Dry skin in atopic dermatitis

Takahashi M. Skin care in atopic dermatitis -Characterizing dry skin in atopic dermatitis and utility of skin care-. J Jpn Cosmetic Science Sciety. 21 50-55(1997). 

Loden, M., Andersson, A.C., Andersson, C., Frodin, T., Oman, H., and Lindberg, M., Instrumental and dermatologist evaluation of the effect of glycerine and urea on dry skin in atopic dermatitis, Skin. Res. 

Chapter 9 Dry Skin in Atopic Dermatitis and Patients on Hemodialysis Motoji Takahashi and Zenro Ikezawa 95... 

Clinically unaffected skin in atopic dermatitis differs from normal skin the underlying barrier defect associated in more than 30% with filaggrin loss of function mutations first published in 2006 [4] leads to dry skin associated with a greater irritant skin response than in normal healthy skin. Microscopic studies revealed a sparse perivascular T cell infiltrate in unaffected atopic dermatitis skin that is not seen in normal healthy skin. 

Dry, scaly skin is characterized by a decrease in the water retention capacity of the stratum corneum (SC),1 with water content diminished to less than 10%. Barrier function of the SC is usually declined, and transepidermal water loss (TEWL) is increased because of an abnormality on barrier homeostasis.2 People feel tightness of their skin, and the skin surface becomes rough, scaly, and sensitive. Hyperkeratosis, abnormal scaling, and epidermal hyperplasia are usually observed in the dry skin.2 Keratinization also shows abnormal features.2 These phenomena are commonly observed in atopic dermatitis and psoriasis.3 Dermatitis induced by environmental factors such as exposure to chemicals, low humidity, and UV radiation also shows these features. Thus, many researchers have been investigating the cause and treatment of dry skin, and there is currently great interest in adequate model systems for dry skin studies. In this chapter, I will describe several model systems of dry skin for clinical research of dermatitis associated with skin surface dryness and also mention recent studies to improve the dry skin. 

Moisturizers and emollients have been used for years in patients with dry skin with some relief in pruritus. Moisturizers are one of the gold standards of treatment in atopic dermatitis, the hallmark... 

RCTs it is therefore possible to gain information about the efficacy of moisturizers as monotherapy. The effect of the cream base varies. In a stable, dry, and scaly dermatosis such as psoriasis, active treatment with calcipotriol reduces disease severity as assessed by PASI scores by 56%, whereas the use of the cream base reduces it 35%.1 Dry skin is also a key diagnostic element in atopic dermatitis and moisturizers are therefore extensively used in this disease. Looking at the placebo-arm in RCTs of topical treatment of atopic dermatitis the placebo effect appears to be in the range of 20%.2 6 The disease is however also more dynamic, and it waxes and wanes more frequently than psoriasis, which may explain the difference seen between the two disseases. 

The level of evidence for the clinical efficacy of 4 to 10% urea in the treatment of dry skin in patients with atopic dermatitis support evidence-level lb. A formal meta-analysis may give further support for level la. 

Evidence from at least one randomized controlled trial (level I) show that 10% urea is effective for the treatment of psorisasis, ichthyosis, and dry feet, and 4 to 10% for the treatment of dry atopic skin and senescent skin. Evidence from another well-designed clinical study (level II) supports the treatment of hand dermatitis with urea. Evidence at level I also exist showing barrier improving effects of urea in both normal and in dry skin disorders (atopic skin, ichthyosis). Furthermore, strong evidence exists (level I) for reduced susceptibility to SLS, but not to other external agents. No evidence has been found for successful treatment of seborrhoic dermatitis, perioral dermatitis, and keratosis pilaris with urea. 

When a 2% nicotinamide solution was applied twice daily for 4 weeks and compared to vehicle in volunteers with dry skin the ceramide levels in the epidermis increased by 34%, the free fatty acid levels by 67% while the transepidermal waterloss decreased by 27%. This indicates an improvement of a deficient epidermal permeability barrier by an increase in intercellular lipids, especially ceramides.116 The level of ceramides in the stratum comeum is known to be reduced in atopic dermatitis and aged skin.117,118... 

In atopic dermatitis, there is evidence that dry skin and eczema are related sphingomyelin is not used for synthesizing the ceramides due to an abnormal sphingomyelin acylase activity. Instead, it is metabolized into the pro-inflammatory sphingosyl-phosphorylcho-line that enhances arachidonic acid or eicosanoid release and increases membrane ICAM-i expression in human keratinocyte cultures (Murata et al. 1996). 

Diagnostic criteria for atopic dermatitis include the presence of pruritus with three or more of the following (1) history of flexural dermatitis of the face in children younger than 10 years of age (2) history of asthma or allergic rhinitis in the child or a first-degree relative (3) history of generalized xerosis (dry skin) within the past year (4) visible flexural eczema (5) onset of rash before 2 years of age. 

