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Children who are recalcitrant to topical therapy for their moderate to severe plaque psoriasis and/or highly visible lesions may be candidates for systemic therapy. Methotrexate has been the most commonly used systemic agent in children. However, at least 25% of patients are now treated with biologics, especially tumor necrosis factor-α inhibitors, and their use is expanding as their availability, demonstrated safety and efficacy, and practitioner experience are increasing. In the United States, etanercept is Food and Drug Administration approved for ages 6 years and older and ustekinumab for 12 years of age and older. In Europe, adalimumab is also approved for pediatric psoriasis for 4 years of age and older. While biologics have the advantage of less frequent administration, greater and more rapid efficacy than methotrexate, fewer side effects, and a less rigorous need for monitoring, their cost is much higher than that of methotrexate and other systemic medications, concerns about the development of neutralizing antibodies necessitate continuous treatment, and their long-term safety profile remains to be determined.

Background Long-term safety of topical calcineurin inhibitors is not well understood. APPLES (A Prospective Pediatric Longitudinal Evaluation to Assess the Long-Term Safety of Tacrolimus Ointment for the Treatment of Atopic Dermatitis; NCT00475605 ) examined incidence of lymphoma and other cancers in a pediatric population with atopic dermatitis. Objective To quantify incident malignancies during 10 years in children with atopic dermatitis who used topical tacrolimus for ≥6 weeks. Methods Standardized incidence ratios for cancer events were analyzed relative to sex-, age-, and race-matched control data from national cancer registries. Results There were 7954 eligible patients enrolled at 314 sites in 9 countries. During 44,629 person-years, 6 confirmed incident cancers occurred (standardized incidence ratio, 1.01; 95% confidence interval, 0.37-2.20). No lymphomas occurred. Limitations Observational prospective cohort study. Conclusion The cancer incidence was as expected, given matched background data. This finding provides no support for the hypothesis that topical tacrolimus increases long-term cancer risk in children with atopic dermatitis.

Objectives To compare prevalence and severity of diaper dermatitis (DD) in infants and toddlers (babies) across three countries (China, USA, and Germany), including diapered skin measures and caregiver practices. Methods A cross‐sectional study of 1791 babies (~600 from each country) was recruited at each clinical site. Based on regional toilet‐training habits, exclusively diaper‐wearing infants were recruited between ages 2‐8 months in China and 2‐18 months in the USA and Germany. DD was measured, as well as skin pH, transepidermal water loss (TEWL), and relative humidity (RH) in the diapered region. Caregiver habits were collected via a questionnaire and included information on hygienic practices. Results Diaper dermatitis was highest in the perianal area, followed by the intertriginous, genital, and buttock regions. In general, DD was significantly lower in babies in China, highest in Germany, and intermediate in the USA. This rank ordering of DD by geography was also observed in baby age 2‐8 months. The lower DD observed in China was associated with lower skin pH and TEWL on diapered skin and decreased RH in the diaper. Chinese caregivers had the highest rate of prophylactic topical product usage, the most robust cleaning of the diapered area, lack of cleansing after urine‐only diaper changes, and Chinese infants spent the least time in an overnight diaper. Conclusions These data suggest caregiver behaviors including prophylactic use of topical products, thorough cleaning after stooling and reduced time in an overnight diaper are associated with less DD, lower superficial skin pH, and enhanced skin barrier.

The Harmonising Outcome Measures for Eczema (HOME) initiative is a multidisciplinary, evidence-based international group developing a core outcome set for atopic eczema trials. HOME has previously recommended four essential domains to be measured; signs, symptoms, quality of life and long-term control, with Eczema Area and Severity Index (EASI) and Patient-Oriented Eczema Measure (POEM) as the instruments to measures signs and symptoms, respectively. The aim of the current study was to define the domain of long-term control, and achieve consensus on what instrument(s) should be used to measure it. Two qualitative studies were conducted by the long-term control working group: online focus groups involving patients and carers, and an online qualitative survey of the HOME membership. These were analysed thematically and combined to provide evidence on what long-term control of atopic eczema means to patients, carers and clinicians. A face-to-face consensus meeting (HOME V) was held on 12-14 June 2017 in Nantes, France, involving moderated small interactive groups and whole-group discussions with anonymous voting. The HOME roadmap and COSMIN and COMET guidelines on outcome measurement instrument selection were followed. Discussions and voting on the definition of long-term control and the face validity and feasibility of different ways of measuring long-term control were informed by these two international qualitative studies and other published evidence (systematic reviews and validation studies). Focus groups involving 99 patients and carers were conducted in the U.K., the U.S.A., the Netherlands, France, Sweden and Japan. The HOME survey included 62 responses, mainly clinicians, representing 16 countries. Patients, carers and clinicians considered long-term control to involve several related concepts: level of disease activity, impact on daily life, and treatment required (such as reducing treatment or using only maintenance treatment). Issues highlighted to consider when measuring long-term control included capturing the perspective of patients, carers and clini-cians, burden of data collection, interpretability and including an objective assessment. The consensus meeting in Nantes was attended by 81 participants from 13 countries. There was consensus (91% of participants voted in favour) that the long-term-control domain consists of repeated measures of the agreed core domains [clinician-reported signs, patient-reported symptoms (including itch intensity) and quality of life] plus a patient global assessment. Pending further discussions, the existing recommended instruments for signs and symptoms (EASI and POEM) should be used. HOME recommends that long-term control of atopic eczema is captured in trials by repeated measures of the existing core domains plus a patient global assessment. Further work is required on the timing of assessments and to determine the patient global assessment instrument.

