Dupilumab Treatment in Pediatric Patients Aged 6-11 Years with Severe Atopic Dermatitis Whose Disease Is Not Adequately Controlled: A Review.

Atopic dermatitis (AD) is the most common inflammatory skin disease in children. Children with severe AD have a multidimensional disease burden characterized by skin lesions, itching, frequent infections, sleep deprivation, and a high rate of comorbidities. These impact the mental health and overall quality of life of not only the children but also of their parents and caregivers. There are few effective available treatment options for young children with severe AD that are suitable for long-term use. Due to their adverse effects, practice guidelines consider systemic agents inappropriate for this age group, although they are still used off-label in extreme cases. The biologic dupilumab has recently been approved for children aged 6-11 years with severe (EU) and moderate-to-severe (USA) AD, offering hope to this population of patients with a high unmet clinical need. The purpose of this review is to describe the unmet needs of AD patients aged 6-11 years prior to dupilumab approval and to summarize existing clinical data supporting dupilumab's safety and efficacy in these children.

Maintenance of an Acidic Skin Surface with a Novel Zinc Lactobionate Emollient Preparation Improves Skin Barrier Function in Patients with Atopic Dermatitis.

INTRODUCTION: The skin of patients with atopic dermatitis (AD) is characterised by elevated pH. As a central homeostatic regulator, an increased pH accelerates desquamation and suppresses lipid processing, resulting in diminished skin barrier function. The aim of this study was to determine whether a novel zinc lactobionate emollient cream can strengthen the skin barrier by lowering skin surface pH. METHODS: A double-blind, forearm-controlled cohort study was undertaken in patients with AD. Participants applied the test cream to one forearm and a vehicle cream to the other (randomised allocation) twice daily for 56 days. Skin surface pH and barrier function (primary outcomes) were assessed at baseline and after 28 days and 56 days of treatment, amongst other tests. RESULTS: A total of 23 adults with AD completed the study. During and after treatment, a sustained difference in skin surface pH was observed between areas treated with the test cream and vehicle (4.50 ± 0.38 versus 5.25 ± 0.54, respectively, p < 0.0001). This was associated with significantly reduced transepidermal water loss (TEWL) on the test cream treated areas compared with control (9.71 ± 2.47 versus 11.20 ± 3.62 g/m2/h, p = 0.0005). Improvements in skin barrier integrity, skin sensitivity to sodium lauryl sulphate, skin hydration, and chymotrypsin-like protease activity were all observed at sites treated with the test cream compared with the control. CONCLUSION: Maintenance of an acidic skin surface pH and delivery of physiologic lipids are beneficial for skin health and may help improve AD control by reducing sensitivity to irritants and allergens.

Association between skin barrier development and early-onset atopic dermatitis: A longitudinal birth cohort study.

BACKGROUND: A diagnosis of atopic dermatitis (AD) is common during infancy; however, it is unclear whether differential skin barrier development defines this period and signals disease onset in predisposed individuals. OBJECTIVE: We sought to study (NCT03143504) and assess the feasibility of remote skin testing from birth to monitor skin barrier maturation and model association with an AD diagnosis by age 12 months. METHODS: Biophysical testing and infrared spectroscopy were conducted at the maternity ward and family home. Tape stripping collected samples for desquamatory protease and natural moisturizing factor analysis. The 4 common European filaggrin risk alleles were screened. RESULTS: A total of 128 infants completed the study, with 20% developing mild disease. Significant changes in permeability barrier function, desquamatory protease activity, and molecular composition assessed spectroscopically were observed longitudinally, but only subtle evidence of differential skin barrier development was noted between infant subgroups. Common filaggrin risk alleles were strongly associated with early-onset disease and conferred a significant reduction in natural moisturizing factor and water content by age 4 weeks. Accounting for a family history of atopy, these parameters alongside a greater lipid/protein ratio and reduced chymotrypsin-like activity at birth were associated with AD. Measured in ambient conditions, transepidermal water loss did not signal disease risk at any stage. CONCLUSIONS: Skin barrier dysfunction lacked an acquired modality but was considered proportional to cohort severity and suggests that a portfolio of tests used in a community setting has the potential to improve current AD risk evaluations from birth.

Characterisation of skin barrier defects in atopic dermatitis patients using Infrared Spectroscopy.