There are several genetic skin diseases with known defects in the lipid metabolism. Atopic dermatitis, lamellar ichthyosis, and psoriasis have been the most widely studied with respect to epidermal barrier function and alterations in the lipid profile. Deviations in the lipid profile have been linked with an impaired stratum corneum barrier function. Atopic dermatitis is characterized by inflammatory, dry and easily irritable skin, and overall reduced ceramide levels in the stratum corneum [58-60]. In particular a significant decrease in the ceramide 1 level is observed, whereas the levels of oleate that is esterified to ceramide 1 are elevated [59]. Both aberrations may be responsible for the reduced order of the lamellar phases as observed with freeze fracture electron microscopy [61]. It has further been established that, in comparison to healthy stratum corneum, the fraction of lipids forming a hexagonal packing is increased [61]. A recent study reveals that the level of free fatty acids... 

Imokawa, G., et al. 1991. Decreased level of ceramides in stratum corneum of atopic dermatitis An etiologic factor in atopic dry skin J Invest Dermatol 96 523. 

Werner, Y. and Lindberg, M. Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis. Acta. Derm. Venereol. (Stockh.) 65 102-105 (1985). 

Previously13 investigators usually used back or forearm skin for the experiment. It was easier to induce scaly skin on back skin than on forearm skin. In the case of back skin, we stripped SC nine times with adhesive cellophane tape. At that time, the transepidermal water loss (TEWL) value was over 10 mg/cm2/h and most of the SC was removed. In the case of forearm, to induce dry, scaly skin, stripping for 30 to 50 times was needed. One week after treatment, TEWL was higher than the normal level, skin surface conductance decreased, and SC cell area also decreased (Table 10.1). The skin surface became scaly and flaky. Figure 10.1 shows skin surface pictures of the forearm skin with and without barrier disruption. Abnormal scaling is observed on the surface of skin, which was treated with tape stripping. These phenomena are commonly observed in natural dry skin, such as atopic dermatitis and psoriasis. 

As described previously, one can induce dry, scaly skin, which shows features very similar to dermatitis such as atopic dermatitis and psoriasis. Use of this experimentally induced dry skin should enable the discovery of a new clinical methodology to cure or care for skin problems. Recently, several excellent in vitro skin models have been reported. Although they are also very useful models for the study of cutaneous metabolism, their function and microstructure are still different from those of intact skin. On the other hand, the mechanisms underlying abnormal desquamation, that is, scaling in the dry skin such as atopic dermatitis, are not completely known. Sato et al. reported55 the inhibition of protease in the SC induced scale without affecting epidermal mitosis. This result seems to be no direct relationship between skin surface appearance and epidermal proliferation. However, decline of SC barrier function induced epidermal hyperplasia, as described earlier.30 The loss of water content from SC also induced epidermal DNA synthesis.30 Further mechanistic studies on each of the dry skin features are required. 

Miyamoto et al. have also demonstrated in the dry skin and itch mouse model (water + acetone ether treated) that the scratching response can be inhibited by the use of atropine, a nonspecific muscarinic acetylcholine receptor (mAChR) antagonist, and 4-diphenyl-acetoxy-N-methyl-piperidine (4-DAMP), an M3 mAChR antagonist.32 They further showed that Mi and M2 mAChR antagonist were not able to inhibit the scratch response. This report suggests the role of acetylcholine, and the M3 specific receptor as a potential player in dry-skin-associated pruritus. In addition, skin biopsies in human subjects with atopic dermatitis were found to have increased levels of acetylcholine compared with normal controls, which suggests that abnormal concentrations of neurotransmitters may also be involved in itch secondary to xeroderma.33... 

Importantly, not all moisturizers provide the same effect in restoration of the barrier function. Certain lipid mixtures or an inadequate concentration of physiologic lipids actually have been demonstrated to inhibit barrier restoration.42,43 Newer ceramide-dominant emollients have been developed in efforts to restore the intrinsic physiologic lipid concentration of the skin. One type of ceramide-dominant emollient was shown to significantly improve the overall severity of atopic dermatitis and demonstrated correction of transepidermal water losses in these patients.44 Unfortunately, studies using ceramide-dominant emollients for patients with atopic dermatitis did not use itch improvement as an endpoint. However, these types of moisturizers likely have a role in the improvement of itch associated with dry skin. 

Reduced NMF levels are also implicated in the more common dry skin conditions. Subjects with atopic dermatitis have decreased levels of NMF,80 and FAA levels have been reported to decrease significantly in dry, scaly skin induced experimentally by repetitive tape stripping.81 Additionally, a significant correlation exists between SC hydration state and the FAA content of elderly individuals with skin xerosis.82... 

Few reports have investigated the therapeutic and cosmetic applications of sphingolipids on skin, except for ceramides, which can be used for treatment of dry skin such as atopic dermatitis. However, various in vitro studies have demonstrated the biological effects of sphingolipids on differentiation... 

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