Background Although atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early-onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need for better treatments. Objective We sought to globally profile the skin of infants with AD compared with that of adults with AD and healthy control subjects. Methods We performed microarray, RT-PCR, and fluorescence microscopy studies in infants and young children ( Results Transcriptomic analyses revealed profound differences between pediatric patients with early-onset versus adult patients with longstanding AD in not only lesional but also nonlesional tissues. Although both patient populations harbored TH2-centered inflammation, pediatric AD also showed significant TH17/TH22 skewing but lacked the TH1 upregulation that characterizes adult AD. Pediatric AD exhibited relatively normal expression of epidermal differentiation and cornification products, which is downregulated in adults with AD. Defects in the lipid barrier (eg, ELOVL fatty acid elongase 3 [ELOVL3] and diacylglycerol o-acyltransferase 2 [DGAT2]) and tight junction regulation (eg, claudins 8 and 23) were evident in both groups. However, some lipid-associated mediators (eg, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase) showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H and DGAT2) showed inverse correlations with transepidermal water loss, a functional measure of the epidermal barrier. Conclusions Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early-onset disease.

This review focuses on the treatment options for adult female patients with acne. Acne in adult female patients may start during adolescence and persist or have an onset in adulthood. Acne has various psychosocial effects that impact patients' quality of life. Treatment of acne in adult women specifically has its challenges due to the considerations of patient preferences, pregnancy, and lactation. Treatments vary widely and treatment should be tailored specifically for each individual woman. We review conventional therapies with high levels of evidence, additional treatments with support from cohort studies and case reports, complementary and/or alternative therapies, and new agents under development for the treatment of patients with acne.

We describe a case of Omenn syndrome displaying exudative erythroderma and other characteristic features, including alopecia, absent B and naïve T cells, hyper immunoglobulin E levels, and eosinophilia. A pathogenic recombination-activating RAG1 homozygous genetic mutation confirmed the diagnosis. She required frequent antibiotics at both treatment and prophylactic doses, which alone did not control her erythroderma, but her high risk of infection precluded the use of systemic agents such as cyclosporine, which would further suppress her already severely compromised immune system. Thrice-weekly topical dilute hypochlorite compresses, combined with skin acidification with a low pH emollient, were initiated to control inflammation and for cutaneous bacterial prophylaxis. She demonstrated a marked improvement in her erythroderma within days after treatment initiation. Further improvement continued with the addition of systemic corticosteroids, with resolution of erythroderma after her first dose. This case reveals for the first time that dilute topical hypochlorite and skin pH restoration holds promise to control severe dermatitis associated with immunodeficiency and inflammatory syndromes with minimal side effects.

Atopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high-level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for "the Agency's current thinking on a particular subject." Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to

Background/objectives Cutaneous juvenile xanthogranuloma is an uncommon, usually benign disease affecting infants and young children. Ocular and other systemic involvement have been reported, but their incidence is unclear, and the utility of routine screening is not well established. Our aim was to characterize the risk of ocular and systemic complications in children with cutaneous juvenile xanthogranuloma. Methods In this retrospective study, we reviewed the medical charts of children with cutaneous juvenile xanthogranuloma seen at Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois, between January 2000 and December 2015. A comprehensive literature review was also performed. Results Of 338 children with cutaneous juvenile xanthogranuloma, 76 (median age 6 months, 51% female) met inclusion criteria. The most frequently involved site was the head and neck region (40%). In 39 patients (51%), there was a single lesion. Multiple lesions (>5) were evident in 20 patients (26%). Most cutaneous juvenile xanthogranulomas were micronodular (77%). None of the patients had ocular involvement. One patient had multiple asymptomatic hepatic nodules on imaging that regressed spontaneously within several months. Literature review of pediatric cutaneous juvenile xanthogranuloma series, including our cohort, revealed that the incidence of ocular manifestations is 0.24% (7/2949) and of systemic manifestations is 0.75% (22/2949). Conclusion Cutaneous juvenile xanthogranulomas are generally limited to the skin. Because eye involvement is rare, a routine eye examination is of low yield and probably not warranted in children with no ocular or visual symptoms. New recommendations for systemic screening could not be drawn from this study.

