THE EFFECT OF A HUMECTANT EMOLLIENT CREAM CONTAINING 5% UREA COMPARED TO A NON-HUMECTANT EMOLLIENT ON THE SKIN BARRIER IN OLDER PEOPLE WITH DRY SKIN

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1 POSTERS WORLD CONGRESS OF DERMATOLOGY 2015 Poster 1: THE EFFECT OF A HUMECTANT EMOLLIENT CREAM CONTAINING 5% UREA COMPARED TO A NON-HUMECTANT EMOLLIENT ON THE SKIN BARRIER IN OLDER PEOPLE WITH DRY SKIN Simon G. Danby 1, Kirsty Brown 1, Tim Higgs-Bayliss 1, John Chittock 1, Michael J. Cork 1,2 1 The Academic Unit of Dermatology Research, Dept. of Infection and Immunity, The University of Sheffield Medical School, Sheffield, UK; 2 The Paediatric Dermatology Clinic, Sheffield Children's Hospital, Sheffield, UK Background: Xerosis affects between 30 and 75% of older people. The development of xerotic skin conditions, such as atopic dermatitis, asteatotic eczema and winter xerosis, is associated with a skin barrier defect. This defect is characterised by reduced levels of natural moisturising factor (a collection of natural humectants including urea, pyrrolidone carboxylic acid [PCA], and lactate), abnormal intercellular lipid levels in the stratum corneum (SC), and elevated skin surface ph (linked to increased skin barrier breakdown). Emollients are widely used to treat xerosis, however there is limited mechanistic evidence of their effects on the skin barrier. Objective: The aim was to compare the effect of a humectant emollient, containing 5% urea and lactate, to a non-humectant emollient on the properties of the skin barrier. Methods: Two cohorts of 21 volunteers aged 60+ years with dry skin were recruited. The first applied 2 fingertip units twice daily of the humectant emollient to one forearm and no treatment to the other for 28-days. The second applied the humectant emollient to one forearm and the non-humectant emollient to the other observing the same treatment parameters. Treatment allocation was randomised. The biophysical and biological properties of the skin were determined approximately 20 hours after cessation of treatment. Local research ethics committee approval was granted. Results: Compared to no treatment, the humectant emollient significantly: improved skin barrier function (decreased TEWL), SC integrity and skin hydration (capacitance); decreased skin surface ph 0.14 units and reduced SC protease activity by 43%. The humectant and nonhumectant emollients had similar effects on TEWL and capacitance, however the humectant emollient was associated with significantly improved SC integrity (TEWL after 20 tape-strips was 24 vs. 35 g/m2/h), lower skin surface ph (5.00 vs. 5.23) and protease activity (1.24 vs. 1.61

2 nu/µg); elevated SC lactate levels (157% vs. 81%) and PCA (not present in either formulation) levels (143 vs 106%) compared to before treatment; and increased water (SC specific hydration) and NMF (carboxylate) content in the upper SC (172 vs 109%) assessed by in vivo ATR-FTIR. Conclusion: In contrast to the non-humectant emollient, the humectant emollient significantly improved skin barrier condition, associated with elevated NMF levels (exogenously and endogenously, putatively via increased filaggrin expression), reduced skin surface ph and decreased protease activity. This highlights the significant difference in effects of emollients on the skin barrier, and their potential to treat xerotic skin conditions.