INTRODUCTION: Atopic dermatitis (AD) is characterised by skin barrier defects often measured by biophysical tools that observe stratum corneum (SC) functional properties. OBJECTIVE: To employ in vivo infrared spectroscopy alongside biophysical measurements to analyse changes in chemical composition of the SC in relation to AD severity. METHODS: We conducted an observational cross-sectional cohort study where attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopy measurements were collected on the forearm alongside surface pH, capacitance, erythema and transepidermal water loss (TEWL) combined with tape stripping (STS) in a cohort of 75 participants; 55 AD patients stratified by phenotypic severity, compared to 20 healthy controls. Common filaggrin (FLG) variant alleles were genotyped. RESULTS: Reduced hydration, elevated TEWL and redness all associated with greater AD severity. Spectral analysis showed a reduction in 1465cm-1 (full width half maximum) and 1340 cm-1 peak areas indicative of less orthorhombic lipid ordering and reduced carboxylate functional groups that correlated with clinical severity (lipid structure r=-0.59, carboxylate peak area r=-0.50). CONCLUSION: ATR-FTIR spectroscopy is a suitable tool for the characterisation of structural skin barrier defects in AD and has potential as a clinical tool for directing individual treatments based on chemical structural deficiencies.

Potential application of PS-OCT in the safety assessment of non-steroidal topical creams for atopic dermatitis treatment.

Crisaborole 2% ointment is a non-steroidal treatment for mild-moderate atopic dermatitis (AD) and may produce fewer adverse effects than topical corticosteroids (TCS). We used PS-OCT to quantify dermal collagen at baseline and after 29 days of treatment with crisaborole and betamethasone valerate (BMV), in 32 subjects. PS-OCT detected a mean increase 1 × 10-6, 95% CI (6.3, 1.37) × 10-6 in dermal birefringence following TCS use (p < 0.0001, ad-hoc, not powered), whereas a change of -4 × 10-6, 95% CI (-32, 24) × 10-6 was detected for crisaborole (p = 0.77, ad-hoc, not powered). These results could suggest a differential effect on dermal collagen between the two compounds. PS-OCT may thus find an important role in safety assessment of novel AD treatment' and larger trials are warranted.

Targeting Skin Barrier Function in Atopic Dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the general population. Skin barrier dysfunction is the central abnormality leading to AD. The cause of skin barrier dysfunction is complex and rooted in genetic mutations, interactions between the immune pathway activation and epithelial cells, altered host defense mechanisms, as well as environmental influences that cause epithelial cell activation and release of alarmins (such as thymic stromal lymphopoietin) that can activate the type 2 immune pathway, including generation of interleukins 4 and 13, which induces defects in the skin barrier and increased allergic inflammation. These inflammatory pathways are further influenced by environmental factors including the microbiome (especially Staphylococcus aureus), air pollution, stress, and other factors. As such, AD is a syndrome involving multiple phenotypes, all of which have in common skin barrier dysfunction as a key contributing factor. Understanding mechanisms leading to skin barrier dysfunction in AD is pointing to the development of new topical and systemic treatments in AD that helps keep skin borders secure and effectively treat the disease.

Different types of emollient cream exhibit diverse physiological effects on the skin barrier in adults with atopic dermatitis.

BACKGROUND: Eczema (atopic dermatitis; AD) is a very common itchy skin condition affecting 1 in 5 children and up to 1 in 10 adults worldwide. The skin of eczema sufferers is prone to redness, irritation and dryness because it does not form an effective barrier, i.e. the ability of the skin to stop irritants, allergens and microorganisms getting into the body. Skin barrier dysfunction is a hallmark of AD. The regular and liberal (600 g/week for an adult) use of emollients is recommended for all patients with eczema), even between episodes of itching and redness, to soften and soothe the skin. In England alone, almost 9 million prescriptions for emollient creams were issued in 2018, at a cost of over £50 million. Despite this widespread use, relatively little is known about how commonly prescribed emollient creams affect the skin's barrier, and thus the role of moisturizers in AD development and progression remains unclear. We set out to compare three different types of emollient cream and a no-treatment control. AIM: To compare the barrier-strengthening properties of a new moisturizer containing urea and glycerol (urea-glycerol cream; UGC), with those of a glycerol-containing moisturizer (glycerol cream; GC), a simple paraffin cream (PC) with no humectant, and a no-treatment control (NTC). METHODS: This was an observer-blinded prospective Phase 2 within-subject multilateral single-centre randomized controlled trial in adults with AD (Clinical Trials #NCT03901144). The intervention involved 4 weeks of treatment, twice daily, with the three products applied to one of four areas on the forearms the (the fourth area was the untreated control, randomized allocation). Skin properties [dryness, transepidermal water loss (TEWL), hydration and natural moisturizing factor (NMF) levels] were assessed before, during and after treatment to see what happened to the skin's barrier. The primary outcome was skin sensitivity to the irritant sodium lauryl sulfate (SLS) after treatment. We performed tests on the skin before and after treatment to see what happened to the skin's barrier. RESULTS: In total, 49 patients were randomized, completed treatment and included in the analysis. UGC significantly reduced the response to SLS as indicated by a reduction in TEWL compared with NTC (-9.0 g/m2 /h; 95% CI -12.56 to -5.49), with PC (-9.0 g/m2 /h; 95% CI -12.60 to -5.44) and with GC -4.2 g/m2 /h; 95% CI 7.76 to -0.63). Skin moisturization improved at sites treated with UGC compared with NTC and PC, and this was accompanied by concordant changes in dryness and NMF levels. Subgroup analysis suggested FLG-dependent enhancement of treatment effects. CONCLUSION: The study showed that not all emollient creams for eczema are equal. The simple paraffin-based emollient, which represents the most widely prescribed type of emollient cream in England, had no effect on the skin's barrier and reduced the skin's NMF. UGC markedly improved the skin's barrier and protected against irritation. GC performed better than PC, but not as well as UGC. UGC strengthened the skin barrier through a mechanism involving increased NMF levels in the skin, and imparted protection from SLS-induced irritation. By helping correct a major pathophysiological process, UGC has the potential to improve the long-term control of AD. The results show that different emollient creams have different effects on our skin, and only certain types have the ability to improve the skin's barrier and protect against irritants that trigger eczema.