Sleep is disturbed in 60% of children with atopic dermatitis (AD).To characterize sleep in a cohort of children with moderate-to-severe AD and determine methods for assessment of sleep disturbance.A case-control study compared children age 6 to 17 years who have moderate-to-severe AD with age- and sex-matched healthy controls. Participants wore actigraphy watches and completed sleep- and disease-specific questionnaires.Nineteen patients with AD and 19 controls completed the study. The patients with AD experienced wake after sleep onset (WASO) for 103 plus or minus 55 minutes as compared with 50 plus or minus 27 minutes in the controls (P .01). They had a higher frequency of restless sleep, daytime sleepiness, difficulty falling back to sleep at night, and teacher-reported daytime sleepiness. Disease severity correlated well with WASO (total SCORing Atopic Dermatitis score: r = 0.61, P .01; objective SCORing Atopic Dermatitis score: r = 0.58, P = .01; and Eczema Area and Severity Index: r = 0.68, P .01). The Children's Dermatology Life Quality Index sleep question correlated with WASO (r = 0.52, P = .03), but self-reported itch severity did not (r = 0.28, P = .30).The study cohort was small.Children with moderate-to-severe AD experience more WASO and lower sleep efficiency than healthy controls but similar bedtime and wake time, sleep duration, and sleep onset latency.

Summary Background Guidelines discourage the use of systemic corticosteroids for atopic dermatitis (AD), but their use remains widespread. Objectives To reach consensus among an international group of AD experts on the use of systemic corticosteroids for AD. Methods A survey consisting of statements accompanied by visual analogue scales ranging from ‘strongly disagree’ to ‘neutral’ to ‘strongly agree’ was distributed to the International Eczema Council (IEC). Consensus was reached in agreement on a statement if, What's already known about this topic? Despite recommendations against their use in practice guidelines, systemic corticosteroids are commonly used for atopic dermatitis (AD). What does this study add? The International Eczema Council reached consensus on circumstances in which systemic corticosteroids can be used for AD, including a lack of other treatment options, as a bridge to other systemic therapies or phototherapy, during acute flares in need of immediate relief, in anticipation of a major life event, or in the most severe cases.Clinicians should limit the use of systemic corticosteroids for severe AD to those circumstances. https://doi.org/10.1111/bjd.16385 available online https://goo.gl/Uqv3dl

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Atopic dermatitis (AD) is a common, chronic, relapsing, inflammatory skin disease that affects children and adults. Until recently, the only Food and Drug Administration–approved systemic treatment option for patients with moderate-to-severe AD was systemic steroids, which are not recommended by current guidelines and are commonly associated with disease rebound. Instead, clinicians choose from several off-label immunosuppressants, which can have serious adverse effects. A significant number of these patients go untreated. Research on the immunopathogenesis of AD has paved the way for new, targeted, systemic therapies for moderate-to-severe AD. In early 2017, the Food and Drug Administration approved dupilumab for adults with moderate-to-severe AD whose disease is not adequately controlled with topical therapies. Although the national guidelines can be very helpful to clinicians, the process for updating them does not allow for timely incorporation of novel therapies. A steering committee of AD experts, including dermatologists, allergists, and a patient advocacy group representative, developed recommendations on the basis of a literature review and expert opinion to help clinicians understand how new therapies fit into the current treatment paradigm and to provide practical recommendations for assessing AD severity, treatment response, and treatment failure.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder caused by mutations in one of nine genes involved in the packaging and formation of specialized lysosomes, including melanosomes and platelet-dense granules. The cardinal features are pigmentary dilution, bleeding diathesis, and accumulation of ceroid-like material in reticuloendothelial cells. Pulmonary fibrosis induced by tissue damage is seen in the most severe forms, and one subtype is characterized by immunodeficiency. We describe two patients with HPS type 1 and review the updated gene-based classification, clinical features, and recommendations for evaluation and follow-up.

Background The lack of standardized nomenclature for atopic dermatitis (AD) creates challenges for scientific communication, patient education, and advocacy. Objective We sought to determine the relative popularity of the terms eczema, AD, and atopic eczema (AE) using global search engine volumes. Methods A retrospective analysis of average monthly search volumes from 2014 to 2016 of Google, Bing/Yahoo, and Baidu was performed for eczema, AD, and AE in English and 37 other languages. Google Trends was used to determine the relative search popularity of each term from 2006 to 2016 in English and the top foreign languages, German, Turkish, Russian, and Japanese. Results Overall, eczema accounted for 1.5 million monthly searches (84%) compared with 247 000 searches for AD (14%) and 44 000 searches for AE (2%). For English language, eczema accounted for 93% of searches compared with 6% for AD and 1% for AE. Search popularity for eczema increased from 2006 to 2016 but remained stable for AD and AE. Conclusions Given the ambiguity of the term eczema, we recommend the universal use of the next most popular term, AD.