3 Poster 2: SOAP-INDUCED DAMAGE TO THE STRATUM CORNEUM ARISES AS A RESULT OF ELEVATED PROTEOLYTIC DEGRADATION OF CORNEODESMOSOMES Simon G. Danby 1, Andrew Wigley 1, Neena Tierney 2, Katharine Martin 2, Georgios Stamatas 2, Michael J. Cork 1 1 The Academic Unit of Dermatology Research, Dept. of Infection and Immunity, The University of Sheffield Medical School, Sheffield, UK; 2 Johnson & Johnson Consumer Companies Inc., Skillman, New Jersey, USA Background: The use of soap and harsh surfactants dehydrates the skin and exacerbates atopic dermatitis (AD). Current guidelines advise against the use of soap and harsh detergents for washing by patients with AD, however the extent of the damage caused by these agents, and their role in aggravating AD is not fully understood. A greater understanding of the negative effects of some detergents is required so that mild detergents suitable for washing the skin of susceptible individuals can be identified. Objective: To determine the effect of washing with soap compared to water alone, and a liquid cleanser containing a synthetic detergent designed for use in babies, on the biophysical and biological properties of the skin. Methods: Three cohorts of volunteers were recruited. In the first 10 participants washed one forearm with soap (traditional bar) and water and the other with water alone once. The biophysical properties of the skin were assessed before and at set time points after washing. In the second, 5 participants repeated the washes 3 times per day for 7 days. The biophysical and biological properties of the skin were measured before and 24 hours following washing. In the third cohort, 12 participants washed one forearm with soap and the other with a liquid cleanser once. Results: Washing the skin once with soap and water significantly elevated skin surface ph (2.0±0.27 units) and stratum corneum (SC) chymotrypsin-like protease activity (5.0±1.27-fold) for more than 4 hours. Repeated washing over a 7 day period resulted in elevated skin surface ph (1.4±0.43 units, p=0.0324), increased SC protease activity (7.6±2.35-fold, p=0.0334), decreased skin barrier function (elevated trans-epidermal water loss by 6.8±2.24 g/m /h, p=0.0378), and a reduction of desmoglein 1 staining on the surface of the uppermost corneocytes. Protease activity was significantly correlated with desmoglein 1 staining (r=0.7697, p=0.0126). A single wash with the mild liquid cleanser was comparable to washing with water alone. Conclusions: Washing with soap elevates protease activity within the SC leading to increased skin barrier breakdown. Accelerated proteolytic breakdown of the skin barrier is a mechanism by which flares of AD develop, explaining why washing with soap exacerbates AD. Moreover the

4 findings suggest that washing with soap could contribute to the development of AD. Washing with a liquid cleanser optimized for use in babies did not affect SC protease activity, and therefore its use may help protect against skin barrier breakdown and the development of AD.

5 Poster 3: A FUNCTIONAL MECHANISTIC STUDY TO INVESTIGATE THE EFFECT OF TOPICAL ANTI- INFLAMMATORIES ON THE EPIDERMAL BARRIER: IMPLICATIONS FOR THE TREATMENT OF ATOPIC DERMATITIS John Chittock 1, Kirsty Brown 1, Michael J. Cork 1,2, Stephen J. Matcher 3, Zenghai Lu 3, Joseph Boadi 3 and Simon G. Danby 1 1 The Academic Unit of Dermatology Research, Department of Infection and Immunity, The University of Sheffield Medical School, UK; 2 The Paediatric Dermatology Clinic, Sheffield Children's Hospital, UK; 3 The Kroto Institute, The University of Sheffield, UK Background: Epidermal barrier breakdown is a key event in the development of Atopic dermatitis (AD). Topical corticosteroids (TCS) are effective first-line treatments for AD but are associated with atrophy and the rebound flare phenomenon. Topical calcineurin inhibitors (TCI) offer a valid alternative but their effect on the epidermal barrier is poorly understood. Here, a novel study design is introduced using subjects with quiescent AD that are flare-free; allowing the interaction of the topical treatments with the epidermal barrier to be determined, independent from their primary anti-inflammatory and immunomodulating properties. Objective: To compare the effect of a twice-daily TCS dose against an equivalent TCI dose on the biophysical and biological properties of the epidermal barrier. Methods: A randomised, observer-blind, functional mechanistic study was conducted in twenty volunteers with quiescent AD. Two fingertip units of betamethasone valerate (0.1%) cream (BMVc) was applied to one forearm, and the same dose of tacrolimus (0.1%) ointment (TACo) to the opposing forearm, twice-daily for a total duration of four weeks to mimic a flare stabilisation regimen. Assessment of epidermal barrier function was performed both prior to, and after treatment using a range of specialised investigative techniques including: Transepidermal water loss (TEWL) measurements combined with tape stripping; assessment of skin-surface ph and stratum corneum (SC) hydration; quantification of SC protease activity and natural moisturising factor from collected tape strips; and measurement of epidermal thickness using optical coherence tomography. For comparison, a cohort of 19 volunteers with active AD or healthy skin were assessed at untreated sites. Results: Subjects with quiescent AD possess an epidermal barrier defect compared to healthy skin that responded differentially to the treatments under investigation. Compared to BMVc, TACo preserved epidermal thickness, barrier function (inside-out), integrity, cohesion and the level of 2-pyrrolidone-5-carboxylic acid (PCA) and urocanic acid (UCA) in conjunction with significantly elevating SC hydration. The damage to SC integrity by BMVc was comparable to that observed in active AD at non-lesional sites. Both treatments lowered SC ph and trypsin-like protease activity with TACo doing so to a significantly greater degree.