Effect of seasonal change on the biomechanical and physical properties of the human skin.

In this study, the effect of one cycle of winter to summer seasonal transition on the mechanical and physical properties of skin was investigated in vivo. Fourteen healthy skin volunteers aged between 22 and 42 years were studied at the volar lower and upper arms. The findings indicate a 22.15% and 34.29% decrease in trans-epidermal water loss (TEWL) and the average epidermal roughness (AER), respectively. Also, improved skin properties were observed such as a 25.48% rise in average epidermal hydration (AEH), 22.59% in skin thickness, 38.64% and 21.92% in melanin and redness, respectively, as well as an 8.25% rise in its firmness and 23.14% in elasticity when strained with uniaxial deformations. An inverse correlation was established between TEWL and AEH with a linear relationship between stratum corneum roughness versus TEWL as well as thickness and hydration. Also, the skin firmness exhibited a direct proportionality with TEWL and an inverse correlation with skin hydration where these relationships were stronger in summer than in winter. Furthermore, time-dependent results demonstrated three-staged elastic, viscoelastic and creep deformations with high, moderate and low strain rates respectively at both anatomical locations. The winter season displayed lower skin firmness and elasticity of 0.37 mm and 0.04 mm compared to 0.40 mm and 0.06 mm in summer accordingly. Anatomically, the two arm regions displayed different results with the upper arm having more consistent results than the lower arm. These results will find relevance in sensor skins and exoskeletons in Medicare, robotic and military technologies as well as innovations in cosmetics and dermatology.

Vehicles for atopic dermatitis therapies: more than just a placebo.

A topical vehicle is a 'carrier system' for an active pharmaceutical (or cosmetic) substance, referred to hereafter as the drug, but a vehicle may also be used on its own as an emollient to ameliorate dry skin. It is well established that the vehicle plays an important role in determining the bioavailability of a given drug at its ultimate target within the skin. Yet in the treatment of atopic eczema/dermatitis (AD), wherein the structure and function of the skin's outer barrier play a pivotal role in the development and course of the condition, the interaction of the vehicle with this barrier carries a particular importance. It is now clear that the often-considered inert excipients of a vehicle bring about changes within the skin at the molecular level that promote barrier restoration and enhance innate immune defenses with therapeutic value to AD patients. Moreover, the vehicle control in randomized controlled trials (RCTs) increasingly displays significant efficacy. In light of this, we consider the implications of vehicle design in relation to AD pathophysiology and the role vehicles play as controls in RCTs of new drug treatments for this condition.

Enhancement of stratum corneum lipid structure improves skin barrier function and protects against irritation in adults with dry, eczema-prone skin.