Epidermolytic ichthyosis (EI) is a rare disorder of cornification caused by mutations in KRT1 and KRT10, encoding two suprabasal epidermal keratins. Because of the variable clinical features and severity of the disease, histopathology is often required to correctly direct the molecular analysis. EI is characterized by hyperkeratosis and vacuolar degeneration of the upper epidermis, also known as epidermolytic hyperkeratosis, hence the name of the disease. In the current report, the authors describe members of 2 families presenting with clinical features consistent with EI. The patients were shown to carry classical mutations in KRT1 or KRT10, but did not display epidermolytic changes on histology. These observations underscore the need to remain aware of the limitations of pathological features when considering a diagnosis of EI.

Background/Objectives Epidermal necrolysis (Stevens–Johnson syndrome and toxic epidermal necrolysis) includes immune-mediated, life-threatening inflammatory blistering disorders that can affect children. The Score of Toxic Epidermal Necrosis (SCORTEN) tool has accurately predicted the outcome of these disorders in adults but has not been tested in children. Methods We performed a retrospective chart review to compare the accuracy of the adult SCORTEN tool with that of two modifications tailored to children in predicting disease outcome. Results The longer the patient's median length of hospital stay was, the higher the adult and two proposed pediatric SCORTENs were. In addition, all patients who died had SCORTENs greater than 4. Conclusion The pediatric-modified tools were not superior to the adult SCORTEN, which accurately predicted outcome.

BACKGROUND: Ichthyoses are rare, debilitating disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking, since the underlying molecular basis is poorly understood. OBJECTIVE: To characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. METHODS: We analyzed biopsies from 21 genotyped ichthyosis patients (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) by immunohistochemistry and RT-PCR and compared them with healthy controls, and with atopic dermatitis (AD) and psoriasis patients. Clinical measures included a severity score for ichthyosis (IASI), which integrates erythema (IASI-E) and scaling (IASI-S), transepidermal water loss (TEWL), and pruritus. RESULTS: Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and K16 expression) and T-cell and dendritic-cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1β), and some Th1/IFN (IFNγ) markers in ichthyosis were comparable to psoriasis or AD. TNFα levels in ichthyosis were elevated only in Netherton syndrome, but were much lower than in psoriasis and AD. Expression of Th2 cytokines (IL-13, IL-31) in ichthyoses was similar to controls. Most notable in ichthyosis was the striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNFα (IL-17A/C, IL-19, CXCL1, PI3, CCL20, IL36G; p

Atopic dermatitis comorbidities extend well beyond the march to allergic conditions (food allergy, asthma, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis), suggesting both cutaneous and systemic immune activation. In reviewing atopic dermatitis comorbidities, Councilors of the International Eczema Council found a strong pattern of immune activation in peripheral blood and the propensity to both skin and systemic infections. Associations with cardiovascular, neuropsychiatric, and malignant diseases were increasingly reported, but confirmation of their link with atopic dermatitis requires longitudinal studies. Given the possibility of atopic dermatitis-related systemic immune activation, future investigations of new interventions should concurrently examine the impact on these comorbidities.

Background Atopic dermatitis (AD) affects 15% to 25% of children and 4% to 7% of adults. Paradigm-shifting discoveries about AD have been based on adult biomarkers, reflecting decades of disease activity, although 85% of cases begin by 5 years. Blood phenotyping shows only T H 2 skewing in patients with early-onset pediatric AD, but alterations in early pediatric skin lesions are unknown, limiting advancement of targeted therapies. Objective We sought to characterize the early pediatric AD skin phenotype and its differences from pediatric control subjects and adults with AD. Methods Using immunohistochemistry and quantitative real-time PCR, we assessed biopsy specimens from 19 children with AD younger than 5 years within 6 months of disease onset in comparison with adults with AD or psoriasis and pediatric and adult control subjects. Results In lesional skin children showed comparable or greater epidermal hyperplasia (thickness and keratin 16) and cellular infiltration (CD3 + , CD11c + , and FceRI + ) than adults with AD. Similar to adults, strong activation of the T H 2 (IL-13, IL-31, and CCL17) and T H 22 (IL-22 and S100As) axes and some T H 1 skewing (IFN-γ and CXCL10) were present. Children showed significantly higher induction of T H 17-related cytokines and antimicrobials (IL-17A, IL-19, CCL20, LL37, and peptidase inhibitor 3/elafin), T H 9/IL-9, IL-33, and innate markers (IL-8) than adults ( P P Conclusion The skin phenotype of new-onset pediatric AD is substantially different from that of adult AD. Although excess T H 2 activation characterizes both, T H 9 and T H 17 are highly activated at disease initiation. Increases in IL-19 levels might link T H 2 and T H 17 activation.