6 Conclusions: A functional mechanistic study using subjects with quiescent AD is a useful tool for assessing the direct interaction of topical anti-inflammatory treatments with the defective epidermal barrier. Using this study design, TACo was found to preserve multiple components of epidermal barrier function, suggesting it is more suitable for the management of atopic dermatitis.

7 Poster 4: COMPARING THE EFFECT OF TACROLIMUS (0.1%) OINTMENT AND BETAMETHASONE (0.1%) VALERATE ON THE EPIDERMAL BARRIER: A TWICE-WEEKLY MAINTENANCE DOSE John Chittock 1, Kirsty Brown 1, Michael J. Cork 1,2, and Simon G. Danby 1 1 The Academic Unit of Dermatology Research, Department of Infection and Immunity, The University of Sheffield Medical School, UK; 2 The Paediatric Dermatology Clinic, Sheffield Children's Hospital, UK. Background: The proactive use of topical anti-inflammatories is an effective method of addressing the subclinical inflammation associated with the remission phase of atopic dermatitis (AD). To date, the interaction of this treatment dose with the subclinical epidermal barrier defect in AD is yet to be determined. Objective: To compare the effect of a proactive topical corticosteroid dose against an equivalent topical calcineurin inhibitor dose on the biophysical and biological properties of the epidermal barrier. Methods: A randomised, observer-blind, functional mechanistic study was performed in seventeen volunteers with quiescent AD, whereby two fingertip units of betamethasone valerate (0.1%) cream (BMVc) was applied to one forearm, and the same dose of tacrolimus (0.1%) ointment (TACo) to the opposing forearm, twice-weekly for a total duration of eight weeks. Epidermal barrier function, stratum corneum (SC) integrity and cohesion was determined by combining Transepidermal water loss (TEWL) measurements with tape-stripping to 20 discs (TS 20). Skin-surface ph and SC hydration was assessed by non-invasive probes. Protease activity in the SC was quantified by a fluorescence cleavage assay from collected tape-strips. Results: Compared to baseline (pre-treatment) measurements, application of BMVc produced a small but significant elevation of skin-surface ph (baseline: ±0.05 units, treated: ±0.07 units, *p = < 0.001) with concomitant loss of SC cohesion represented by the greater mass of SC removed during tape-stripping (TS 20) (baseline: Area under the curve [AUC] ±54.55 μg/cm 2.TS 20, treated: AUC ±75.24 μg/cm 2.TS 20, *p = < 0.05). BMVc preserved epidermal barrier function and SC integrity. By contrast, TACo improved SC integrity, as evidenced by significantly reduced Transepidermal water loss (TEWL) recorded at disc 20 (baseline: TEWL 20: ±5.13g/m 2 /h, treated: TEWL 20: ±3.94g/m 2 /h, *p = < ). This was coupled with an overall hydrating action on the SC (baseline: ±1.23 Relative Capacitance Units [RCU], treated: ±1.45 RCU, *p = < 0.01). TACo significantly suppressed caseinolytic (baseline: 4.73 ±0.23 nu/μg, treated: 4.21 ±0.27 nu/μg, *p = < 0.05) and trypsin-like protease activity (baseline: 1.66 ±0.09 nu/μg, treated: 1.20 ±0.12 nu/μg, *p = < 0.05). Conclusions: The differential results observed support the use of TACo to promote reparation of the subclinical barrier defect associated with quiescent AD. Repairing the defective epidermal

8 barrier during long-term treatment regimens could have significant influence on reducing the severity of AD, and be disease modifying.