BACKGROUND: The skin of patients with atopic dermatitis is characterized by abnormal stratum corneum lipid levels. Consequently, the lamellar matrices are disrupted and skin barrier function is diminished, increasing skin sensitivity to irritants and allergens. OBJECTIVES: To determine whether a cream containing ceramides, triglycerides and cholesterol in a multivesicular emulsion can reinforce the skin barrier and protect against skin irritation. METHODS: A randomized observer-blind intrapatient-controlled study in 34 adults with dry, eczema-prone skin was conducted. Each participant underwent 4 weeks of treatment with the test cream on one forearm and lower leg and a reference emollient cream on the other. Skin properties were determined before and after treatment. Lipid structure was assessed by Fourier-transform infrared spectroscopy using a novel interface. RESULTS: Skin barrier integrity was greater at sites treated with the test cream [effect size for area under the transepidermal water loss curve -162, 95% confidence interval (CI) -206 to -118]. Skin sensitivity to sodium lauryl sulfate was reduced (-0·5 points visual redness, 97·57% CI -1·00 to -0·25), as was transepidermal water loss (-15·3 g m-2 h-1 , 95% CI -20·3 to -10·4) compared with the reference. Sites treated with the test cream displayed enhanced lipid chain ordering, which was significantly associated with skin barrier integrity (r = 0·61). Compared with the reference, treatment with the test cream increased hydration (8·61 capacitance units, 95% CI 6·61-10·6) and decreased signs of dryness. CONCLUSIONS: The test cream facilitates skin barrier restoration and protects the skin from dryness and irritation. Compared with a commonly prescribed emollient in the UK, the test cream is highly suited to the management of dry, sensitive skin.

Imaging striae distensae: a comparison between PS-OCT and digital dermoscopy.

Stretch marks or striae distensae (SD) cause emotional distress and negatively affect the psychological well-being of patients. We investigate and compare two methods for quantifying the severity of SD: visual scoring of images captured using a clinical visible-light dermatological camera (C-Cube, Pixience Inc) and measuring the local birefringence of skin using polarization-sensitive optical coherence tomography (PS-OCT). Data on skin visually affected by SD and visually normal skin were collected from 19 human volunteers. Our results show a weak correlation between visual scores of the C-Cube images and the birefringence values obtained from the PS-OCT system. SD datasets have a significantly larger birefringence values compared to visually normal datasets.

An Investigation of the Skin Barrier Restoring Effects of a Cream and Lotion Containing Ceramides in a Multi-vesicular Emulsion in People with Dry, Eczema-Prone, Skin: The RESTORE Study Phase 1.

INTRODUCTION: The replenishment of skin lipids depleted in the dry skin state is a desirable therapeutic target to restore skin moisturization; however, there is limited evidence demonstrating the success of this approach through the use of topical emollients. The purpose of this study was to provide evidence of the benefits of a cream and equivalent lotion containing skin lipids in a multi-vesicular emulsion for the management of dry skin. The hypothesis was that the test cream and test lotion could sustain skin moisturization for longer than traditional emollients by sustainably delivering skin lipids. METHODS: A double-blind intra-subject vehicle-controlled single open-application test on the lower legs in people with dry, atopic dermatitis (atopic eczema)-prone, skin was conducted. There were six treatment sites, three per lower leg in each participant, which were treated with the test cream, the test lotion, three reference creams commonly prescribed in the UK and no treatment as a control. After baseline measurements of skin hydration, 100 µl of the test/reference creams was applied to each of the relevant treatment sites (random site allocation). Following treatment, measurements of skin hydration and scoring of visual dryness was conducted at timed intervals (3, 6, 12 and 24 h post-product application). RESULTS: The test cream and lotion both significantly increased skin hydration and reduced skin dryness for at least 24 h following a single application compared to a no treatment control site. Compared to three reference emollient creams the test cream and test lotion were the only products capable of sustaining clinically meaningful improvements in skin moisturization for 24 h. CONCLUSION: The sustained moisturization imparted by the test products reduces the need for frequent emollient application, often requiring 3-4 applications per day for traditional emollients, and should reduce the high burden of managing dry skin conditions like atopic dermatitis.

Atopic dermatitis epidemiology and unmet need in the United Kingdom.

Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin condition associated with a significant health-related and socioeconomic burden, and is characterized by intense itch, disruption of the skin barrier, and upregulation of type 2-mediated immune responses. The United Kingdom (UK) has a high prevalence of AD, affecting 11-20% of children and 5-10% of adults. Approximately 2% of all cases of childhood AD in the UK are severe. Despite this, most AD treatments are performed at home, with little contact with healthcare providers or services. Here, we discuss the course of AD, treatment practices, and unmet need in the UK. Although the underlying etiology of the disease is still emerging, AD is currently attributed to skin barrier dysfunction and altered inflammatory responses. Management of AD focuses on avoiding triggers, improving skin hydration, managing exacerbating factors, and reducing inflammation through topical and systemic immunosuppressants. However, there is a significant unmet need to improve the overall management of AD and help patients gain control of their disease through safe and effective treatments. Approaches that target individual inflammatory pathways (e.g. dupilumab, anti-interleukin (IL)-4 receptor α) are emerging and likely to provide further therapeutic opportunities for patient benefit.