Introduction Le dupilumab, un anticorps monoclonal entierement humain inhibant les interleukines IL-4 et IL-13, est approuve dans plusieurs pays pour le traitement des patients adultes atteints de dermatite atopique (DA) moderee a severe insuffisamment controlee. L’efficacite et la tolerance du dupilumab ont egalement ete evaluees chez des adolescents. Nous presentons les donnees biologiques d’une etude de phase 3, randomisee, en double aveugle, controlee par placebo ([PBO] ; etude AD-1526 : NCT03054428 ) chez des adolescents (12 a 17 ans) atteints de dermatite atopique moderee a severe insuffisamment controlee par des traitements topiques. Materiel et methodes Les patients ont ete randomises, ratio 1/1/1, pour recevoir du dupilumab soit une fois 300 mg toutes les 4 semaines (1×/4 s), soit une fois 200 ou 300 mg toutes les 2 semaines (1×/2 s), ou un PBO 1×/2 s, pendant 16 semaines. Resultats La tolerance a ete evaluee chez 250 patients (1×/4 s, n = 83 ; 1×/2 s, n = 82 ; PBO n = 85). Les caracteristiques cliniques et biologiques a l’inclusion etaient comparables entre les differents groupes. Les nombres moyens d’eosinophiles (×109/L) se situaient dans les valeurs normales. Une elevation transitoire par rapport a la valeur initiale a ete observee dans les deux groupes, l’augmentation moyenne la plus elevee se situant a la semaine 8 (1×/4 s 0,177 ; 1×/2 s 0,189 ; PBO −0,086). Cette elevation n’a pas eu de consequences cliniques et un retour a la valeur initiale a ete constate a la semaine 16. Pour les autres parametres hematologiques, bien que non statistiquement significatifs entre groupes, les differences moyennes par rapport aux valeurs a l’inclusion jusqu’a la semaine 16, etaient : leucocytes (×109/L, 1×/4 s 7,61 ; 1×/2 s 8,01 ; PBO 7,55) ; hemoglobine (g/L, 1×/4 s −0,8 ; 1×/2 s −1,2 ; PBO −0,8) ; plaquettes (×109/L, 1×/4 s −15,4 ; 1×/2 s −17,6 ; PBO −8,1). Les differences moyennes pour les electrolytes et parametres de la fonction renale etaient egalement similaires entre les groupes, notamment le potassium (mmol/L, 1×/4 s Conclusion Au cours de l’etude AD-1526, aucune modification cliniquement significative des parametres de laboratoire n’est survenue lors du traitement par le dupilumab chez des adolescents atteints de dermatite atopique moderee a severe. Ces observations suggerent que le resume de caracteristique du produit de dupilumab pour adultes, qui n’exige pas d’analyses de laboratoire avant et pendant le traitement, est egalement appropriee pour les adolescents.

Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population.To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD.A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included.Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight60 kg), or dupilumab, 300 mg (n = 39; baseline weight ≥60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85).Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator's Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16.A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%).In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults.ClinicalTrials.gov identifier: NCT03054428.

Background Data regarding the treatment of periorificial dermatitis with topical calcineurin inhibitors (TCI) in the pediatric population are limited. Objective To assess the clinical utility of TCI in pediatric patients with periorificial dermatitis. Methods A retrospective medical record review of all pediatric patients with periorificial dermatitis treated with TCIs was performed. Follow-up via telephone was performed to capture missing data. Results A total of 132 patients met the inclusion criteria. The median age at diagnosis was 4.2 years (interquartile range, 2.3-8.2). The median follow-up was 5.2 months (interquartile range, 2.1-11.7). Seventy-two patients had evaluable follow-up data. Of these, 48 (67%) patients were treated with TCI alone, 12 (16.7%) were treated with a combination of TCI and topical metronidazole, and 9 (12.5%) were treated with a combination of TCI and a systemic antibiotic. Complete response was noted in 68.8% of patients treated with TCI alone, in 75% of patients treated with TCI and metronidazole, and in 77.8% of patients treated with TCI and a systemic antibiotic. Adverse events were rare and mild in severity. Conclusion Topical calcineurin inhibitors are an effective therapeutic option for pediatric patients with periorificial dermatitis and were well tolerated in this cohort.

Background Although epigenetic mechanisms are important risk factors for allergic disease, few studies have evaluated DNA methylation differences associated with atopic dermatitis (AD), and none has focused on AD with eczema herpeticum (ADEH+). We will determine how methylation varies in AD individuals with/without EH and associated traits. We modeled differences in genome-wide DNA methylation in whole blood cells from 90 ADEH+, 83 ADEH−, and 84 non-atopic, healthy control subjects, replicating in 36 ADEH+, 53 ADEH−, and 55 non-atopic healthy control subjects. We adjusted for cell-type composition in our models and used genome-wide and candidate-gene approaches. Results We replicated one CpG which was significantly differentially methylated by severity, with suggestive replication at four others showing differential methylation by phenotype or severity. Not adjusting for eosinophil content, we identified 490 significantly differentially methylated CpGs (ADEH+ vs healthy controls, genome-wide). Many of these associated with severity measures, especially eosinophil count (431/490 sites). Conclusions We identified a CpG in IL4 associated with serum tIgE levels, supporting a role for Th2 immune mediating mechanisms in AD. Changes in eosinophil level, a measure of disease severity, are associated with methylation changes, providing a potential mechanism for phenotypic changes in immune response-related traits. Electronic supplementary material The online version of this article (10.1186/s13148-019-0714-1) contains supplementary material, which is available to authorized users.

