather and cause sweat rash or miliaria. Photosensitivity dermatitis is another very rare adverse effect that can be caused by wide variety of ingredients. Sunscreens, fragrances, and halogenated preservatives are the most frequent offenders. Systemic side effects of moisturizers are extremely rare. Ingredients reported to be capable of inducing systemic toxicity are salicylic acid and propylene glycol. Salicylic acid has weak antimicrobial activity and is used to reduce the amount of scales in hyperkeratotic skin.151 When used as a preservative in cosmetics, a maximum concentration of 0.5% is allowed in Europe. The acid is readily absorbed by the skin, and symptoms of salicylate poisoning have been reported after excessive application of high concentrations (5%) to large areas of the body.151 Propylene glycol has been given an acceptable daily intake value of 25 mg/kg by the joint FAO/World Health Organization Expert Committee of Food.161 Poi-

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soning has been found after oral doses of about 100-200 mg/kg in children and after topical treatment with high concentrations in burn patients.162165 Hence, repeated applications of high concentrations (20%) of propylene glycol should be avoided on large body areas in children with diseased skin (Figure 5).

Conclusions
The SC should be protected against deleterious substances and strengthened by the use of moisturizers in patients with atopic dermatitis. The SC is a sophisticated biosensor that responds to external perturbations; the epidermal abnormality in atopic eczema is a critical exacerbant of the dermatitis and not just a secondary phenomenon to an internal disease.4 The majority of currently available branded and generic moisturizers are aimed at treatment of dry skin in general and do not scientifically address the pathogenesis of atopic dermatitis. Emerging evidence indicates that certain lipid mixtures and humectants are more efficient than others in improving skin barrier function, in addition to diminishing signs of dryness.5 Ingredients such as emulsifiers, pH, chelating agents, antioxidants, and preservatives may need to be addressed in future studies on patients with atopic dermatitis.5

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