Morphological parametric mapping of 21 skin sites throughout the body using optical coherence tomography.

BACKGROUND: Changes in body posture cause changes in morphological properties at different skin sites. Although previous studies have reported the thickness of the skin, the details of the postures are not generally given. This paper presents the effect of a change in posture on parameters such as thickness and surface roughness in 21 load-bearing and non-load-bearing sites. MATERIALS AND METHODS: A total of 12 volunteers (8 males and 4 females) were selected in an age group of 18-35 years and of Fitzpatrick skin type I-III. Images were captured using a clinically-approved VivoSight® optical coherence tomography system and analysed using an algorithm provided by Michelson Diagnostics. RESULTS: Overextension (extending joints to full capacity) resulted in changes to thickness, roughness and undulation of the skin around the body. DISCUSSION AND CONCLUSION: The load-bearing regions have thicker skin compared to non-load-bearing sites. This is the first time that undulation topography of the stratum corneum-stratum lucidum and the dermal-epidermal junction layers have been measured and reported using statistical values such as Ra. The data presented could help to define new skin layer models and to determine the variability of the skin around the body and between participants.

Infant Skin Barrier, Structure, and Enzymatic Activity Differ from Those of Adult in an East Asian Cohort.

Skin physiology is dynamically changing over the first years of postnatal life; however, ethnic variations are still unclear. The aim of this study was to characterize infant skin barrier function, epidermal structure, and desquamation-related enzymatic activity as compared to that of adult skin in an East Asian population. The skin properties of 52 infants (3-24 months) and 27 adults (20-40 years) were assessed by noninvasive methods at the dorsal forearm and upper inner arm. Transepidermal water loss and skin surface conductance values were higher and more dispersed for infants compared to adults. Infant skin surface pH was slightly lower than adult on the dorsal forearm. The infant SC and viable epidermis were thinner compared to adults with differences that were site-specific. Although the chymotrypsin-like activity for infant skin was comparable to adult level, the caseinolytic specific activity was significantly higher for the infant cohort. These observations indicate a differently controlled pattern of corneocyte desquamation in infants. In conclusion, structural and functional differences exist between infant and adult skin in the East Asian population pointing to dynamic maturation of the epidermal barrier early in life.

pH in Atopic Dermatitis.

Atopic dermatitis (synonym atopic eczema, AD) is a chronic inflammatory skin disorder essentially characterised by a red "itchy" skin rash. The condition is prevalent around the world, affecting 15-30% of children and 2-10% of adults [Odhiambo et al.: J Allergy Clin Immunol 2009;124:1251-1258.e23]. The pathophysiological mechanisms underpinning AD are complex, broadly involving skin barrier dysfunction, an altered immune response (affecting both the adaptive and innate immune systems) and an unfavourable environment (external stressors) [Werfel et al.: J Allergy Clin Immunol 2016;138:336-349]. Intriguingly at the centre of this maelstrom of events, linking them together, is a very basic skin property - skin pH. Skin pH is a central regulator of skin barrier homeostasis and an important innate defence mechanism. Moreover, recent evidence suggests that elevated pH can also drive altered immune responses placing it squarely in the centre of AD pathogenesis, but just how important is skin pH to the development of AD? In this chapter, the current evidence entangling skin pH in AD pathogenesis is reviewed.

Sub-clinical assessment of atopic dermatitis severity using angiographic optical coherence tomography.

Measurement of sub-clinical atopic dermatitis (AD) is important for determining how long therapies should be continued after clinical clearance of visible AD lesions. An important biomarker of sub-clinical AD is epidermal hypertrophy, the structural measures of which often make optical coherence tomography (OCT) challenging due to the lack of a clearly delineated dermal-epidermal junction in AD patients. Alternatively, angiographic OCT measurements of vascular depth and morphology may represent a robust biomarker for quantifying the severity of clinical and sub-clinical AD. To investigate this, angiographic data sets were acquired from 32 patients with a range of AD severities. Deeper vascular layers within skin were found to correlate with increasing clinical severity. Furthermore, for AD patients exhibiting no clinical symptoms, the superficial plexus depth was found to be significantly deeper than healthy patients at both the elbow (p = 0.04) and knee (p<0.001), suggesting that sub-clinical changes in severity can be detected. Furthermore, the morphology of vessels appeared altered in patients with severe AD, with significantly different vessel diameter, length, density and fractal dimension. These metrics provide valuable insight into the sub-clinical severity of the condition, allowing the effects of treatments to be monitored past the point of clinical remission.