IGF-1 receptor (IGF1R) signaling promotes keratinocyte proliferation, migration, and survival. However, the mechanism of IGF1R endocytosis in normal keratinocytes remains unclear. Confocal, super resolution structured illumination microscopy, total internal reflection fluorescence microscopy, and coimmunoprecipitation studies reveal that IGF1R associates with flotillin-1 (Flot-1), which currently has no known role in normal receptor tyrosine kinase endocytosis, under basal conditions in monolayer keratinocyte cultures. Ligand stimulation of IGF1R promotes its clathrin-dependent endocytosis, mediated by two distinct adaptors, Flot-1 in noncaveolar lipid rafts and the AP2A1/2 complex in clathrin vesicles. Concurrent, but not individual, short hairpin RNA knockdown of FLOT1/2 and AP2A1/2 reduced IGF1R association with clathrin, internalization, and pathway activation by more than 50% (of phosphorylated IGF1R, phosphorylated protein kinase B, and phosphorylated MAPK kinase), suggesting the complementarity of these two adaptor-specific pathways. The Flot-1 pathway is more responsive to low IGF-1 concentrations, whereas the AP2A1/2 pathway predominates at higher IGF-1 concentrations. Selective association of IGF1R–Flot-1–clathrin with Rab4, but IGF1R–AP2A1/2–clathrin with Rab11, implicates Flot-1 as the adaptor for faster recycling and AP2A1/2 as the adaptor for slower IGF1R recycling. These dual pathways, particularly flotillin-dependent, clathrin-mediated endocytosis, provide a new avenue for drug targeting in disorders with aberrant regulation of IGF1R signaling.

IMPORTANCE: Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. OBJECTIVE: To identify genetic mutations associated with linear porokeratosis. DESIGN, SETTING, AND PARTICIPANTS: Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. INTERVENTIONS OR EXPOSURES: Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. MAIN OUTCOMES AND MEASURES: Germline and somatic genomic characteristics of participants with linear porokeratosis. RESULTS: Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). CONCLUSIONS AND RELEVANCE: Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.

