Clinically Meaningful Responses to Dupilumab Among Children Aged 6 Months to 5 Years with Moderate-to-severe Atopic Dermatitis who did Not Achieve Clear or Almost Clear Skin According to the Investigator's Global Assessment: A Post Hoc Analysis of a Phase 3 Trial.

In young children, atopic dermatitis (AD) imposes a multidimensional burden on many aspects of their quality of life (QoL) and that of their families. LIBERTY AD PRESCHOOL part B was a randomized, double- blinded, placebo-controlled phase 3 trial in 162 children (aged 6 months to 5 years) with moderate-to- severe AD receiving dupilumab or placebo, plus low-potency topical corticosteroids. Post hoc analyses were performed on the full analysis set (FAS) and a subset of patients with Investigator's Global Assessment score > 1 at week 16. The primary outcome was the proportion of patients at week 16 achieving a composite endpoint encompassing clinically meaningful changes in AD signs, symptoms and QoL: ≥ 50% improvement in Eczema Area and Severity Index; and/or ≥ 4-point reduction in worst scratch/itch numerical rating scale; and/or ≥ 6-point reduction in Children's Dermatology Life Quality Index/Infants' Dermatitis Quality of Life Index. Significantly more patients receiving dupilumab vs placebo achieved the composite endpoint in both the FAS (77.7% vs 24.6%, p < 0.0001) and subgroup (68.9% vs 21.5%, p < 0.0001). Dupilumab provided rapid and significant, clinically meaningful improvements in AD signs, symptoms, and QoL in the overall group and subgroup of patients who did not achieve clear or almost clear skin at week 16.

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.

Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.

BACKGROUND: Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children. METHODS: We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment. FINDINGS: 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09). INTERPRETATION: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn. FUNDING: National Institute for Health Research Health Technology Assessment.

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.

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.

Effectiveness and cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children (The BEEP trial): protocol for a randomised controlled trial.

BACKGROUND: Atopic eczema (AE) is a common skin problem that impairs quality of life and is associated with the development of other atopic diseases including asthma, food allergy and allergic rhinitis. AE treatment is a significant cost burden for health care providers. The purpose of the trial is to investigate whether daily application of emollients for the first year of life can prevent AE developing in high-risk infants (first-degree relative with asthma, AE or allergic rhinitis). METHODS: This is a protocol for a pragmatic, two-arm, randomised controlled, multicentre trial. Up to 1400 term infants at high risk of developing AE will be recruited through the community, primary and secondary care in England. Participating families will be randomised in a 1:1 ratio to receive general infant skin-care advice, or general skin-care advice plus emollients with advice to apply daily to the infant for the first year of life. Families will not be blinded to treatment allocation. The primary outcome will be a blinded assessment of AE at 24 months of age using the UK Working Party Diagnostic Criteria for Atopic Eczema. Secondary outcomes are other definitions of AE, time to AE onset, severity of AE (EASI and POEM), presence of other allergic diseases including food allergy, asthma and hay fever, allergic sensitisation, quality of life, cost-effectiveness and safety of the emollients. Subgroup analyses are planned for the primary outcome according to filaggrin genotype and the number of first-degree relatives with AE and other atopic diseases. Families will be followed up by online and postal questionnaire at 3, 6, 12 and 18 months with a face-to-face visit at 24 months. Long-term follow-up until 60 months will be via annual questionnaires. DISCUSSION: This trial will demonstrate whether skin-barrier enhancement through daily emollient for the first year of life can prevent AE from developing in high-risk infants. If effective, this simple and cheap intervention has the potential to result in significant cost savings for health care providers throughout the world by preventing AE and possibly other associated allergic diseases. TRIAL REGISTRATION: ISRCTN registry; ID: ISRCTN21528841 . Registered on 25 July 2014.

Improved emollient use reduces atopic eczema symptoms and is cost neutral in infants: before-and-after evaluation of a multifaceted educational support programme.

BACKGROUND: Parents and carers of children with eczema often underuse emollient therapy, essential to repairing and protecting the defective skin barrier in atopic eczema. Educational interventions delivered by specialist dermatology nurses in hospital settings have been shown to improve emollient use and reduce symptoms of atopic eczema, but benefits of community-based interventions are uncertain. Support and information about appropriate care may often be inadequate for patients and carers in the community. METHODS: A multifaceted educational support programme was evaluated as a method of increasing emollient use and reducing atopic eczema in children. Support provided for parents and carers included an educational DVD, online daily diary and telephone helpline. The before and after study included 136 British children and their parents, providing baseline and 12 week follow-up data while receiving the programme. Measures included emollient use, POEM and PEST scores, and cost of care. RESULTS: Average emollient use increased by 87.6 g (95% CI: 81.9 to 119.5 g, p = 0.001) from baseline with the change being immediate and persistent. The POEM score reduced on average by 5.38 (95% CI: 4.36 to 6.41, p = 0.001), a 47% reduction from baseline. Similarly the PEST score reduced on average by 0.61 (95% CI: 0.47 to 0.75, p = 0.001), a 48% reduction from baseline. Sleep disturbance was reduced by 1.27 nights per week (95% CI: 0.85 to 1.68, p = 0.001) and parental feeling of control improved by 1.32 points (95% CI: 1.16 to 1.48, p = 0.001). From the NHS perspective, the programme was cost neutral overall within the study period. CONCLUSION: A community-based multifaceted educational support programme greatly increased emollient use, reducing symptoms of atopic eczema and general practitioner contacts, without increasing cost. Significant benefits may accrue to the families and carers of children with atopic eczema due to improved sleep patterns and greater feeling of control. PEST, a new simple measure of acute and remitting atopic eczema severity designed to help parents and children to monitor and manage eczema, merits further evaluation.