Existing vital signmonitoring systems in the neonatal intensive care unit (NICU) requiremultiple wires connected to rigid sensors with strongly adherent interfaces to the skin.We introduce a pair of ultrathin, soft, skin-like electronic devices whose coordinated, wireless operation reproduces the functionality of these traditional technologies but bypasses their intrinsic limitations.The enabling advances in engineering science include designs that support wireless, battery-free operation; real-time, in-sensor data analytics; time-synchronized, continuous data streaming; soft mechanics and gentle adhesive interfaces to the skin; and compatibility with visual inspection and with medical imaging techniques used in the NICU. Preliminary studies on neonates admitted to operating NICUs demonstrate performance comparable to the most advanced clinical-standard monitoring systems. INTRODUCTION In neonatal intensive care units (NICUs), continuous monitoring of vital signs is essential, particularly in cases of severe prematurity. Currentmonitoring platforms requiremultiple hard-wired, rigid interfaces to a neonate’s fragile, underdeveloped skin and, in some cases, invasive lines inserted into their delicate arteries. These platforms and theirwired interfaces pose risks for iatrogenic skin injury, create physical barriers for skin-to-skin parental/neonate bonding, and frustrate even basic clinical tasks. Technologies that bypass these limitations and provide additional, advanced physiological monitoring capabilities would directly address an unmet clinical need for a highly vulnerable population. Wireless, skin-like systems for vital signs monitoring in neonatal intensive care. (A) Images and finite-element modeling results for ECG and PPG devices bent around glass cylinders. (B) A neonate with an ECG device on the chest. (C and D) A mother holding her infant with a PPG device on the foot and an ECG device on the chest (C) and on the back (D). RATIONALE It is now possible to fabricate wireless, battery-free vital signs monitoring systems based on ultrathin, “skin-like” measurement modules. These devices can gently and noninvasively interface onto the skin of neonateswith gestational ages down to the edge of viability. Four essential advances in engineering science serve as the foundations for this technology: (i) schemes for wireless power transfer, low-noise sensing, and high-speed data communications via a single radio-frequency linkwith negligible absorption in biological tissues; (ii) efficient algorithms for real-time data analytics, signal processing, and dynamic baseline modulation implemented on the sensor platforms themselves; (iii) strategies for time-synchronized streaming of wireless data from two separate devices; and (iv) designs that enable visual inspection of the skin interface while also allowing magnetic resonance imaging and x-ray imaging of the neonate. The resulting systems can be much smaller in size, lighter in weight, and less traumatic to the skin than any existing alternative. RESULTS We report the realization of this class ofNICU monitoring technology, embodied as a pair of devices that, when used in a timesynchronized fashion, can reconstruct full vital signs information with clinical-grade precision. One device mounts on the chest to capture electrocardiograms (ECGs); the other rests on the base of the foot to simultaneously record photoplethysmograms (PPGs). This binodal system captures and continuously transmits ECG, PPG, and (fromeach device) skin temperature data, yieldingmeasurements of heart rate, heart rate variability, respiration rate, blood oxygenation, and pulse arrival time as a surrogate of systolic blood pressure. Successful tests on neonates with gestational ages ranging from 28 weeks to full term demonstrate the full range of functions in two level III NICUs. The thin, lightweight, low-modulus characteristics of these wireless devices allow for interfaces to the skinmediated by forces that are nearly an order ofmagnitude smaller than those associated with adhesives used for conventional hardware in the NICU. This reduction greatly lowers the potential for iatrogenic injuries. CONCLUSION The advances outlined here serve as the basis for a skin-like technology that not only reproduces capabilities currently provided by invasive, wired systems as the standard of care, but also offers multipoint sensing of temperature and continuous tracking of blood pressure, all with substantially safer device-skin interfaces and compatibility with medical imaging. By eliminating wired connections, these platforms also facilitate therapeutic skin-to-skin contact between neonates and parents, which is known to stabilize vital signs, reduce morbidity, and promote parental bonding. Beyond use in advanced hospital settings, these systems also offer costeffective capabilities with potential relevance to global health.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects around 13% of children and 7% of adults in the US. It can have a significant impact on the quality of life (QoL) of affected individuals due to pruritus and the visibility of lesions on the skin. AD is increasingly recognized as a systemic disease, since dysregulation of the adaptive and innate immune systems plays a key role in the underlying disease pathogenesis, which has important implications for how the condition is treated. Patients with moderate-to-severe disease who have failed to achieve disease control may benefit from systemic immunomodulatory treatments. Recently published expert perspectives outlined recommendations for the diagnosis and treatment of moderate-to-severe AD in adults, reflecting evidence-based, practical recommendations to support allergists and dermatologists in selecting appropriate treatment in the era of biologic therapies. To help clinicians understand how these practical recommendations can be implemented into clinical practice, we describe two real life case studies of adult patients with AD. In these case studies, we demonstrate how AD severity, treatment response, and treatment failure can be assessed, and the role of emerging systemic treatments in the management of moderate-to-severe AD. J Drugs Dermatol. 2019;18(2):122-129.

Background Children with discoid lupus erythematosus (DLE) are at risk for disfigurement and progression to systemic lupus erythematosus (SLE). Consensus is lacking regarding optimal care for children with DLE. Objectives The aim of this study was to compare practice patterns among paediatric dermatologists/rheumatologists treating paediatric DLE. Methods An online survey was sent to 292 paediatric rheumatologists in the Childhood Arthritis and Rheumatology Research Alliance and 200 paediatric dermatologists in the Pediatric Dermatology Research Alliance. Consensus was defined as ≥ 70% agreement. Results Survey response rates were 38% (76 of 200) for dermatology and 21% (60 of 292) for rheumatology. Both specialties agreed that screening labs should include complete blood counts with differential, urinalysis, complement levels, erythrocyte sedimentation rate, antinuclear antibody and other autoantibodies, hepatic function and renal function/electrolytes. Both specialties agreed that arthritis or nephritis should prompt intensified evaluation for SLE. No other patient features achieved consensus as disease-modifying risk factors. Hydroxychloroquine was agreed upon as first-line systemic therapy, but consensus was lacking for second- or third-line treatment. Conclusions We found few areas of consensus and significant practice differences between paediatric dermatologists and rheumatologists treating DLE. Knowledge gaps include risk factors for SLE, optimal screening and treatment of refractory skin disease.

Real-world evidence on treatment patterns of pediatric patients with atopic dermatitis (AD) is sparse.To assess current treatment patterns in pediatric AD patients.Retrospective observational analysis of commercial insurance and Medicaid administrative claims data (January 2011-December 2016) for pediatric AD patients, stratified by age and provider type.The analytic sample comprised 607,258 pediatric AD patients. Median observation period was 30.3 months. Overall, 78.6% were prescribed ≥1 AD medication; 86.7% were prescribed topical corticosteroids, and 5.4% were prescribed a calcineurin inhibitor. Systemic corticosteroids (SCSs) were prescribed for 24.4% of patients, 51.8% of whom did not have asthma or allergic comorbidities. Of the 46.6% prescribed an antihistamine and 16.2% prescribed montelukast, 62.0% and 41.3%, respectively, did not have asthma or allergic comorbidities. Systemic immunosuppressants were rarely prescribed (0.5%). Higher potency topical corticosteroid and SCS use increased with age. Treatment patterns varied by provider type; specialists were more likely to prescribe higher potency topicals and/or systemics, regardless of patient age. A minority of patients were treated by or referred to a specialist.Identification of AD patients relied on billing diagnoses; the disease severity was proxied by the treatment prescribed.Results indicate that SCSs, despite known risks, and other medications with disproven efficacy in AD are frequently prescribed, suggesting a need for safer and more effective alternatives.

IMPORTANCE: Children with epidermolysis bullosa (EB) comprise a rare population with high morbidity and mortality. An improved understanding of the clinical trajectory of patients with EB, including age at time of clinical diagnosis and major clinical events, is needed to refine best practices and improve quality of life and clinical outcomes for patients with EB. OBJECTIVES: To describe demographics, clinical characteristics, milestone diagnostic and clinical events (such as initial esophageal dilation), and outcomes in patients with EB using the Epidermolysis Bullosa Clinical Characterization and Outcomes Database and to determine what characteristics may be associated with overall EB severity and/or disease progression. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included data on patients with EB who were enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database from January 1, 2011, to June 30, 2017; 17 participating EB centers in the United States and Canada contributed data to this study. EXPOSURES: Type of EB, including recessive dystrophic epidermolysis bullosa (RDEB), junctional epidermolysis bullosa (JEB), dominant dystrophic epidermolysis bullosa (DDEB), and epidermolysis bullosa simplex (EBS). MAIN OUTCOMES AND MEASURES: Demographic information, clinical characteristics (including age at onset of signs of EB and subsequent clinical diagnosis), types of diagnostic testing performed, and milestone clinical events for patients with RDEB. RESULTS: Of 644 enrolled patients from 17 sites included in this study, 323 were male (50.2%), with a mean (SD) age of 14.4 (11.7) years; 283 (43.9%) had RDEB, 194 (30.1%) had EBS, 104 (16.2%) had DDEB, and 63 (9.8%) had JEB. Signs of disease were present at birth in 202 patients with RDEB (71.4%), 39 with JEB (61.9%), 60 with DDEB (57.7%), and 74 with EBS (38.1%). For those with signs of disease at birth, a clinical diagnosis was made at the time of birth in 135 patients with RDEB (67.0%), 31 with DDEB (52.6%), 35 with EBS, (47.3%) and 18 with JEB (46.2%). Patients with JEB had the highest rate of any confirmatory testing (51 of 63 [81.0%]), followed by RDEB (218 of 283 [77.0%]), DDEB (71 of 104 [68.3%]), and EBS (100 of 194 [51.5%]). For all types of EB, both electron microscopy and immunofluorescence microscopy were performed at younger ages than genetic analysis. Among 283 patients with RDEB, 157 (55.5%) had esophageal dilation, 104 (36.7%) had gastrostomy tube placement, 62 (21.9%) had hand surgery, 18 (6.4%) developed squamous cell carcinoma, and 19 (6.7%) died. CONCLUSIONS AND RELEVANCE: The findings suggest that diagnostic testing for EB is more common for patients with severe phenotypes. Earlier diagnostic testing may enable improved characterizations of patients so that appropriate counseling and clinical care may be offered, especially pertaining to milestone events for those with RDEB.

Background Pathogenic mutations in caspase recruitment domain-containing protein 14 (CARD14) lead to CARD14-associated papulosquamous eruption, which shares clinicopathologic findings with psoriasis and pityriasis rubra pilaris. We aimed to describe distinguishing histopathologic features of CARD14-associated papulosquamous eruption. Methods This retrospective study examined the histopathologic features of specimens from patients with confirmed CARD14-associated papulosquamous eruption and adult patients with plaque psoriasis and pityriasis rubra pilaris. Results Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging. Conclusion CARD14-associated papulosquamous eruption has a range of findings, with a predominance of features typically associated with pityriasis rubra pilaris.

BACKGROUND/OBJECTIVES Epidemiological studies have shown an increased prevalence of attention deficit hyperactivity disorder (ADHD) in children with atopic dermatitis (AD), but many of the features of ADHD may occur as a result of the poor sleep and itch distraction associated with AD. METHODS A case-control study was performed in children aged 6-17 years with moderate/severe AD compared with age-/sex-matched healthy controls. Participants were screened for ADHD using Vanderbilt assessments. RESULTS Seventeen patients with AD and 18 controls completed the study. Two children with AD (11.7%) and one control (5.56%) met screening criteria for ADHD via parent-completed Vanderbilt assessments; AD patients were not significantly more likely to screen positive for ADHD (P = 0.47), or comorbid behavior disorders (P = 0.23). However, AD patients were more likely than controls to exhibit ADHD-associated behaviors, most significantly inattention. CONCLUSIONS Our AD cohort did not have a significantly increased prevalence of ADHD. Certain neurocognitive symptoms are increased in children with moderate-to-severe AD compared to controls.